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Pathaphysiology of septic arthritis and clinical manifestation and relate to case study

International Journal of

Molecular Sciences

Review

Neutrophils: Beneficial and Harmful Cells in
Septic Arthritis

Daiane Boff 1,2, Helena Crijns 1,2, Mauro M. Teixeira 1, Flavio A. Amaral 1, † ID and
Paul Proost 2,*, † ID

1 Imunofarmacologia, Department of Biochemistry and Immunology, Instituto de Ciências Biológicas,
Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil; daiane.bff@hotmail.com (D.B.);
helena.crijns@kuleuven.be (H.C.); mmtex@gmail.com (M.M.T.); dr.famaral@gmail.com (F.A.A.)

2 Laboratory of Molecular Immunology, Department of Microbiology and Immunology,
Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium

* Correspondence: paul.proost@kuleuven.be; Tel.: +32-16-322-471
† These authors contributed equally to this work.

Received: 31 December 2017; Accepted: 1 February 2018; Published: 5 February 2018

Abstract: Septic arthritis is an inflammatory joint disease that is induced by pathogens such as
Staphylococcus aureus. Infection of the joint triggers an acute inflammatory response directed by
inflammatory mediators including microbial danger signals and cytokines and is accompanied
by an influx of leukocytes. The recruitment of these inflammatory cells depends on gradients of
chemoattractants including formylated peptides from the infectious agent or dying cells, host-derived
leukotrienes, complement proteins and chemokines. Neutrophils are of major importance and play a
dual role in the pathogenesis of septic arthritis. On the one hand, these leukocytes are indispensable
in the first-line defense to kill invading pathogens in the early stage of disease. However, on the
other hand, neutrophils act as mediators of tissue destruction. Since the elimination of inflammatory
neutrophils from the site of inflammation is a prerequisite for resolution of the acute inflammatory
response, the prolonged stay of these leukocytes at the inflammatory site can lead to irreversible
damage to the infected joint, which is known as an important complication in septic arthritis patients.
Thus, timely reduction of the recruitment of inflammatory neutrophils to infected joints may be an
efficient therapy to reduce tissue damage in septic arthritis.

Keywords: neutrophil; septic arthritis; chemoattractant; Staphylococcus aureus; tissue
damage; infection

1. Introduction

Septic arthritis can be defined as an inflammatory disease of the joints, induced by an
infectious agent [1,2]. Bacteria, viruses, fungi and protozoa may invade joints and cause injury.
However, Gram-positive bacteria, especially Staphylococcus aureus (S. aureus), are the most prevalent
microorganisms causing septic arthritis [3]. In addition, S. aureus is responsible for the most severe
cases of septic arthritis. Any synovial joint can be involved; however, most frequently one large
joint such as the knee or hip is affected [1,4]. Invasion of bacteria into the synovial space can occur
predominantly by two routes: either through hematogenous spread (most common) or by direct
invasion [5] as shown in Figure 1A. The synovium is extremely vascularized and contains no limiting
basement membrane, facilitating the access to the synovial space. Thus, bacteria may spread directly
from adjacent osteomyelitis or from a local soft tissue infection and could reach the joint during
diagnostic or therapeutic procedures, penetrating trauma, or prosthetic surgery, or, less commonly,
by animal bites [2,6,7].

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Int. J. Mol. Sci. 2018, 19, 468 2 of 28

Septic arthritis patients typically present with a single swollen, warm and painful joint with a
decreased range of motion. Fever is present in only 30–40% of cases [8]. Normally a single synovial
joint is affected such as the knee, hip, ankle or elbow. The hip is the more frequently affected joint in
children. Atypical joint infection, including the sternoclavicular, costochondral and sacroiliac joints,
may be common in intravenous drug users [9]. Polyarticular septic arthritis is not common and usually
accompanied by a number of risk factors. The articular damage is an important feature and a challenge
in this disease, since about 25–50% of patients have irreversible articular damage with total loss of
joint function [1,10].

Int. J. Mol. Sci. 2018, 19, x FOR PEER REVIEW 2 of 27

children. Atypical joint infection, including the sternoclavicular, costochondral and sacroiliac joints,
may be common in intravenous drug users [9]. Polyarticular septic arthritis is not common and
usually accompanied by a number of risk factors. The articular damage is an important feature and
a challenge in this disease, since about 25–50% of patients have irreversible articular damage with
total loss of joint function [1,10].

Figure 1. Routes of bacterial infection and risk factors for septic arthritis development. (A) Bacteria
can access the joint through 5 routes: (1) by hematogenous spread; (2) from an adjacent infected tissue;
(3) through infected bones; (4) as a consequence of trauma or (5) during diagnostic procedures. (B)
Additionally, some risk factors are related to septic arthritis such as presence of other rheumatic or
immunosuppressive diseases, prosthetic surgery and higher age.

Once microorganisms have gained entry into the joint, the low fluid shear conditions in the joint
space allow adherence and infection. The attachment of S. aureus to the joint extracellular matrix or
to implanted medical devices, such as prosthetic joints, is mediated by microbial surface component
recognizing adhesive matrix molecules (MSCRAMMs). After colonizing the joint, the bacteria can
rapidly proliferate and trigger an acute inflammatory response [11]. The synovium responds with a
proliferative lining-cell hyperplasia and there is an influx of inflammatory cells [12]. Phagocytes,
including neutrophils and macrophages, chemotactically migrate to the infected joint, directed by
gradients of bacterial products displaying chemotactic activity and mediators of the immune
response [13]. Neutrophils play a major role in the first-line defense against invading pathogens,
including bacteria, and these leukocytes are the first to migrate to the site of infection. Activated
macrophages are recruited to the joint slightly later and they are followed by T lymphocytes [1,14–16]. In
this manuscript, we will review current knowledge on septic arthritis with an emphasis on the role
of neutrophils. We will discuss neutrophil activation and recruitment, not only resulting in their
beneficial role in the elimination of microbial infection, but also regularly causing tissue damage and
permanent joint dysfunction.

Septic Arthritis

Figure 1. Routes of bacterial infection and risk factors for septic arthritis development. (A) Bacteria
can access the joint through 5 routes: (1) by hematogenous spread; (2) from an adjacent infected
tissue; (3) through infected bones; (4) as a consequence of trauma or (5) during diagnostic procedures.
(B) Additionally, some risk factors are related to septic arthritis such as presence of other rheumatic or
immunosuppressive diseases, prosthetic surgery and higher age.

Once microorganisms have gained entry into the joint, the low fluid shear conditions in the joint
space allow adherence and infection. The attachment of S. aureus to the joint extracellular matrix or
to implanted medical devices, such as prosthetic joints, is mediated by microbial surface component
recognizing adhesive matrix molecules (MSCRAMMs). After colonizing the joint, the bacteria can
rapidly proliferate and trigger an acute inflammatory response [11]. The synovium responds with a
proliferative lining-cell hyperplasia and there is an influx of inflammatory cells [12]. Phagocytes,
including neutrophils and macrophages, chemotactically migrate to the infected joint, directed
by gradients of bacterial products displaying chemotactic activity and mediators of the immune
response [13]. Neutrophils play a major role in the first-line defense against invading pathogens,
including bacteria, and these leukocytes are the first to migrate to the site of infection. Activated
macrophages are recruited to the joint slightly later and they are followed by T lymphocytes [1,14–16].
In this manuscript, we will review current knowledge on septic arthritis with an emphasis on the
role of neutrophils. We will discuss neutrophil activation and recruitment, not only resulting in their
beneficial role in the elimination of microbial infection, but also regularly causing tissue damage and
permanent joint dysfunction.

Int. J. Mol. Sci. 2018, 19, 468 3 of 28

2. Septic Arthritis

Septic arthritis is an uncommon pathology of which the yearly incidence is estimated to be 3 to 12
cases per 100,000 people in industrialized countries [17–20]. Septic arthritis can affect people at any
age, but elderly people and very young children are more frequently affected [21,22]. Approximately
half of the patients are younger than three years and one-third are under the age of two. The incidence
is low in children younger than three months. Furthermore, males are slightly more susceptible
than females [2,23]. The incidence of septic arthritis appears to decrease in children in the United
States [23]. However, several factors including an ageing population, a growing resistance to antibiotics,
an increase in infections related to orthopedic procedures and an enhanced use of immune modulating
agents, contribute to an increase of septic arthritis in the general population [7,24–26]. Furthermore,
the presence of previous joint diseases, such as rheumatoid arthritis (RA), osteoarthritis, crystal
arthropathies and other forms of inflammatory arthritis is a predisposing factor for the development
of infectious arthritis (Figure 1B). In particular, the incidence of septic arthritis is approximately
10-fold higher in patients with RA, in comparison to the general population [27,28]. The incidence of
septic arthritis increases not only in previous arthritic patients, but also in people who suffer from
other chronic and immunosuppressive diseases, such as diabetes, leukemia, cirrhosis, granulomatous
diseases, cancer, hypogammaglobulinemia, human immunodeficiency virus (HIV)-infected patients
and intravenous drug users [29–31]. Hemodialysis has been reported as an important risk factor
for septic arthritis [32]. Also, penetrating trauma, including animal bites and local therapeutic
intra-articular corticosteroid injections may cause septic arthritis in atypical joints [11,33,34]. Recent
joint surgery is also associated with an increased risk of infection [35,36]. In addition, several cases of
joint infections have been reported in patients that received immunosuppressive therapy and/or
glucocorticoids [37]. In this context, the use of classic disease modifying anti-rheumatic drugs
(DMARDs) in RA patients can be an additional risk factor that facilitates the development of infectious
arthritis [38,39]. Although data from observational registers have suggested an increased incidence of
joint infections in patients receiving anti-tumor necrosis factor (TNF) therapy, the incidence does not
seem to be different from the incidence in patients treated with classical DMARDs [40].

Septic arthritis is associated with significant mortality and morbidity. Moreover, it is a
rheumatologic emergency, since irreversible joint destruction and consequently loss of function of the
joint can occur rapidly [24,25,41]. Septic arthritis has a mortality ranging from approximately 10%
to, depending on the report, more than 50% in case of polyarticular disease [3,7,41]. Persisting joint
damage occurs in more than 30% of the patients [41]. Early diagnosis and immediate and effective
treatment are essential to prevent severe outcomes such as irreversible joint destruction or death [2,23].
Furthermore, the general state of the patient and the number, type and resistance pattern of the causing
agent are also of significance to the outcome [42].

The most common causative agent associated with septic arthritis is S. aureus, which accounts
for about 50% of cases [43]. Recently, an increase in methicillin-resistant S. aureus (MRSA) infections
has been reported in several health-care systems, particularly in the elderly and intravenous drug
abuser populations as well as in patients who underwent orthopedic procedures [44]. MRSA has
been associated with 18% and 41% of septic arthritis cases in studies in São Paulo, Brazil and Tainan,
Taiwan, respectively [44,45]. Other bacteria such as group B streptococci, Streptococcus pneumoniae,
Neisseria gonorhoeae, Pseudomonas aeruginosa, Escherichia coli, Proteus genus and Klebsiella species can
be associated with septic arthritis, but are less frequent [46]. Common causative agents in children
include S. aureus, Streptococcus pneumonia and Kingella kingae [47]. The infectious capacity of S. aureus
in different tissues is provided by the presence of several virulence factors [48].

S. aureus has a capsule composed of polysaccharides, which acts as a physical barrier that
protects the bacteria from phagocytosis by immune cells [49]. Peptidoglycan (PGN) is the major
component of the cell wall of Gram-positive bacteria. Bacterial PGN was detected in synovial
tissue of patients with septic arthritis [50] and studies demonstrated that intra-articular injection
of PGN in mice can cause arthritis [51]. S. aureus is a bone pathogen because it possesses several

Int. J. Mol. Sci. 2018, 19, 468 4 of 28

cell-surface adhesion molecules that facilitate its binding to the bone matrix [52]. Binding involves
a family of adhesins that interact with extracellular matrix components and these adhesins have
been termed MSCRAMMs [53]. Specific MSCRAMMs are needed for the colonization of specific
tissues. Particular MSCRAMMs include fibronectin-binding proteins, fibrinogen-binding proteins,
elastin-binding and collagen-binding adhesion molecules. Once the bacteria adhere to and colonize
bone matrix, they elaborate several virulence factors such as proteases, which can break down matrix
components [54]. Further experimental studies demonstrated that collagen adhesin is an important
virulence determinant in S. aureus-induced arthritis [55].

S. aureus secretes a large number of enzymes and toxins, many of which have been implicated as
potential virulence factors. Alpha and gamma toxins are lytic to red blood cells and various leukocytes,
but not to neutrophils [56]. The combination of these two toxins has been experimentally demonstrated
to be important for the development of septic arthritis [57]. Another toxin is Panton–Valentine
leukocidin (PVL, consisting of the LukS and LukF proteins) that can lyse leukocytes, especially
human neutrophils, and is related to fulminant cases of septic arthritis [58]. Enterotoxins, such
as the superantigen toxic shock syndrome toxin-1 (TSST-1) can cause shock by stimulating the
release of interleukin (IL)-1, IL-2, TNF and other cytokines [59]. Experimentally, the presence of
TSST-1 favors the development of septic arthritis [60]. Another important virulence factor is bacterial
deoxyribonucleic acid (DNA) with non-methylated CpG motifs, which is considerably less frequent in
vertebrate DNA [61]. The CpG DNA can bind to Toll-like receptor 9 (TLR9) in immune cells, leading
to the production of cytokines such as IL-1β, TNF, IL-6 and IL-12 [62,63]. Some studies showed that
intra-articular injection of S. aureus CpG DNA can induce arthritis in mice [64,65].

3. Diagnosis and Treatment of Septic Arthritis

Gram staining and cultures of synovial fluid should be investigated in any case of suspected septic
arthritis. Antibiotic therapy is started ideally after synovial fluid samples have been obtained [64].
Gram stains of synovial fluid are helpful when positive, but they are not always sensitive enough
for the diagnosis of septic arthritis [65]. Patients should be treated empirically for septic arthritis
when synovial fluid leukocyte counts exceed 50,000 cells/mm3, although gout and pseudogout also
commonly present with leukocyte counts of this magnitude [66]. Thus, the analysis of the presence
of urate crystals in synovial fluid by polarized light microscopy is very important for the exclusion
of a gouty attack [67–69]. Furthermore, the analysis of the delta neutrophil index (DNI) could be
a valuable tool to distinguish septic arthritis and gout. DNI is a value that corresponds to the
fraction of circulating immature granulocytes, reflecting a burden of infection. In this context, a study
demonstrated that septic arthritic patients presented with a significantly higher DNI as compared
to acute gouty attack patients, suggesting DNI as complementary predicting tool for septic arthritis
diagnosis [70]. However, the serum procalcitonin level also appears to be a promising marker for
septic arthritis [71]. On the other hand, mono-arthritis can also be misdiagnosed with cases of SAPHO
(Synovitis-acne-pustulosis-hyperostosis-osteitis) syndrome, characterized by a combination of skin
and osteoarticular manifestations [72]. Although S. aureus and other pathogens have been isolated
from affected tissues [73], radiology features, such as radiography and MRI mainly in sternoclavicular
joints are necessary for SAPHO syndrome diagnosis, especially in the absence of dermatological
clinical manifestations [72]. Blood cultures should be obtained in all patients with suspected septic
arthritis. However, the cultures must be obtained before starting antibiotic treatment to optimize
the possibility of isolating the causative bacteria [74]. DNA-based techniques, hybridization probes,
polymerase chain reaction (PCR)-based techniques and detection of typical bacterial compounds by
mass spectrometry provide quick results [75]. The detection of microorganisms by PCR has shown
more accurate results [76]. However, the risk of contamination, the presence of background DNA,
the lack of a gold standard and the fact that PCR techniques detect DNA instead of living pathogens
make the interpretation of these tests difficult [77].

Int. J. Mol. Sci. 2018, 19, 468 5 of 28

Imaging can be used as complementary diagnosis since a computed tomography (CT) scan
may not depict abnormalities during the early stages of infection. However, CT is a better imaging
technique for visualization of local edema, bone erosions, osteitic foci and sclerosis [77]. Magnetic
resonance imaging (MRI) provides better resolution for the detection of joint effusion and for
differentiation between bone and soft-tissue infections. MRI findings in patients with septic arthritis
include joint effusion, cartilage and bone destruction, soft-tissue abscesses, bone edema and cortical
interruption [78].

Septic arthritis is so rapidly destructive that broad-spectrum antibiotics are usually warranted until
culture data are available or bacteria have been identified by mass spectrometry. Given the increasing
importance of MRSA as a cause of septic arthritis, initial antibiotic regimens should generally include an
antibiotic active against MRSA, such as vancomycin [79]. Cefazolin is a reasonable alternative in areas
with a low prevalence of MRSA. If serious vancomycin allergy is present, empiric therapy utilizing
linezolid or daptomycin must be considered [80]. Septic arthritis associated with animal bites should
be treated with agents such as ampicillin-sulbactam, which are active against oral microbiota [81].

In general, septic arthritis in adults should be treated for at least 3 weeks, which may include a
period of step-down oral therapy [25]. In children with uncomplicated septic arthritis, as few as 10 days
of antibiotic therapy may be sufficient [82]. Septic arthritis can be managed with antibiotics combined
with joint drainage by arthroscopy, arthrocentesis, or arthrotomy [83–85]. Joint drainage decompresses
the joint, improves blood flow, and removes bacteria, toxins, and proteases [84]. Arthrocentesis should
be repeated daily until effusions resolve and cultures are negative. Aggressive rehabilitation is essential
to prevent joint contractures and muscle atrophy [2].

4. Immune Response against S. aureus

4.1. Introduction

Pathogens are controlled by innate and adaptive immune responses and the recognition of
microorganisms is the first step in host defense [86]. In the joint, resident cells, such as synoviocytes,
can recognize S. aureus through pattern recognition receptors (PRRs). In that way, those cells produce
inflammatory mediators such as cytokines, chemokines, complement proteins and lipids that will
attract neutrophils and macrophages [87]. The complement system plays an important role in host
defense against infection. Products of complement activation affect many functions of neutrophils in
host defense. The complement system can opsonize microorganisms, thereby stimulating phagocytosis.
Phagocytosis of S. aureus by neutrophils is of major importance for the outcome in the early stage
of septic arthritis. Moreover, chemotaxis of neutrophils to the site of inflammation is facilitated by
complement factors such as C5a. Complement depletion, by using cobra venom factor, in a murine
model of hematogenously induced S. aureus septic arthritis caused an aggravation of septicemia
and arthritis [88]. The prevalence and severity of septic arthritis and septicemia-induced mortality
were augmented upon complement depletion. Manifestations of the disease, such as synovitis
and destruction of cartilage and/or bone, occurred earlier and were more common and severe
in the decomplemented mice compared to the control group. Altogether, complement depletion
disturbed phagocytosis by impairing opsonization of bacteria, and interfered with the extravasation
and migration of neutrophils, leading to a deterioration of the disease [88]. During the onset of the
inflammatory process, neutrophils are the main cells recruited to the site of infection and they play
a fundamental role in both the phagocytosis and killing of the microorganism [85]. The importance
of neutrophils in controlling S. aureus in the joint was demonstrated in a study in which neutrophils
were depleted. This caused the impairment of bacterial control [15]. Other immune cells such as
macrophages [6], natural killer (NK) cells [6] and B lymphocytes [89] are described to have a role in
experimental models of septic arthritis. Dendritic cells in S. aureus-induced arthritis are fundamental
for the activation of the adaptive immune response. The depletion of dendritic cells during S. aureus
infection in the lungs showed an increase in bacterial load and mortality [90]. During S. aureus infection,

Int. J. Mol. Sci. 2018, 19, 468 6 of 28

dendritic cells can induce a Th1 response probably through IL-12 production. Experimentally, the lack
of systemic IL-12 increased the bacterial load in the joint during S. aureus-induced septic arthritis [91].
Dendritic cells can also stimulate Th17 activation, an important source of IL-17. The cytokine IL-17
has been shown to be important for bacterial clearance and to prevent tissue damage in experimental
S. aureus-induced arthritis [92].

4.2. Neutrophils

Neutrophils are continuously generated in the bone marrow from myeloid precursors. Humans
and mice differ in their numbers of circulating neutrophils. In humans, 50–70% of circulating leukocytes
are neutrophils, whereas this number drops to only 10–25% in mice [93]. In the circulation, mature
neutrophils have a segmented nucleus and their cytoplasm is enriched with granules and secretory
vesicles. After the first moments following infection, neutrophils can be recruited from blood vessels to
the site of infection, a process that involves a close interaction between neutrophils and endothelial cells
and is mediated by different chemotactic agents that activate the cells and guide their migration [94].
Chemotactic factors for neutrophils include bacterial peptides [95], products of complement activation
(such as C5a) [96], extracellular matrix degradation products (laminin digests) [97], arachidonic
acid metabolites (leukotriene B4/LTB4) [98], other lipid mediators such as platelet activating factors
(PAF) [99] and chemokines [100].

Neutrophils are recruited in a cascade of events that involves the following commonly recognized
steps that precede the transmigration: tethering, rolling, adhesion, and crawling on the endothelial cell
surface [101,102]. Neutrophil recruitment is initiated by changes on endothelial cells during the early
steps of inflammation. Endothelial cells can be activated directly by pathogens through PRR activation,
causing an increase of the expression and exposure of adhesion molecules on their surface. Once
on the endothelial surface, P selectin and E selectin bind to their glycosylated ligands on leukocytes,
leading to the tethering (capturing) of free-flowing neutrophils to the surface of the endothelium and
subsequent rolling of neutrophils along the vessel in the direction of the blood flow [103]. Rolling
requires rapid formation and breakage of adhesive bonds. The rolling of neutrophils facilitates
their contact with chemokine-decorated endothelium to induce activation. Full activation may be
a two-step process initiated by specific priming by pro-inflammatory cytokines, such as TNF and
IL-1β, or by contact with activated endothelial cells followed by an exposure to pathogen-associated
molecular patterns (PAMPs), chemoattractants or growth factors [104,105]. The adhesion step of
the recruitment cascade prepares neutrophils for transmigration, but migration does not necessarily
occur at the initial site of their arrest on the endothelium. Some of the adherent neutrophils reveal so
called crawling behavior as they elongate and continue to send out pseudopods, apparently actively
scanning and probing the surroundings while remaining firmly attached to a single location within
the microvasculature [106]. During the transmigration process, neutrophils cross the endothelium
in a process dependent on integrins. The migration across the endothelial cell layer occurs either
paracellularly (between endothelial cells) or transcellularly (through an endothelial cell without mixing
the cytoplasmic content of both cells). Next, neutrophils migrate towards the infectious/inflammatory
focus in the tissue [107].

4.3. Neutrophil Functions during Infections

In order to kill microorganisms, neutrophils can phagocyte, secrete the content of their granules,
produce reactive oxygen species (ROS) and antimicrobial peptides, and release neutrophil extracellular
traps (NETs) as demonstrated in Figure 2A [108]. S. aureus may produce several virulence factors
that neutralize neutrophil-dependent killing. These include the pore-forming toxin Panton-Valentine
leukocidin, antioxidants staphyloxanthin, catalase and superoxide dismutase and the surface factor
promoting resistance to oxidative killing (SOK) to neutralize the action of ROS [58,109–111] (Figure 2B).
Neutrophil defensin-dependent killing of bacteria is inhibited by the binding of neutrophil defensins
to staphylokinase [112]. In addition, the neutrophil-derived antibacterial peptide and neutrophil

Int. J. Mol. Sci. 2018, 19, 468 7 of 28

attractant LL37 may be degraded by the S. aureus metalloproteinase aureolysin [113,114]. Finally, NETs
may be degraded by a S. aureus nuclease, resulting in diminished antibacterial efficiency of NETs [115].

Once at the site of infection, the neutrophils bind and ingest invading microorganisms
by phagocytosis, a critical first step in the removal of bacteria during infection. Neutrophils
recognize numerous surface-bound and freely secreted bacterial products such as PGN, lipoproteins,
lipopolysaccharide, CpG-containing DNA, and flagellin [116]. Such conserved bacterial PAMPs are
recognized directly by PRRs expressed on the extracellular membrane or on organelles in the cytosol
of the neutrophil [117]. The process of neutrophil phagocytosis triggers synthesis of a number of
immunomodulatory factors that will recruit additional neutrophils, modulates subsequent neutrophil
responses, and coordinates early responses of other cell types such as monocytes, macrophages,
dendritic cells and lymphocytes, thereby providing an important link between innate and acquired
immune responses [118].Int. J. Mol. Sci. 2018, 19, x FOR PEER REVIEW 7 of 27

Figure 2. Killing of S. aureus by neutrophils and immune evasion. (A) Neutrophils phagocytose S.
aureus and kill the bacteria by the production of ROS, liberation of lytic enzymes from granules and
production of NETs. (B) S. aureus may possess virulence factors including enzymes that kill
neutrophils or allow the bacteria to evade killing by neutrophils. ROS: reactive oxygen species; NET:
neutrophil extracellular traps; SOK: surface factor promoting resistance to oxidative killing; SOD:
superoxide dismutase.

Phagocytosis is accompanied by the generation of microbicidal ROS (oxygen-dependent) and
fusion of cytoplasmic granules with microbe-containing phagosomes (degranulation). Degranulation
enriches the phagosome lumen with antimicrobial peptides and proteases (oxygen-independent
process), which in combination with ROS create an environment non-conducive to survival of the
ingested microbe [119]. In the most classical sense, neutrophil activation is intimately linked with the
production of superoxide and other secondarily derived ROS, an oxygen-dependent process known
as the oxidative or respiratory burst. High levels of superoxide are generated upon full assembly of
the multi-subunit nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase in
both the plasma- and phagosomal membranes [120,121].

Neutrophils present three fundamental types of granules: primary or azurophilic, secondary or
specific and tertiary or gelatinase-containing granules [122,123]. Primary granules are the largest and
are formed first during neutrophil maturation. They are named after their ability to take up the basic
dye azure A and contain myeloperoxidase (MPO), defensins, lysozyme, bactericidal/permeability-
increasing protein (BPI), and a number of serine proteases such as neutrophil elastase, proteinase 3
and cathepsin G [124]. Granules of the second class are smaller, do not contain MPO and are
characterized by the presence of the glycoprotein lactoferrin and antimicrobial compounds including
neutrophil gelatinase-associated lipocalin, human cationic antimicrobial protein-18 and lysozyme
[125]. The gelatinase granules are also MPO-negative, are smaller than specific granules and contain
few antimicrobials, but they serve as a storage location for a number of metalloproteases, such as
gelatinase and leukolysin [123]. Neutrophils also present secretory vesicles that serve as a reservoir
for a number of important membrane-bound molecules active during neutrophil migration. As a
neutrophil proceeds through the activation process, granules are mobilized and fuse with either the
plasma membrane or the phagosome, releasing their content into the respective environments [126].

Figure 2. Killing of S. aureus by neutrophils and immune evasion. (A) Neutrophils phagocytose
S. aureus and kill the bacteria by the production of ROS, liberation of lytic enzymes from granules
and production of NETs. (B) S. aureus may possess virulence factors including enzymes that kill
neutrophils or allow the bacteria to evade killing by neutrophils. ROS: reactive oxygen species; NET:
neutrophil extracellular traps; SOK: surface factor promoting resistance to oxidative killing; SOD:
superoxide dismutase.

Phagocytosis is accompanied by the generation of microbicidal ROS (oxygen-dependent) and
fusion of cytoplasmic granules with microbe-containing phagosomes (degranulation). Degranulation
enriches the phagosome lumen with antimicrobial peptides and proteases (oxygen-independent
process), which in combination with ROS create an environment non-conducive to survival of the
ingested microbe [119]. In the most classical sense, neutrophil activation is intimately linked with the
production of superoxide and other secondarily derived ROS, an oxygen-dependent process known as
the oxidative or respiratory burst. High levels of superoxide are generated upon full assembly of the
multi-subunit nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase in both the
plasma- and phagosomal membranes [120,121].

Int. J. Mol. Sci. 2018, 19, 468 8 of 28

contain MPO and are characterized by the presence of the glycoprotein lactoferrin and antimicrobial
compounds including neutrophil gelatinase-associated lipocalin, human cationic antimicrobial
protein-18 and lysozyme [125]. The gelatinase granules are also MPO-negative, are smaller than
specific granules and contain few antimicrobials, but they serve as a storage location for a number
of metalloproteases, such as gelatinase and leukolysin [123]. Neutrophils also present secretory
vesicles that serve as a reservoir for a number of important membrane-bound molecules active during
neutrophil migration. As a neutrophil proceeds through the activation process, granules are mobilized
and fuse with either the plasma membrane or the phagosome, releasing their content into the respective
environments [126].

Neutrophils produce peptides and proteins that directly or indirectly kill microbes. There are
three main types of antimicrobials: cationic peptides and proteins that bind to microbial membranes,
enzymes, and proteins that deprive microorganisms of essential nutrients [127]. Many of these peptides
disrupt the membrane integrity, whereas some antimicrobials are thought to disrupt essential microbial
functions, such as DNA replication, transcription or production of energy [128]. In addition, some of
these neutrophil-derived antimicrobial peptides also attract additional leukocytes to the inflammatory
site [113,129]. Recently, it was demonstrated that neutrophils can produce neutrophil extracellular
traps (NETs) that contain decondensed chromatin, bound histones, azurophilic granule proteins and
cytosolic proteins. They have a demonstrated capacity to bind to and kill a variety of pathogens
including S. aureus [130]. Extrusion of such structures by neutrophils is predicted to limit microbial
spread and dissemination, while enhancing effective local concentrations of extruded microbicidal
agents, thereby promoting synergistic killing of attached microorganisms [131].

Several mechanisms used by neutrophils to eliminate pathogens can also cause host tissue
damage [132]. In that way, recruitment of inflammatory neutrophils needs to be tightly controlled
and such neutrophils must be removed before they have serious, detrimental effects on inflamed
tissues. Once neutrophils have executed their antimicrobial function, they die via a built-in cell-death
program. However, not only does apoptosis reduce the number of neutrophils present, it also produces
signals that abrogate further neutrophil recruitment [133]. In addition, evidence is accumulating for
the existence of anti-inflammatory neutrophils that produce IL-10 [103]. Indeed, different neutrophil
populations were collected from MRSA-resistant versus MRSA-sensitive mice [134]. It is not clear
whether these are generated as different populations or evolve separately as a consequence of
stimulation with microorganisms, different growth factors or cytokines.

4.4. The Chemokine System in Neutrophil Recruitment

Chemokines are small proteins with molecular masses of ~7–12 kDa that belong to the family of
chemotactic cytokines. Chemokines are the only group of cytokines that bind to G protein-coupled
receptors (GPCRs) [135]. Chemokines were named based on their chemoattractant property, described
first in 1987 when CXCL8 was shown to be involved in chemotaxis of neutrophils in vitro [136,137].
Additionally, chemokines were described to be involved in other processes such as embryogenesis,
homeostasis, angiogenesis and inflammation [138,139]. Chemokines can be divided into 4 subfamilies
based on the position of the two cysteine residues in their N-terminal amino acid sequence: (1) CC
chemokines have two adjacent cysteines; (2) CXC chemokines present with one amino acid between the
two cysteines; (3) the CX3C chemokine has 3 amino acids between the cysteines, and; (4) C chemokines
lack one of the two N-terminal cysteines [140]. The ELR+ CXC chemokines that have a specific amino
acid sequence of glutamic acid-leucine-arginine (ELR) immediately before the first cysteine of the
CXC motif, are associated with neutrophil recruitment and include CXCL1, 2, 3, 5, 6, 7 and 8. Those
without an ELR motif rather recruit T and B lymphocytes, monocytes or hematopoietic precursor
cells [141–147].

Chemokines can bind to two types of receptors: GPCRs and atypical chemokine receptors
(ACKRs) that do not signal through G proteins and lack chemotactic activity. GPCRs are classified
as CCR, CXCR, CX3CR and XCR according to the cysteine motif in their ligands [148,149]. The

Int. J. Mol. Sci. 2018, 19, 468 9 of 28

interactions of human and murine chemokines with GPCRs reported to be expressed on neutrophils
are shown in Table 1. CXCR1 and CXCR2 are the abundantly expressed receptors on circulating
neutrophils. However, under inflammatory condition, neutrophils in tissues have been reported
to express multiple other CXC and CC chemokine receptors including CXCR3, CCR1, CCR2 and
CCR3 [150,151]. CXCR4 expression on neutrophils enhances upon aging of neutrophils and has
been suggested to be linked to resolution of inflammation [152,153]. As can be seen, one chemokine
(e.g., CXCL8) can bind to several receptors and one receptor (e.g., CXCR2) may transduce signals for
different ligands. The chemokine interactions that at the first moment were considered as “redundant”
gave rise to the term “promiscuity” of the chemokine system. However, much attention is given now
to the “bias of the chemokine system”, including ligand bias, receptor bias and tissue bias, which tend
to explain and allow us to understand how those chemokines bind to their receptors and promote
different responses in different situations [154]. For instance the chemokines CXCL4 and

CXCL7

are typical platelet products [155]. In contrast, CCL3, CCL3L1 and CCL4 are primarily produced in
leukocytes [156]. Other chemokines such as the major human neutrophil attractant CXCL8 or IL-8 may
be induced in almost any cell type [157].

GPCRs have seven transmembrane helices with three extra and three intracellular loops,
an extracellular N-terminus and intracellular C-terminus. Chemokines bind to the extracellular
domain and to a pocket in the transmembrane area and the signal is transmitted to the intracellular
compartment. Cells are activated by the direct coupling to G proteins or β arrestins [154,158,159].
The intracellular signaling in the chemokine receptors is related to second messengers such as calcium,
cyclic adenosine monophosphate (cAMP) and GTPases (Ras and Rac). The GPCRs can also signal
through β arrestins, a pathway that can regulate the receptor signal through the desensitization
process [159,160]. β arrestins can block the binding to the phosphorylated G proteins and they
are responsible for internalization of receptors to endosomes and degradation. Desensitization
may be critical for maintaining the capacity of the cell to sense a chemoattractant gradient [161].
Multiple ACKRs, which fail to signal through the G proteins, have been reported to signal through β
arrestins [154,162,163].

Table 1. Chemokine receptors expressed on neutrophils and their human and murine ligands 1.

Receptor Human Ligand(s) Murine Ligand(s)

CXCR1 CXCL6, CXCL8 CXCL6

CXCR2
CXCL1, CXCL2, CXCL3, CXCL5, CXCL6,

CXCL7, CXCL8
CXCL1, CXCL2, CXCL3, CXCL6,

CXCL7

CXCR3
CXCL4, CXCL4L1, CXCL9, CXCL10,

CXCL11,
CXCL4, CXCL9, CXCL10, CXCL11

CXCR4 CXCL12 CXCL12

CCR1
CCL3, CCL3L1, CCL4L1, CCL5, CCL7,
CCL8, CCL14, CCL15, CCL16, CCL23

CCL3, CCL5, CCL6, CCL7, CCL9

CCR2 CCL2, CCL7, CCL8, CCL13, CCL16 CCL2, CCL7, CCL12

CCR3
CCL3L1, CCL5, CCL7, CCL8, CCL11,

CCL13, CCL15, CCL24, CCL26, CCL28
CCL5, CCL7, CCL9, CCL11,

CCL14, CCL24, CCL26, CCL28

CCR5
CCL3, CCL3L1, CCL4, CCL4L1, CCL5,

CCL8, CCL11, CCL14, CCL16
CCL3, CCL4, CCL5

ACKR2 Inflammatory CC chemokines Inflammatory CC chemokines
1 CXCR1 and CXCR2 are highly expressed on circulating neutrophils, CXCR4 is enhanced on “aging” neutrophils
and other chemokine receptors may be upregulated on neutrophils in inflamed tissues.

In total, 20 chemokine receptors are described and they are all expressed on leukocytes. Based on
their functions, they can be divided into constitutive and inducible or homeostatic and inflammatory

Int. J. Mol. Sci. 2018, 19, 468 10 of 28

receptors. Initially, inflammatory chemokines and their receptors were only studied in the context of
inflammation, but some receptors were identified as co-receptors for HIV entrance into the cell and
others are associated with tumor metastasis [164–168]. Regarding homeostasis, the chemokine system
is involved in embryogenesis, leukocyte trafficking to lymphoid organs, tissue/organ development and
angiogenesis. For instance, much attention has been given to the contribution of the CXCR4 receptor
to embryogenesis, hematopoiesis, and leukocyte trafficking from bone marrow. The importance of
CXCR4 in this condition is critical for survival, since the deletion of CXCR4 or its ligand CXCL12
in mice is embryonically lethal [169,170]. Already at its discovery it was recognized that CXCR4 is
expressed on neutrophils [171]. CXCR4 upregulated on “aging” neutrophils was shown to induce
reverse migration of senescent neutrophils from the circulation to bone marrow [172]. CXCR1 and
CXCR2 were the first members of the chemokine receptor family to be cloned, sharing a high degree
of homology with formyl peptide receptors (FPRs) [173,174]. Inflammatory neutrophils express high
levels of CXCR1 and CXCR2 on their surface once activated and the receptors and their ligands have
an important role in neutrophil recruitment [175].

The atypical chemokine receptors (ACKRs) are related to classical chemokine receptors and also
have seven transmembrane domains but they are not able to activate G proteins [176–179]. These
receptors are expressed on leukocytes and non-hematopoietic cells. ACKRs signal through the β
arrestin pathway, but they also work as scavenger receptors, since they can internalize the bound
chemokines without chemotactic actions. Neutrophils express ACKR2 (or D6), a receptor for most
inflammatory CC chemokines [180,181]. ACKR2 is supposed to restrict migration of CCR1 expressing
neutrophils to its ligands including the highly potent CC chemokine CCL3 [177]. CCRL2, a receptor
with high homology with chemokine receptors and with chemerin as identified ligand, on the other
hand was shown to heterodimerize with CXCR2 and to promote neutrophil migration in mice [178,182].

4.5. Regulation of Chemokine-Dependent Neutrophil Recruitment

Chemokine activity can be regulated at multiple levels, including gene duplication, gene
transcription and translation. Upon stimulation with PAMPs several connective tissue cells will
produce the inflammatory cytokine IL-1β. IL-1β induces the production of chemokines, CXCL8
being the most potent neutrophil attracting chemokine in human. In addition, neutrophils that are
recruited to the inflammatory joint may enhance the response through the secretion of additional active
IL-1β further enhancing the production of CXCR1/CXCR2 ligands and neutrophil accumulation [183].
Some pre-formed chemokines are stored in endothelial cells, inside secretory granules including
Weibel-Palade bodies, and are quickly released upon cell insult [184]. Once produced, chemokine
activity can be regulated by binding to glycosaminoglycans on endothelial cell layers of lymph and
blood vessels, by binding to and expression of GPCRs and ACKRs on cells, or by receptor-mediated
synergy and antagonism among chemokines [184–186]. Recently, microRNAs, regulating the
chemokine and chemokine receptor mRNA levels, were discovered as a novel mechanism for
fine-tuning chemokine and chemokine receptor expression [187,188]. Finally, chemokines and their
receptors become post-translationally modified. Chemokines can be modified post-translationally
through: (1) proteolytic cleavage by enzymes such as metalloproteinases, CD26 and enzymes from
pathogens [189–192]; (2) citrullination, that is the formation of citrulline by the deimination of
arginine by peptidylarginine deiminases (PAD) [193–195]; (3) N-glycosylation on asparagine within
an Asn-Xaa-Ser/Thr motif, or O-glycosylation on serine (Ser) or threonine (Thr) residues [196];
and (4) nitration, where peroxynitrite, produced during oxidative stress, can selectively oxidize
and nitrate several residues, including the oxidation of histidine and the nitration of tyrosine and
tryptophan [197–199]. Reduced or enhanced receptor affinity and chemokine activity have been
reported, depending on the chemokine and on the type of posttranslational modification [189]. Most
posttranslational modifications of inflammatory chemokines are dependent on proteolytic cleavage,
mainly affecting the N-terminal region of the protein with highly specific proteases.

Int. J. Mol. Sci. 2018, 19, 468 11 of 28

In addition to specific GPCRs, glycosaminoglycans (GAGs) play an important role in the
regulation of neutrophil migration. GAGs are linear carbohydrate structures, consisting of a repeating
disaccharide unit, that comprises a hexuronic acid linked to an N-acetyl-hexosamine that can
be sulfated at different positions [200–202]. GAGs are negatively charged and can be divided
into six groups: heparan sulfate, heparin, chondroitin sulfate, dermatan sulfate, keratan sulfate
and hyaluronic acid. These sugar units can bind or attach to protein cores of proteoglycans or
can be found associated with the extracellular matrix. GAGs are heterogeneous in length and
composition and they can bind to a huge number of proteins. GAGs have fundamental roles in
cell signaling and development, angiogenesis, tumor progression, embryogenesis, wound healing,
and have anti-coagulant properties [203,204]. Interestingly, GAGs can interact directly with pathogens.
Particularly related to this study, hyaluronic acid favors to increase lubrication in synovial joints.
The loss of hyaluronic acid in osteoarthritic patients is associated with an increase of pain and
stiffness [205].

Each tissue produces specific GAG repertoires and cells can alter their GAG expression in response
to specific stimuli or in pathologic states. GAGs are important in cell recruitment during homeostatic
and inflammatory processes by their direct interaction with chemokines [202,206]. The binding of
chemokines to GAGs can generate an immobilized chemokine gradient that directs cell migration, as
shown in Figure 3. Cell surface immobilization of chemokines enables them to act locally rather than as
paracrine molecules, and likely prevents inappropriate activation and desensitization of receptors on
cells outside the region of interest for a given physiological situation [207]. Moreover, GAG expression
on the leukocyte also influences the chemokine interaction with GPCRs on the same cell [208,209].

Int. J. Mol. Sci. 2018, 19, x FOR PEER REVIEW 11 of 27

chemokines are described to be BBXB and BBBXXB motifs, where B represents a basic amino acid
[210]. It has been shown that some chemokines act as monomers, whereas many chemokines can
oligomerize and form diverse quaternary structures including dimers, tetramers and polymers,
increasing the number of epitopes that bind to GAGs [211,212]. Oligomerization increases the affinity
of chemokines for GAGs through an avidity effect and this interaction also stabilizes the chemokine
oligomers. Moreover, oligomerization may have a dramatic effect on GAG affinity and specificity
[213,214].

Figure 3. Neutrophil recruitment by chemokines and leukotriene B4. Neutrophils are recruited to the
tissue through chemoattractants such as chemokines and LTB4. Chemokines bind to GAGs, which
are expressed on endothelial cells and tissue. The retention of chemokines on GAGs generates a
chemokine gradient that favors the binding of chemokines to their GPCR. LTB4 binds to specific
GPCRs on the neutrophil to induce firm adhesion of the cell to the endothelium. GAGs:
glycosaminoglycans, LTB4: leukotriene B4, GPCR: G protein-coupled receptor.

4.6. The 5-Lipoxygenase Pathway: Mechanisms of Neutrophil Recruitment and Inflammation

At the onset of inflammation, classic lipid mediators are produced, including LTB4, which
activate and amplify the cardinal signs of inflammation [215]. 5-lipoxygenase (5-LO) is a main
enzyme involved in the production of these lipid mediators. This enzyme is expressed in leukocytes
such as neutrophils, macrophages, dendritic cells, B cells and T cells [216]. During the inflammatory
process, another class of arachidonic acid (AA)-derived lipids, prostaglandins E2 and D2, induce the
switch of leukotriene synthesis to pro-resolving lipid production, including lipoxin A4 (LXA4)
[189,217,218]. The generation of anti-inflammatory resolvins assists in the control of the inflammatory
process [219]. The synthesis of LXA4 is also dependent on 5-LO. LXA4 has an important role in the
resolution of inflammation by decreasing neutrophil migration. On the other hand, LXA4 increases
the recruitment of macrophages. Additionally, LXA4 increases the phagocytosis of apoptotic
neutrophils by macrophages, a process named efferocytosis, to avoid tissue damage [220].

4.6.1. Leukotriene B4

Figure 3. Neutrophil recruitment by chemokines and leukotriene B4. Neutrophils are recruited to the
tissue through chemoattractants such as chemokines and LTB4. Chemokines bind to GAGs, which are
expressed on endothelial cells and tissue. The retention of chemokines on GAGs generates a chemokine
gradient that favors the binding of chemokines to their GPCR. LTB4 binds to specific GPCRs on the
neutrophil to induce firm adhesion of the cell to the endothelium. GAGs: glycosaminoglycans, LTB4:
leukotriene B4, GPCR: G protein-coupled receptor.

Almost all chemokines are basic proteins, often with a pI of 10 or higher, with many Arg, Lys
and His residues and GAGs bind to proteins with positive charges. The epitopes for GAG binding on
chemokines are described to be BBXB and BBBXXB motifs, where B represents a basic amino acid [210].
It has been shown that some chemokines act as monomers, whereas many chemokines can oligomerize
and form diverse quaternary structures including dimers, tetramers and polymers, increasing the

Int. J. Mol. Sci. 2018, 19, 468 12 of 28

number of epitopes that bind to GAGs [211,212]. Oligomerization increases the affinity of chemokines
for GAGs through an avidity effect and this interaction also stabilizes the chemokine oligomers.
Moreover, oligomerization may have a dramatic effect on GAG affinity and specificity [213,214].

4.6. The 5-Lipoxygenase Pathway: Mechanisms of Neutrophil Recruitment and Inflammation

At the onset of inflammation, classic lipid mediators are produced, including LTB4, which activate
and amplify the cardinal signs of inflammation [215]. 5-lipoxygenase (5-LO) is a main enzyme involved
in the production of these lipid mediators. This enzyme is expressed in leukocytes such as neutrophils,
macrophages, dendritic cells, B cells and T cells [216]. During the inflammatory process, another class
of arachidonic acid (AA)-derived lipids, prostaglandins E2 and D2, induce the switch of leukotriene
synthesis to pro-resolving lipid production, including lipoxin A4 (LXA4) [189,217,218]. The generation
of anti-inflammatory resolvins assists in the control of the inflammatory process [219]. The synthesis
of LXA4 is also dependent on 5-LO. LXA4 has an important role in the resolution of inflammation by
decreasing neutrophil migration. On the other hand, LXA4 increases the recruitment of macrophages.
Additionally, LXA4 increases the phagocytosis of apoptotic neutrophils by macrophages, a process
named efferocytosis, to avoid tissue damage [220].

4.6.1. Leukotriene B4

LTB4 is a very potent chemoattractant for neutrophils. LTB4 is produced from AA in a pathway
dependent on lipoxygenases (LO) [98]. AA is a 20-carbon fatty acid that is present in all cells and it is
the main eicosanoid precursor. Some stimuli such as N-formyl-methionyl-leucyl-phenylalanine (fMLF),
CXCL8, microorganisms, phagocytic particles and damage or injury can activate phospholipases and
release AA from the cell membrane [221]. In the cytosol AA can be metabolized into leukotrienes
and lipoxins via a pathway dependent on LO. The main LO enzymes are 5-LO, that is expressed
in leukocytes, and 12/15-LO, expressed in reticulocytes, eosinophils, immature dendritic cells
(DCs), epithelial and airway cells, pancreatic islets and resident peritoneal macrophages [222].
The first step in leukotriene biosynthesis is the conversion of AA into a hydroperoxide, named
5-hydroperoxyeicosatetraenoic acid (5-HPETE), by the insertion of an oxygen at position 5. In this step
the activation of 5-LO is dependent on the 5-LO activating protein (FLAP). 5-HPETE can be reduced to
5-hydroxyeicosatetraenoic acid (5-HETE) or can be converted in a 5,6-epoxide containing a conjugated
triene structure, named leukotriene A4 (LTA4) by removal of a water molecule [223]. LTA4 is instable
and can be converted into LTB4 by insertion of a hydroxyl group at carbon 12 by the enzyme LTA4
hydrolase. Another possibility is the conversion in leukotriene C4 (LTC4) by addition of a glutathionyl
group at carbon 6 by γ-glutamyl-S-transferase [224]. LTB4 is produced and released within minutes by
neutrophils, macrophages, and mast cells and is an important element of the immediate inflammatory
response [225].

Leukotrienes bind to extracellular GPCRs, which are members of the rhodopsin-like receptors
family and related to chemokine receptors. LTB4 is known to bind to two LTB4 receptors, BLT1 and
BLT2 [226]. BLT1 is a 43 kDa GPCR expressed in inflammatory cells, such as neutrophils, alveolar
macrophages, eosinophils, differentiated T cells, dendritic cells and osteoclasts, and has a high affinity
for LTB4. The BLT2 receptor has low affinity for LTB4 and is expressed more ubiquitously [227]. BLT1
is widely related to chemotaxis. The axis LTB4/BLT1 is needed for neutrophil recruitment in arthritis
and for the recruitment of neutrophils to lymph nodes during bacterial infection. On the other hand,
the axis LTB4/BLT2 is involved in the generation of reactive oxygen species and can enhance wound
healing [225,228,229].

4.6.2. Lipoxin A4

Lipoxins can be generated by three main pathways. In the first one, AA is released from the
cell membrane and one oxygen is inserted at carbon 15 by 15-LO in eosinophils, monocytes or
epithelial cells, resulting in the intermediate 15S-HPETE. 15S-HPETE can be taken up by neutrophils or

Int. J. Mol. Sci. 2018, 19, 468 13 of 28

monocytes and converted in the 5,6-epoxytetraene by 5-LO and then is hydrolyzed by LXA4 or lipoxin
B4 (LXB4) hydrolases in LXA4 and LXB4 [230,231]. The second route involves the interaction between
leukocytes and platelets. The 5-LO present in leukocytes, such as neutrophils, converts AA into LTA4
as described before. The LTA4 is released and taken up by adherent platelets. These express 12-LO
that converts LTA4 in LXA4 and LXB4 [232]. The third route occurs after the exogenous administration
of aspirin. In this case, aspirin triggers the formation of the 15R-epimer of lipoxins, 15-epi-LXA4 and
15-epi-LXB4. These epimers carry a carbon 15 alcohol group in the R configuration. They arise from
aspirin-acetylated by cyclooxygenase-2 (COX-2) and share the actions of LXA4 [233].

LXA4 binds to the GPCR receptor ALX/FPR2. ALX is expressed on leukocytes, astrocytoma
cells, epithelial cells, hepatocytes, microvascular endothelial cells and neuroblastoma cells. Unlike
classic GPCRs for chemoattractants that mobilize intracellular Ca2+ to evoke chemotaxis, lipoxins
instead induce changes in the phosphorylation of proteins of the cytoskeleton, resulting in β arrestin
activation [234,235]. LXA4 presents pro-resolving actions such as decreased neutrophil infiltration,
increased recruitment of mononuclear cells and an increase in the uptake of apoptotic neutrophils by
macrophages. LXA4 has also effects on the return of vascular permeability to normal levels [236].

Both lipids LTB4 and LXA4 have been described to be involved in articular diseases. LTB4 and
5-LO mRNA was found in synovial tissue of patients with rheumatoid arthritis [237,238]. LTB4 is
also associated with pathogenesis in the collagen-induced arthritis model, the K/BxN serum transfer
arthritis model [239–241] and the experimental model of gout [242]. LXA4 was also detected in
synovial tissue of patients with rheumatoid arthritis [243]. Nonetheless, in zymosan-induced arthritis,
LXA4 was related to attenuation of the disease [244]. During infection, LTB4 and LXA4 are related
to clearance of pathogens and improvement of the disease. Some studies show that LTB4 has a
role in the control of lung Paracoccidioidomycosis and is important for phagocytosis and killing
of Borrelia burgdorferi [245,246]. In lung infection by Cryptococcus neoformans and sepsis, LXA4 is
associated with the control of infection and an increase in survival [247,248]. However, in pneumosepsis
induced by Klebsiella pneumoniae, the LXA4 in the early stage of the disease is associated with systemic
infection-induced mortality and can improve survival at a late stage of the disease [249].

5. Dual Functions of Neutrophils during Septic Arthritis

Based on the aforementioned mechanisms of the pathology of septic arthritis, this disease is
associated with severe articular damage and pain. During the immune response against S. aureus
infection, neutrophils are the main cells recruited to the joint. As previously mentioned, neutrophils
contain potent antimicrobial molecules that are important in the control of infection, including joint
infections. The depletion of neutrophils prior to the systemic injection of S. aureus in mice impaired
the bacterial control and increased mortality. Furthermore, the absence of neutrophils increased the
circulating levels of pro-inflammatory cytokines and the frequency of arthritis after three days of
infection, suggesting that a systemic inflammatory response against a high titer of S. aureus could also
cause arthritis independent of the toxic effects of neutrophils [15]. Similarly, the increased concentration
of neutrophils in the joint due to a photodynamic therapy applied locally improves the clearance of
MRSA and decreases tissue damage [250]. These examples highlight the importance of neutrophils to
control S. aureus-induced arthritis. However, neutrophils are associated with articular damage and
pain development [251,252]. Lögters et al. identified increased NETosis in synovial fluid of septic
arthritis patients, mainly patients infected with S. aureus, compared to noninfectious or osteoarthritic
joints. Importantly, there was a positive correlation with levels of IL-6 and IL-1 in the joints [253].

The blockade of neutrophil migration and activity could be an interesting strategy to avoid
excessive articular damage and pain during S. aureus-induced septic arthritis in mice [254,255].
Formylated peptides are potent neutrophil chemoattractants. In mice, the intravenous injection
of S. aureus carrying a mutation that prevents the synthesis of formylated peptides decreases the
accumulation of neutrophils in the joint when compared to wild type S. aureus injection. In mice
injected with mutated bacteria, the incidence of arthritis was lower, associated with decreased synovitis

Int. J. Mol. Sci. 2018, 19, 468 14 of 28

and cartilage damage as compared to injection with wild type S. aureus. However, the bacterial
load analyzed in the joints is comparable between the two bacteria at seven days after injection,
suggesting that the neutrophils guided by formylated peptides are important for joint inflammation
and damage [13].

The specific blockage of neutrophil recruitment in order to avoid or reduce tissue damage was
also successful using CXCR1/2 inhibitors in some animal models of inflammatory articular diseases
such as antigen-induced arthritis, collagen-induced arthritis, autoantibody-mediated arthritis and
gout [254–258]. Since neutrophils have a crucial role during the infection, the blockade of these cells
in septic arthritis can be protective or detrimental. CXCR2-binding chemokines are present in the
joint of Brucella mellitensis-infected mice, guiding the recruitment of neutrophils. Neutrophil counts
correlated with joint inflammation and damage. Indeed, CXCR2-deficient mice displayed delayed
incidence, reduced clinical scores, and decreased swelling as compared to WT mice, although there is
no difference on bacterial load between both groups [259]. We previously demonstrated in a septic
arthritis model induced by the intra-articular injection of S. aureus that the treatment with an antagonist
of CXCR1/2 starting from the beginning of the infection was able to decrease neutrophil recruitment,
articular damage and hypernociception. Nonetheless, the bacterial load increased, showing that
neutrophils are important for bacterial control [24]. In addition, we also evaluated if the blockage of
neutrophils at a later time point of the infection could be effective. The treatment starting 3 days after
the infection, partially reduced hypernociception, prevented the increase in bacterial load, but failed in
inhibiting articular damage. Besides the blockage of neutrophil migration, the decrease of neutrophil
activation could also be useful to control joint inflammation and damage in septic arthritis. Activated
neutrophils produce hypochlorous acid (HOCl) by a reaction of myeloperoxidase with hydrogen
peroxide. The accumulation of HOCl is toxic and its blockage could be beneficial to avoid excessive
tissue damage. Taurine is an amino acid found abundantly in the cytosol of neutrophils and acts as
scavenger of HOCl. Interestingly, the injection of taurine chloramine (a product of taurine and HOCl)
in the joint at the same time of S. aureus significantly reduced the histopathological score, especially
cartilage and bone destruction [260]. Thus, the benefits of targeting neutrophil activation or migration
during septic arthritis still need to be better clarified, considering effects of different bacterial strains
and disease progression. Therefore, it is clear that the neutrophils recruited to the joint in the initial
phase of the infection play a role in the control of infection, but can cause articular damage. Thus the
blockage of neutrophils as a potential therapy for septic arthritis needs to be carefully evaluated in
order to create a balance between control of infection (with or without co-treatment with antibiotics)
and induction of articular damage.

6. Conclusions

In most cases, the host has the ability to induce a protective inflammatory response resulting in
elimination of the invading pathogen and subsequent resolution of infection. However, if the infection
cannot be controlled and persists, strong activation of the immune response can cause destruction of
the joint [11]. Accordingly, most of the detrimental effects of infection result from the exaggerated
immune response of the host rather than from direct cytotoxicity of bacteria [6].

The role of neutrophils in the pathogenesis of septic arthritis is dual. On the one hand, they are
indispensable in the early phase of disease for effective defense against bacteria and consequently
for host survival. On the other hand, these leukocytes act as mediators of tissue-destructive
events. The massive infiltration of neutrophils into the infected joint can contribute to cartilage
and bone destruction by the release of free radicals and bacteria- and tissue-degrading enzymes,
including products of the NADPH oxidase complex and proteolytic enzymes targeting collagen
and/or proteoglycans. Permanent destruction of cartilage and subchondral bone loss can occur
within three days after infection [11,13,15]. Elimination of neutrophils from the site of inflammation
is a prerequisite for resolution of the acute inflammatory response. This implicates that prolonged

Int. J. Mol. Sci. 2018, 19, 468 15 of 28

presence of neutrophils at the site of inflammation can lead to persistence of the inflammatory response,
associated with complications such as tissue damage [261,262].

Other factors playing a role in joint damage include: high levels of cytokines, which enhance
the release of MMPs (such as MMP-2, MMP-3 and MMP-9) and other enzymes degrading collagen,
and bacterial toxins and enzymes [11]. Furthermore, the inflammatory process following infection
alters the synovium as well as the composition and cellular content of the synovial fluid. These
changes in the synovial fluid might affect the articular cartilage, since synovial fluid is indispensable
for lubrication and nutrition of the articular cartilage. Moreover, synovial fluid dynamics can be
disrupted by the infectious process, leading to a fluid effusion in the joint. Subsequently, intra-articular
pressure increases, preventing the supply of blood and nutrients to the joint, thereby resulting in
destruction of the synovium and cartilage [2,11].

Early and effective treatment may enable resolution of the inflammatory process. In case of
unsuccessful or no treatment, articular cartilage may be lost entirely, resulting in fibrous or bony joint
ankylosis. When inhibition of neutrophil infiltration is considered as a treatment option, co-treatment
with antibiotics will probably be essential to combine diminished tissue destruction with efficient
clearance of the microorganisms.

Acknowledgments: This work was supported by the Brazilian National Council for Scientific and Technological
Development (CNPq), the “Fundação de Amparo a Pesquisa de Minas Gerais” (FAPEMIG—APQ 03072-15),
INCT in dengue and host pathogen interactions, the Research Foundation—Flanders (FWO-Vlaanderen, grants
G.0D66.13, G.0764.14 and G.0808.18), the Interuniversity Attraction Poles Programme initiated by the Belgian
Science Policy Office (I.A.P. Project 7/40), and C1 funding (C16/17/010) of the KU Leuven. Helena Crijns holds
an FWO-SB PhD scholarship from FWO-Vlaanderen.

Author Contributions: Daiane Boff and Helena Crijns wrote the initial text of the manuscript and Mauro M.
Teixeira, Flavio A. Amaral and Paul Proost further modified the paper.

Conflicts of Interest: The authors declare no conflict of interest. The founding sponsors had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the
decision to publish the results.

Abbreviations

AA Arachidonic acid
ACKR Atypical chemokine receptor
DC Dendritic cell
FPR Formyl peptide receptor
GAG glycosaminoglycan
GPCR G protein-coupled receptor
HETE hydroxyeicosatetraenoic acid
HPETE hydroperoxyeicosatetraenoic acid
IL- Interleukin-
LTA4 Leukotriene A4
LTB4 Leukotriene B4
LTC4 Leukotriene C4
LO Lipoxygenase
LXA4 Lipoxin A4
MPO myeloperoxidase
MRSA methicillin-resistant Staphylococcus aureus
MSCRAMM microbial surface component recognizing adhesive matrix molecules
NETs neutrophil extracellular traps
PAMP pathogen-associated molecular pattern
PGN peptidoglycan
PRR pattern recognition receptor

Int. J. Mol. Sci. 2018, 19, 468 16 of 28

RA rheumatoid arthritis
ROS reactive oxygen species
S. aureus Staphylococcus aureus
TLR Toll-like receptor
TNF tumor necrosis factor

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Introduction

Septic Arthritis

Diagnosis and Treatment of Septic Arthritis
Immune Response against S. aureus

Introduction
Neutrophils
Neutrophil Functions during Infections
The Chemokine System in Neutrophil Recruitment
Regulation of Chemokine-Dependent Neutrophil Recruitment
The 5-Lipoxygenase Pathway: Mechanisms of Neutrophil Recruitment and Inflammation
Leukotriene B4
Lipoxin A4

Dual Functions of Neutrophils during Septic Arthritis
Conclusions

References

51451

K e y t e r m s
ankylosing spondylitis, 538
arthritis, 53

avulsion, 519
bowing fractures, 516
bursitis, 520
closed fracture, 558
clubfoot, 55

comminuted fracture, 515
complete fracture, 515
contractures, 549
delayed union, 518
developmental dysplasia of the hip,

556
dislocation, 519
disuse atrophy, 550
Duchenne’s muscular dystrophy, 554
endogenous osteomyelitis, 546
epicondylitis, 520
exogenous osteomyelitis, 546
fatigue fracture, 516
fibromyalgia, 550
fracture, 515
gout, 539
gouty arthritis, 539
greenstick fracture, 516
incomplete fracture, 515
inflammatory joint disease (arthritis),

533
insufficiency fractures, 516
juvenile rheumatoid arthritis, 537
kyphosis, 527
Legg-Calvé-Perthes disease, 53

linear fracture, 515
malunion, 518
muscle strain, 521
myoglobinuria, 52

non-union, 518
oblique fracture, 515
open fracture, 558
Osgood-Schlatter disease, 532
osteoarthritis, 542
osteochondroses, 531
osteomyelitis, 546
osteoporosis, 524
Paget’s disease (osteitis deformans),

530
pathological fracture, 516
post-exercise muscle soreness, 521
rheumatoid arthritis, 533
scoliosis, 532
septic arthritis, 549
spiral fracture, 516
sprains, 519
strain, 519
stress fractures, 516
subluxation, 519
tendonitis, 520
tophi, 539
torus fracture, 516
transchondral fracture, 516
transverse fracture, 516

Introduction, 515
Musculoskeletal injuries, 515
Skeletal trauma, 515
Support structures, 519
Disorders of bone and joints, 524
Metabolic bone disease, 524
Disorders of joints, 533
Infectious bone disease, 546
Disorders of skeletal muscle, 549
Contractures, 549

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Disuse atrophy, 550
Fibromyalgia, 550
Integrative conditions related to the

musculoskeletal system, 552
Lower back pain, 552
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Myasthenia gravis, 553

C h a p t e r o u t l i n e

Alterations of musculoskeletal
function across the life span
Derek Nash and Paul McLiesh

C H A P T E R

Downloaded for Thi Thu Hien Nguyen (17611028@student.westernsydney.edu.au) at Western Sydney University from ClinicalKey.com.au/nursing by Elsevier on August 01, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 515

referred to as compound) if the skin is broken and closed
(formerly called simple) if it is not. A fracture in which a
bone breaks into two or more fragments is termed a
comminuted fracture. Fractures are also classified according
to the direction of the fracture line: a linear fracture runs
parallel to the long axis of the bone; an oblique fracture

Introduction
The musculoskeletal system is subject to a large number
of disorders that affect people of all ages. Congenital
conditions affect the newborn; the major cause of dysfunction
through to adulthood is trauma; and in the elderly the
effects of reducing bone density or accumulated wear and
tear on the skeleton cause fractures and failure of joints.

Musculoskeletal injuries have a major impact on patients,
families and the community because of the increased support
necessary to counteract the physical and psychological effects
of reduced capability, pain and decreased quality of life.
There are also financial and economic impacts, from direct
costs of diagnosis and treatments to costs related to the
loss of employment and decreased productivity.

Musculoskeletal injuries
Musculoskeletal trauma is referred to as the ‘neglected
disease’. Musculoskeletal injuries can occur due to a
multitude of environments and situations, such as the
workplace, home, motor vehicles and falls. Collectively,
these injuries create a large burden to the healthcare system.
For instance, in Australia, injury accounts for almost
500 000 hospitalisations annually1 with an estimated
4 million musculoskeletal injury encounters per year in
general practice.2 Furthermore, trauma, often resulting
in musculoskeletal injuries, is the leading cause of death
in people aged 1 to 34 years for all socioeconomic levels.
The different types of injuries are discussed in detail below.

Skeletal trauma
Fractures
A fracture is a break in a bone. A bone fractures when
force is applied that exceeds its tensile or compressive
strength. The incidence of fractures varies for individual
bones according to age and gender, with the highest
incidence of fractures occurring in young males (between
the ages of 15 and 24) and the elderly (65 years and
older). Fractures of healthy bones, particularly the tibia,
clavicle and distal (lower) humerus, tend to occur in young
people as a result of trauma. Fractures of the hands and
feet are often caused by accidents in the workplace. The
incidence of fractures of the proximal (upper) femur,
proximal humerus, vertebrae, wrist and pelvis is highest
in older adults and is often associated with osteoporosis.
Hip and other fragility fractures, the most serious outcome
of osteoporosis, are occurring much more frequently
as the populations of Australia and New Zealand are
ageing.3

CLASSIFICATION OF FRACTURE

Fractures can be classified as complete or incomplete and
open or closed (see Fig. 21.1). In a complete fracture the
bone is broken all the way through, whereas in an incomplete
fracture the bone is damaged but still in one piece. Complete
and incomplete fractures also can be called open (formerly

FIGURE 21.1

Examples of types of bone fractures.
A Oblique: fracture at oblique angle across both cortices. Cause:
direct or indirect energy, with angulation and some compression.
B Occult: fracture that is hidden or not readily discernible. Cause:
minor force or energy. C Open: skin broken over fracture; possible
soft-tissue trauma. Cause: moderate-to-severe energy that is
continuous and exceeds tissue tolerances. D Pathological:
transverse, oblique or spiral fracture of bone weakened by tumour
pressure or presence. Cause: minor energy or force, which may
be direct or indirect. E Comminuted: fracture with two or more
pieces or segments. Cause: direct or indirect moderate-to-severe
force. F Spiral: fracture that curves around cortices and may
become displaced by twist. Cause: direct or indirect twisting
energy or force with distal part held or unable to move. G
Transverse: horizontal break through bone. Cause: direct or
indirect energy towards bone. H Greenstick: break in only one
cortex of bone. Cause: minor direct or indirect energy. I Impacted:
fracture with one end wedged into opposite end of inside
fractured fragment. Cause: compressive axial energy or force
directly to distal fragment.

516 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

disease, osteomalacia, rickets, hyperparathyroidism and
radiation therapy all cause bone to lose its normal ability
to deform and recover — that is, the stress of normal
weight-bearing or activity fractures the bone. Many of these
conditions are referred to later in this chapter.

A transchondral fracture consists of break-up and
separation of a portion of the articular cartilage that covers
the end of a bone at a joint as a result of trauma (joint
structures are discussed in Chapter 20). Single or multiple
sites may be fractured and the fragments may consist of

occurs at an oblique angle to the shaft of the bone; a spiral
fracture encircles the bone; and a transverse fracture occurs
straight across the bone.

Incomplete fractures tend to occur in the more flexible,
growing bones of children. The three main types of
incomplete fracture are greenstick, torus and bowing
fractures. A greenstick fracture disrupts the outer surface
of the bone (cortex), leaving the inner surface intact. The
name is derived from the similar appearance of the damage
sustained by a young tree branch (a green stick) when it
is bent sharply. Greenstick fractures typically occur in the
proximal metaphysis or diaphysis of the tibia, radius and
ulna. In a torus fracture, the cortex buckles but does not
break. Bowing fractures usually occur when longitudinal
force is applied to bone. This type of fracture is common
in children and usually involves the paired radius–ulna or
fibula–tibia. A complete diaphyseal fracture occurs in one
of the bones of the pair, which disperses the stress sufficiently
to prevent a complete fracture of the second bone, which
bows rather than breaks. A bowing fracture resists correction
(reduction) because the force necessary to reduce it must
be equal to the force that bowed it. Treatment of bowing
fractures is also difficult because the bowed bone interferes
with reduction of the fractured bone. Types of fractures
are summarised in Table 21.1.

Fractures may be further classified by cause as
pathological, stress or transchondral fractures. A pathological
fracture is a break at the site of a preexisting abnormality,
usually by force that would not fracture a normal bone.
Any disease process that weakens a bone (especially the
cortex) predisposes the bone to pathological fracture.
Pathological fractures are commonly associated with
tumours, osteoporosis, infections and metabolic bone
disorders.

Stress fractures occur in normal or abnormal bone that
experiences repeated stress, such as occurs during athletics.
The stress is less than the stress that usually causes a fracture.
Two types of stress fractures are recognised: fatigue fracture
and insufficiency fracture. A fatigue fracture is caused by
abnormal stress or torque applied to a bone with normal
ability to deform and recover. Fatigue fractures usually occur
in individuals who engage in a new or different activity
that is both strenuous and repetitive (e.g. joggers, skaters,
dancers, military recruits). Because gains in muscle strength
occur more rapidly than gains in bone strength, the newly
developed muscles place exaggerated stress on the bones
that are not yet ready for the additional stress. The imbalance
between muscle and bone development causes microfractures
to develop in the cortex. If the activity is controlled and
increased gradually, new bone formation catches up to the
increased demands and microfractures do not occur.
Runners employ the 10% rule to help avoid this problem,
restricting their increase in distance (or time) to 10% per
week.

Insufficiency fractures are stress fractures that occur
in bones lacking the normal ability to deform and recover;
a fracture can occur as a result of normal weight-bearing
or activity. Rheumatoid arthritis, osteoporosis, Paget’s

TABLE 21.1 Types of fractures

TYPE OF FRACTURE DEFINITION

Typical complete fractures
Closed Non-communicating wound between

bone and skin

Open Communicating wound between bone
and skin

Comminuted Multiple bone fragments

Linear Fracture line parallel to long axis of bone

Oblique Fracture line at an angle to long axis of
bone

Spiral Fracture line encircling bone (as a spiral
staircase)

Transverse Fracture line perpendicular to long axis
of bone

Impacted Fracture fragments pushed into each
other

Pathological Fracture at a point where bone has been
weakened by disease (e.g. by tumours or
osteoporosis)

Avulsion A fragment of bone connected to a
ligament or tendon breaks off from the
main bone

Compression Fracture wedged or squeezed together
on one side of bone

Displaced Fracture with one, both or all fragments
out of normal alignment

Extracapsular Fragment close to the joint but remains
outside the joint capsule

Intracapsular Fragment within the joint capsule

Typical incomplete fractures
Greenstick Break in one cortex of bone with

splintering of inner bone surface;
commonly occurs in children and the
elderly

Torus Buckling of cortex

Bowing Bending of bone

Stress Microfracture

Transchondral Separation of cartilaginous joint surface
(articular cartilage) from main shaft of
bone

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 517

Within 48 hours after the injury, new blood vessels grow
(in a process called angiogenesis) from surrounding soft
tissue and the marrow cavity into the fracture area and
blood flow to the entire bone increases. Phagocytic cells
begin cleaning up the debris (there are many dead blood
cells in the haematoma). Fibroblasts (collagen-forming cells)
and osteoblasts (bone-forming cells) migrate into the
damaged area (see Fig. 21.2). The fibroblasts lay down
collagen to form a fibrocartilaginous callus and the
osteoblasts produce matrix, which they mineralise to form
spongy bone. The osteoblasts migrate inwards to mineralise
the whole callus, forming a bony callus. The bone is
effectively ‘splinted’ at this stage, which takes from 3 to 10
weeks to achieve but is still not as strong as pre-fracture.
As the repair process continues, remodelling occurs (for
months), during which unnecessary callus is resorbed and
trabeculae are formed along lines of stress (see Fig. 21.3).
The final structure is a response to the mechanical stress
experienced by the bone (Wolff ’s law, see Chapter 20).

C L I N I C A L MA N I F E S TAT I O N S
The signs and symptoms of a fracture include pain, unnatural
alignment (deformity), swelling, muscle spasm, tenderness,
impaired sensation and decreased mobility or limb function.
The position of the bone segments is determined by the
pull of attached muscles, gravity and the direction and size
of the force that caused the fracture.

Immediately after a bone is fractured, there is usually
numbness in the fracture site because of trauma to the
nerve or nerves at the site. The numbness may last up to

A
B
C
D
E

FIGURE 21.2

Bone healing (schematic representation).
A Bleeding at broken ends of the bone with subsequent
haematoma formation. B Organisation of haematoma into fibrous
network. C Invasion of osteoblasts, lengthening of collagen
strands and deposition of calcium. D Callus formation; new bone
is built up as osteoclasts destroy dead bone. E Remodelling is
accomplished as excess callus is reabsorbed and trabecular bone
is laid down.

FIGURE 21.3

Exuberant callus formation following fracture.
The excessive growth of callus is seen as the rough appearance
rather than the smooth bone.

cartilage alone or cartilage and bone. Typical sites of
transchondral fracture are the distal femur, ankle, kneecap,
elbow and wrist. Transchondral fractures are most prevalent
in adolescents.

PAT H O P HYS I O LO G Y
When a bone is fractured, the periosteum and blood vessels
in the cortex, marrow and surrounding soft tissues are
disrupted. Bleeding occurs from the damaged ends of the
bone and from the neighbouring soft tissue. The volume
of blood lost can be significant. For example, a simple
fracture of the humerus can account for 200–300 mL of
blood loss, a simple fracture of the femur loses 500–1000 mL
of blood and a unilateral fracture of the pelvis can bleed
1000–1500 mL. A clot (haematoma) forms within the
medullary canal, between the fractured ends of the bone
and beneath the periosteum (see Fig. 21.2). Because blood
flow to the injured area is disrupted (there is no oxygen
supply) bone tissue immediately adjacent to the fracture
dies. This dead tissue (along with any debris in the fracture
area) stimulates an intense inflammatory response
characterised by vasodilation, increased permeability
allowing exudation of plasma, and infiltration by
inflammatory leucocytes, growth factors and mast cells that
simultaneously decalcify the fractured bone ends.

518 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

of weight used for skeletal traction can be much higher
than skin traction and will be determined in response to
the location and severity of the fracture.

Open reduction is a surgical procedure that exposes
the fracture site; the fragments are brought into alignment
under direct visualisation. Some form of prosthesis, screw,
plate, nail or wire is used to maintain the reduction (internal
fixation), the soft tissues and skin are then closed. External
fixation, a system of surgically placed pins and stabilising
bars, is another method of maintaining fracture alignment.
This method may be used when there is a need for fast
surgical intervention (emergency situation) or there is
significant risk of infection from contamination of the
area. Bone grafts, using donor bone from the individual
(autograft), cadaver (allograft) or bone substitutes
(ceramic composites, bioactive cement), can fill voids in
the bone.

Regardless of whether reduction (realignment) is
necessary, splints and plaster casts are used to immobilise
and hold the bones in their correct anatomical position to
allow for bone healing. Improper reduction or immobilisation
of a fractured bone may result in non-union, delayed union
or malunion:
• Non-union is failure of the bone ends to grow together.

The gap between the broken ends of the bone fills with
dense fibrous and fibrocartilaginous tissue instead of
new bone.

• Delayed union is union that does not occur until
approximately 8–9 months after a fracture.

• Malunion is the healing of a bone in an incorrect
anatomic position.

20 minutes, during which time the injured person may use
the fractured bone or bones while moving from the area.
It is also possible to reduce (realign) the fracture during
this time without any anaesthetic. However, once the
numbness disappears, the subsequent pain is quite severe
and incapacitating until relieved with medication and
treatment of the fractured bones. The pain is related to
muscle spasms at the fracture site, overriding of the fracture
segments or damage to adjacent soft tissues.

Pathological fractures usually cause changes in the angle
of a limb or its apparent point of articulation (the point
about which it bends compared to the body), painless
swelling or generalised bone pain. Stress fractures are
generally painful during and after activity. The pain is usually
relieved by rest. Stress fractures also cause local tenderness
and soft-tissue swelling. Transchondral fractures may be
entirely asymptomatic or may be painful during movement.
Range of motion in the joint is limited and movement may
produce audible clicking sounds (crepitus).

E VA LUAT I O N A N D T R E AT M E N T
Treatment of a displaced fracture involves two key
approaches: (1) reduction: realigning the bone fragments
close to their normal anatomic position; and (2)
immobilisation: holding the fragments in place so that bone
union can occur. Adequate immobilisation is often all that
is required for healing of fractures that are not misaligned,
such as by the application of a cast or splint.

If the bones are misaligned, realignment of the bone
segments needs to be commenced — several methods are
available to reduce a fracture: closed reduction, traction
and open reduction. Most fractures can be reduced by closed
reduction, in which the bone is manually moved or
manipulated into place without opening the skin, and can
be maintained well with immobilisation by the use of a
cast or splint.

Traction may be used to accomplish or maintain
reduction. When bone fragments are displaced (misaligned),
weights are used to apply firm, steady traction (pull) and
countertraction (pull in the other direction on the other
side of the break) to the long axis of the bone. Traction
stretches and fatigues muscles that have pulled the bone
fragments out of place, allowing the distal fragment to align
with the proximal fragment. Traction can be applied to the
skin (skin traction), directly to the involved bone or distal
to the involved bone (skeletal traction). Skin traction is
used to a limit of 5 kg (may vary depending on the quality
of the person’s skin however) of pulling force to realign the
fragments or when the traction will be used for brief times
only, such as before surgery or, for children with femoral
fractures, for 3–7 days before applying a cast. A traction
boot is applied to the skin, closed with self-adhering straps
and then weights are attached to the foot area of the traction
boot. In skeletal traction, a pin or wire is drilled through
the bone below the fracture site and a traction bow, rope
and weights are attached to the pin or wire to apply tension
and to provide the pulling force to overcome the muscle
spasm and help realign the fracture fragments. The amount

R E S E A R C H I N F C U S
Vitamin D and fracture risk
The beneficial effects of vitamin D on fracture risk are
attributed to two explanations: (1) the prevention of bone
loss in the elderly; and (2) the increase in muscle strength
and balance mediated through vitamin D receptors in muscle
tissue.

In addition, vitamin D has been correlated with a significant
reduction (22%) in the risk of falling in older people. Pooled
analyses reveal that higher doses of 700–800 IU/day are
better for reducing fractures than 400 IU/day. Previously, the
recommendation for vitamin D in middle-aged and older
adults was 400–600 IU/day. With new data and the uncertainty
of intake recommendations, higher doses may be more
effective (up to 2000 IU/day). However, because calcium was
administered in combination with vitamin D in all but one
of the higher-dose vitamin D trials, the independent effects
of vitamin D alone could not be determined. Although the
evidence is building, further research is still needed into
whether and in what dose calcium adds value to fracture
prevention with vitamin D.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 519

there is a risk of an avulsion fracture. An avulsion fracture
is where a part of a bone, attached to a ligament or tendon,
is pulled off the rest of the bone.

C L I N I C A L MA N I F E S TAT I O N S
Signs and symptoms of dislocations or subluxations include
pain, swelling, limitation of motion and joint deformity.
Pain may be caused by the presence of inflammatory
chemicals (such as bradykinin; see Chapter 13) and exudate
in the joint or associated tendon and ligament injury. Joint
deformity is usually caused by muscle contractions that
exert pull on the dislocated or subluxated joint. Limitation
of the range of motion of the joint or limb results from
swelling in the joint (with associated pain) or the
displacement of bones.

E VA LUAT I O N A N D T R E AT M E N T
Evaluation of dislocations and subluxations is based on
clinical manifestations and x-ray imaging. Treatment consists
of reduction and immobilisation for 2–6 weeks and exercises
to maintain normal range of motion in the joint. Ensuring
that there is no lasting neurological damage to the nerves
in that area is also important, so ongoing neurovascular
assessment is vital. Depending on which joint is injured,
healing is usually complete within months to sometimes
years, although some joints may be at risk of further
dislocations again in the future (particularly from a reduced
force than was originally required).

Support structures
Sprains and strains of tendons and ligaments
Tendon and ligament injuries can accompany fractures and
dislocations. A tendon is a fibrous connective tissue that
attaches skeletal muscle to bone. A ligament is a band of
fibrous connective tissue that connects bones where they
meet in a joint. Tendons and ligaments support the bones
and joints and either allow or limit motion. Tendons and
ligaments can be torn, ruptured or completely separated
from bone at their points of attachment.

A tear in a tendon is commonly known as a strain.
Major trauma can tear or rupture a tendon at any site in
the body. Most commonly injured are the tendons of the
hands and feet, knee (patellar), upper arm (biceps and
triceps), thigh (quadriceps), ankle and heel (Achilles).

Ligament tears are commonly known as sprains.
Ligament tears and ruptures can occur at any joint but are
most common in the wrist, ankle, elbow and knee joints.
A complete separation of a tendon or ligament from its
bony attachment site is known as an avulsion and is
commonly seen in young athletes, especially sprinters,
hurdlers and runners.

Strains and sprains are classified as first degree (least
severe), second degree and third degree (most severe).

PAT H O P HYS I O LO G Y
When a tendon or ligament is torn, an inflammatory exudate
(a fluid that has been filtered from the blood, containing
inflammatory chemicals) develops between the torn ends.

Dislocation and subluxation
Dislocation and subluxation are usually caused by trauma.
Dislocation is the temporary displacement of one or more
bones in a joint in which the opposing bone surfaces lose
contact entirely. If the contact between the opposing bone
surfaces is only partially lost, the injury is called a
subluxation.

Dislocation and subluxation are most common in persons
younger than 20 years of age, as their bones are strong and
resist fracture but the force disrupts the joint. However,
they may be the result of congenital or acquired disorders
that cause: (1) muscular imbalance, as occurs with congenital
dislocation of the hip or neurological disorders; (2) failure
of the articulating surfaces of the bones to match, as occurs
with rheumatoid arthritis (see later in the chapter); or (3)
joint instability.

The joints most often dislocated or subluxated are the
joints of the shoulder, elbow, wrist, finger, hip and patella.
The shoulder joint most often injured is the glenohumeral
joint. Traumatic dislocation of the elbow joint is common
in the immature skeleton. In adults, an elbow dislocation
is usually associated with a fracture of the ulna or head of
the radius. Traumatic dislocation of the wrist usually involves
the distal ulna and carpal bones. Any one of the eight carpal
bones can be dislocated after an injury. Dislocation in the
hand usually involves the metacarpophalangeal and
interphalangeal joints.

Considerable trauma is needed to dislocate the hip
unless there has been a previous injury or surgery to
this joint. Anterior hip dislocation is rare; it is caused by
forced abduction, for example, when an individual lands
on their feet after falling from an elevated height. Posterior
dislocation of the hip can occur as a result of a car accident
in which the flexed knee strikes the dashboard, causing
the head of the femur to be pushed posteriorly from the
hip joint.

The knee is an unstable weight-bearing joint that depends
heavily on the soft-tissue structures around it for support.
It is exposed to many different types of motion (flexion,
extension, rotation), and the dislocation can be anterior,
posterior, lateral, medial or rotary. It is usually the result
of an injury that occurs during motor vehicle accidents or
sports activities. In addition, the meniscus within the knee
joint may become damaged, usually by trauma.
PAT H O P HYS I O LO G Y
Dislocations and subluxations can be accompanied by
fracture because stress is placed on areas of bone not usually
subjected to stress. In addition, as the bone separates from
the joint, it may bruise or tear adjacent nerves, blood vessels,
ligaments, supporting structures and soft tissue. Dislocations
of the shoulder may damage the shoulder capsule and the
axillary nerve. Damage to axillary nerves can cause
anaesthesia to a small area of the upper arm and paralysis
of the deltoid muscle. Dislocations may also disrupt
circulation, leading to ischaemia (low blood supply) and
possibly permanent disability of the affected extremity’s
tissues. As joints disrupt during dislocation or subluxation

520 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

‘tennis elbow’ (although most affected people are not tennis
players), is likely caused by irritation of the extensor carpi
radialis brevis tendon and the resulting degradation. Medial
epicondylitis, referred to as ‘golfer’s elbow’, is inflammation
of the medial humeral epicondyle (see Fig. 21.4). Epicondylitis
is also related to work activities that involve cyclic flexion
and extension of the elbow or cyclic pronation, supination,
extension and flexion of the wrist that generate loads to
the elbow and forearm region.4 A longitudinal study indicates
that three sets of risk factors affect the incidence of
epicondylitis. They include biochemical constraints and
psychosocial and personal factors (including social support
at work).5

Bursae are small sacs lined with synovial membrane
and filled with synovial fluid that act to provide a
slippery, cushioning surface to reduce friction for tissues
of the body. They are typically located between tendons,
muscles and bones near major joints in the body. Acute
bursitis occurs primarily in the middle years and is caused
by trauma. Chronic bursitis can result from repeated

Later, granulation tissue containing macrophages (to remove
the damaged tissue), fibroblasts (to make collagen) and
capillary buds (growing new blood vessels — angiogenesis)
grow inwards from the surrounding soft tissue and cartilage
to begin the repair process. Within 4–5 days after the injury,
collagen formation begins. At first, collagen formation is
random and disorganised. As the collagen fibres become
associated with preexisting tendon fibres, they become
organised to run along the lines of stress. Eventually the
new and surrounding tissues fuse into a single mass. As
reorganisation takes place, the healing tendon or ligament
separates from the surrounding soft tissue. Usually a healing
tendon or ligament lacks sufficient strength to withstand
strong pull for at least 4–5 weeks after the injury (a ruptured
Achilles tendon may take 6 months to heal). If strong
muscle pull does occur during this time, the tendon or
ligament ends may separate again, causing the tendon or
ligament to heal in a lengthened shape with an excessive
amount of scar tissue that renders the tendon or ligament
functionless.

C L I N I C A L MA N I F E S TAT I O N S
Tendon and ligament injuries are painful and are usually
accompanied by soft-tissue swelling, changes in tendon or
ligament contour and dislocation or subluxation of bones.
The pain is generally sharp and localised and tenderness
persists over the distribution of the tendon or ligament.
Following a ruptured Achilles tendon, patients often report
a sensation of being kicked in the heel by someone else
despite this not occurring. Depending on the tendon or
ligament involved, such injuries may result in decreased
mobility, instability and weakness of the affected joints,
even with prompt treatment.

E VA LUAT I O N A N D T R E AT M E N T
Evaluation is based on clinical manifestations, stress
radiography, arthroscopy (using an endoscope to view the
interior of the tissue) or arthrography (an x-ray examination
in which a contrast medium is used to better visualise the
damage). When possible, treatment consists of suturing
the tendon or ligament ends closely together. If this is
not possible because of the extent of damage, tendon or
ligament grafting may be necessary. Long-term rehabilitation
exercises help ensure regaining of nearly normal functions,
but recovery may be complicated by posttraumatic
arthritis.

Tendonitis, epicondylitis and bursitis
Trauma can cause painful inflammation of tendons
(tendonitis) and bursae (bursitis). Other causes of damage
to tendons include reduced tissue perfusion, mechanical
irritation, crystal deposits, postural misalignment and
hypermobility in a joint. Achilles tendonitis is inflammation
of the Achilles tendon, one that is often inflamed.

Epicondylitis is inflammation of a tendon where it
attaches to a bone at its origin. Epicondylar areas of the
humerus, radius or ulna and around the knee are most
often inflamed. Lateral epicondylitis, commonly called

Gastrocnemius muscle
(Lateral head)
(Medial head)

Soleus muscle

Achilles tendon

Calcaneus

Humerus

Lateral epicondyle
Annular ligament

Olecranon bursa
Medial epicondyle
Olecranon
Coronoid process

Ulna

A
B

FIGURE 21.4

Tendonitis and epicondylitis.
A Medial or lateral epicondyles of humerus, site of epicondylitis.
B Achilles tendon, site of commonly occurring tendonitis.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 521

E VA LUAT I O N A N D T R E AT M E N T
The evaluation of tendonitis, epicondylitis and bursitis is
based on clinical manifestations, physical examination,
arthroscopy, arthrography and possibly MRI. Treatment
includes immobilisation of the joint with a sling, splint or
cast; systemic analgesics; ice or heat applications; or local
injection of an anaesthetic and a corticosteroid to reduce
inflammation. Physical therapy to prevent loss of function
begins after acute inflammation subsides.

Muscle strains
Mild injury such as muscle strain is usually seen after
traumatic or sports injuries. Muscle strain is a general term
for local muscle damage. It is often the result of sudden,
forced motion causing the muscle to become stretched
beyond normal capacity. Strains often involve the tendon
as well. Muscles are ruptured more often than tendons in
young people; the opposite is true in the older population.
Muscle strain may be chronic when the muscle is repeatedly
stretched beyond its usual capacity. Haemorrhage into the
surrounding tissue and signs of inflammation may also be
present. Regardless of the cause of trauma, skeletal muscle
cells are usually able to regenerate. Regeneration may take
up to 6 weeks and the affected muscle should be protected
during that time. Degrees of acute muscle strain, together
with their manifestations and treatment, are summarised
in Table 21.2.

Post-exercise muscle soreness
Also known as delayed onset muscle soreness (DOMS)
post-exercise muscle soreness relates to soreness of the
muscles most usually after unaccustomed eccentric
contraction. The degree of soreness is related to the duration
and intensity of exercise, with the degree of pain being
more related to the intensity. Fewer motor units are activated

trauma. Septic bursitis is caused by wound infection or
bacterial infection of the skin overlying the bursae. Bursitis
commonly occurs in the shoulder, hip, knee and elbow (see
Fig. 21.5).

PAT H O P HYS I O LO G Y
In addition to tearing of the tendon, evidence also exists
of tissue degeneration and disorganised collagen formation.6
Initial inflammatory changes cause swelling of the area,
limiting movements and causing pain. Microtears cause
bleeding, oedema and pain in the involved tendon or
tendons. At times, after repeated inflammations, calcium
may be deposited in the tendon. The calcium is usually
spontaneously reabsorbed by the body.

Usually bursitis is an inflammation that is reactive to
overuse or excessive pressure. The inflamed bursal sac
becomes engorged and the inflammation can spread to
adjacent tissues. The inflammation may decrease with rest,
ice and aspiration of the fluid. (Inflammation is discussed
in Chapter 13.)

C L I N I C A L MA N I F E S TAT I O N S
Clinical manifestations are usually localised to one side of
the joint. Generally there is local tenderness and more pain
with active motion than with passive motion. With
tendonitis, the pain is localised over the involved tendon.
Pain and sometimes weakness limit joint movement. The
onset of pain may be gradual or sudden in bursitis and
pain may limit active movement in the joint. Shoulder
bursitis impairs arm abduction. Bursitis in the knee produces
pain when climbing stairs, and crossing the legs is painful
in bursitis of the hip. Lying on the side of the inflamed
bursa is also very painful. Signs of infectious bursitis may
include the presence of a puncture site, warmth and
erythema (red appearance of the skin due to dilation
of capillaries), prior corticosteroid injection, severe
inflammation or an adjacent source of infection, such as
an infected total joint replacement.

FIGURE 21.5

Olecranon bursitis.
A case of olecranon bursitis in a patient with rheumatoid arthritis.
A rheumatoid nodule is also shown.

TABLE 21.2 Muscle strain

TYPE MANIFESTATIONS TREATMENT

First degree
(example: bench
press in untrained
athlete)

Muscle
overstretched

Ice should be applied
5 or 6 times in the
first 24–48 hours;
gradual resumption
of full weight-bearing
after initial rest for up
to 2 weeks; exercises
individualised to
specific injury

Second degree
(example: any
muscle strain with
bruising and pain)

Muscle intact
with some
tearing of fibres,
pain

Treatment similar to
that for first-degree
strains

Third degree
(example:
traumatic injury)

Caused by
tearing of fascia

Surgery to
approximate
ruptured edges;
immobilisation and
non-weight-bearing
for 6 weeks

522 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

swelling) that raises the pressure within the fascia can result
in a compartment syndrome, as the pressure increases within
the enclosed space of the muscle compartment. An increase
in compartment volume may be caused by haematoma
associated with a fracture or trauma and associated
inflammation causing oedema. Even the weight of a limp
extremity can generate enough pressure to reduce venous
return. With continuing arterial supply the volume of the
compartment increases. Whatever the cause, as the pressure
within the compartment rises, the circulation becomes
further compromised. Muscle necrosis occurs within 4–8
hours after releasing myoglobin. The myoglobin is toxic
to the tubular cells of the kidneys. The pathogenesis of
compartment syndrome and crush syndrome is outlined
in Fig. 21.7.

C L I N I C A L MA N I F E S TAT I O N S
When myoglobin is released from the muscle cells into the
circulation, it can cause a visible, dark reddish brown
pigmentation of the urine.7 Only 200 grams of muscle need
be damaged to cause visible changes in the urine. The
damaged cells also release intracellular enzymes, potassium
and phosphate into the serum. One of the enzymes, creatine
kinase (involved in creating phosphocreatine, a rapidly
available energy source in skeletal muscle and the brain),
may reach 2000 times normal levels (normal levels are
5–25 U/mL for women and 5–35 U/mL for men). The risk
of renal failure correlates directly with the amount of serum
creatine kinase, potassium and phosphorus levels in the
blood. The most significant clinical manifestation of acute
compartment syndrome is unresolved and disproportionate
pain associated with changes to the neurovascular status
of the involved limb.

to produce the same force during eccentric exercise
compared to concentric exercise. Thus higher forces are
experienced by the muscle fibres and their surrounding
connective tissue structures. There is evidence of free
erythrocytes and mitochondria in the extracellular spaces
suggesting cellular damage. Neutrophils increase and
phagocytes are present in the muscle fibres after 1–3 days
post exercise. In animal models, regeneration of muscle
injured in this way is complete within 2 weeks. In humans,
although it is a common condition, the morbidity (soreness
and reduced muscle performance) is temporary.

Myoglobinuria
Myoglobinuria — the presence of myoglobin in the urine
— can be a life-threatening complication of severe muscle
trauma or secondary to a rare, genetically linked condition
known as malignant hyperthermia. Myoglobinuria is so
named because the principal manifestation of the condition
is an excess of myoglobin (an oxygen-carrying intracellular
muscle protein) in the urine. Muscle damage, with disruption
of the sarcolemma (cell membrane of the muscle fibre),
releases the myoglobin from the cells, which then enters
the bloodstream. This death of some skeletal muscle cells
is known as rhabdomyolysis. However, large amounts of
myoglobin released into the blood becomes nephrotoxic
(toxic to nephrons) and may cause acute renal failure (see
Chapter 30).

The most severe form is often called crush syndrome.
Less severe local forms are called compartment syndromes.
Crush syndrome first gained notoriety in the reports of
injuries seen after the London air raids in World War II.
More recently, it has been reported in individuals found
unresponsive and immobile for long periods, usually after
a drug overdose as the compression of the muscle for an
extended time restricts the blood circulation in the area, and
leads to rhabdomyolysis, which then causes myoglobinuria.
Myoglobinuria also can be seen after viral infections,
administration of cholesterol-lowering drugs known as
statins, certain anaesthetic agents, cocaine, amphetamines,
heroin, alcoholism with subsequent muscle tremors, tetanus,
heat stroke, electrolyte disturbances and fractures. Excessive
muscular activity also has been implicated in reports of
myoglobinuria in athletes (such as long-distance runners
and skiers) and military recruits. Status epilepticus,
electroconvulsive therapy and high-voltage electrical
shock are also associated with severe and sometimes fatal
myoglobinuria.

PAT H O P HYS I O LO G Y
The primary requirement to develop myoglobinuria is
damage to muscle fibres allowing the release of myoglobin.
This damage may occur directly, as in the case of trauma,
or as a result of any event that injures the sarcolemma.
In the case of compartment syndromes the usual cause is
ischaemia. The muscles of the limbs are organised within
their non-elastic fascias. Many of the blood vessels (and
nerves) are located deep to the fascia (see Fig. 21.6). Thus
any event (like a fracture, direct trauma with bleeding and

Deep posterior

compartment

Fibula

Lateral
compartment

Anterior
compartment

Anterior tibial
neurovascular bundle

Posterior tibial
neurovascular bundle

Tibia

Interosseous
membrane

Superficial
posterior

compartment

Fascia

2
3

FIGURE 21.6

The muscle compartments of the lower leg.
The muscle compartments consist mainly of the (1) superficial, (2)
deep posterior, (3) lateral and (4) anterior compartments.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 523

F O C U S O N L E A R N I N G

1 Describe the process of fracture repair.

2 Compare and contrast the repair processes involved with
strains and sprains.

E VA LUAT I O N A N D T R E AT M E N T
The manifestation of myoglobinuria for those with the
genetic condition of malignant hyperthermia occurs during
anaesthesia. Clinicians need to carefully assess the
background of these individuals to diagnose potential
malignant hyperthermia — a family history of anaesthetic
problems and previous untoward anaesthetic experiences
(muscle cramping, unexplained fevers, dark urine) are
criteria that require further clarification before administration
of a volatile halogen anaesthetic, such as isoflurane, or the
muscle relaxant succinylcholine.

Priorities in treatment of myoglobinuria include
identifying and treating the underlying disorder and
preventing life-threatening renal failure. Malignant
hyperthermia and myoglobinuria can be treated by infusing
dantrolene sodium. Diluting the pigment using intravenous
fluids and administration of mannitol, sodium bicarbonate
and frusemide to ‘flush’ the kidneys have been advocated
to prevent renal failure. Secondary problems include
electrolyte imbalance, volume depletion, acidosis,
hyperuricaemia, hyperkalaemia and calcium imbalance.
These imbalances need specific treatment. Short-term
dialysis may also be necessary.

Compartment syndromes may require emergency
treatment when blood flow to the affected extremity is
compromised because of increased compartmental pressure,
leading to ischaemia and oedema.8 When clinical evaluation
is inconclusive, the rising compartment pressure can be
directly measured by inserting a wick catheter, needle or
slit catheter into the muscle. Pressures greater than 30 mmHg
(normal = 0–8 mmHg) impair capillary flow.9 When
conservative treatment fails to relieve the pressure, a
fasciotomy may be necessary.9 In this procedure the fascia
is incised parallel to the muscle to reduce the
intracompartmental pressure. Because of the risk of infection
and the added complication of wound closure, this procedure
is one of last resort. Compartments often affected are the
anterior tibial and deep posterior tibial compartments in
the leg and the gluteal compartments in the buttocks.

C
O

N
C

T M
A

P
Limb compression

causes

leading to

resulting in

releasing
potassium

promoting

promoting
further promoting

compressing
blood vessels

compressing
nerves

contributing to

contributing toleading to

causing

causing
leading to

releasing myoglobin

precipitating

Local pressure

Local tamponade

Muscle/capillary necrosis

Oedema

Rising compartment pressure

Compartment tamponadeMuscle ischaemia Neural injury Compartment syndrome

Initial events

Muscle infarction

Shock

ECF shift

Renal failure

Myoglobinaemia
Crush syndrome

Cardiac arrhythmia

Acidosis/hyperkalaemia

FIGURE 21.7

The pathogenesis of compartment syndrome and crush syndrome caused by prolonged muscle compression.
ECF = extracellular fluid.

524 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

2015 fact sheet 9% of the population over 50 years of age
was identified as having osteoporosis.11 Osteoporosis, or
porous bone, is a disease in which bone tissue is normally
mineralised but the mass (density) of bone is decreased
and the structural integrity of trabecular (spongy) bone is
impaired. Cortical (compact) bone becomes more porous
and thinner, making bone weaker and prone to fractures
(see Figs 21.8 and 21.9). The World Health Organization
(WHO) has defined postmenopausal osteoporosis based
on bone density.12 Individual bone density is compared
with the mean bone mineral density of a young-adult
reference population; in other words, the degree of loss of
bone mineral density (osteoporosis) is compared to the
optimal level of that of a young adult. Fig. 21.10 shows the
progression from normal bone mineral density to severe
osteoporosis. The disease can be: (1) generalised, involving

FIGURE 21.8

Vertebral body.
Osteoporotic vertebral body (right) shortened by compression
fractures compared with a normal vertebral body. Note that the
osteoporotic vertebra has a characteristic loss of horizontal
trabeculae and thickened vertical trabeculae.

NORMAL OSTEOPENIA OSTEOPOROSIS SEVERE

OSTEOPOROSIS

Compact
(cortical bone)

Spongy
(trabecular bone)

FIGURE 21.9

Osteoporosis in cortical and trabecular bone.
While both compact and trabecular (spongy) bone vulnerable to osteoporosis, the effects on the trabecular bone can appear to be worse
to the loss of the trabecules or beams of bone tissue.

Normal bone mineral density

Low bone density (osteopenia)

Osteoporosis

Severe osteoporosis

FIGURE 21.10

The progression from normal bone mineral density through
various stages to severe osteoporosis.
With each stage, there is further loss of bone mineral density.

Disorders of bone and joints
Metabolic bone disease
Metabolic bone disease is a generalised term that accounts
for a range of disorders characterised by abnormal bone
structure that is caused by an altered metabolism, which
may be the result of genetics, diet or hormones. These
disorders often cause disability that becomes worse with
ageing. In Australia, approximately 30% of the population
had arthritis, and other musculoskeletal disorders affect
6.9 million people.10

Osteoporosis
As the populations of Australia and New Zealand age, the
incidence of osteoporosis will increase. In an Australian

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 525

Osteoporosis is a complex, multifactorial chronic disease
that often progresses silently for decades until fractures
occur. It is the most common disease that affects bone. It
is not necessarily a consequence of the ageing process
because some elderly people retain strong, relatively dense
bones.24 A progressive loss of bone mass may continue until
the skeleton is no longer strong enough to support itself.
Eventually, bones can fracture spontaneously. As bone
becomes more fragile, falls or bumps that would not have
caused fracture previously now do cause a fracture.
Osteoporosis appears to be most severe in the spine, wrists
and hip (see Fig. 21.11).

Postmenopausal osteoporosis is bone loss that occurs in
middle-aged and older women. It can occur because of
oestrogen deficiency as well as oestrogen-independent
age-related mechanisms (e.g. secondary causes such as
hyperparathyroidism and decreased mechanical stimulation)
(see Fig. 21.12). Oestrogen deficiency can also increase with
stress, excessive exercise (particularly weight-bearing
activities) and low body weight. Postmenopausal changes
include a substantial increase in bone removal. There is an
imbalance between the activities of the osteoclasts (bone

R E S E A R C H I N F C U S
Osteoporosis in men
With the emphasis on osteoporosis in women, the cellular
and molecular aspects of male idiopathic osteoporosis
(idiopathic meaning cause unknown) are poorly understood.
The major difference in bone physiology between males
and females is in the level of gonadal hormones. Although
hypogonadism is related to bone loss in men, and androgen
levels decline with age in men, it is not at all clear that reduced
androgen levels are related to bone loss in older men.
Testosterone is possibly anabolic at the bone level, and
testosterone increases muscle mass, which indirectly results
in higher bone density. In peripheral tissue, testosterone is
converted to oestrogen, which prevents excessive bone
resorption. Oestrogen is necessary to bone in men as well
as in women. Men who have a deficiency of the enzyme
that converts testosterone to oestrogen develop osteoporosis
and are excessively tall because of the failure to fuse growth
plates. Thus, oestrogen plays a vital role in the maintenance
of bone in men as well as women.

Guidelines produced in the United States in 2016 show that
the risk of fractures is increased in both men and women
taking glucocorticoid medications that is usually controlled
by use of antiresorptive therapy. The use of antiresorptive
therapy is recommended at a bone mineral density (T-score)
of less than -2.5 or a history of hip or spine fracture. Long
term use of this therapy increases the risk of atypical femur
fractures that can be reduced in women, or men taking
glucocorticoid therapy, who achieve a bone mineral density
greater than -2.5 and have no other risk factors by having
a ‘holiday’ from the medication for 2 to 3 years.

major portions of the axial skeleton; or (2) regional, involving
one segment of the appendicular skeleton.

Throughout a lifetime bone responds to the stresses
placed on it through the process of remodelling (see Chapter
20). This process involves removal of old bone (resorption)
and creation of new bone (formation). Weight-bearing
exercise increases bone mineral density. During childhood
and the teenage years, new bone is added faster than old
bone is removed. Consequently, bones become larger, heavier
and denser. Peak bone mass or maximum bone density
and strength is reached around age 30. After age 30, bone
resorption slowly exceeds bone formation. In women, bone
loss is most rapid in the first years after menopause, but
persists throughout the postmenopausal years.13 Men lose
bone density with ageing but because they begin with a
higher bone density and their rate of loss is less than that
of women, they reach osteoporotic levels at an older age
than do women (see Research in Focus: Osteoporosis in
men).

The major risks for those with osteoporosis are fractures.
By the age of 90, about 17% of males have had a hip fracture,
compared with 32% of females. Over half of all adults
hospitalised for hip fracture do not return to their former
level of functioning.14 In Australia the lifetime risk of a
fracture due to osteoporosis after 50 years of age is 42%
for women and 27% for men.15

Vertebral fractures also occur in the later years of life;
however, they are more difficult to ascertain because people
are unaware of the fracture. The degree of compression
necessary to define a vertebral fracture is not standardised.15
Thus, the true prevalence is unknown, but fractures do
increase in frequency by the sixth and seventh decades.
Vertebral fracture prevalence in men is close to that in
women.16 Osteoporosis is the foremost underlying cause
of fractures in the elderly. It affects more than half of women
aged 60 and older and nearly one-third of men aged 60
and older in both New Zealand17 and Australia.18 Total
costs related to osteoporosis are estimated at A$7 billion
annually in Australia19 and at NZ$1.5 billion annually in
New Zealand.20

Osteoporosis is most common in smaller statured people.
Interestingly, larger people have a lower incidence of
osteoporosis because their skeletons have become more
massive through the process of remodelling and achieved
a higher peak bone mass.21 The cause of generalised
osteoporosis remains uncertain.

Bone strength is not defined by bone mass alone (as
measured by bone mass density) but also by the microscopic
structure of the bone. Thus, other variables include mineral
crystal size and shape, brittleness, vitality of the bone cells,
structure of the bone proteins, integrity of the trabecular
network and the ability to repair tiny cracks.22,23 In spongy
bone, the positioning of trabecular structures is important
in providing strength. Because bone density relates to
quantity of bone, quality of bone is not accurately identified
by bone density testing. Therefore, bone density testing
may or may not accurately identify those who will go on
to suffer a fracture.

526 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

A B

FIGURE 21.11

Osteoporosis as a result of disuse.
A X-ray taken just before wrist ligament reconstruction. B X-ray
obtained 2 months later. Notice the extent of the osteopenia
evident in the second image.

Genetic factors

Physical activity Nutrition

MENOPAUSE
• Decreased serum
oestrogen
• Increased IL-1, IL-6,
TNF levels
• Increased osteoclast
activity

AGEING
• Decreased replicative activity
of osteoprogenitor cells
• Decreased synthetic activity
of osteoblasts
• Decreased biological activity
of matrix-bound growth factors
• Reduced physical activity

OSTEOPOROSIS

PEAK BONE MASS

FIGURE 21.12

The pathophysiology of postmenopausal and senile
osteoporosis.
Factors which can contribute to the decline of bone density after
menopause include lowering of oestrogen levels with increased
osteoclast activity (which cause bone resorption). Factors which
contribute to further decline of bone density with increased age
include loss of function of the osteoblasts (which cause bone
deposition) and decreased physical activity.

destroyers) and osteoblasts (bone formers). Oestrogen helps
osteoclast apoptosis (programmed cell death), so its decline
is associated with survival of the bone-removing osteoclasts.
Other causes may include a combination of inadequate
dietary calcium intake and lack of vitamin D, possibly
decreased magnesium, lack of exercise (particularly
weight-bearing exercise), low body mass and family history.25

Excessive phosphate intake, chiefly through the intake of
soft drinks and junk foods, interferes with the calcium/
phosphate balance. Glucocorticoids (e.g. cortisone) also
induce osteoporosis.

Oestrogen replacement (through hormone replacement
therapy, known as HRT) can slow bone loss around the
time of menopause; however, osteoporosis and fractures
are still common in older women who have used oestrogen
continuously since menopause.25,26 It has been found that
serum androgens may influence bone density in women.
Androgens (i.e. testosterone) have long been recognised as
stimulants of bone formation. Increasing age in both men
and women is associated with declining levels of oestrogen
and androgen, leading to losses in bone mineral density.27
In addition, progesterone deficiency may be related to
osteoporosis. Decreases in weight-bearing exercise are
associated with osteoporosis as well. Other risk factors are
identified in Box 21.1.

Intake of dietary minerals is important for skeletal health.
Reduced intake or malabsorption of dietary minerals is
a factor in the development of osteoporosis.28 Calcium
absorption from the intestine decreases with age and studies
of individuals with osteoporosis show that their calcium
intake is lower than that of age-matched controls. Other
mineral deficiencies may also be important, including
magnesium. Deficiencies of vitamins, particularly vitamins
C and D, and both deficiencies and excesses of protein
also contribute to bone loss. Excessive intakes of caffeine,
phosphorus, alcohol and nicotine along with low body
weight (less than 57 kg) have also been considered risk
factors. In addition, significant differences in the trace
elements (zinc, copper, manganese) have been noted in
the bones and hair of unaffected individuals compared to
those with osteoporosis.29

Skeletal homeostasis depends on a narrow range of
plasma calcium and phosphate concentrations, which are
maintained by the endocrine system. Therefore, endocrine
dysfunction ultimately can cause metabolic bone disease.
In addition to declining levels of sex steroids, the hormones
most commonly associated with osteoporosis are parathyroid
hormone, cortisol, thyroid hormone and growth hormone
(see Fig. 21.13). (Endocrine function is discussed in Chapters
10 and 11.)

PAT H O P HYS I O LO G Y
It has been emphasised that remodelling is a normal feature
of bone. Osteoclasts (bone-destroying cells) and osteoblasts
(bone-building cells) are continually working to maintain
bone with a structure that is responsive to, and structurally
able to withstand the stresses it experiences. To understand
osteoporosis it is useful to have some knowledge of the
interrelationship between osteoclasts and osteoblasts.
Ultimately the number of osteoblasts is controlled by
hormones, cytokines (intracellular communication molecules
that control cell activity — cyto for cell and kines for action)
and other chemical messengers. There is one cytokine
that appears particularly important. It exerts its effect by
binding to a receptor on osteoclast precursor cells (cells

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 527

Genetic
• Family history of osteoporosis
• Family origins from any of the original peoples of Europe,

the Middle East or North Africa
• Increased age
• Female sex
Anthropometric
• Small stature
• Thin build
• Low bone mineral density
Hormonal and metabolic
• Early menopause
• Late menarche
• Nulliparity (not bearing offspring)
• Obesity
• Cushing’s syndrome
• Weight below healthy range
• Acidosis
• Hyperparathyroidism
Dietary
• Low dietary calcium and vitamin D
• Low endogenous magnesium
• Excessive sodium intake
• High caffeine intake
• Anorexia
• Malabsorption
Lifestyle
• Sedentary
• Smoker
• Alcohol consumption (excessive)
• Low-impact fractures as an adult
• Inability to rise from a chair without using one’s arms
Illness and trauma
• Renal insufficiency
• Rheumatoid arthritis
• Spinal cord injury
• Systemic lupus
Drugs
• Corticosteroids
• Dilantin
• Gonadotrophin-releasing hormone agonists
• Aromatase inhibitors
• Loop diuretics
• Methotrexate
• Heparin
• Cyclosporin

BOX 21.1 Risk factors for osteoporosis
that combine to form osteoclasts) causing them to multiply
and become activated. The bone matrix creates a decoy
receptor for this same cytokine. If the cytokine binds to the
decoy receptor there will be no effect on the osteoclasts.
Thus the balance between the amounts of cytokine, the
number of receptors on the osteoclast precursors and the
number of decoy receptors determines the rate at which
bone is resorbed. Any alteration to this balance can lead to
osteoporosis.

Glucocorticoid-induced osteoporosis is characterised by
increased bone resorption and decreased bone formation.
Glucocorticoids (e.g. cortisone) increase formation of the
cytokine and reduce production of its decoy receptor by
osteoblasts.

Age-related bone loss begins in the fourth decade. The
cause remains unclear, but it is known that decreased serum
growth hormone and insulin-like growth factor levels (both
of which stimulate osteoclasts), along with increased binding
of the cytokine and decreased production of the decoy
receptor, affect osteoblast and osteoclast function. Loss of
trabecular bone in men proceeds with thinning of trabecular
bone rather than complete loss, as is noted in women (see
Fig. 21.14).30 Men have approximately 30% greater bone
mass than women, which may be a factor in their later
involvement with osteoporosis (see Fig. 21.15). In addition,
men have a more gradual decrease in testosterone and
oestrogen (and possibly progesterone), thereby maintaining
their bone mass longer than women.31 The reduction in
weight-bearing activity with increasing age is another factor
promoting bone loss.

C L I N I C A L MA N I F E S TAT I O N S
The specific clinical manifestations of osteoporosis depend
on the bones involved. The most common manifestations,
however, are pain and bone deformity. Unfortunately the
condition develops insidiously and these manifestations
occur only in an advanced disease state. By the time a
person experiences symptoms there is little possibility
of them being able to reverse the effect of bone loss to
previous levels. Fractures are likely to occur because the
trabeculae of spongy bone become thin and sparse and
compact bone becomes porous. As the bones lose volume,
they become brittle and weak and may collapse or become
misshapen. Vertebral collapse causes kyphosis (from the
Greek kyphos meaning hump) and diminishes height (see
Fig. 21.16). Fractures of the long bones (particularly the
femur and humerus), distal radius, ribs and vertebrae
are most common. Fracture of the neck of the femur —
a broken hip — tends to occur in older or elderly women
with osteoporosis. Fatal complications of fractures include
fat or pulmonary embolism, pneumonia, haemorrhage
and shock. Approximately 20% of individuals may die
as a result of surgical complications. Male osteoporosis
is usually secondary osteoporosis. The following seem to
help prevent primary osteoporosis: adequate dietary intake
of calcium, vitamin D, magnesium and possibly boron; a
regular regimen of weight-bearing exercise; and avoidance
of tobacco, glucocorticoids and alcoholism.

528 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

Women

ThinningPerforation

Trabecular
bone

Men

FIGURE 21.14

The mechanism of loss of trabecular bone in women and
trabecular thinning in men.
Bone thinning predominates in men because of reduced bone
formation. Loss of connectivity and complete trabeculae
predominates in women.

Young

Old

Men

Resorbed

Formed Net
bone loss

Women

Absolute
amount
of bone

FIGURE 21.15

Bone loss in men and women.
The absolute amount of bone resorbed on the inner bone surface
and formed on the outer bone surface is more in men than in
women during ageing.

C
O
N
C

E
P

T
M

A
P

Production or effect of
dihydroxyvitamin D

Physical activity

Hypo-oestrogenism

PTH secretion

In�ammation

Bone loss

Intestinal calcium
absorption

Enhanced osteoclast
activity (excessive
bone resorption)

Impaired osteoblast
actions (decreased
bone formation)

Calcium intake

cause

resulting in

stimulating

leading toleading
to

leads to

causing
result in

causes
leads to

Secretion of
growth hormone
or anabolic steroids

Sun exposure
Age
Dietary intake of vitamin D

Vitamin K
intake or
effectiveness

FIGURE 21.13

The pathophysiology of osteoporosis.
The changes that lead to bone loss. Dihydroxyvitamin D = vitamin D component that aids calcium absorption; PTH = parathyroid
hormone.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 529

risk of some disease may not be as high as previously
thought. Other steroid agents — for example, raloxifene,
a selective oestrogen receptor modulator that provides the
beneficial effects of oestrogen on bone without the negative
effects on breast and endometrial tissue — may also be
prescribed.

Regular, moderate weight-bearing exercise can slow down
the bone loss and, in some cases, reverse demineralisation
because the mechanical stress of exercise stimulates bone
formation. It is important to reduce the risk of falls and
enhance bone quality. An exercise program to enhance
strength has the added benefits of reducing the risk of falls
and promoting bone quality. The elderly population are
at a greater risk of falls due to normal changes associated
with ageing such as worsening eyesight, inner ear related
imbalances, touch sensitivities and slowing response times.
These normal changes when combined with other risk factors
can increase the risk of falls and contribute to a much higher
incidence of fall-related trauma. The consequence of a simple
fall that results in a fragility fracture can be severe. Following
a fracture of the proximal femur up to 28% of sufferers
will die within one year and 24–75% of individuals will
not return to their pre-fracture level of independence.34

New medications formulated to prevent or treat
osteoporosis are currently being prescribed and evaluated.
There are new treatments that may rebuild the skeleton.
The anabolic or bone-building drug parathyroid hormone
has been widely studied and the results are encouraging.
Parathyroid hormone directly stimulates bone formation,
particularly in trabecular bone.35

E VA LUAT I O N A N D T R E AT M E N T
Generally, osteoporosis is detected on x-rays as increased
radiolucency (transparency) of bone. By the time
abnormalities are detected by radiological examination, up
to 25–30% of bone tissue may have been lost.

Dual x-ray absorptiometry (DXA) (commonly known
as the bone density test) is the gold standard for detecting
and monitoring osteoporosis. Ultrasound is more cost
effective but it does not directly measure the fracture risk
sites. Quantitative CT scans are also helpful. Other evaluation
procedures include tests for levels of serum calcium,
phosphorus and alkaline phosphatase and protein
electrophoresis. Serum and urinary biochemical markers
are useful in monitoring bone turnover.12

The goals of osteoporosis treatment are to slow down
the rate of calcium and bone loss and to stop the deterioration
before it progresses too far. Treatment includes increasing
the dietary intake of calcium to 1500 mg/day along
with vitamin D supplements to increase the intestinal
absorption of calcium. High intake of phosphorus may
neutralise calcium, interfering with its benefits. Magnesium
supplementation may increase bone growth by stimulating
cytokine activity in bone.32,33

Postmenopausal women may be given oestrogen and
progestins to prevent bone loss. However, combined
oestrogen–progestin therapy increases the risk for invasive
breast cancer, and may increase the risk for heart disease
(see ‘Women and coronary heart disease’ in Chapter 23),
stroke and pulmonary embolism, and therefore is not
warranted for routine osteoporosis prevention although the

A B

FIGURE 21.16

Kyphosis.
A This elderly woman’s condition was caused by a combination of spinal osteoporotic vertebral collapse and chronic degenerative
changes in the vertebral column. B The x-ray demonstrates the marked curvature of the spine seen in kyphosis. The head and neck are
bent forward and the total chest volume is markedly reduced.

530 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

by x-ray and radioisotope bone scan. Autopsy data from
England and Germany indicate that approximately 3–4%
of the population older than 40 years of age have Paget’s
disease. It is most prevalent in Australia, Great Britain, New
Zealand and the United States. The disease affects several
members of the same family in 5–25% of cases.

The cause of Paget’s disease is unknown, but there appears
to be a strong genetic component.36 A viral connection to
Paget’s disease has also been proposed.37

PAT H O P HYS I O LO G Y
Paget’s disease is a focal process that begins with frantic
excessive osteoclastic resorption of spongy bone, followed
by furious deposition of bone by large numbers of osteoblasts.
The deposited bone is disorganised rather than lamellar
and is soft as a result. The trabeculae diminish and bone
marrow is replaced by extremely vascular fibrous tissue.

Paget’s disease causes lesions that may be solitary or
occur in multiple sites. Lesions tend to localise in the axial
skeleton, including the skull, spine and pelvis. If the disease
becomes more widespread, the proximal femur and tibia
may become involved.

C L I N I C A L MA N I F E S TAT I O N S
Paget’s disease varies in presentation from a single lesion
to involvement of multiple bones. The manifestations depend
on which bones are affected. In the skull, abnormal
remodelling is first evident in the frontal or occipital regions;
then it encroaches on the outer and inner surfaces of the
entire skull. The skull thickens and assumes an asymmetric
shape. Thickened segments of the skull may compress areas
of the brain, producing altered mentality and dementia.
Growth of new bone putting pressure on cranial nerves
causes sensory abnormalities, impaired motor function,
deafness (because of involvement of the middle ear ossicles
or compression of the auditory nerve), atrophy of the optic
nerve and obstruction of the lacrimal duct. As a result,
headache is commonly noted.

In the spinal column the vertebral bodies collapse leading
to kyphosis. In long bones, resorption begins in the
subchondral regions of the epiphysis and extends into the
metaphysis and diaphysis. Softening of the femur and tibia
causes them to bow. Stress fractures are common in the
lower extremities and they often heal poorly with excessive
and poorly distributed callus.
E VA LUAT I O N A N D T R E AT M E N T
Evaluation of Paget’s disease is made on the basis of
characteristic bone deformities and radiographic findings of
irregular bone trabeculae with a thickened and disorganised
pattern. Early disease is detected by bone scanning that
shows increased metabolic activity. Alkaline phosphatase
and urinary hydroxyproline (a derivative of the amino acid
proline, involved in collagen production) are elevated.

Many individuals require no treatment if the disease is
localised and not symptomatic. Treatment during active
disease is for pain relief, prevention of deformity or fracture.
Bisphosphonates are the treatment of choice: they bind to
bone minerals, rapidly reducing resorption.

PAGET’S DISEASE
Paget’s disease (osteitis deformans) is a state of increased
metabolic activity in bone characterised by abnormal and
excessive bone remodelling, both resorption and formation.
Chronic accelerated remodelling eventually enlarges and
softens the affected bones. Paget’s disease can occur in any
bone but most often affects the vertebrae, skull, sacrum,
sternum, pelvis and femur. The disease process may occur
in one or more bones without causing significant clinical
manifestations.

Paget’s disease occurs with increasing frequency in people
as they age; it is rarely identified before 50 years of age and
reaches a prevalence of almost 10% in the ninth decade of
life. Men are more often affected than women at a ratio of 1.8
to 1. The disease is often symptomless and diagnosis is made

R E S E A R C H I N F C U S
Current treatments for osteoporosis
Over the last 15 years a number of newer pharmaceutical
treatment options have been developed and released for
use in the treatment of osteoporosis. Previously the standard
treatment was hormone replacement therapy which more
recently has been shown to increase, in some groups, the
risk of cancer, cardiac disease and venous thromboembolism.

The first of the newer treatment options were the
bisphosphonates group such as alendronate, risedronate,
ibandronate and zoledronic acid which act to limit osteoclast
bone resorption. A number of earlier medications had
demonstrated some increased adverse outcomes and required
specific administration regimens such as administering the
medication early in the day and ensuring the person was
sitting upright. Some of the newer generation of medications
such as denosumab, raloxifene and calcitonin also act to
reverse or slow bone loss. These too have some limitations
in treatment times and there is debate about increased risk
of some cancers and the benefit of longer-term treatment.
Medications such as teriparatide, a type of parathyroid
hormone, act to stimulate bone growth but can also have
side effects that limit their use in treatment to 2 years.

The use of calcium and vitamin D supplements should
continue in the treatment of osteoporosis as well as the
maintenance of a balanced diet (high in calcium), appropriate
exposure to sunlight and regular weight-bearing exercise.

The American Society for Bone and Mineral Research has
recommended that for patients with a low risk of fracture
therapy and a higher bone density, treatment can be
discontinued after 3–5 years. Some of the medications will
remain stored in the skeletal system and continue to influence
bone loss for years following discontinuation of the
medication. For those individuals with a higher risk of fracture
and a lower bone density consideration of long-term
treatment or medication change is advised. Some researchers
are investigating other more ‘natural’ non-pharmaceutical
alternatives for the treatment of osteoporosis.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 531
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Paediatrics and disorders of bones
Osteochondroses
The osteochondroses are a series of childhood diseases
involving areas of significant tensile or compressive stress
(i.e. tibial tubercle, Achilles insertion, hip). They are
characterised into two groups according to cause. The
first group are caused by localised death of bone
(osteonecrosis) in an apophyseal or epiphyseal centre
(e.g. Legg-Calvé-Perthes disease), while the second group
is the result of abnormalities of mineralisation of cartilage
due to a genetically determined normal variation or
trauma (e.g. Osgood-Schlatter disease).
Legg-Calvé-Perthes disease
Legg-Calvé-Perthes disease is a common osteochondrosis
usually occurring in children between the ages of 3 and
10 years, with a peak incidence at 6 years. The disorder
affects both legs in 10–20% of children and boys are
affected five times more often than girls, perhaps because
boys have a more poorly developed blood supply to the
femoral head (hip joint) than do girls of the same age.
The role of genetics is unclear, but family history is
positive in 20% of cases.
This disease which runs its natural course in 2–5 years,
is presumably produced by recurrent interruption of
the blood supply to the femoral head. The ossification
centre first becomes necrotic (osteonecrosis) and then
is gradually replaced by live bone.
Several causative theories have been proposed, including
a generalised disorder of epiphyseal cartilage growth,
thyroid deficiency, trauma, infection and blood-clotting
disorders. However increases in thrombotic disorders
in children with Legg-Calvé-Perthes were not found.
Children are often delayed in skeletal age by 2 years,
making some believe that Legg-Calvé-Perthes is actually
a systemic skeletal dysplasia. Another study has shown
the risk of Legg-Calvé-Perthes is five times greater in
children exposed to passive smoke than those who are not.

The primary feature of Legg-Calvé-Perthes is an avascular
necrosis of the epiphyseal growth centre in the femoral
head. The disease has four stages:
1 In the first (incipient) stage lasting several weeks, the

synovial membrane and joint capsule are swollen,
due to oedema (fluid accumulation) and hyperaemia
(an increased blood supply; see Fig. 21.17).

2 In the second (necrotic) stage (lasting 6–12 months),
there is death of bone tissue, such that the femoral
head actually shrinks. The epiphyseal centre also
becomes necrotic.

3 In the third (regenerative) stage lasting 1–3 years,
the dead femoral head assumes a more normal
shape as it is replaced by procallus formation. The
procallus consists of early stages of healing, and
progresses to include substances needed for mature
bone, including fibrous connective tissue matrix,
deposition of collagen and calcification.

4 During the fourth (residual) stage the femoral
head is remodelled and the newly formed bone is
organised into spongy bone.

Injury or trauma precedes the onset in approximately
30–50% of children with Legg-Calvé-Perthes. For several
months the child complains of a limp and pain that can
be referred to the knee, inner thigh and groin. The pain
is usually aggravated by activity and relieved by rest and
anti-inflammatory drugs.
The typical physical findings include spasm on rotation
of the hip, limitation of internal rotation and abduction
(movement away from the centre of the body) and hip
flexion–adduction deformity. If the child is walking,
an abnormal gait termed an antalgic abductor lurch,
or ‘Trendelenburg’ gait, is apparent. Associated muscle
atrophy may occur.
The goals of treatment are to reduce deformity, preserve
the soundness of the femoral head and acetabulum, and
maintain spasm-free and pain-free range of motion in the

Joint
space
(black
area)

Femoral
head

Femoral neck

Epiphyseal
plate

Metaphysis

Necrotic
bone

Cyst

Procallus Remodelled
bone

Normal hip joint Incipient stage Necrotic stage Regenerative stage Residual stage

FIGURE 21.17

Stages of Legg-Calvé-Perthes disease, a form of osteochondrosis.
This disease is characterised by loss of normal bone tissue which is eventually remodelled over time.

Continued

532 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

hip joint. Currently, most children can be managed with
anti-inflammatory medications and activity modification
during periods of synovitis (inflammation of the synovial
membrane). Serial radiographs over a number of years
are obtained to monitor the progress of the disease and
to ensure that the femoral head remains in contact with
the acetabulum. Surgery may be necessary if the femoral
head becomes subluxated or displaced from its normal
position in the acetabulum (see Figs 21.18 and 21.19).
Children older than 6 years of age (by bone age) have
a worse prognosis due to poorer remodelling potential.
Older children require surgery more often to avoid
poor structural agreement of the femoral head in the
acetabulum (congruence). Poor congruence predisposes
to early osteoarthritis, with nearly 50% requiring hip
arthroplasty by age 40.

Osgood-Schlatter disease
Osgood-Schlatter disease causes microfractures of the
tubercle of the tibia (the insertion point of the patellar
tendon) and associated patella tendonitis. The disease
occurs most often in preadolescents and adolescents who
participate in sports and is more prevalent in boys than
in girls. It is one of the most common ailments reported
in adolescents involved in sports.
The severity of the lesion varies from mild tendonitis to
a complete separation of part of the tibial tubercle. The
mildest form of Osgood-Schlatter disease causes ischaemic
(avascular) necrosis in the region of the tibial tubercle,

with excessive cartilage formation during the stages of
repair. In more severe cases, the abnormality involves
a true apophyseal separation of the tibial tubercle with
avascular necrosis.
The child complains of pain and swelling in the region
around the patellar tendon and tibial tubercle, which
becomes prominent and is tender to direct pressure. The
pain is most severe after physical activity that involves
vigorous quadriceps contraction (jumping or running)
or direct local trauma to the tibial tubercle area.
The goal of treatment is to decrease the stress at the
tubercle. Often a period of 4–8 weeks of restriction
from strenuous physical activity is sufficient. Bracing
with a tubercle band can be very helpful. If the pain is
not relieved, a cast or knee immobiliser is required, a
situation that is particularly difficult if the condition is
bilateral. Gradual return to activity is permitted after 8
weeks, but a further 8 weeks is necessary before strenuous
physical activity to allow for revascularisation, healing and
ossification of the tibial tubercle. With skeletal maturity
and closure of the apophysis, Osgood-Schlatter disease
resolves.
Scoliosis
Scoliosis is principally a lateral deviation of the spine.
There are three main types of scoliosis: (1) idiopathic
(unknown cause); (2) congenital (due to bone deformity);
and (3) teratological (because of another systemic
syndrome such as cerebral palsy). Eighty per cent of all

FIGURE 21.18

Pelvis of a 7-year-old boy with Legg-Calvé-Perthes disease.
The femoral head is flat and extruded from the edge of the
joint. This hip is at risk for early arthritis if left to
revascularise and heal in this position.

FIGURE 21.19

Surgical replacement of the femoral head of a 7-year-old
boy with Legg-Calvé-Perthes disease.
As the Perthes heals, the ball has taken on a round shape
that matches the socket well.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 533

scoliosis is idiopathic, which may have a genetic
component. True structural scoliotic deformity involves
not only a side-to-side curve but also rotation; curves
without rotation may result from another cause such
as unequal limb length or splinting from pain (see
Fig. 21.20).
Although girls and boys are equally affected, once the
curve becomes more than 20°, girls are five times more
likely to be affected. Ninety-eight per cent of curves are
apex right thoracic. If a left thoracic curve appears in the
adolescent with idiopathic scoliosis, MRI is performed
to rule out a neurological aetiology. MRI should also
be used to assess kypho- (round back) scoliosis, loss of
abdominal reflexes, children who also have exertional
headaches or a congenital curve.
Idiopathic curves increase while a child is growing
and progression can be very rapid during growth
spurts. When idiopathic curves become 25° or greater
and the child is skeletally immature, bracing is
required. Curves of more than 50° will progress after
skeletal maturity, so spinal fusion is required to stop
progression. Early diagnosis is therefore necessary so
that bracing can be attempted in the hope of halting
progression before the need for surgery. Children are
required to wear the brace for 16 hours per day and
gaining full compliance can be difficult. Nevertheless,
bracing is the only non-operative measure known to
slow scoliotic progression. Chiropractic manipulation,

physical therapy, exercise and diet regimens have not
been shown to alter natural history. Bracing is less
successful in teratological or congenital curves; therefore,
these conditions may require surgical intervention
more often.

FIGURE 21.20

Idiopathic scoliosis.
Scoliosis screening involves viewing the individual from
behind, which discloses scapular asymmetry caused by not
only curvature but also true rotation of the spine.

F O C U S O N L E A R N I N G

1 Discuss the development of osteoporosis.

2 Compare and contrast osteoporosis and Paget’s disease.

3 Describe the pathophysiology of Legg-Calvé-Perthes
disease.

4 Discuss the development of Osgood-Schlatter disease.

Disorders of joints
Joint disorders are usually accompanied by joint
inflammation and hence may be referred to as inflammatory
joint diseases. Interestingly, osteoarthritis has been previously
referred to as a non-inflammatory joint disease; however,
because there are some inflammatory processes involved,
osteoarthritis may now be referred to as an inflammatory
condition.38

Inflammatory joint disease
Inflammatory joint disease is commonly called arthritis.
Typical of inflammatory joint disease is inflammatory
damage or destruction in the synovial membrane or
articular cartilage and systemic signs of inflammation:

fever, leucocytosis (elevated numbers of leucocytes),
malaise, anorexia and increased levels of fibrinogen in
the blood.

Inflammatory joint disease can be infectious or
non-infectious. In infectious inflammatory joint disease,
invasion of the joint by bacteria, mycoplasmas (bacteria
without a cell wall), viruses, fungi or protozoa (single-celled
animals) causes inflammation. These agents gain access to
the joint through a traumatic wound, surgical incision or
contaminated needle, or they can be delivered by the
bloodstream from sites of infection elsewhere in the body
— typically bones, heart valves or blood vessels. There are
two causes of non-infectious inflammatory joint disease:
(1) inappropriate immune reactions; and (2) deposition of
crystals of monosodium urate in the synovial fluid.
Rheumatoid arthritis and ankylosing spondylitis (from the
Greek ankylos, bent, and spondylos, meaning vertebrae) are
non-infectious inflammatory diseases caused by immune
reactions and possibly hyper-sensitivity reactions;39,40 gouty
arthritis is a non-infectious inflammatory disease caused
by crystal deposition.

RHEUMATOID ARTHRITIS
Rheumatoid arthritis is a systemic, inflammatory
autoimmune disease associated with swelling and pain in

534 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

multiple joints (autoimmune diseases are described in
Chapter 15). Because this is an autoimmune condition it
tends to have a bilateral presentation and includes systemic
symptoms. The condition first affects the synovial membrane,
which lines the joint cavity (see Fig. 20.9). Eventually,
inflammation may spread to the articular cartilage, fibrous
joint capsule and surrounding ligaments and tendons,
causing pain, joint deformity and loss of function (see Fig.
21.21). The joints most commonly affected are in the fingers,
feet, wrists, elbows, ankles and knees, but the shoulders,
hips and cervical spine may also be involved, as well as the
tissues of the lungs, heart, kidneys and skin. Rheumatoid
arthritis is classified according to factors including the
number of joints affected (Box 21.2).

Rheumatoid arthritis is estimated to affect over 445 000
Australians with a prevalence rate of 2.1%, the majority
(63%) of which are females. Indigenous people have a
higher prevalence of the disease at almost double the rate
for non-Indigenous individuals.41 In 2007 the prevalence in
New Zealand was 3.5% of the population. There is evidence
of hormonal involvement because disease symptoms lessen
during pregnancy and intensify in the postpartum period.
The frequency of rheumatoid arthritis increases from

A
B

FIGURE 21.21

Rheumatoid arthritis of the hand.
A Note swelling from chronic synovitis of the
metacarpophalangeal joints, marked ulnar drift, subcutaneous
nodules and subluxation of the metacarpophalangeal joints with
extension of the proximal interphalangeal joints and flexion of the
distal joints. Note also the deformed position of the thumb. B An
x-ray of a patient with rheumatoid arthritis. There is joint
narrowing (triangles) and lateral deformation.

American College of Rheumatology/European League
Against Rheumatism 2010 criteria
1 Joint involvement (0–5)

One medium-to-large joint (0)
Two to ten medium-to-large joints (1)
One to three small joints (large joints not counted) (2)
Four to ten small joints (large joints not counted) (3)
More than ten joints (at least one small joint) (5)

2 Serology (0–3)
Negative RF and negative ACPA (0)
Low positive RF or low positive ACPA (2)
High positive RF or high positive ACPA (3)

3 Acute-phase reactants (0–1)
Normal CRP and normal ESR (0)
Abnormal CRP or abnormal ESR (1)

4 Duration of symptoms (0–1)
Less than 6 weeks (0)
6 weeks or more (1)

Points are shown in parentheses. Cutpoint for rheumatoid
arthritis 6 points or more. Patients can also be classified
as having rheumatoid arthritis if they have: (a) typical
erosions; (b) long-standing disease previously satisfying the
classification criteria.
KEY: RF – rheumatoid factor, ACPA – anti-citrullinated
protein antibody, CRP – C-reactive protein, ESR – erythrocyte
sedimentation rate.

BOX 21.2 Classification criteria for rheumatoid
arthritis

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 535

manifestations of inflammation, including fever, fatigue,
weakness, anorexia, weight loss and generalised aching and
stiffness. Local manifestations also appear gradually over
a period of weeks or months. Typically, the joints become
painful, tender and stiff. Pain early in the disease is caused
by pressure from swelling. Later in the disease, pain is caused
by sclerosis of subchondral bone and new bone formation.
Stiffness usually lasts for about an hour after rising in
the morning and is thought to be related to synovitis.
Initially the joints most commonly involved are the
metacarpophalangeal joints (base of the finger), proximal
interphalangeal joints (middle of the finger) and wrists,
with later involvement of larger weight-bearing joints.

Joint swelling, which is widespread and symmetric, is
caused by increasing amounts of inflammatory exudate
(leucocytes, plasma, plasma proteins) in the synovial
membrane, hyperplasia (an increase in cell numbers) of
inflamed tissues and formation of new bone. On palpation,
the swollen joint feels warm and the synovial membrane
feels boggy. The skin over the joint may have a ruddy,
cyanotic hue and may look thin and shiny.

An inflamed joint may lose some of its mobility. Even
mild synovitis can lead to loss of range of motion, which
becomes evident after inflammation subsides. Extension
becomes limited and is eventually lost if flexion contractures
form. Loss of range of motion can progress to permanent
deformities of the fingers, toes and limbs, including ulnar
deviation of the hands, boutonnière and swan-neck

the third decade onwards, affecting 5% or more of the
population aged 70 years and older. Besides inflammation
of the joints, rheumatoid arthritis can cause fever, malaise,
rash, lymph node or spleen enlargement and Raynaud’s
phenomenon (transient lack of circulation to the fingertips
and toes).

Despite intensive research, the cause of rheumatoid
arthritis remains obscure. It is likely to be a combination
of genetic factors interacting with inflammatory mediators.
Long-term smoking and a positive family history are
associated with the development of rheumatoid arthritis.42,43
Rheumatoid arthritis also has seasonal variations and is
worse in the winter months.

PAT H O P HYS I O LO G Y
Cartilage damage in rheumatoid arthritis is the result of at
least three processes: (1) neutrophils and other cells in the
synovial fluid become activated, breaking down the surface
layer of articular cartilage; (2) cytokines (see Chapter 12),
particularly TNF-α, stimulate the release of pro-inflammatory
compounds (especially IL-1) and cause the chondrocytes
to attack cartilage; and (3) the synovium digests nearby
cartilage, releasing inflammatory molecules.

Several types of leucocytes are attracted out of the
circulation and to the synovial membrane. The inflammatory
phagocytes (neutrophils, macrophages) ingest the immune
complexes and are stimulated to release powerful enzymes
that degrade synovial tissue and articular cartilage (see Fig.
21.22). The immune system’s B and T lymphocytes are also
activated. The B lymphocytes are stimulated to produce
more rheumatoid factors (auto-antibodies) and the T
lymphocytes produce enzymes that amplify and continue
the inflammatory response (see Fig. 21.23).

Inflammatory and immune processes have several
damaging effects on the synovial membrane. The synovial
membrane thickens and puts pressure on nearby small
venules, reducing the supply of blood. The reduced
circulation, coupled with the increased metabolism from
the proliferation and enlargement of the cells in the synovial
membrane, leads to a local hypoxia and metabolic acidosis.
Acidosis stimulates the release of enzymes from synovial
cells into the surrounding tissue that break down tissue,
initiating erosion of the articular cartilage and causing
inflammation in the supporting ligaments and tendons.

Inflammation causes haemorrhage, coagulation and
fibrin deposition on the synovial membrane, in the
intracellular matrix and in the synovial fluid. Over denuded
areas of the synovial membrane, fibrin develops into
granulation tissue called pannus. (Granulation tissue is the
initial tissue produced in the process of healing; see Chapter
13.) Pannus formation does not lead to synovial or articular
regeneration but rather to formation of scar tissue, which
immobilises the joint.

C L I N I C A L MA N I F E S TAT I O N S
The onset of rheumatoid arthritis is usually insidious,
although as many as 15% of cases have an acute onset.
Rheumatoid arthritis begins with general systemic

Plasma
cell

Subintima

Interdigitating
cell

Lymphocytes

Pannus

Cartilage

Synovial fluid

Macrophage

FIGURE 21.22

Synovitis.
Inflamed synovium showing typical arrangements of macrophages
(red) and fibroblastic cells.

536 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

passages called fistulae (singular: fistula). The second
complication is rupture of a cyst or of the synovial joint
itself, usually caused by strenuous physical activity that
places excessive pressure on the joint. Rupture releases
inflammatory exudate into adjacent tissues, thereby spreading
inflammation.

Extrasynovial rheumatoid nodules, or swellings, are
observed in areas of pressure or trauma in 20% of individuals
with rheumatoid arthritis. Each nodule is a collection of
inflammatory cells surrounding a central core of fibrinoid
and cellular debris. T lymphocytes are the main leucocytes
in the nodule. B lymphocytes, plasma cells and phagocytes
are found around the edges. Nodules are most often found
in subcutaneous tissue over the extensor surfaces of the
elbows and fingers. Less common sites are the scalp, back,
feet, hands, buttocks and knees.

deformities of the finger joints, plantar subluxation of the
metatarsal heads of the foot and hallux valgus (angulation
of the great toe towards the other toes). Flexion contractures
of the knees and hips are also common.

Joint deformities cause the physical limitations
experienced by those with rheumatoid arthritis (see Fig.
21.21). Loss of joint motion is quickly followed by secondary
atrophy of the surrounding muscles. With secondary muscle
atrophy, the joint becomes unstable, which further aggravates
joint pathology.

Two complications of chronic rheumatoid arthritis are
caused by excessive amounts of inflammatory exudate in
the synovial cavity. One complication is the formation
of cysts in the articular cartilage or subchondral bone.
Occasionally, these cysts communicate with the skin
surface (usually the sole of the foot) and can drain through

C
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Enzyme release

Pannus formation
Joint destruction
Cartilage �brosis

Fibroblasts
Chondrocytes
Synovial cells

Synovial macrophages
and �broblasts

Formation of autoimmune
complexes and probable
deposition in joint tissue

Cytokines

Joint injury

B lymphocytes

Proliferate

Antigen — environmental
agent, infectious agent?

Formation of
rheumatoid factor

Activates
osteoclasts

Activation of
helper T cells and

probably B lymphocytes

Genetic
susceptibility

leads to
predisposes

that release
cytokines
stimulating

liberating
more

stimulate that

activating

are stimulated to

stimulating
causing
leading to
resulting in

that damages the
joint leading to

ultimately
leading to

FIGURE 21.23

Model of pathogenesis of rheumatoid arthritis.
Rheumatoid arthritis is an autoimmune disease of a genetically susceptible host triggered by an unknown antigenic agent. This
chronic autoimmune reaction occurs with activation of CD4+ helper T cells, possibly other lymphocytes, and the local release of
inflammatory cytokines and mediators that eventually destroys the joint. T cells stimulate cells in the joint to produce cytokines that
are key mediators of synovial damage. Apparently, immune complex deposition also plays a role. TNF-α and IL-1, as well as some
other cytokines, stimulate synovial cells to proliferate and produce other mediators of inflammation and enzymes that all contribute to
destruction of cartilage. Pannus is a mass of synovium and synovial stroma with inflammatory cells, granulation tissue and fibroblasts
that grows over the articular surface and causes its destruction.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 537

rheumatoid factor and circulating immune complexes. The
American College of Rheumatology lists the following
diagnostic criteria for rheumatoid arthritis that have
widespread use, including within Australia and New Zealand:
1 morning stiffness lasting more than 1 hour
2 arthritis of three or more joint areas
3 arthritis of the hand joints
4 symmetric arthritis
5 rheumatoid nodules over extensor surfaces or bony

prominences
6 serum rheumatoid factor
7 x-ray changes (hand and wrist).44

The presence of four or more of the numbered criteria
is diagnostic of rheumatoid arthritis. Criteria 1–4 with joint
signs or symptoms must be present for 6 weeks.

Treatment for the orthopaedic components of the disease
can be nonsurgical or surgical. Nonsurgical treatment
includes resting the inflamed joint and whole-body rest for
several hours daily; use of hot and cold packs; physical
therapy; patient education; aggressive, early intervention
using disease-modifying antirheumatic drugs and biological
response modifiers; a diet high in kilojoules and vitamins;
corticosteroids; and anti-inflammatory drugs taken orally
or injected into the joint. Intraarticular injection of a
radionuclide can be used to treat synovitis. Surgical
synovectomy may be done early in the disease to decrease
inflammatory effusion and remove pannus. Surgery is used
to correct deformity or mechanical deficiency in intermediate
or late stages of the disease and includes arthrodesis (surgical
fusion of the two bones so the joint becomes immoveable),
arthroplasty (surgical repair of the joint) or total joint
replacement. There is evidence that total fasting substantially
reduces joint pain, swelling, morning stiffness and other
symptoms in individuals with rheumatoid arthritis.

Rheumatoid nodules may also invade the skin, cardiac
valves, pericardium, pleura, lung tissue and spleen. These
nodules are identical to those encountered in some
individuals with rheumatic fever and are characterised by
central tissue necrosis surrounded by proliferating connective
tissue. Also noted are large numbers of lymphocytes and
occasional plasma cells. Acute glaucoma may result with
nodules forming on the sclera. Pulmonary involvement
may result in diffuse pleuritis (inflammation of the pleura)
or multiple nodules within the tissue of the lungs. Diffuse
pulmonary fibrosis may occur because of immunologically
mediated immune complex deposition.

Rheumatoid nodules within the heart may cause valvular
deformities, particularly of the aortic valve leaflets, and
pericarditis (inflammation of the pericardium).
Lymphadenopathy (swelling) of the nodes close to the
affected joints may develop. Rheumatoid nodules within
the spleen result in splenomegaly (enlarged spleen). Blood
vessels may show an acute inflammatory response as is
noted in other immunological/inflammatory states.
Thromboses in involved vessels may give rise to myocardial
infarctions (see Chapter 23), cerebrovascular occlusions
(see Chapter 9), mesenteric infarction (often causing necrosis
in the gut), kidney damage (typical of systemic autoimmune
conditions) and vascular insufficiency in the hands and
fingers (Raynaud’s phenomenon). The vascular changes are
primarily noted in individuals receiving steroid therapy;
thus, there is some concern that the therapy may play a
role in initiating these lesions. Changes in skeletal muscle
are often noted in the form of nonspecific atrophy secondary
to joint dysfunction.

E VA LUAT I O N A N D T R E AT M E N T
Evaluation of rheumatoid arthritis is done by physical
examination, x-ray of the joint and serological tests for

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Paediatrics and disorders of joints
Juvenile rheumatoid arthritis
Juvenile rheumatoid arthritis is the childhood form of
rheumatoid arthritis and accounts for 5% of all cases of
rheumatoid arthritis. Juvenile rheumatoid arthritis has
three distinct modes of onset: oligoarthritis (fewer than
three joints), polyarthritis (more than three joints) and
Still’s disease (severe systemic onset). Juvenile rheumatoid
arthritis differs from rheumatoid arthritis in several ways:
• Oligoarthritis is more common.
• Large joints are most commonly affected.
• Chronic uveitis (an inflammation of the

anterior chamber of the eye) is common if the
antinuclear antibody is positive; examination by an
ophthalmologist is required every 6 months to avoid
vision loss.

• Rheumatoid nodules and rheumatoid factor are
usually absent. Rheumatoid factor–positive children
have a worse prognosis.

• Subluxation and ankylosis may occur in the cervical
spine if disease progresses.

• Rheumatoid arthritis that continues through
adolescence can have severe effects on growth and
adult morbidity.

Many children with oligoarthritis who are ‘seronegative’
(whose blood tests negative for rheumatoid factor or
antinuclear antibody) will resolve their symptoms over
time. Systemic onset, or ‘seropositivity’, of the disease is
more likely consistent with lifelong arthritis. Long-term
studies have shown that one-third to half of patients
with juvenile rheumatoid arthritis have active disease 10
years later. Treatment is therefore supportive, not curative.
Non-steroidal anti-inflammatories are a mainstay, and
methotrexate (typically an anti-cancer medication) is
also being used with success. The aims are to minimise
inflammation and deformity.

538 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

R E S E A R C H I N F C U S
New rheumatoid arthritis treatments
and diagnosis
Classification and diagnosis
Changes to the previous criteria (the American College of
Rheumatology) for classification of rheumatoid arthritis were
made in 2015 in response to limitations to identifying
individuals with early arthritis that went on to become
rheumatoid arthritis. Risk factors such as elevated body mass
index and vitamin D status have a potential impact on the
development of the disease (although the evidence is weak).
However smoking has been shown to double the risk of
developing the disease.

Current literature shows the severity of the overall disease
burden may be lessening.

Treatment
Innovative new therapies for rheumatoid arthritis treatment
continue to emerge. In addition to pharmaceutical agents,
biological and genetic agents are gaining increasing
attention. New treatments are targeted at specific cytokines,
inhibition of chemokines, and complement activation, and
investigational therapies include T cell or T cell receptor
vaccination. In the meantime, the disease-modifying
antirheumatic drugs (DMARDs) continue to be widely used
for these patients.

A N KYLO S I N G S P O N DYL I T I S
Ankylosing spondylitis is a chronic, inflammatory joint
disease characterised by stiffening and fusion (ankylosis)
of the spine and sacroiliac joints. Like rheumatoid arthritis,
ankylosing spondylitis is a systemic, autoimmune disease.
However, the two conditions respond to different antigens.
In the case of rheumatoid arthritis the synovial membrane
is affected, whereas in ankylosing spondylitis it is the point
at which the tendons and ligaments attach to bone that is
affected (known as the enthesis). The end result is fibrosis,
ossification and fusion of the joint, usually beginning
with the sacroiliac joints and progressing up the vertebral
column.

Ankylosing spondylitis usually develops in late
adolescence and young adulthood, with peak incidence at
about 20 years of age, and affects slightly more men than
women. There is a wide range of presentations from
asymptomatic sacroiliitis (inflammation of the sacroiliac
joint) to progressive disease that affects many body
systems.

Secondary ankylosing spondylitis affects older age groups
and is often associated with other inflammatory diseases
(e.g. psoriatic arthropathy, inflammatory bowel disease,
Reiter’s syndrome — a reactive arthritis).

The cause of ankylosing spondylitis is unknown, but a
genetic predisposition to the disease has been suggested.45

PAT H O P HYS I O LO G Y
Ankylosing spondylitis begins with inflammation of
fibrocartilage in cartilaginous joints (see Chapter 14) between
the sacrum and ilia (plural of ilium). Inflammatory cells
infiltrate the joint and begin to damage fibrocartilage and
bone in the joint structures. Repair of the damage is mediated
by fibroblasts that produce and secrete collagen. This collagen
forms scar tissue that is eventually calcified. With time, all
the cartilaginous structures of the joint are replaced by
ossified scar tissue, causing the joint to fuse or lose flexibility.

The eroded bone is repaired in the normal process of
bone repair and remodelling (see Chapter 20). The new
bone has to grow outwards to connect with the ligaments
that have been eroded by the inflammatory response and,
as a consequence, the shape of the vertebral bodies changes
— they lose their concave anterior contour and appear
square. The spine assumes the classic bamboo spine
appearance of ankylosing spondylitis (see Fig. 21.24).

C L I N I C A L MA N I F E S TAT I O N S
The most common signs and symptoms of early ankylosing
spondylitis are low back pain and stiffness that may be
persistent or intermittent. It is often worse after prolonged
rest and is alleviated by physical activity. Early morning
stiffness usually accompanies the low back pain and the
individual typically has difficulty sitting up or twisting the

Ossification of discs,
joints and ligaments

of spinal column

FIGURE 21.24

Ankylosing spondylitis.
Characteristic posture and primary pathological sites of
inflammation and resulting damage.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 539

GOUT
Gout is a syndrome caused by defects in uric acid metabolism
and characterised by inflammation and pain of the joints.
Either excessive uric acid production or underexcretion of
uric acid by the kidneys will cause hyperuricaemia. When
the uric acid becomes sufficiently concentrated, it crystallises,
forming insoluble crystals that are deposited in connective
tissues throughout the body. Crystallisation in synovial fluid
causes acute, painful inflammation of the joint, a condition
known as gouty arthritis. With time, crystal deposition in
subcutaneous tissues causes the formation of small, white
nodules, or tophi, that are visible through the skin. Crystal
aggregates deposited in the kidneys can form urate renal
stones and lead to renal failure.

Gout is predominantly a disease of men. The peak age
of onset in males is between 40 and 60 years, whereas it is
somewhat later in females. The plasma urate concentration
is the single most important determinant of the risk of
developing gout (see Table 21.3).

The solubility of urate is critical to the development of
crystals. Urate is more soluble in plasma and urine than
in synovial fluid. The solubility of urate also decreases with
decreasing temperature. Initial deposits are often in the
joint of the great toe where temperatures are lower than
the body core. The pathways of production of uric acid are
shown in Fig. 21.25.

PAT H O P HYS I O LO G Y
The pathophysiology of gout is closely linked to purine
metabolism (or cellular metabolism of purines — adenine
and guanine from DNA and RNA) and kidney function.
At the cellular level, purines are used for the production
of several products, including ATP and nucleic acids. Uric
acid is a breakdown product of purine nucleotides (urate
production and elimination are illustrated in Fig. 21.25).
Some individuals with gout have an accelerated rate of
purine production accompanied by an overproduction of
uric acid. Even with restricted purine consumption, these
individuals continue to overproduce uric acid. Other
individuals break down purine nucleotides at an accelerated
rate that also results in an overproduction of uric acid. In

spine. Forward flexion, rotation and lateral flexion of the
spine are restricted and painful. Early pain and resultant
loss of motion are caused by the underlying inflammation
and reflex muscle spasm rather than by soft tissue or bony
fusion.

As the disease progresses, the normal convex curve of
the lower spine (lumbar lordosis) diminishes and concavity
of the upper spine (kyphosis) increases. The individual
becomes increasingly stooped. The thoracic spine becomes
rounded, the head and neck are held forward on the
shoulders and the hips are flexed (see Fig. 21.16).

Inflammation in the tendon insertions of the muscles
of the chest wall can cause pleuritic chest pain and restricted
chest movement. The pain is usually worse on inspiration.
Movement in the diaphragm is normal and full. Pressure
on the anterior chest wall over the sternum, ribs and costal
cartilages may show tenderness. Tenderness over the pelvic
brim may cause discomfort at night and interfere with sleep
because turning onto the iliac crests causes pain. Tenderness
over the ischial tuberosities may make sitting on hard seats
unbearable. Tenderness in the heels may contribute to a
limp or cautious placement of the feet during walking.

Along with low back pain, many individuals have
peripheral joint involvement, uveitis, fibrotic changes in
the lungs and cardiomegaly, aortic incompetence, amyloidosis
and Achilles tendonitis. Symptoms may include fatigue,
weight loss, low-grade fever, hypochromic anaemia and an
increased erythrocyte sedimentation rate.

E VA LUAT I O N A N D T R E AT M E N T
Diagnosis of ankylosing spondylitis is made from the history
and physical examination, x-ray and serum analysis for the
presence of the relative antigen (HLA-B27). The erythrocyte
sedimentation rate and C-reactive protein are elevated
throughout the disease. Alkaline phosphatase levels are
often elevated. Early precise diagnosis allows implementation
of a usually effective, conservative, life-long treatment.

Treatment of individuals with ankylosing spondylitis is
directed at controlling pain, maintaining mobility and
controlling inflammation. Prevention of deformity and
maintenance of mobility require a continuous program of
physical therapy. Exercises are performed several times
each day to maintain chest expansion, full extension of
the spine and complete range of motion in the proximal
joints.

Non-steroidal anti-inflammatory drugs often provide
temporary symptom relief within 48 hours. Analgesic
medications are prescribed to suppress some of the pain
and stiffness and to facilitate exercise. The medications do
not prevent disease progression, but they do provide relief
from symptoms. Biological response modifying agents, such
as infliximab, which inhibits TNF-α, may be useful in
treating ankylosing spondylitis.46,47 Surgical procedures,
such as osteotomy, total hip replacement and cervical spinal
fusion, and radiation therapy are sometimes used to provide
relief for individuals with end-stage disease or intolerable
deformity. Individuals should stop smoking to lessen
pulmonary problems.

TABLE 21.3 Mean urate concentrations by age
and gender

CHARACTERISTIC MEAN URATE LEVELS

Prepuberty 0.20 mmol/L

Males Steep rise to 0.30 mmol/L

Females (puberty to after
premenopause)

Slow rise to approximately
0.24 mmol/L

Females (after menopause) 0.28 mmol/L

Hyperuricaemia

Males > 0.42 mmol/L
Females > 0.36 mmol/L

540 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

Production Metabolism Elimination

Dietary
purine

Purine
production

Body purine
nucleotides Purines

Tissue nucleic
acids

Uric acid Intestinal
excretion

Renal
excretion

FIGURE 21.25

Uric acid production and elimination.
Uric acid is derived from purines ingested or produced from
ingested foods, as well as being recycled after cell breakdown.
Uric acid is then eliminated through the kidneys and
gastrointestinal tract.

addition, production of uric acid can be caused by an
increased turnover of nucleic acids, which is associated
with an increased turnover of cells at other body sites. The
increased turnover of nucleic acids leads to increased levels
of uric acid with a compensatory increase in purine
production.

Most uric acid is eliminated from the body through the
kidneys. Urate is filtered at the glomerulus and undergoes
reabsorption, as well as being excreted into urine. In primary
gout, urate excretion by the kidneys is sluggish, which may
result from a decrease in glomerular filtration of urate or
increased urate reabsorption. In addition, monosodium
urate crystals are deposited in renal interstitial tissues,
causing impaired urine flow. (Kidney function is described
in Chapter 28.)

The exact process by which crystals of monosodium
urate are deposited in joints and induce gouty arthritis is
unknown, but several mechanisms may be involved,
including the following:
• monosodium urate precipitates at the periphery of the

body, where lower body temperatures may reduce the
solubility of monosodium urate

• albumin or glycosaminoglycan levels decrease, which
causes decreased urate solubility

• changes in ion concentration and decreases of pH
enhance urate deposition

• trauma promotes urate crystal precipitation.
The monosodium urate crystals may form in the synovial

fluid or in the synovial membrane, cartilage or other
connective tissues in joints and elsewhere, such as in the
heart, earlobes and kidneys. Evidence suggests that an acute
attack of gout is the result of the formation of crystals rather

than the releasing of the crystals from connective tissues
into the synovial fluid.

Monosodium urate crystals can stimulate and perpetuate
the inflammatory response (see Fig. 21.26), during which
neutrophils are attracted out of the circulation and
phagocytose (ingest) the crystals. The neutrophils
subsequently die and release both the crystals and the
lysosomal enzymes that cause tissue damage and further
stimulate inflammation.

C L I N I C A L MA N I F E S TAT I O N S
Gout is manifested by: (1) an increase in serum urate
concentration (hyperuricaemia); (2) recurrent attacks of
monarticular arthritis (inflammation of a single joint); (3)
deposits of monosodium urate monohydrate (tophi) in and
around the joints; (4) renal disease involving glomerular,
tubular and interstitial tissues and blood vessels; and (5)
the formation of renal stones. These manifestations appear
in three clinical stages:
1 Asymptomatic hyperuricaemia. The serum urate level is

elevated but arthritic symptoms, tophi and renal stones
are not present; may persist throughout life.

2 Acute gouty arthritis. Attacks develop with increased
serum urate concentrations; tends to occur with sudden
or sustained increases of hyperuricaemia but also can
be triggered by trauma, drugs and alcohol.

3 Tophaceous gout. The third and chronic stage of disease;
can begin as early as 3 years or as late as 40 years after
the initial attack of gouty arthritis. Progressive inability
to excrete uric acid leads to tophi appearing in cartilage,
synovial membranes, tendons and soft tissue.
Trauma is the most common aggravating factor. The

great toe is subject to chronic strain in walking and
subsequently an acute gout attack may follow long walks.
Trauma associated with occupations such as truck driving
also may precipitate an attack.

Attacks of gouty arthritis occur abruptly, usually in a
peripheral joint (see Fig. 21.26C). The primary symptom
is severe pain. Approximately 50% of initial attacks occur
in the metatarsophalangeal joint of the great toe (a condition
known as podogra). The other 50% involve the heel, ankle,
instep of the foot, knee, wrist or elbow. The pain is usually
noted at night. Within a few hours the affected joint becomes
hot, red and extremely tender and may be slightly swollen.
Lymphangitis (inflammation of lymph vessels) and systemic
signs of inflammation (leucocytosis, fever, elevated
sedimentation rate) are occasionally present. Untreated,
mild attacks usually subside in several hours but may persist
for 1 or 2 days. Severe attacks may persist for several days
or weeks. When the individual recovers, the symptoms
resolve completely. The helix of the ear (outer fold) is the
most common site of tophi, which are the characteristic
diagnostic lesions of chronic gout.

Tophi do not usually appear until at least 10 years after
the first gout attack. They produce irregular swellings of
the fingers, hands, knees and feet. Tophi commonly form
lumps along the ulnar surface of the forearm, the tibial

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 541

tophi in the lower extremities may cause tarsal tunnel
syndrome. They also may erode and drain through the
skin.

Kidney stones (see Chapter 30) are 1000 times more
prevalent in individuals with primary gout than in the
general population. The stones may be any size, from the
size of a grain of sand or a piece of gravel to much larger

surface of the leg, the Achilles tendon and olecranon bursae.
Tophi may produce marked limitation of joint movement
and eventually cause grotesque deformities of the hands
and feet. Although the tophi themselves are painless, they
often cause progressive stiffness and persistent aching of
the affected joint. Tophi in the upper extremities may cause
nerve compressions, such as carpal tunnel syndrome, while

Hyperuricaemia

Formation of monosodium urate crystals

IgG coating Crystals in synovial �uid

Lipoprotein coating

stimulates inhibits

CollagenaseChemotactic
factors

Lysosomal
enzymes

PGE 2
IL-1
IL-6

Oxygen
radicals

Overproduction
of uric acid

Underexcretion
of uric acid

Neutrophil, leucocyte, monocyte,
�broblast, synoviocyte, renal cell

Responding cell

Phagocytosis
by leucocyte

Fusing of vacuolar
and lysosomal
membranes

Hydrogen bonding
between crystal surface
and lysosomal membrane

Rupture of
phagolysosome and
disruption of leucocyte

Shedding of
preformed
crystals
from tophi

Monosodium
urate
crystallisation

A
B
C

Tissue damage and continued in�ammation

In�ammation

FIGURE 21.26

The pathogenesis of acute gouty arthritis.
A Depending on the urate crystal coating, a variety of cells may be stimulated to produce a wide range of inflammatory mediators. IgG =
immunoglobulin G; PGE2 = prostaglandin E2; IL = interleukin. B The sequence of events in the production of inflammatory response to
urate crystals. C Gouty tophus on the right foot.

542 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

urinary output. Uricosuric drugs (e.g. probenecid or
sulfinpyrazone) increase the excretion of urate by blocking
its reabsorption by the kidney tubules. Antihyperuricaemic
drugs (e.g. allopurinol) reduce serum urate concentrations
by inhibiting the formation of urate. Ensuring those at risk
of acute gouty attack are well hydrated is essential, especially
following admission due to trauma.

OSTEOARTHRITIS
Osteoarthritis is effectively a wearing out of the joint (see
Fig. 21.27). It therefore predominantly affects the
weight-bearing joints. Osteoarthritis tends to occur in men
and women older than 40 years of age and becomes more
common with increasing age. It is a leading cause of pain
and disability in the elderly. Australian data from the
2011–2012 National Health Survey48 show age-adjusted
prevalence is higher in females (10.2%) than males (5.6%).
In 2007 the prevalence of osteoarthritis in New Zealand
was 8.7% of the population.49 It usually occurs in those
who put exceptional stress on joints, as do obese people,
gymnasts, long-distance runners and marathoners, and
basketball, soccer and football players. Many of these people
develop osteoarthritis at earlier ages than usual. A previously
torn anterior cruciate ligament or meniscectomy (surgical

deposits. Renal stones can form in the collecting tubules,
pelvis or ureters, causing obstruction, dilation and atrophy
of the more proximal tubules and leading eventually to
acute renal failure. Stones deposited directly in renal
interstitial tissue initiate an inflammatory reaction that leads
to chronic renal disease and progressive renal failure.

T R E AT M E N T
The first objective of gout treatment is to terminate the
acute gouty attack as promptly as possible. Once the
inflammatory process has subsided, attention is directed
to prevent recurring attacks, prevent or reverse complications
associated with urate deposits in the joints and kidneys,
and prevent formation of kidney stones. Acute gouty arthritis
is treated with anti-inflammatory drugs. The drugs of choice
are colchicine, non-steroidal anti-inflammatory agents
(especially indomethacin) and allopurinol. Colchicine
is useful in those unable to take non-steroidal anti-
inflammatories. Once infection has been ruled out,
hydrocortisone may be injected into the joint to relieve
pain. Ice also may relieve some of the inflammation of the
joint. Weight-bearing on the involved joint is to be avoided
until the acute attack subsides. After the attack the individual
is put on a low-purine diet, with high fluid intake to increase

Cartilage

Bone

Joint
capsule

Bone
cysts

Sclerotic
bone Osteophytes

Calcified
cartilage

Periarticular
fibrosis

Cartilage
fragments

NORMAL OSTEOARTHRITIS
• Irregular joint space
• Fragmented cartilage
• Loss of cartilage
• Sclerotic bone
• Cystic change

OSTEOARTHRITIS — ADVANCED
• Osteophytes
• Periarticular fibrosis
• Calcified cartilage

FIGURE 21.27

Osteoarthritis.
A schematic of the pathology of osteoarthritis. Fragmentation and loss of cartilage denude the bone, which undergoes sclerosis
(stiffening). Osteophytes (bone spurs) form on the lateral sides and protrude into the soft tissue, causing irritation, inflammation and
fibrosis (excessive fibrous connective tissue).

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 543

removal of the meniscus of the knee) increases the risk for
accelerated osteoarthritis of the knee.50,51 See Box 21.3 for
risk factors for osteoarthritis.

Osteoarthritis is characterised by localised loss and
damage of articular cartilage, new bone formation of joint
margins (osteophytosis), subchondral bone changes, variable
degrees of mild synovitis and thickening of the joint capsule
(see Fig. 21.28). Pathology centres on load-bearing areas.
Advancing disease reveals narrowing of the joint space

because of cartilage loss, osteophytes (bone spurs) and
sometimes changes in the subchondral bone. Osteoarthritis
can arise in any synovial joint but is commonly found in
the hips, hands and spine (see Fig. 21.29). It involves a
complex interaction of cytokines, growth factors, matrix
molecules and enzymes.

PAT H O P HYS I O LO G Y
Articular cartilage is normally a dynamic tissue: the
chondrocytes (cartilage-forming cells) continuously replace
the tissue in the same way that bone is continually replaced.
In osteoarthritis this process becomes disrupted — the
primary defect in osteoarthritis is loss of articular cartilage.52
Early in the disease, articular cartilage loses its glistening
appearance, becoming yellow-grey or brownish grey. As
the disease progresses, surface areas of the articular cartilage
flake off and deeper layers develop longitudinal fissures
that extend to the subchondral bone. Synovial fluid fills
the fissures and may enter the underlying bone, forming
cysts. The cartilage becomes thin and may be absent over
some areas, leaving the underlying bone (subchondral bone)
unprotected. Consequently, the unprotected subchondral
bone becomes sclerotic (dense and hard). Fragments of
bone and cartilage become free floating and enter the joint
cavity. Formation of new bone and cysts usually occurs
near the joint margins, forming osteophytes. As the joint
loses its integrity there is trauma to the synovial membrane
causing a nonspecific inflammation, or synovitis.

C L I N I C A L MA N I F E S TAT I O N S
Clinical manifestations of osteoarthritis typically appear
during the fifth or sixth decade of life, although asymptomatic,

• Trauma, sprains, strains, joint dislocations and fractures
• Long-term mechanical stress — athletics, ballet dancing

or repetitive physical tasks
• Inflammation in joint structures
• Joint instability from damage to supporting structures
• Neurological disorders (e.g. diabetic neuropathy,

neuropathic joint disease) in which pain and
proprioceptive reflexes are diminished or lost

• Congenital or acquired skeletal deformities
• Haematological or endocrine disorders, such as

haemophilia (which causes chronic bleeding into the
joints) or hyperparathyroidism (which causes bone to
lose calcium)

• Drugs (e.g. colchicine, indomethacin, steroids) that
stimulate the collagen-digesting enzymes in the synovial
membrane

BOX 21.3 Risk factors for osteoarthritis

C
O
N
C
E
P
T M
A
P

Genetic in�uences
• Biochemical abnormalities
in collagen and
proteoglycans and bone
formation
• Congenital hip dysplasia

Enzyme release with
degradation of
collagen and
proteoglycans

Synovial in�ammation

Alteration in
chondrocyte function

Structural damage
to cartilage

Acquired risk factors
• Age
• Obesity
• Metabolic conditions
• Malalignment
• Joint trauma or injury

Cytokine release

Muscle weakness

Bone remodelling

predispose to

results in

stimulating

stimulates causes

promoting
results in
leading to
contributing to

increase the
risk of

causing

FIGURE 21.28

Summary of the pathophysiology of osteoarthritis with emphasis on structural damage to the cartilage and alteration in
chondrocyte function.

544 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

articular surface changes will have been occurring for 10
or 20 years. Pain that is initially described as aching and
difficult to localise and is aggravated by weight-bearing is
a common presentation of the disease. It is usually aggravated
by use of the joint and relieved by resting the joint and is
unilateral in nature. Later in the course of the disease night
pain may be experienced that is not relieved by rest and
may be accompanied by paraesthesias (numbness, tingling
or prickling).

Sometimes pain is referred to another part of the
body. For example, osteoarthritis of the lumbosacral
spine may mimic sciatica, causing severe pain in the
back of the thigh along the course of the sciatic nerve.
Osteoarthritis in the lower cervical spine may cause brachial
neuralgia (pain in the arm) aggravated by movement of
the neck. Osteoarthritic conditions in the hip cause pain
that may be referred to the lower thigh and knee area.
Sleep deprivation adds to the stress of the chronic pain of
osteoarthritis.

Physical examination of the person with osteoarthritis
usually shows general involvement of both peripheral and
central joints. Peripheral joints most often involved are in
the hands, wrists, knees and feet. Central joints most often

Rheumatoid arthritis Osteoarthritis

FIGURE 21.29

The distribution of involved joints in the two most common forms of arthritis — rheumatoid arthritis and osteoarthritis.
Dark circles are shown over the involved joint areas.

afflicted are in the lower cervical spine, lumbosacral spine,
shoulders and hips (see Fig. 21.29).

Joint structures are capable of generating a limited
number of signs and symptoms. The primary signs and
symptoms of joint disease are pain, stiffness, enlargement
or swelling, tenderness, limited range of motion, muscle
wasting, partial dislocation and deformity. Range of
motion is limited to some degree, depending on the
extent of cartilage degeneration and any swelling of the
affected joint. Frequently, joint motion is accompanied
by crepitus (a crackling sound or grating sensation in
a joint).

As osteoarthritis of the lower extremity progresses,
the person may begin to limp noticeably (see Fig. 21.30).
Having a limp is distressing because it affects the person’s
independence and ability to do usual activities of daily
living. The affected joint is also more symptomatic
after use, such as at the end of a period of strenuous
activity.

E VA LUAT I O N A N D T R E AT M E N T
Evaluation consists of clinical assessment and radiological
studies, CT scan, arthroscopy and MRI. Treatment is either

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 545

conservative or surgical. Conservative treatment includes
rest of the involved joint until inflammation, if present,
subsides; range of motion exercises to prevent joint capsule
contraction; use of a cane, crutches or walker to decrease
weight-bearing; and analgesic and anti-inflammatory
drug therapy to reduce swelling and pain. In addition,
weight loss is recommended if obesity is present (obese
people are five times more likely to have osteoarthritis of
the knees and twice as likely to have osteoarthritis of the
hips as people of normal weight; see Research in Focus:
Body weight and osteoarthritis). Intraarticular injection
of hyaluronic acid has also been successful in decreasing
knee pain with osteoarthritis.53 Speculation regarding the
use of the cartilage-supporting agents glucosamine and
chondroitin has prompted mixed results from studies,
some claiming benefit and others finding no effect.54,55
There is a contemporary focus on developing and testing
medications for the treatment of osteoarthritis such as
disease-modifying osteoarthritis drugs (DMOAD) although
there is no clear evidence yet of effective treatments.56
Surgery is used to improve joint movement, correct
deformity or malalignment or implant an artificial joint (see
Fig. 21.31).

The intervention rate (which is much lower than the
incidence rate) for major joint surgery is 1.9 per 1000 in
Australia and 1.2 per 1000 in New Zealand. These rates are
increasing.57

FIGURE 21.30

Typical varus deformity of knee osteoarthritis.
The osteoarthritis causes deformity of the knee such that the legs
lose their normal alignment.

Inguinal ligament

Femoral
artery

Ischiogluteal
bursa

Trochanteric
bursa

Iliopsoas bursa

B
A

FIGURE 21.31

Musculoskeletal anatomy of the hip.
A An artificial hip is shown at a 4.5 year follow-up x-ray alongside
B, an anatomical drawing of an actual hip joint.

546 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

R E S E A R C H I N F C U S
Body weight and osteoarthritis
Longitudinal studies have shown obesity to be a major risk
factor in developing osteoarthritis of the knee. In addition
to altered biomechanics, increased weight may make
subchondral bone stiffer and thus less capable of handling
joint impact loading.

F O C U S O N L E A R N I N G

1 Analyse the effects of juvenile and adult rheumatoid
arthritis.

2 Discuss both the causes and the development of gout.

3 Briefly describe the pathophysiology of osteoarthritis and
critically analyse the risk factors for this condition.

Newborns
Staphylococcus aureus
Group B streptococcus
Gram-negative enteric rods
Infants
Staphylococcus aureus
Haemophilus influenzae (decreasingly less common
secondary to immunisation)
Older children
Staphylococcus aureus
Pseudomonas
Salmonella
Neisseria gonorrhoea
Adolescents and adults
Pseudomonas
Mycobacterium tuberculosis

BOX 21.4 Causative microorganisms of
osteomyelitis according to age

Infectious bone disease
Infectious bone disease is expensive, difficult to treat and
often culminates in extensive physical disability. Several
factors contribute to the difficulty in treating bone infection:
• Bone contains multiple microscopic channels that are

too small to be accessed by the cells and biochemicals of
the body’s immune system. Once bacteria gain access to
these channels, they are able to proliferate undisturbed.

• The microcirculation of bone is highly vulnerable to
damage and destruction by bacterial toxins. Vessel
damage causes local thrombosis (blockage) of the
small vessels, which leads to ischaemic necrosis (lack
of perfusion causing death) of bone.

• Bone cells have a limited capacity to replace bone
destroyed by infections. Osteoclasts are stimulated
by infection to resorb bone, opening up channels in
the bone so that cells of the immune system can gain
access to the infected bone. At the same time, however,
resorption weakens the structural integrity of the bone.
New bone formation usually lags behind resorption and
the haversian systems in the new bone are incomplete.

Osteomyelitis
Osteomyelitis (osteo meaning bone and myelo meaning
marrow) is an infection of the bone and marrow that can
be caused by an infective agent (see Box 21.4). Antibiotic
medications and often surgical interventions are used to
fight these infections. With modern treatments morbidity
and mortality resulting from osteomyelitis have fallen
drastically. With present management, serious long-term
effects occur for less than 15% of cases.

Osteomyelitis is usually caused by bacteria; however,
fungi, parasites and viruses can also cause bone infection.
The infection may originate from the bloodstream or from
a surgical procedure (Fig. 21.32).

2
4
3
1
5

FIGURE 21.32

The routes of infection to the joint.
1 Via the blood stream. 2 Dissemination from osteomyelitis.
3 Spread from an adjacent soft-tissue infection. 4 Diagnostic or
therapeutic measures. 5 Penetrating damage by puncture or
cutting.

Exogenous osteomyelitis is an infection that enters from
outside the body — for example, through open fractures,
penetrating wounds or surgical procedures. The infection
spreads from soft tissues into adjacent bone.

Endogenous osteomyelitis (also referred to as
haematogenous osteomyelitis) is caused by pathogens carried
in the blood from sites of infection elsewhere in the body.
The infection spreads from bone to adjacent soft tissues.
Endogenous osteomyelitis is commonly found in infants,
children and the elderly. In infants, incidence rates among

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 547

Local injections and venous punctures are significant causes
of exogenous osteomyelitis. Exogenous osteomyelitis of the
arm and hand bones tends to occur in those who abuse
drugs. In general, persons who are chronically ill, have
diabetes or alcoholism or are receiving large doses of steroids
or immunosuppressive drugs are particularly susceptible
to exogenous osteomyelitis or recurring episodes of this
disease.

PAT H O P HYS I O LO G Y
Regardless of the source of the pathogen, the pathological
features of bone infection are similar to those in any other
body tissue. The invading pathogen provokes an intense
inflammatory response. As always, the inflammatory
response dilates blood vessels flowing to the affected area
and constricts those leading away from it, leading to vascular
engorgement. An associated increase in permeability causes
oedema. Leucocytes attend, releasing inflammatory
chemicals and phagocytosing bacteria; abscesses form. Once
inflammation is initiated, the small terminal vessels
thrombose and exudate seals the bone’s canaliculi.
Inflammatory exudate extends into the metaphysis and the
marrow cavity and through small metaphyseal openings
into the cortex.

In children, exudate that reaches the outer surface of
the cortex forms abscesses that lift the periosteum off
underlying bone. Lifting of the periosteum disrupts blood
vessels that enter bone through the periosteum, depriving
underlying bone of its blood supply; this leads to necrosis
of the affected bone, producing sequestrum, an area of
devitalised bone. Lifting of the periosteum also stimulates
the osteoblasts into intense activity as they lay down new
bone that can partially or completely surround the infected
bone. This layer of new bone surrounding the infected bone
is called an involucrum. Openings in the involucrum allow
the exudate to escape into surrounding soft tissue
and ultimately through the skin by way of sinus tracts (see
Fig. 21.33).

In adults, this complication is rare because the periosteum
is firmly attached to the cortex and resists displacement.

males and females are approximately equal. In children
and older adults, however, males are more commonly
affected.

Osteomyelitis in children usually begins as an abscess
in the metaphysis of a long bone where blood flow is sluggish
and bacteria can collect. The periosteum may peel off the
affected bone leading to necrosis of the bone. New bone
can develop inside the now extended periosteum. These
changes may be visualised by x-ray and signify the need
for surgical debridement as well as antibiotic treatment.

In adults, endogenous osteomyelitis is more common
in the spine, pelvis and small bones. Microorganisms reach
the vertebrae through arteries, veins or lymphatic vessels.
The spread of infection from pelvic organs to the vertebrae
is well documented. Vaginal, uterine, ovarian, bladder and
intestinal infections can lead to iliac or sacral osteomyelitis.

Cutaneous, sinus, ear and dental infections are the
primary sources of bacteria in endogenous bone infections.
Soft-tissue infections, disorders of the gastrointestinal tract,
infections of the genitourinary system and respiratory
infections are also sources of bacterial contamination. In
addition, infections that occur after total joint replacements
are sometimes the cause. The vulnerability of a specific
bone depends on the anatomy of its vascular supply.
Staphylococcus aureus is the usual cause of osteomyelitis.58–60

Exogenous osteomyelitis can be caused by human bites
or fist blows to the mouth. Superficial animal or human
bites inoculate local soft tissue with bacteria that later spread
to underlying bone. Deep bites can introduce microorganisms
directly onto bone. The most common infecting organism
in human bites is Staphylococcus aureus. In animal bites,
the most common infecting organism is Pasteurella
multocida, which is part of the normal mouth flora of cats
and dogs.

Direct contamination of bones with bacteria can also
occur in open fractures or dislocations with an overlying
skin wound from contaminated material present during
the injury. Intervertebral disc surgery and surgical procedures
involving insertion of foreign objects such as metal plates
or artificial joints are associated with exogenous osteomyelitis.

Initial
site of
infection

Periosteum

Blood
supply
blocked

Subperiosteal
abscess
(pus)

Epiphyseal
line
Sequestrum
(dead bone)

Pus
escape

Involucrum
(new bone
formation)

Initial infection First stage Second stage

FIGURE 21.33

Osteomyelitis showing sequestration and involucrum.
The bone infection in ostoemyelitis can have significant adverse effects on a large region of bone tissue.

548 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

A
B

FIGURE 21.34

The pathogenesis of acute osteomyelitis differs with age.
A In infants younger than 1 year the epiphysis is nourished by
arteries penetrating through the physis, allowing development of
the condition within the epiphysis. B In children up to 15 years of
age, the infection is restricted to below the physis because of
interruption of the vessels.

Instead, infection disrupts and weakens the cortex, which
predisposes the bone to pathological fracture.

C L I N I C A L MA N I F E S TAT I O N S
Clinical manifestations of osteomyelitis vary with the age
of the individual, the site of involvement, the initiating
event, the infecting organism and whether the infection is
acute, subacute or chronic.

Acute osteomyelitis causes abrupt onset of inflammation.
If an acute infection is not completely eliminated, the disease
may become subacute or chronic.
• In subacute osteomyelitis, signs and symptoms are usually

vague.
• In the chronic stage, infection develops slowly or is silent

between exacerbations. The microorganisms persist
in small abscesses or fragments of necrotic bone and
produce occasional flare-ups of acute osteomyelitis.
The progression from acute to subacute osteomyelitis

may be the result of inadequate or inappropriate therapy
or the development of drug-resistant microorganisms.

In children, radiographic bone changes take 2–3 weeks
to develop. Initially, osteomyelitis presents as pain, swelling
and warmth. Children will often present with fever, an
elevated white blood cell count (50–70%), elevated C-reactive
protein (98%) and elevated erythrocyte sedimentation rate
(90%). Blood culture is positive in only 40% of cases. Without
changes on plain radiograph, bone scans can help define
the location of infection. In infants, where osteomyelitis
can be multifocal in up to 40% of cases, bone scans identify
other locations of infection that may need surgical
intervention (see Fig. 21.34).

Treatment of osteomyelitis consists of appropriate
antibiotic management for 6 weeks. If blood cultures are
negative, bone aspirate must determine the bacterial cause
of the infection. If bony changes exist on plain radiographs,
surgical debridement accompanies antibiotic treatment.

In the adult, osteomyelitis has an insidious onset. The
symptoms are usually vague and include fever, malaise,
anorexia, weight loss, and pain in and around the infected
areas. Oedema may or may not be evident. Recent
infection (urinary, respiratory, skin) or instrumentation
(catheterisation, cystoscopy (endoscopy of the urinary
bladder), myelography (x-ray visualisation of the spinal
cord after injection of contrast medium), discography (x-ray
of the spinal column disc/s after injection of contrast
medium)) usually precedes the onset of symptoms.

Single or multiple abscesses (Brodie’s abscesses)
characterise subacute or chronic osteomyelitis. Brodie’s
abscesses are well-defined lesions 1–4 cm in diameter, usually
in the ends of long bones and surrounded by dense ossified
bone matrix. The abscesses are thought to develop when
the infectious microorganism has become less virulent or
the individual’s immune system is resisting the infection
somewhat successfully.

In exogenous osteomyelitis, signs and symptoms of
soft-tissue infection predominate. Inflammatory exudate
in the soft tissues disrupts muscles and supporting structures

and forms abscesses. Low-grade fever, lymphadenopathy
(enlargement of the lymph nodes), local pain and swelling
usually occur within days of contamination by a puncture
wound.

E VA LUAT I O N A N D T R E AT M E N T
Laboratory data show an elevated white cell count.
Radiographic studies include radionuclide bone scanning,
CT scans and MRI. MRI with gadolinium contrast shows
both bone and soft tissue, providing more accurate
assessment of infection.60 A specimen of the infected bony
tissue or associated exudate may be obtained to identify
the specific pathogen present. Treatment of osteomyelitis
includes antibiotics and debridement with bone biopsy.
Each individual is treated according to their signs.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 549

Biodegradable antibiotic-impregnated bioabsorbable beads
have benefited many individuals.61,62 Chronic conditions
may require surgical removal of the inflammatory exudate
followed by continuous wound irrigation with antibiotic
solutions in addition to systemic treatment with antibiotics.
Chronic infections may not be able to be treated fully and
long-term antibiotic therapy may be required to suppress
the infection. Treatment options should also involve an
infectious disease healthcare professional. Any artificial
implant (prosthesis) may need to be removed surgically as
it significantly reduces the ability to treat the infection
efficiently.

P
A
E
D
IA
T
R
IC
S

Paediatrics and septic arthritis
Septic arthritis is an infection of the joint space. This
condition is always a surgical emergency. The bacteria,
and the activities of white cells (leucocytes) fighting the
bacteria, can quickly destroy the articular cartilage of
the joint and affect the blood supply to the epiphyseal
bone nearby. Neither of these complications is easy to
treat, and either one can lead to a lifetime of disability.
Septic arthritis can occur primarily or secondarily to
osteomyelitis that breaks out of the metaphysis of the
bone into the joint space. The metaphysis of the paediatric
hip, shoulder, proximal radius and distal lateral tibia
are all located within the joint capsule and therefore
osteomyelitis in these regions must be carefully monitored
for secondary septic arthritis. The most common sites
for septic arthritis are the knees, hips, ankles and elbows.
Children with septic arthritis present with severe joint
pain, ‘pseudoparalysis’ (apparent loss of muscle power

without actual paralysis) or marked guarding to motion of
the joint, inability to bear weight and malaise, often with
anorexia. Children appear quite ill with this diagnosis.
Non-pyogenic (not pus forming) arthritis, such as juvenile
rheumatoid arthritis, can be difficult to distinguish
clinically from septic arthritis because both can lead to
malaise and an elevated erythrocyte sedimentation rate.
An elevation in C-reactive protein, fever and complete
inability to bear weight is more common with septic
arthritis. Blood cultures are positive in 30–40% of
cases. Culture taken from the affected joint positive for
pus defines the diagnosis and determines the bacterial
aetiology. As in osteomyelitis, Staphylococcus aureus is
the most common bacterial cause.
After surgical debridement of the joint, antibiotics are
required for 2–3 weeks. Long-term follow-up to assess
damage to the joint cartilage or bone is required.

F O C U S O N L E A R N I N G

1 Compare and contrast the routes of infection in
osteomyelitis.

2 Describe the pathophysiology of osteomyelitis.

3 Discuss the reasons for reduced mobility in septic arthritis.

Disorders of skeletal muscle
Muscle and associated soft-tissue damage through trauma
and overuse is an issue faced by many athletes and
sportspeople. Muscle weakness and fatigue are common
symptoms. In many cases, neural, traumatic and psychogenic
causes are the reason for the failure to generate force
(weakness) or maintain force (fatigue) seen in myopathies.
Muscular symptoms also arise from a variety of causes
unrelated to the muscle itself. Secondary muscular

phenomena (contracture, stress-related muscle tension,
immobility) are common disorders that influence muscular
function. The ability of the nervous system to modify or
control motor performance means that it has a large effect
on muscular function. In this section we restrict our
discussion to inherited and acquired disorders.

Contractures
Contractures can be physiological or pathological. A
physiological muscle contracture occurs even though there
is no action potential in the sarcolemma. Muscle shortening
occurs because of failure of the calcium pump in the
presence of plentiful ATP. A physiological contracture is
seen in McArdle’s disease and malignant hyperthermia.
The contracture is usually temporary if the underlying
pathology is reversed.

A pathological muscle contracture is a permanent muscle
shortening caused by muscle spasm or weakness. Heel cord
(Achilles tendon) contractures are examples of pathological
contractures. They are associated with plentiful ATP and
occur in spite of a normal action potential. The most
common form of contracture is seen in conditions such as
muscular dystrophy and central nervous system injury.

The restriction of joint movement as a result of scar
tissue formation in the flexor tissues of a joint is also known
as contracture. This type of contracture is most common
after a burn injury. An example could be contracture of
burned tissues in the palm of the hand leading to a flexion
contracture of the fingers.

Stress-induced muscle tension
Abnormally increased muscle tension has been associated
with chronic anxiety as well as a variety of stress-related

550 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

density is influenced by the load magnitude of the exercise
rather than the frequency. If reuse is not restored within
1 year, regeneration of muscle fibres becomes impaired.

Fibromyalgia
Fibromyalgia is a chronic musculoskeletal syndrome
characterised by diffuse pain, fatigue and tender points
(increased sensitivity to touch). The absence of systemic
or localised inflammation and the presence of fatigue
and disturbed sleep are common. However, fibromyalgia
has often been misdiagnosed or completely dismissed by
clinicians due to the similar clinical presentations to other
conditions (see the list below). A common misdiagnosis
has been chronic fatigue syndrome. Eighty to ninety per
cent of individuals affected are women and the peak age is
30–50 years. While the incidence is unknown, the prevalence
is reported to be 2% and increases with age.64 Although
more common than rheumatoid arthritis, its cause is still
unknown.

The aetiology of fibromyalgia has been debated for more
than a century. It is unlikely that it is caused by a single
factor. The most common precipitating factors include the
following:
• flu-like viral illness
• chronic fatigue syndrome
• human immunodeficiency virus (HIV) infection
• Lyme’s disease (a tick-transmitted bacterial infection)
• physical trauma
• persistent stress
• chronic sleep disturbance.

Certain rheumatic diseases, such as rheumatoid
arthritis or systemic lupus erythematosus, may coexist
with fibromyalgia.65

PAT H O P HYS I O LO G Y
It is unproven but has long been suspected that muscle is
the end organ responsible for the pain and fatigue. Some
studies have documented metabolic alterations — lower
ATP, lower adenosine diphosphate (ADP) and higher
concentrations of adenosine monophosphate — and more
alterations in the number of capillaries and fibre area in
individuals with fibromyalgia than in study control subjects.
Most studies have demonstrated that increased muscle
tenderness in fibromyalgia is a result of generalised pain
intolerance, possibly related to functional abnormalities
within the central nervous system (see Fig. 21.35).66

A chronic stress response may be involved in producing
lower levels of serotonin (a neurotransmitter). There is
increasing evidence that fibromyalgia involves the
sympathetic nervous system. Individuals with fibromyalgia
may have an adrenal hyporesponsiveness.

C L I N I C A L MA N I F E S TAT I O N S
The prominent symptom of fibromyalgia is diffuse, chronic
pain. The locations of 9 pairs of tender points for diagnostic
classification of fibromyalgia are shown in Fig. 21.36.
Tenderness in 11 of these 18 points is necessary for diagnosis,

muscular symptoms, including neck stiffness, back pain
and headache. Tension-type headaches have a very high
prevalence. There is no convincing description of the
pathophysiology of stress-induced muscle tension.

Various forms of treatment have been used to reduce
the muscle tension associated with stress. Biofeedback,
progressive relaxation training, yoga and meditation are
examples of stress-reduction therapies. Biofeedback uses
an integrated electromyogram to make recordings from
the skin surface. It is particularly useful in individuals who
have a connection between skeletal muscle tension and
pain. Progressive relaxation training emphasises the
individual’s ability to perceive the difference between tension
and relaxation. This technique involves sequential tensing
and a relaxing environment. The individual is taught to
practise this routine daily, often with the use of audio
instructions. By teaching the individual to recognise
excessive contraction of skeletal muscle, the idea is to
enhance the person’s ability to relax specific muscle groups
to relieve tension and thus reduce central nervous system
arousal, as well as autonomic nervous system arousal.

Disuse atrophy
The term disuse atrophy describes the reduction in normal
size of muscle fibres after prolonged inactivity from bed
rest, trauma (as a result of application of a cast), local nerve
damage or from chronic injuries or disease such as spinal
cord injury. It is an example of the body responding to lack
of use. Decreased muscle activity reduces muscle mass
through reduced protein production and increased
proteolysis (breakdown of protein), probably by reactive
oxygen radical regulation.63 The effects of lack of use can
become apparent rather quickly. With bed rest, the normal
individual loses muscle strength from baseline levels at a
rate of 3% per day. Immobilisation leads to a reduction in
strength as well as increasing fatigability. Oxidative capacity
of the mitochondria is decreased.

The connective tissues supporting muscle also undergo
change. Ligaments, tendons and articular cartilage require
use to maintain functionality. Alterations of structure and
function of connective tissues become apparent after 4 to
6 days and remain after normal activity resumes. Changes
to the structure of collagen fibres may underlie these changes.

Bed rest is also associated with cardiovascular, respiratory
and urinary system changes putting those individuals at
increased risk of complications such as infections, venous
thromboembolism and loss of strength. Having a cast in
place on a limb produces noticeable atrophy in a month.
Also, as people age, their muscles atrophy and become
weaker, a condition known as sarcopenia.

Inactivity also affects the integrity of bone. As the bone
experiences less stress the resorption of bone continues but
formation ceases. The effects of reduced stress on the skeletal
system are particularly apparent in astronauts spending
extensive time in zero gravity conditions.

Measures to prevent atrophy include frequent forceful
isometric muscle contractions (contractions without muscle
shortening) and passive lengthening exercises. Bone mineral

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 551

Low cervical
Anterior aspects
of the intertransverse
spaces at C5–C7

Second rib
Second
costochondral
junctions

Lateral
epicondyle
2 cm distal to
the epicondyles

Knee
Medial fat pad
proximal to the
joint line

Greater
trochanter
Posterior to
the trochanteric
prominence

Gluteal
Upper outer
quadrants
of buttocks

Supraspinatus
Above the
medial border
of the scapular
spine

Trapezius
Midpoint of the
upper border

Occiput
Suboccipital
muscle
insertions

FIGURE 21.36

The location of specific tender points for diagnostic classification of fibromyalgia.
Main sites include the cervical (neck) and trapezius (shoulder), as well as various other locations.

C
O
N
C
E
P
T M
A
P

Somatosensory
cortex

Hypothalamus
regulatory
change

Serotonin

Endorphins

Substance P
Skin hyperactivity

Muscle contraction, deconditioning Spinal cord

Pain
Fatigue
Depression

muscle microtrauma,
deconditioning, sleep disturbances

Precipitating factors:

Pre-existing factors:

together with

lead to

manifest by

serotonin receptors, endorphins

Ascending and descending pathways

Muscle nociception
further stimulating

feed information to

feed information to
Sympathetic outflow

Cutaneous nociception

FIGURE 21.35

A theoretical pathophysiological model of fibromyalgia.

552 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

Integrative conditions
related to the
musculoskeletal system
Lower back pain
Lower back pain is a common health issue and a considerable
problem for many individuals in Australia and New Zealand.
Approximately 80% of individuals will experience lower
back pain in their lifetime, but for 90% the pain will be
short lived. Back pain is the second most common symptom
reported at general practitioners. It has been estimated that
more than 3 million Australians67 and approximately 1
million New Zealanders68 have lower back pain. Furthermore,
it has been estimated that the cost of lower back pain in
Australia is more than $1 billion annually.69

Lower back pain affects the area between the lower rib
cage and gluteal muscles and often radiates into the thighs.
About 1% of individuals with acute lower back pain have
sciatica — pain along the distribution of a lumbar nerve
root. Sciatica is often accompanied by neurosensory and
motor deficits, such as tingling, numbness and weakness.
Men and women are equally affected, with women reporting
lower back symptoms more often after 60 years of age. In
addition, back pain is common in children, especially in
the adolescent years. The increase in back pain in children
has been associated with heavy, inappropriate schoolbags
and inappropriate posture when sitting.

PAT H O P HYS I O LO G Y
Most cases of lower back pain are idiopathic and no precise
diagnosis is possible. The local processes involved in lower
back pain range from tension caused by tumours or disc
prolapse, bursitis, synovitis, rising venous and tissue pressure
(found in degenerative joint disease), abnormal bone
pressures, problems with spinal mobility, inflammation
caused by infection (as in osteomyelitis), bony fractures or
ligamentous sprains to pain referred from viscera or the
posterior peritoneum. General processes resulting in lower
back pain include bone diseases such as osteoporosis or
osteomalacia.

Risk factors include occupations that require repetitious
lifting in the forward bent-and-twisted position; exposure
to vibrations caused by vehicles or industrial machinery;
obesity; and cigarette smoking. Osteoporosis increases the

along with a history of diffuse pain. The only reliable finding
on examination is the presence of multiple tender points.
The pain often begins in one location, especially the neck
and shoulders, but then becomes more generalised. People
describe the pain as burning or gnawing. Fatigue is profound.
The effect on everyday life is considerable. Fatigue is most
notable when arising from sleep and in mid-afternoon.
Headaches and memory loss are common complaints. There
is a strong association between fibromyalgia, Raynaud’s
phenomenon and irritable bowel syndrome. Individuals
with fibromyalgia are light sleepers and wake frequently.

Almost 25% of individuals seek psychological support
for depression. Anxiety, particularly in regard to their
diagnosis and future, is almost universal.

E VA LUAT I O N A N D T R E AT M E N T
As manifestations of chronic, generalised pain and fatigue
are present in many musculoskeletal (e.g. rheumatic)
disorders, these disorders should be discounted before
diagnosis of fibromyalgia. Treatment should be highly
individualised.65

No one regimen of medication has been proven to treat
fibromyalgia successfully. Certain central nervous system
active medications, most notably the tricyclic antidepressants,
amitriptyline and cyclobenzaprine, have performed
significantly better than placebos in controlled trials.65 These
medications administered 1–2 hours before bedtime provide
a better sleep. Amitriptyline significantly improves pain,
morning stiffness and sleep but not tender points.
Low-impact exercise in the amounts suggested for normal
health and fitness may also help. One of the most important
aspects of treatment is education and reassurance (see
Box 21.5).

• Stress that the illness is real, not imagined.
• Explain that fibromyalgia is presumably not caused by

infection.
• Explain that fibromyalgia is not a deforming or

deteriorating condition.
• Explain that fibromyalgia is neither life threatening nor

markedly debilitating, although it is an irritating presence.
• Discuss the role of sleep disturbances and the relationship

of neurohormones to pain, fatigue, abnormal sleep and
mood.

• Reassure that although the cause is unknown, some
information is known about the physiological changes
responsible for the symptoms.

• Use muscle ‘spasms’ and, perhaps, low muscle blood flow
to lay the groundwork for exercise recommendations.

• Assist the individual to use aerobic exercise to reduce
stress and increase rapid eye movement (REM) sleep.

BOX 21.5 Educating and providing reassurance
for individuals with fibromyalgia

F O C U S O N L E A R N I N G

1 Describe the causes and analyse the effects of contracture.

2 Analyse the treatment options for stress-induced muscle
tension.

3 Discuss cellular responses to increased and decreased
functional demand and how these responses relate to
disuse atrophy.

4 Describe the clinical manifestations of fibromyalgia.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 553

by rest. With scoliosis the pain is described as very severe
and often related to the degree of curvature. Patients with
Paget’s disease experience a pain that is usually described
as dull, but may be shooting and knife-like. Various other
conditions, such as multiple myeloma, pancreatitis and
sickle cell disease, can give rise to a bone pain that may be
debilitating. With multiple myeloma the pain is usually
precipitated by movement, while in pancreatitis bone pain
may be severe enough to require the use of narcotics.

In children, bone and joint pain is associated with a
wide variety of conditions such as rheumatic fever, systemic
lupus erythematosus, juvenile rheumatoid arthritis, bursitis,
osteomyelitis, osteosarcoma, acute leukaemia and some
viral conditions like measles, influenza and chickenpox.

Myasthenia gravis
Myasthenia gravis is a very rare autoimmune condition
that is outlined here because it illustrates the specificity of
the immune response and normal cellular function in the
region of the neuromuscular junction.

The disease process begins when the immune system
recognises the acetylcholine receptor of the neuromuscular
junction as an antigen. The B cells of the immune system
are stimulated and produce antibodies that specifically bind
to the receptor. This binding blocks the receptor and
stimulates a local inflammatory response. The muscle fibre
responds by withdrawing the affected receptors from the
sarcolemma and producing new ones that are displayed in
the neuromuscular junction. Cells bearing receptors for
neurotransmitters and hormones normally have a continual
process of recycling the receptors where old ones are
internalised and new ones are produced. In the case of the
muscle fibre, as soon as new receptors are displayed they
are bound by antibodies. This action highlights both the
specificity and the effectiveness of antibodies. The muscle
fibre eventually becomes exhausted and reduces its rate of
production of receptors.

Individuals with myasthenia gravis will suffer progressive
muscle weakness usually initially causing drooping of the
eyelids and later resulting in a generalised weakness.
Medication seeks to counteract the cause of the condition.
Acetylcholine esterase inhibitors (e.g. neostigmine) increase
the effectiveness of the released acetylcholine and prednisone
reduces the inflammatory response. Because this is an
autoimmune condition, the person faces medication for
the rest of their life.

risk of spinal compression fractures and may be why elderly
women report more symptoms than men. Genetic
predispositions for lower back pain have also been reported.

The most commonly encountered causes of lower back
pain include lumbar disc herniation, degenerative disc
disease, spondylosis and spinal stenosis. Anatomically, lower
back pain must come from innervated structures, but deep
pain is widely referred and varies. The nucleus pulposus
has no intrinsic innervation, but when extruded or herniated
through a prolapsed disc, it irritates the dural membranes
and causes pain referred to the segmental area. The
interspinous bursae can be a source of pain between L3,
L4, L5 and S1, but also may affect L1, L2 and L3 spinous
processes. The anterior and posterior longitudinal ligaments
of the spine and the interspinous and supraspinous ligaments
are abundantly supplied with pain receptors, as is the
ligamentum flavum. All of these ligaments are vulnerable
to traumatic tears (sprains) and fracture. Muscle injury
may contribute to lower back pain, with sprains and strains
the most common diagnoses.

E VA LUAT I O N A N D T R E AT M E N T
Diagnosis of lower back pain is based on physical
examination, electromyelography, CT scans with or without
myelography, MRI and nerve conduction studies. Most
individuals with acute lower back pain benefit from a
nonspecific short-term treatment of bed rest, analgesic
medications, exercises, physical therapy and education.
Surgical treatments, specifically discectomy and spinal
fusions, are used for individuals not responding to
conservative, nonsurgical management. Individuals with
chronic lower back pain are also prescribed anti-inflammatory
and muscle-relaxant medications and are instructed to follow
exercise programs. Aerobic exercises are a popular treatment
and seem to be more effective than traction or lower back
exercises. Spinal surgery has a limited role in curing chronic
lower back pain.

Bone pain
Pain is associated with trauma to the skeletal system.
Although no nociceptors (pain receptors) have been found
within the osteon, the periosteum and endosteum are richly
supplied. Pain may be experienced due to stimulation of
these receptors, the release of inflammatory chemicals (e.g.
bradykinin), the presence of any oedema or the spasm of
muscles. Bone pain is also associated with many metabolic
diseases.

The pain can be very severe, and in many conditions
attempts to manage the pain can dominate the treatment
of the condition. The pain of osteoarthritis becomes more
evident as the condition progresses. Early in the course of
the condition it is aggravated by use and relieved by rest,
but later it may become persistent and no longer relieved

F O C U S O N L E A R N I N G

1 Explain the cause of bone pain.

2 Analyse the treatment for myasthenia gravis.

554 PART 3 ALterAtIonS to proteCtIon AnD MoveMent
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Paediatrics and integrative conditions
Muscular dystrophy
The muscular dystrophies are a group of familial disorders
that cause degeneration of skeletal muscle fibres. Ongoing
genetic research has helped improve detection of carriers
and define not only the inheritance pattern but also the
DNA sequence of the various types. The most common
singular type, Duchenne’s muscular dystrophy, is discussed
here.

PATHOPHYSIOLOGY
Duchenne’s muscular dystrophy is a myopathy caused
by mutations in a gene located on the short arm of the
X chromosome. This mutation causes a protein thought
to be responsible for maintaining the cytoskeleton of the
muscle cell to be produced with an abnormal structure,
to be reduced or to be absent (see Fig. 21.37). The same
protein also occurs in the brain and about one-third of

A
B
C
D

FIGURE 21.37

Duchenne’s muscular dystrophy.
A Patient with late-stage Duchenne’s muscular dystrophy showing severe muscle loss. B Gower’s sign in a young boy with
Duchenne’s muscular dystrophy. C Transverse section of gastrocnemius muscle from a normal boy. D Transverse section of
gastrocnemius muscle from a boy with Duchenne’s muscular dystrophy. Normal muscle fibre is replaced with fat and connective
tissue.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 555

people with Duchenne’s muscular dystrophy show mental
retardation. As an X-linked inherited disorder, Duchenne’s
muscular dystrophy affects only boys, with any male
child of a known female carrier having a 50% risk of
showing the condition. The overall incidence is 1 : 3500
male births.
CLINICAL MANIFESTATIONS
Duchenne’s muscular dystrophy causes muscle bulk to
reduce through removal of muscle fibres. In the younger
child the fibres regenerate, but become nonfunctional
with time. Fibrous connective tissue and fat eventually
replace muscle fibres. Duchenne’s muscular dystrophy
is usually identified at about 3 years of age, with parents
noting slow motor development or regression of motor
tasks. Sitting, standing and walking become laboured
and the child is clumsy, falls frequently and has difficulty
climbing stairs.
Muscular weakness always begins in the pelvic girdle,
causing a waddling gait. Hypertrophy (enlargement)
of the calf muscles is apparent in 80% of cases. The
method of rising from the floor by ‘climbing up the
legs’ (Gowers’ sign) is characteristic and is caused by
weakness of the lumbar and gluteal muscles. The foot
assumes a talipes equinovarus position (rotated internally;
see Fig. 21.38) and the child tends to walk on the toes
because of weakness of the muscles in the front of the
lower leg (tibialis and peroneus). The deep tendon
reflexes are usually depressed or absent. Contractures
and wasting of the muscles lead to muscular atrophy
and deformity of the skeleton. Scoliosis can occur and
is relentlessly progressive; curves of more than 20° are
treated surgically to maintain pulmonary function and
to slow the progression to a wheelchair.
Children usually lose their ability to walk by age 8–10
years. Progressive osteopenia (low bone density), due

to inactivity, leads to pathological fractures. Studies cite
that bisphosphonates, such as those used in osteogenesis
imperfecta or osteoporosis, slow bone loss. Death, usually
from progressive pulmonary or cardiac weakness, ensues
by the 20s. Only 25% of individuals with Duchenne’s
muscular dystrophy reach the age of 21 years.
EVALUATION AND TREATMENT
Diagnosis is confirmed by measurement of the serum
enzyme, creatine kinase. Creatine kinase is increased to
more than 20 times the normal level because it is liberated
into the bloodstream with muscle death.
Although there is no effective cure for Duchenne’s
muscular dystrophy, maintaining function for as long
as possible is the primary goal. Activity helps maintain
muscle function, but strenuous exercise may hasten the
breakdown of muscle fibres. Both Muscular Dystrophy
Australia and the Muscular Dystrophy Association of New
Zealand note the possibility of treatment with steroids to
maintain muscle strength and function. This treatment
significantly lengthens the period of time a child can still
walk but does not alter the life span. Range-of-motion
exercises, bracing and surgical release of contracture
deformities are used to maintain normal function. Genetic
counselling is recommended. With X-linked inheritance,
male siblings of an affected child have a 50% chance of
being affected and female siblings have a 50% chance
of being carriers.
Because of its tragic course, prenatal screening for
Duchenne’s muscular dystrophy is encouraged. Possible
female carriers are urged to have serum creatine kinase
levels determined, which can be elevated in 60–80% of
those affected. Female carriers have an increased risk
of developing dilated cardiomyopathy (enlarged heart)
later in life.
Congenital defects
Clubfoot
Clubfoot, or congenital equinovarus, describes a
deformity in which the forefoot is adducted and supinated
(turned inwards and ‘face up’; see Table 21.4) and the
heel is in varus (turned inwards) and equines (points
down) (see Figs 21.38 and 21.39). Clubfoot deformity
can be positional (correctable passively), idiopathic or
teratological (as a result of another syndrome, such as
spina bifida). Idiopathic clubfoot usually occurs in 1 : 1000
live births, with males twice as likely as females to be
affected. Incidence of clubfoot shows ethnic variation;
for example, in the Polynesian Islands incidence is close
to 75 : 1000 live births.
EVALUATION AND TREATMENT
In idiopathic clubfoot, manipulation and casting above
the knee, as described by Ponseti, begun soon after birth
and correctly done, can correct the forefoot deformity
in more than 95% of cases. Hindfoot equinus often
requires lengthening of the Achilles tendon, which can

FIGURE 21.38

An infant with bilateral congenital talipes equinovarus.
This infant shows significant deformity in the feet, which
can potentially have good outcomes after corrective
measures.

Continued
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556 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

be performed in a clinic under local anaesthetic. Achilles
tenotomy (cutting the tendon) can be safely performed
with local anaesthetic until 8 or 9 months of age. After
this age, a formal lengthening and repair under general
anaesthesia is required. Bracing is required until age 3.
Idiopathic feet that are not correctable by these procedures

require surgical posteromedial release, which includes
lengthening of the Achilles, posterior tibialis and flexor
tendons, and surgical release of the capsules of the ankle,
subtalar and midfoot joints. Some sculpting of the bones
around the ankle (most often the talus and calcaneus)
is usually necessary to align the foot. Teratological feet
are usually stiffer and up to 90% require posteromedial
release. From 25% to 50% of children requiring
posteromedial release may need a second operative
procedure with growth; a large number of those with
teratological feet also may need a second procedure.
Developmental dysplasia of the hip
Developmental dysplasia of the hip describes imperfect
development of the hip joint and can affect the femoral
head or the acetabulum, or both. Although most often
present congenitally, dysplasia may develop later in the
newborn or infant period. Like clubfoot, developmental
dysplasia of the hip can be idiopathic or teratological.
Teratological hips (because of another cause such as
cerebral palsy or spina bifida) are more difficult to treat
and often need surgical intervention. In idiopathic
developmental dysplasia of the hip, 70% of cases involve
the left side only, 10–15% are bilateral and girls are four
times as likely to be affected. A positive family history,

TABLE 21.4 Terms used to describe foot
abnormalities

TERM DEFINITION

Position
Abduction Lateral deviation away from the

midline of the body

Adduction Lateral deviation towards the midline
of the body

Eversion Twisting of the foot outwards along its
long axis

Inversion Twisting of the foot inwards on its
long axis

Dorsiflexion Bending of the foot upwards and
backwards

Plantar flexion Bending of the foot downwards and
forwards

Abnormality
Talipes Congenital abnormality of the foot

(clubfoot)

Pes Acquired deformity of the foot

Varus Inversion and adduction of the heel
and forefoot

Valgus Eversion and abduction of the heel
and forefoot

Equinus Plantar flexion of the foot in which the
heel is lower than the toes

Calcaneus Dorsiflexion of the foot in which the
heel is lower than the toes

Planus Flattening of the medial longitudinal
arch of the foot (flatfoot)

Cavus Elevation of the medial longitudinal
arch of the foot (high arch)

Equinovarus Coexistent equinus and varus
deformities

Calcaneovarus Coexistent calcaneus and varus
deformities

Equinovalgus Coexistent equinus and valgus
deformities

Calcaneovalgus Coexistent calcaneus and valgus
deformities

Note: The positions listed can all be achieved by voluntary movement
of the normal foot; an abnormality exists if the foot is fixed in one or
more of the positions while at rest.

FIGURE 21.39

Idiopathic clubfoot.
Idiopathic clubfoot displaying forefoot adduction (towards
the midline of body), supination (upturning) and hindfoot
equinus (pointing downwards). Note the skin creases along
the arch and back of heel.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 557

breech presentation and oligohydramnios (low amniotic
fluid) all predispose children to developmental dysplasia
of the hip. Children in these groups are considered high
risk and must be carefully evaluated with physical
examination and, possibly, ultrasound.
Variants of idiopathic developmental dysplasia of the hip
are dislocated hip (no contact between the femoral head
and acetabulum), subluxated hip (partial contact only)
and acetabular dysplasia (the femoral head is located
properly but the acetabulum is shallow). Idiopathic
instability of the hip ranges from 3 : 1000 to 7 : 1000, but
a true dislocation is only 1 : 1000.
EVALUATION AND TREATMENT
Clinical examination is the mainstay of diagnosis. The
examination must be performed on a relaxed infant for
accuracy. A positive Ortolani’s sign (hip dislocated, but
reducible) or Barlow’s sign (hip reduced, but dislocatable)
is an absolute indication for treatment. Other indicators
for further evaluation are limitation of abduction or
apparent shortening of the femur (Galeazzi’s sign).
Asymmetric skin folds at the groin crease may also be
observed.
In children younger than 4 months old, bracing with a
Pavlik harness is successful in 90% of cases. A Barlow-
positive hip (hip reduced, but dislocatable) is easier to
treat with a Pavlik harness and success reaches 95–98%.
An Ortolani-positive hip (hip dislocated, but reducible)
must be followed closely with ultrasound and exam; the
success rate with Pavlik is 70% in this situation. If a
stable reduction is not attained within 2–3 weeks of
treatment, the Pavlik harness should be abandoned.
A partially reduced hip puts pressure on the rim of
the acetabulum by the femoral head and can worsen
dysplasia (abnormal cell proliferation and growth) and
make treatment more difficult. In older children or cases
where the Pavlik harness has failed, closed reduction of
the hip and spica (body) casting under general anaesthesia
is required. The spica cast is worn for 3 months. Children
older than 12 months require surgery on the joint, femur
or acetabulum, or all three (see Fig. 21.40). The incidence
of excellent outcome falls steadily with age, emphasising
the need for early diagnosis and treatment.
Non-accidental trauma
The incidence of non-accidental trauma is high. Over
225 000 children are suspected of being harmed or at

risk of harm from abuse and/or neglect in Australia yearly,
with comparable rates in New Zealand. Although evidence
for cases of abuse is often incomplete, cases of abuse of
over 40 000 children in both Australia and New Zealand
have been reported recently. The rate of child abuse in
both countries shows an increasing trend. Maltreatment
may be psychological, sexual or physical. Thirty per cent
of children who have been physically abused are seen
by an orthopaedist. Accurate and appropriate referrals
to child protection agencies are not only legally mandated
but also essential for the wellbeing of the child. An abused
child who is returned to the same situation without
intervention has a 10–15% chance of subsequent mortality.
Children who are not yet walking and present with a
long bone fracture have more than a 75% chance of that
fracture being caused by non-accidental trauma. ‘Corner’
metaphyseal fractures (where a small fragment shears off
the side of the metaphysis) are nearly always indicative
of abuse, but occur only 25% of the time. Fractures at
multiple stages of healing also suggest abuse; however,
osteogenesis imperfecta or other causes of systemic
osteomalacia must be ruled out. The most common
presentation is a transverse tibia fracture. After walking
age, only 2% of long bone fractures are the result of
non-accidental trauma.

FIGURE 21.40

Surgically treated bilateral hip dislocation.
Postoperative x-ray of 5-year-old child after femoral,
acetabular and joint surgery bilaterally. The plates will be
removed once the child heals. The extent of surgery
necessitated staged (i.e. one side at a time) intervention.

F O C U S O N L E A R N I N G

1 Outline the genetic basis of Duchenne’s muscular dystrophy.

2 Outline the treatment options for clubfoot.

3 Define 2 variations of developmental dysplasia of the hip
and discuss the treatment of each.

4 List 3 warning signs that might indicate non-accidental
trauma.

558 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

chapter SUMMARY

Musculoskeletal injuries
• The most serious musculoskeletal injury is a fracture. A

bone can be completely or incompletely fractured. A
closed fracture leaves the skin intact. An open fracture
has an overlying skin wound. The direction of the
fracture line can be linear, oblique, spiral or transverse.
Greenstick, torus and bowing fractures are examples of
incomplete fractures that occur in children. Stress
fractures occur in normal or abnormal bone that is
subjected to repeated stress. Fatigue fractures occur in
normal bone subjected to abnormal stress. Normal
weight-bearing can cause an insufficiency fracture in
abnormal bone.

• Dislocation is complete loss of contact between the
surfaces of two bones. Subluxation is partial loss of
contact between two bones. As a bone separates from a
joint, it may damage adjacent nerves, blood vessels,
ligaments, tendons and muscle.

• Tendon tears are called strains and ligament tears are
called sprains. A complete separation of a tendon or
ligament from its attachment is called an avulsion.

• Myoglobinuria (rhabdomyolysis) can be a serious life-
threatening complication of severe muscle trauma.

Disorders of bones and joints
• Metabolic bone diseases are characterised by abnormal

bone structure.
• In osteoporosis the density or mass of bone is reduced

because the bone-remodelling cycle is disrupted.
• Excessive and abnormal bone remodelling occurs in

Paget’s disease.
• Avascular diseases of the bone are collectively referred

to as osteochondroses and are caused by an insufficient
blood supply to growing bones.

• Legg-Calvé-Perthes disease is one of the most common
osteochondroses. This disorder is characterised by
epiphyseal necrosis or degeneration of the head of the
femur, followed by regeneration or recalcification.

• Osgood-Schlatter disease is characterised by tendonitis
of the anterior patellar tendon and inflammation or
partial separation of the tibial tubercle caused by chronic
irritation, usually as a result of overuse of the quadriceps
muscles. The condition is seen primarily in muscular,
athletic adolescent males.

• Scoliosis is a lateral curvature of the spinal column that
can be caused by congenital malformations of the spine,
poliomyelitis, skeletal dysplasias, spastic paralysis and
unequal leg length, but it is most often idiopathic.

• As a result of improved imaging technology,
inflammation has been identified as an important
feature of osteoarthritis.

• Rheumatoid arthritis is an inflammatory joint disease
characterised by inflammatory destruction of the
synovial membrane, articular cartilage, joint capsule, and
surrounding ligaments and tendons. Rheumatoid
nodules may also invade the skin, lung and spleen, and
involve small and large arteries. Rheumatoid arthritis is a
systemic disease that affects the heart, lungs, kidneys
and skin, as well as the joints.

• Juvenile rheumatoid arthritis is an inflammatory joint
disorder characterised by pain and swelling. Large joints
are most commonly affected.

• Ankylosing spondylitis is a chronic, inflammatory joint
disease characterised by stiffening and fusion of the
spine and sacroiliac joints. It is a systemic, immune
inflammatory disease.

• Gout is a syndrome caused by defects in uric acid
metabolism, with high levels of uric acid in the blood
and body fluids. Uric acid crystallises in the connective
tissue of a joint where it initiates inflammatory
destruction of the joint.

• Osteoarthritis is a common, age-related disorder of the
synovial joints. The primary defect is loss of articular
cartilage.

• Osteomyelitis is a bone infection most often caused by
bacteria. Bacteria can enter bone from outside the body
(exogenous osteomyelitis) or from infection sites within
the body (endogenous osteomyelitis).

• Septic arthritis is always a surgical emergency. The
bacteria present and the leucocytes fighting them act to
degrade the articular cartilage and the blood supply to
the nearby epiphyseal bone. The condition can lead to a
lifetime of disability.

Disorders of skeletal muscle
• A pathological contracture is permanent muscle

shortening caused by muscle spasticity, as seen in
central nervous system injury or severe muscle
weakness.

• Stress-induced muscle tension can be treated using
progressive relaxation training and biofeedback to
reduce muscle tension.

• Fibromyalgia is a chronic musculoskeletal syndrome
characterised by diffuse pain and tender points.
Unknown but suspected is that muscle is the end organ
responsible for the pain and fatigue. Most sufferers are
female and the peak age is 30–50 years.

• Atrophy of muscle fibres and overall diminished size
of the muscle are seen after prolonged inactivity.
Isometric contractions and passive lengthening exercises
decrease atrophy to some degree in immobilised
patients.

CHAPTER 21 ALterAtIonS oF MuSCuLoSkeLetAL FunCtIon ACroSS the LIFe SpAn 559

Integrative conditions related to the
musculoskeletal system
• Lower back pain is a common health problem in

Australia and New Zealand.
• Lower back pain affects the area between the lower rib

cage and gluteal muscles and often radiates into the
thighs.

• Lower back pain must come from innervated structures,
but deep pain is widely referred and varies.

• Bone pain is often associated with skeletal trauma and
metabolic diseases.

Paediatrics and integrative conditions
• The muscular dystrophies are a group of genetically

transmitted diseases characterised by progressive
atrophy of skeletal muscles. There is an insidious loss of
strength in all forms of the disorder with increasing
disability and deformity. The most common type is
Duchenne’s muscular dystrophy.

• Clubfoot is a common deformity in which the foot is
twisted out of its normal shape or position. Clubfoot can
be positional, idiopathic or teratological.

• Developmental dysplasia of the hip is an abnormality in
the development of the femoral head or acetabulum, or
both. Like clubfoot, it can be idiopathic or teratological.
It is a serious and disabling condition in children if not
diagnosed and treated.

• Non-accidental trauma must be considered with any
long bone injury in the preambulatory child.

• The presence of soft-tissue injury, corner fractures and
multiple fractures at different stages of healing is
extremely helpful for making a diagnosis of non-
accidental trauma.

• When non-accidental trauma is suspected, a child must
be evaluated radiographically for other fractures, heat
trauma and retinal haemorrhage.

• All social strata are at risk of non-accidental trauma and
healthcare providers are legally responsible to report
suspected cases of non-accidental trauma.

A D U L T
Michael is a 52-year-old self-employed bricklayer who
normally lives independently with his wife and three children
in rural South Australia. Michael has always been active and
played sport all his life; he was a keen runner and would
regularly take long runs in the evenings until 4 or 5 years ago.
He has been experiencing a gradual increase in pain in his
right knee over the past 2 years. The pain is diffuse around
the knee and seems to be worse after he leaves work at night.
He does not remember a specific injury or time when the
pain started. He takes paracetamol or medications containing
ibuprofen regularly but these are not so effective at managing
the pain lately. There are no episodes of his knee locking or
‘giving way’ but the pain has been getting worse which is
restricting his ability to walk and work normally so he has just
been to see his local doctor.

1 Identify the diagnostic studies that Michael should have
requested by his doctor.

2 Make a provisional diagnosis for Michael.
3 Identify what lifestyle factors may have played a role in

the development of this disease process.
4 What are the possible conservative treatment options for

Michael now?
5 What are the modifiable lifestyle factors that may assist

in reducing the severity of the symptoms and stop the
disease progressing?

6 Explain the potential surgical options for Michael in the
future.

CASE STUDY

560 PART 3 ALterAtIonS to proteCtIon AnD MoveMent

A G E I N G
Cveta is 65 years old and experienced menopause 15 years
ago. She remembers having her first period at the age of
16 years. Throughout her life she has maintained a slim
appearance, which may be due in part to her smoking, which
has been at the rate of a pack of cigarettes a day since her late
teens. Cveta spent the first 30 years of her life in Yugoslavia
before emigrating to Australia. Although she now has a good
diet, this was not always the case. When she lived in Yugoslavia
vegetables were plentiful, but dairy products were scarce. She
has not had a very active life, but she enjoys her life in Brisbane
as the climate allows her to be outside frequently. Lately, she
has felt the odd twinge of lower back pain and her 35-year-
old daughter has wondered whether her mother is a little
shorter than previously. This week Cveta experienced a visit

to the local Accident and Emergency Department after she
slipped and fell on a wet floor, fracturing her distal left radius.
Cveta has been referred back to her general practitioner for
a check-up as the magnitude of the trauma would not have
been expected to fracture a bone.
1 Outline the most important diagnostic study to request

for Cveta.
2 Explain the risk factors evident in Cveta’s life that would

justify requesting the study in Question 1.
3 Name the condition that Cveta most likely has.
4 Discuss the alterations that Cveta can make to her

lifestyle to minimise the effects of this condition.
5 Advise Cveta’s daughter to help her avoid the same

outcome as her mother.

CASE STUDY

1 Draw a flow diagram to summarise fracture repair.
2 Differentiate between a sprain and a strain.
3 Explain why myoglobinuria can be a dangerous

development after trauma to the muscular system.
4 Provide a strategy that could be communicated to a

middle-aged person about how to minimise sarcopenia.
5 Outline the risk factors for osteoporosis.
6 How does juvenile rheumatoid arthritis differ from the

adult form?

7 Describe how rheumatoid arthritis affects other organ
systems (skin, heart, lungs and kidneys).

8 Explain how uric acid (or urates) causes gout to develop.
9 Outline the risk factors for osteoarthritis.

10 Explain why people experience bone pain if there are no
pain receptors in the bone itself.

REVIEW QUESTIONS

21 Alterations of musculoskeletal function across the life span

Chapter outline
Key terms
Introduction
Musculoskeletal injuries
Skeletal trauma
Fractures
Classification of fractures
Pathophysiology
Clinical manifestations
Evaluation and treatment

Dislocation and subluxation
Pathophysiology
Clinical manifestations
Evaluation and treatment

Support structures
Sprains and strains of tendons and ligaments
Pathophysiology
Clinical manifestations
Evaluation and treatment
Tendonitis, epicondylitis and bursitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Muscle strains
Post-exercise muscle soreness
Myoglobinuria
Pathophysiology
Clinical manifestations
Evaluation and treatment

Disorders of bone and joints
Metabolic bone disease
Osteoporosis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Paget’s disease
Pathophysiology
Clinical manifestations
Evaluation and treatment

Disorders of joints
Inflammatory joint disease
Rheumatoid arthritis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Ankylosing spondylitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Gout
Pathophysiology
Clinical manifestations
Treatment
Osteoarthritis
Pathophysiology
Clinical manifestations
Evaluation and treatment

Infectious bone disease
Osteomyelitis
Pathophysiology
Clinical manifestations
Evaluation and treatment

Disorders of skeletal muscle
Contractures
Stress-induced muscle tension
Disuse atrophy
Fibromyalgia
Pathophysiology
Clinical manifestations
Evaluation and treatment

Integrative conditions related to the musculoskeletal system
Lower back pain
Pathophysiology
Evaluation and treatment
Bone pain
Myasthenia gravis
Review questions

ORIGINAL RESEARCH Clinical Medicine 2017 Vol 17, No 6: 150–8CME INFECTIOUS DISEASES Clinical Medicine 2018 Vol 18, No 2: 150–4

Authors: A academic clinical lecturer in microbiology and infectious
diseases, Oxford University Hospitals NHS Foundation Trust,

Oxford, UK ;

B
consultant microbiology and infectious diseases,

Nuffield Orthopaedic Centre, Oxford University Hospitals NHS

Foundation Trust, Oxford, UK

Authors: Julia Colston A and Bridget Atkins B

Bone and joint infections include septic arthritis, prosthetic
joint infections, osteomyelitis, spinal infections (discitis,
vertebral osteomyelitis and epidural abscess) and diabetic
foot osteomyelitis. All of these may present through the
acute medical take. This article discusses the pathogenesis of
infection and highlights the importance of taking a careful
history and fully examining the patient. It also emphasises the
importance of early surgical intervention in many cases. Con-
sideration of alternative diagnoses, appropriate imaging and
high-quality microbiological sampling is important to allow
appropriate and targeted antimicrobial therapy. This article
makes some suggestions as to empiric antibiotic choice; how-
ever, therapy should be guided by local antimicrobial policies
and infection specialists. Involvement of a multidisciplinary
team is essential for optimal outcomes .

Introduction

Bone and joint infections cause serious morbidity and pose

significant management challenges. They may cause acute

sepsis with bone and joint destruction, chronic pain, discharging

wounds and permanent disability. With expanding populations

and increasing age, bone and joint infections, especially those

involving devices, will have a growing impact on healthcare

resources. For effective management, well-coordinated

multidisciplinary working is important.

General considerations

Pathogens can gain access into bone and joints through the blood

stream (haematogenous route) or via direct inoculation from a

contiguous focus of infection. Acute haematogenous infections

are most common in children and the elderly.

The presence of foreign material such as implanted devices or

dead bone significantly reduces the number of organisms required

to cause infection.
1
Foreign or non-viable material also allows normal

skin commensals, such as coagulase-negative Staphylococcus spp,

to become significant pathogens. Micro-organisms adhere to the

inert surface where they are relatively protected from the blood

supply, immune processes and antibiotics. Organisms, such as

A
B

S
T

R
A

C
T

Bone and joint infection

Key points

In suspected bone and joint infections quality microbiological

sampling is important. In those with features of sepsis or acute

skin and soft tissue infection (SSTI), blood cultures and, where

possible, aspirates should be taken immediately followed by

prompt empiric antibiotic therapy. In other cases antibiotic

therapy should wait until intraoperative samples are taken. In all

acute bone and joint infections, orthopaedic surgeons, infection

specialists and radiologists should be involved early

Acute septic arthritis should be managed with diagnostic

aspiration followed by prompt arthroscopy or arthrotomy and

washout in conjunction with antibiotics. In some cases, where

surgery may not be possible, serial closed joint aspirations might

be an alternative option

Acute haematogenous osteomyelitis needs prompt surgical

drainage if there is a purulent collection. Other cases can be

managed by antibiotics alone but with repeat imaging if there is

failure to settle

Patients with possible spinal infection need blood cultures,

prompt MRI and spinal surgery review. In stable patients not

requiring surgical intervention, a radiological biopsy should be

considered to direct antimicrobial therapy. Tuberculosis, Brucella ,

Nocardia and/or fungal cultures should be requested in patients

with appropriate risk factors

In diabetic foot infections it is important to recognise severe

limb-threatening infections that require urgent surgical

management. Signs of this are systemic sepsis, poor glycemic

control, gas in soft tissues, abscess and infection from an ulcer

tracking deeply through the foot to another site (eg plantar ulcer

to dorsum of foot)

KEYWORDS: bone and joint infection, osteomyelitis, septic

arthritis, prosthetic joint infection, biofilm, diabetic foot infection,

discitis, vertebral osteomyelitis ■

Staphylococcus spp can produce extracellular polymeric substance

(EPS). Micro-organisms embedded in EPS create a biofilm on the inert

surfaces. By communicating with each other they are able to up and

downregulate gene expression enabling regulation of growth and

adaptation to the environment. Biofilm formation is an important

mechanism for bacterial survival in chronic bone and joint infection.
2

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Chronically established bone and joint infection can be persistent,

evolve or relapse, even in the face of prolonged antimicrobial

therapy. Biofilm has important implications for diagnostics, as well as

surgical and antibiotic management.

The ‘hot’ joint

An inflamed ‘hot’ joint has a wide differential including

inflammatory causes (septic arthritis, reactive, rheumatoid

arthritis, spondyloarthropathies, SLE, gout or pseudo-gout) and

non-inflammatory causes (degenerative joint diseases, trauma,

avascular necrosis and Charcot’s arthropathy).
3,4

Septic arthritis

is important to exclude, as delayed or inadequate treatment can

lead onto cartilage and then joint destruction.

Acute septic arthritis

Acute septic arthritis can affect any joint. It most commonly

affects the knee but may also involve wrists, ankles, hips and the

symphysis pubis. Polyarticular septic arthritis is more common

in patients with inflammatory joint disease or overwhelming

sepsis.
5
Injecting drug use is a risk factor for septic arthritis of the

sternoclavicular, sternomanubral or sacroiliac joints, often also

associated with endocarditis.
6

The presentation can be similar to other inflammatory causes, such

as crystal arthropathy, with an acutely painful, swollen, warm, red

joint and a reduced range of movement. Features suggesting septic

arthritis include fever and/or chills and absence of prior history or

risk factors for gout, but dual pathology can occur. Risk factors for

septic arthritis include extremes of age, bacteraemia, inflammatory

joint disease, diabetes, intravenous drug use, alcoholism,

immunosuppression, malignancy, recent trauma, intra-articular

injections, arthroscopy or a prosthetic joint. The clinical history should

include a sexual history (for gonococcal arthritis). A history of tick bite

in an endemic area may raise the possibility of Lyme arthritis.

Blood cultures may be positive in up to 50% of cases but are usually

negative in gonococcal septic arthritis.
7
Plain X-rays should be done

to exclude other causes of hot joint, but are usually normal in early

septic arthritis. Ultrasound is sensitive for detecting joint effusions

and synovitis. Synovial fluid should be aspirated and examined for

leucocytes, urate and pyrophosphate crystals and by Gram stain and

culture. A semiquantitative synovial leucocyte count can differentiate

inflammatory from non-inflammatory causes but cannot differentiate

infection from other inflammatory causes.
4
Gram stain has low

sensitivity (<75%) especially in gonococcal arthritis (<25%). 4 Cultures are also often negative in the latter and, if suspected, molecular

diagnostics (16S polymerase chain reaction) on synovial fluid may be

considered and a urethral swab or urine should be sent for culture /

nucleic acid amplification testing. Rectal and pharyngeal swabs may

be indicated. If Lyme arthritis is suspected diagnosis is by serology.

Diagnostic joint aspiration should be performed before antibiotics

are given, except when the patient is acutely septic and aspiration

delayed. Table 1 highlights the common bacterial causes and

example antibiotic choices. All cases of suspected acute septic

arthritis should be referred urgently to orthopaedics. Prompt

arthroscopic or open washout is generally recommended despite

the absence of good quality clinical trials. Observational studies

show that in patients where surgery may be high risk, a more

conservative approach of repeated aspirations may be effective.
8

There is no good evidence to guide duration of antibiotic therapy

for septic arthritis in adults. If synovial fluid Gram stain and cultures

Table 1. Suggested empiric antibiotics for native joint septic arthritis in adults (but consult local guidelines).
Modify, with microbiological advice, when culture results are available

Suggested empiric antibiotic choice (after blood cultures and joint aspirate)

Patient group Possible organisms No known drug
allergies

Penicillin allergy
(non-severe eg rash)

Penicillin allergy (severe eg
anaphylaxis)

No specific risk factors Staphylococcus spp, beta-

haemolytic streptococci

IV flucloxacillin IV anti-staphylococcal

cephalosporin (eg

cefuroxime)

Clindamycin

Frail, recurrent UTIs, end-

stage renal failure, recent

abdominal surgery?

Aerobic Gram-negative rods IV co-amoxiclav

IV 3rd generation

cephalosporin (eg

ceftriaxone)

Clindamycin plus

ciprofloxacin

MRSA risk Meticillin-resistant S aureus Add IV

glycopeptide

Add IV glycopeptide
a
Add IV glycopeptide

Suspected gonococcal

septic arthritis
18

Neisseria gonorrhoeae IV 3rd generation

cephalosporin (eg
ceftriaxone)
IV 3rd generation
cephalosporin (eg
ceftriaxone)

Clindamycin plus ciprofloxacin

(stop clindamycin if proven

Neisseria infection)

Intravenous drug usage S aureus . Less likely

Pseudomonas aeruginosa ,

Fungal

IV flucloxacillin IV anti-staphylococcal
cephalosporin (eg
cefuroxime)
Clindamycin

Known colonised with multidrug resistant organism

MRSA, ESBL, CPE etc Discuss with microbiology

Table adapted from
3,4

a
Glycopeptides include vancomycin and teicoplanin. These should be used at high doses in bone and joint infection ie vancomycin at 10–12 mg/kg and teicoplanin at

10 mg/kg. Modifications to dosing will need to be made in the setting of low body weight and/or impaired renal function.

b
Consult local infectious diseases / micro or genitourinary medicine physicians

ESBL = extended-spectrum beta-lactamases; CPE = carbapenemase-producing enterobacteriaceae; IV = intravenous; MRSA = Meticillin-resistant Staphylococcus aureus

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(taken before antibiotics) are negative, gonococcal arthritis is not

suspected and surgical findings are inconclusive then antibiotics

should be reviewed, and stopped if there is a likely alternative

diagnosis (eg crystal arthropathy). In proven septic arthritis, antibiotics

are typically given for 2–4 weeks. The longer (4-week) course may be

indicated with difficult organisms, such as Staphylococcus aureus or

Pseudomonas aeruginosa infections. Failure to settle or relapse may

mean a repeat washout is required; however, inflammatory changes

often persist for several weeks after presentation. There is no evidence

as to when antibiotics can be changed to the oral route. This would

depend on clinical progress, extent of infection, bioavailability of oral

agents and likely patient compliance. In likely gonococcal arthritis,

the patient should also be referred to a genitourinary clinic for a full

sexually transmitted infection screen.

Infections involving prosthetic joints (PJI) should always be

referred back to orthopaedics, who should also involve infection

specialists. Acute PJI occurs either postoperatively (up to 3 months

after the initial arthroplasty) or through haematogenous spread

after a period in which the prosthesis has been sound. For acute PJIs,

blood cultures, plain X-ray, ultrasound and aspiration of the joint

are the initial diagnostic modalities.
9
The prosthesis at this stage is

usually sound (not loose) and the most appropriate management

is a DAIR procedure (a radical open Debridement with exchange

of modular components but Retention of the Implant followed by

Antibiotics).
10

This needs to be done by an orthopaedic surgeon

experienced in managing PJIs. Joint aspiration / arthroscopic

washout may be required as an interim measure to drain pus if

the relevant expertise is not immediately available. More chronic

infections (usually presenting as increasing pain, loose prosthesis or

a discharging sinus) may be managed by revision of the prosthesis

in one or two stages or excision arthroplasty. When the prosthesis is

sound, a DAIR may be considered. Expert management of the soft

tissues and dead space is important and may require plastic surgery

input eg a muscle flap. When surgery is performed for chronically

infected prosthetic joints, this should be done off antibiotics and

multiple samples taken using separate instruments for separate

sites, for microbiology and histology. Postoperative antibiotics need

to be managed by infection specialists and may be prolonged.
11

Osteomyelitis

In children the most common site for acute haematogenous

osteomyelitis is the growing end of long bones. In adults, it is the spine.

The most common organism is S aureus but other pathogens such as

beta-haemolytic Streptococcus spp, Haemophilus influenzae , Kingella

kingae or Mycobacterium tuberculosis are possible. In patients with

sickle cell disease, osteomyelitis is commonly due to Salmonella spp.

Osteomyelitis in children may relapse decades later in adulthood.

Osteomyelitis may also occur in relation to infected fracture fixation

devices. Infection may then contribute to delayed or non-union of the

fracture. Figure 1 demonstrates the pathogenesis of osteomyelitis.

Acute osteomyelitis usually presents with fever and pain at the site

of infection. Other skeletal sites should be examined as multifocal

osteomyelitis can occur. Blood cultures and plain films should be

performed. The purpose of plain films is to look for other causes of

pain (eg fracture) and evidence of periosteal reaction or lucency. The

imaging modality of choice for osteomyelitis, however, is MRI, which

may show bone oedema, abscess formation, and periosteal reaction.

If infection is chronic there may also be evidence of a sinus, cloacae,

periostitis, sequestrum and/or involucrum (Fig 2 ). Occasionally,

Subperiosteal
abscess

Periosteum

(a) (b)

Seeding of
infec�on

Metaphyseal
vessels

Sequestrum

Sinus

Involucrum
Cloacae:
discharging
pus and bone

Fig 1. The pathogenesis of osteomyelitis. (a) Haematogenous bone
infection results in medullary pus formation, acute infl ammation, systemic

illness and often, secondary bacteraemia. Pus may then track into joints or

through the cortex. (b) In cases that progress to chronicity, a subperiosteal
abscess may form leading to periosteal stripping and devitalisation of bone.

Viable bone is resorbed leading to lucency. (c) Bacteria on the surface of dead
bone persist leading to chronic suppuration, tissue destruction, sinus formation

and often further bone death. Dead bone form sequestra. Involucrum is new

bone formation outside existing bone as a result of periosteal stripping and

then new bone growth from the periosteum. (d) This may be breached by
cloacae, through which pus and fragments of dead bone escape.

(a) (b)

Fig 2. X-ray (a) and MRI (b) of the left femur, showing an area of
osteomyelitis, with a central sequestrum (dead bone) and involucrum
(new bone formation) around this – marked with white arrows. Chronic
disease is noted through the shaft of the femur, as well as visible overlying

soft tissue deformity.

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pathological fractures occur. If there are soft tissue collections, prompt

aspiration for microbiology is appropriate. In acute osteomyelitis,

many patients will respond to antibiotic treatment but those with

evidence of pus on imaging require urgent surgical drainage /

decompression. When osteomyelitis is chronic and/or related to a

fracture fixation device it needs management by a multidisciplinary

team experienced in the management of bone infections. Ideal

management is with a combination of surgical resection with

meticulous intraoperative sampling with/without stabilisation, with/

without reconstruction, soft tissue management by plastic surgeons

and appropriately managed postoperative antibiotics.

Spinal infections (vertebral osteomyelitis, discitis,
epidural abscess)

Spinal infections are most commonly either haematogenous or

postsurgical. Haematogenous infections are most commonly due

to S aureus . Streptococcus spp, aerobic Gram-negative bacilli and

M tuberculosis should also be considered as should Brucella spp

in endemic areas and fungi in immunocompromised patients.
12

All patients with known fever and weight loss and/or bacteraemia

and/or endocarditis should have prompt spinal imaging if they

have new or worsening back pain. Imaging, usually by MRI (or

computed tomography if MRI is contraindicated), should look

for evidence of epidural abscess, discitis, vertebral osteomyelitis

and, critically, for evidence of cord / cauda equina compression

or vertebral instability requiring urgent surgical intervention.
13

Epidural collections usually require surgical drainage.
14

Unless

blood cultures have already revealed a causative organism, deep

microbiological samples should be obtained. This can be with

intraoperative samples if surgery is indicated, or by radiological

biopsy in other cases. This should be done urgently and, where

possible, antibiotics withheld until after the biopsy has been

taken (antibiotic therapy should not be delayed however in septic/

unstable patients). Cases should be discussed with microbiology to

ensure the relevant tests are done in the laboratory.

Native vertebral osteomyelitis should be managed with 6 weeks

of appropriately targeted therapy (possibly longer in complicated

cases or where organisms such as Brucella spp are identified).
15

Duration of therapy for epidural abscesses depends upon whether

it was surgical drained and clinical/radiological response.

Diabetic foot osteomyelitis

Diabetic foot infections usually occur following skin ulceration

in patients with neuropathy and/or vascular insufficiency.
16

Infections can go on to cause adjacent osteomyelitis. In severe

infections this can rapidly become limb and life threatening. It is

essential for all patients, especially diabetics, presenting though

acute medical services to have a full foot examination including

Table 2. Diabetic foot infections: pathogens and suggested empiric antimicrobial therapy (but consult local
guidelines)

Severity a Usual pathogens Treatment

No known drug allergy Penicillin allergy (non-
severe eg rash)

Penicillin allergy
(severe eg anaphylaxis)

Uninfected

Mild (usually treated

with oral

agents)

Meticillin-sensitive

Staphylococcus aureus

(MSSA); Streptococcus spp

Flucloxacillin or

co-amoxiclav

Doxycycline, clindamycin or trimethoprim/

sulfamethoxazole

Meticillin-resistant S

aureus (MRSA)

A glycopeptide A

glycopeptide

Moderate (may be

treated with oral or

initial parenteral agents)

MSSA; Streptococcus

spp; Enterobacteriaceae;

anaerobes

Co-amoxiclav 3rd generation cephalosporin

eg ceftriaxone plus

metronidazole

Clindamycin and

ciprofloxacin

Risk of Pseudomonas

aeruginosa

Anti-pseudomonal beta-

lactam eg piperacillin-

tazobactam or ceftazidime

plus metronidazole

Anti-pseudomonal beta-

lactam eg ceftazidime plus

metronidazole

MRSA If high risk of MRSA, add a

glycopeptide

Severe (usually treated

with parenteral

agents)

MRSA; Enterobacteriacae;

Pseudomonas ; anaerobes

Antipseudomonal beta-lactam eg ceftazidime and

metronidazole

If high risk of MRSA, add a glycopeptide

Clindamycin and
ciprofloxacin

a
Severity based on the Infectious Diseases Society of America severity score

16
as follows:

Uninfected : No symptoms or signs of infection present (symptoms/signs defined as at least two of local swelling or induration, erythema, local tenderness or pain,
local warmth, purulent discharge)

Mild : Local infection involving only the skin and subcutaneous tissue. If erythema, must be >0.5–≤2 cm around the ulcer. Exclude other causes of inflammatory
response of the skin

Moderate : Local infection (as above) with erythema >2 cm, or involving structures deeper than skin and subcutaneous tissue, and no systemic inflammatory
response signs

Severe : Local infection with signs of systemic inflammatory response with two or more of temperature >38°C or <36°C, heart rate >90 beats/min, respiratory rate
>20 breaths/min or PaCO2 <32 mmHg, white blood cell count >12,000 or <4000 cells/μL or ≥10% immature (band) forms

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the removal of dressings. An audit (England and Wales) in 2015

showed that two-thirds of diabetic inpatients did not have a

specific diabetic foot risk examination while an inpatient.
17

Urgent surgical intervention may be required in those

patients with abscesses, necrotising soft tissue infections and/

or uncontrolled sepsis. Clinical evidence of pus tracking from

one area (eg ulcer) to another may be indicative of deep

spreading infection. Less urgent surgery may be required for

those with substantial non-viable tissue or extensive bone or joint

involvement. An early vascular assessment and involvement of

a vascular surgeon to consider revascularisation in appropriate

cases, especially those with critical ischaemia, is essential.

Table 2 gives a guide to empiric antibiotic management based

upon the severity of disease. Tissue sampling can be helpful for

antimicrobial management. Superficial swabs often represent

colonisation only, whereas deep tissue curettings / bone sampling

can allow for appropriately targeted treatment.

Conclusions

Bone and joint infections can present through the acute medical

take. It is important to take a careful history and remove any

dressings during initial assessment and to recognise when

urgent surgical intervention is required. Microbiological sampling

should be done in all cases, to allow for targeted antimicrobial

management. Comorbidities must be adequately managed.

Involvement of the multidisciplinary team is essential. ■

References

1 Elek SD , Conen PE . The virulence of Staphylococcus pyogenes for

man. A study of the problems of wound infection . Br J Exp Pathol

1957 ; 38 : 573 – 86 .

2 Flemming HC , Wingender J , Szewzyk U et al . Biofilms: an emergent

form of bacterial life . Nat Rev Microbiol 2006 ; 14 : 563 – 75 .

3 Coakley G , Mathews C , Field M et al . BSR & BHPR, BOA, RCGP and

BSAC guidelines for management of the hot swollen joint in adults .

Rheumatology (Oxford) 2006 ; 45 : 1039 – 41 .

4 Atkins BL , Bowler IC . The diagnosis of large joint sepsis . J Hosp

Infect 1998 ; 40 : 263 – 74 .

5 Dubost JJ , Fis I , Denis P et al . Polyarticular septic arthritis . Medicine

(Baltimore) 1993 ; 72 : 296 – 310 .

6 Kak V , Chandrasekar PH . Bone and joint infections in injection drug

users . Infect Dis Clin North Am 2002 ; 16 : 681 – 95 .

7 Rice PA . Gonococcal arthritis (disseminated gonococcal infection) .

Infect Dis Clin North Am 2005 ; 19 : 853 – 61 .

8 Ravindran V , Logan I , Bourke BE . Medical vs surgical treatment for

the native joint in septic arthritis: a 6-year, single UK academic

centre experience . Rheumatology (Oxford) 2009 ; 48 : 1320 – 2 .

9 Osmon DR , Berbari EF , Berendt AR et al . Diagnosis and

management of prosthetic joint infection: clinical practice guide-

lines by the Infectious Diseases Society of America . Clin Infect Dis

2013 ; 56 : e1 – e25 .

10 Grammatopoulos G , Kendrick B , McNally M et al . Outcome

following Debridement, Antibiotics and Implant Retention (DAIR)

in hip peri-prosthetic joint infection – An 18-year experience .

J Arthroplasty 2017 ; 32 : 2248 – 55 .

11 Moran E , Byren I , Atkins BL . The diagnosis and management of

prosthetic joint infections . J Antimicrob Chemother 2010 ; 65 : 45 – 54 .

12 Cornett CA , Vincent SA , Crow J , Hewlett A . Bacterial spine infec-

tions in adults: evaluation and management . J Am Acad Orthop

Surg 2016 ; 24 : 11 – 8 .

13 Nickerson EK , Sinha R . Vertebral osteomyelitis in adults: an update .

Br Med Bull 2016 ; 117 : 121 – 38 .

14 Suppiah S , Meng Y , Fehlings MG et al . How best to manage

the spinal epidural abscess? A current systematic review . World

Neurosurg 2016 ; 93 : 20 – 8 .

15 Berbari EF , Kanj SS , Kowalski TJ et al . 2015 Infectious Diseases

Society of America (IDSA) clinical practice guidelines for the

diagnosis and treatment of native vertebral osteomyelitis in adults .

Clin Infect Dis 2015 ; 61 : e26 – e46 .

16 Lipsky BA , Berendt AR , Cornia PB et al . 2012 Infectious Diseases

Society of America clinical practice guideline for the diagnosis

and treatment of diabetic foot infections . Clin Infect Dis

2012 ; 54 : e132 – 73 .

17 Health and Social Care Information Centre . National Diabetes

Inpatient Audit (NaDIA) – 2015 . London : NHS Digital , 2016 .

http://digital.nhs.uk/catalogue/PUB20206 [ Accessed 12 June 2017 ].

18 Bignell C , FitzGerald M . UK national guideline for the management

of gonorrhoea in adults, 2011 . Int J STD AIDS 2011 ; 22 : 541 – 7 .

Address for correspondence: Dr Bridget Atkins, Bone Infection
Unit, Nuffield Orthopaedic Centre, Oxford University
Hospitals NHS Foundation Trust, Windmill Road, Headington,
Oxford OX3 7LD, UK.
Email: Bridget.Atkins@ouh.nhs.uk

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Reproduced with permission of copyright owner. Further reproduction prohibited
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137

C h a p t e r o u t l i n e

C H A P T E RC H A P TT E R

Introduction, 138

The definition of pain, 138

Types of pain, 139

Nociceptive pain, 139

Neuropathic pain, 140

Psychogenic pain, 140

Pain terminology, 140

The physiology of pain, 141

Nociceptors, 142

Spinothalamic tract neurons, 144

Thalamocortical neurons, 144

Cortical representation of pain, 144

Neuromodulation of pain, 146

Clinical manifestations of pain, 146

Evaluation and treatment, 146

Pathophysiology of pain, 148

Peripheral neuropathic pain, 148

Paediatrics and pain, 149

Central pain syndromes, 151

Ageing and pain, 151

Pain
Mark Plenderleith

K e y t e r m s
acute pain, 140
affective-motivational aspect, 138
allodynia, 141
analgesia, 139
anterior cingulate cortex, 144
beta-endorphin, 145
burning pain, 143
central pain syndromes, 151
central sensitisation, 151
chronic pain, 140
complex regional pain syndrome

(CRPSs), 150
endorphins, 145
encephalin, 145
fast-sharp pain, 143
high-threshold mechanoreceptors,

143
hyperalgesia, 141
interoceptive cortex, 144
mononeuropathy, 148
neuromodulators, 146
neuropathic pain, 140
nociceptive pain, 139
nociceptors, 142
opioid receptors, 145
pain threshold, 146
pain tolerance, 146
painful diabetic neuropathy, 150
peripheral neuropathic pain, 148
polyneuropathy, 150
polymodal nociceptors, 143
postherpetic neuralgia, 150
psychogenic pain, 140
referred pain, 140
sensory-discriminative aspect, 138
sharp pain, 143
slow-burning pain, 143
spinothalamic tract, 144
thalamocortical neurons, 144

7
C H A P T E R

138 PART 2 ALTERATIONS TO REGULATION AND CONTROL

Introduction
Of all the sensations that arise from the human body, pain
is one of the most clinically important. It is the sensation
of pain that often motivates people to seek medical help as
a result of a traumatic injury or a progressive disease,1 and
it is often a consequence of surgical interventions used to
treat injuries or disease. Pain is also clinically important as
it encourages patients to adopt behaviours that enhance
healing (such as limb immobilisation following a fracture).

Pain also has a very important physiological role, as it
acts as the conditioning stimulus that teaches us to avoid
environmental stimuli that cause harm. As children, we
learn not to touch sharp objects because it hurts, and
even as adults this sensation helps us to adapt to new or
unusual environments. For example, as a postgraduate
student in England I remember staring in disbelief as a
visiting scientist from Australia (wearing only shorts)
walked into a bush of head-high stinging nettles to retrieve
a Frisbee. Never having been exposed to the leaves of this
particular plant, he had no idea of the effect that they have
on exposed skin — until he emerged screaming in agony
from the bushes that many of us had learned as children
cause intense pain.

In this chapter we consider the physiological basis of
pain and then explore some of the clinical consequences of
this very important sensation.

The definition of

pain

Pain is a complex and highly subjective sensation that is
affected by a large number of variables and consequently
can be difficult to describe. In 1979 the International
Association for the Society of Pain (IASP) defined pain
is ‘an unpleasant sensory and emotional experience
associated with actual or potential tissue damage or
described in terms of such damage’.2 Although this
definition is a little cryptic it does highlight some of the key
concepts related to pain. So to help you understand some
of the most important elements of this complex sensation,
let us have a closer look at this definition.

The first thing that the IASP definition reminds us
of is that pain is unpleasant. Whether the pain is caused
by touching something hot or is the result of a surgical
procedure or the growth of a tumour, the experience is
likely to be a negative one. Although the intensity of the
experience may vary from individual to individual and
has been shown to be influenced by sex, race, age, culture,
beliefs, previous experience, fear and anxiety,3–5 pain is
invariably unpleasant and therefore is something we avoid
or try to minimise.

The second concept that emerges from the definition
is that pain is a sensory experience. In some respects pain
is no different from other senses such as hearing, taste or
vision. Just as we can look up into the sky at night and
define the position of a star, describe how bright it is and
even attribute to it a colour, so we can identify the site
and intensity of a painful stimulus applied to our bodies.

Humans are, in general, very good at identifying the site
of an injury that causes pain and can readily distinguish
between stimuli of different intensities and indeed
modalities. A pin prick applied to the anterior surface of
the arm is thus easily distinguishable from a drop of acid
applied to the wrist, not just by location but by the sharp
quality of the former and the burning sensation produced
by the latter. Indeed, psychophysical experiments using
carefully controlled thermal stimuli have shown that
humans can distinguish between two high-intensity
thermal stimuli that differ by as little as 0.1°C.6 This ability
to locate a painful stimulus and describe both its intensity
and its quality is referred to as the sensory-discriminative
aspect of pain.

The definition then goes on to point out that pain is much
more than a sensation — it is also an emotional experience.
Because it is unpleasant (i.e. it is a negative experience)
it also elicits an emotional response in that it produces
changes in both mental (affective) state and behaviour
(motivation). Individuals exposed to a painful stimulus
become anxious, tense, distressed or scared and, if the pain
is ongoing, they may become depressed, develop a feeling of
hopelessness and, ultimately, may even consider suicide. In
addition, individuals are motivated to remove themselves
from the source of the pain, avoid similar environments in
the future and/or adopt behaviours that enhance healing.
The degree to which these responses manifest themselves
depends on a number of factors, including the intensity of
the pain, its duration, the individual’s past experience and
the availability of treatment. However, it is the emotional
aspect of pain that predominates in severe and/or ongoing
pain. The changes in mental state and behaviour that are
part of the emotional component of pain are collectively
referred to as the affective-motivational aspect of pain.

The next part of the definition states that pain is
caused by ‘actual or potential tissue damage’. This serves to
remind us of two very important components about pain.
The first is that it is normally produced by stimuli that
are sufficiently intense to cause peripheral tissue damage
(i.e. damage to peripheral tissues such as skin, muscle or
visceral organs). So cutting the skin, impaired blood flow
to the heart or damage to the wall of the digestive tract all
cause pain because they result in ‘actual’ tissue damage. In
other words the stimulus is of sufficiently high intensity
for the integrity of the tissue to be compromised and we
become aware of this because it results in pain. The second
point that is implied by this part of the definition is that
pain can also result from stimuli that have the ‘potential’
to cause tissue damage. Therefore, touching something
hot or stepping on a sharp object may cause pain, but little
or no tissue damage, because the rapid withdrawal reflex
removes your limb from the pain source (see Chapter 6).
This is possible because the threshold for pain in some
tissues is lower than the threshold for tissue damage, so
behavioural modifications allow us to remove ourselves
from the source of the stimulus or adopt behaviours
that minimise tissue damage. Therefore, one important
function of pain is to advise us of the presence of stimuli

ch07-137-154-9780729541602.indd 138 18/09/14 9:26 AM

CHAPTER 7 PAIN 139

that could cause us harm and thereby provide us with
the opportunity to prevent it happening (or reduce its
impact).

The last part of the definition is probably the most
cryptic as it is not immediately obvious what is meant
by the phrase ‘or described in terms of such damage’. We
know that pain is usually caused by stimuli that cause
tissue damage (or have the potential to), but this part
of the definition implies that you can experience pain
that feels like it is caused by tissue damage without there
being any peripheral tissue damage. Although this sounds
counterintuitive, this is exactly the point. People can
experience pain in parts of their body that do not exhibit
any sign of disease or trauma. For example, a patient may
complain of a severe burning pain in their left foot without
the limb having been exposed to a heat source or showing
any signs of peripheral tissue damage. The pain feels like it
was caused by a burn injury, but there is no evidence of any
peripheral tissue damage. In the absence of any physical
evidence, in the past individuals experiencing this type of
pain were sometimes considered hysterical or delusional
and the pain was attributed to a psychological disorder. We
now know that most such types of pain are the result of
damage to the parts of the peripheral and central nervous
systems responsible for sensations that arise from the
affected tissue. Thus, although there is no peripheral tissue
damage, the pain feels like it is caused by such damage.

One of the factors that can contribute to the variable
nature of the pain experienced is that the pain can be
modified. In other words, the intensity of the sensation
can be affected by behaviour, cognitive factors and
clinical intervention. For example, in response to minor
burns or cuts many people immediately rub the site of
the injury. We do this because we have learned that this
reduces the intensity of the pain (i.e. produces analgesia).
Furthermore, soldiers in combat situations may suffer quite
severe injuries but experience comparatively little pain
because of the stress associated with the life-threatening

situation. This type of pain modification is not limited to
the battlefield, as anyone who has watched any Australian
or New Zealand football code can attest. Analgesia can
occur in trance-like states associated with certain religious
and cultural rituals, and in the clinical environment
analgesia can be produced by pharmacological agents,
such as opioids, but also through other avenues, such as
transcutaneous electrical nerve stimulation, acupuncture
and cognitive behaviour modification.

Collectively, pain can be considered a negative multi-
dimensional experience that is typically associated with
peripheral tissue damage but in some pathological circ-
um stances may exist in the absence of tissue damage. As
a subjective experience, pain is highly labile and may be
modified by cultural, situational and psychological as well
as clinical interventions.

Just how important pain is to the wellbeing of
humans is perhaps best illustrated by considering the
rather serious consequences of being unable to feel pain.
Individuals born with a congenital insensitivity to pain
suffer horrendous injuries because they are unaware of the
damage they are doing to their bodies when, for example,
they sit too close to a fire or bite into their tongue while
eating (see Figure 7-1).7,8 They do not make the regular
adjustments to their posture necessary to avoid damaging
joints and can be completely oblivious to internal damage
caused by disease. Not surprisingly, these types of injuries
often become infected, are slow to heal and can be life-
threatening.

Types of pain
Most common types of pain fall into one of three categories
that vary in terms of their aetiology (or cause), duration
and ease of treatment.

Nociceptive pain
Nociceptive pain is the most common type of pain
and its defining characteristic is that it is produced by

A B

FIGURE 7-1

Congenital insensitivity to pain.
Photographs illustrating tissue damage in a 9-month-old boy with congenital insensitivity to pain. A Damage to the left thumb and index

finger caused by biting. B Severe mutilation of the tongue.

ch07-137-154-9780729541602.indd 139 18/09/14 9:26 AM

140 PART 2 ALTERATIONS TO REGULATION AND CONTROL

nociceptive stimuli, which cause or have the potential to
cause peripheral tissue damage. Nociceptive pain can be
subdivided into two subtypes:
• External damage. Pain due to external damage is the

most common form of nociceptive pain and you are
likely to have experienced it. As the name implies, this
type of pain usually involves trauma to the skin but
may extend to the underlying tissues. It is relatively
mild and has a comparatively short time course,
lasting a few seconds to a few days. Treatment of this
type of pain usually involves simple interventions
that assist the healing process of the affected tissues.
Moreover, pain relief is relatively easy to achieve
through the use of milder forms of analgesics, such as
non-steroidal anti-inflammatory drugs (NSAIDs).

• Internal damage. Pain due to internal damage is less
common and usually more severe than that associated
with external damage. It has numerous causes. One
of the principal causes is severe trauma, for instance
due to bone fractures, surgery or childbirth. This
type of pain is also associated with disease. In fact,
pain is a symptom of virtually every disease (e.g.
cancer, arthritis) at some point during the disease
progression. The duration is usually quite a bit longer
than that following external injury and typically is in
the order of a few days to weeks. Treatment involves
removing the cause of the tissue damage, but interim
management of pain can be achieved with more
powerful opioid analgesics.

Neuropathic pain
As the term implies, neuropathic pain is caused by injury
or disease of the nervous system rather than a peripheral
tissue.9 Fortunately, this type of pain is less common than
nociceptive pain. Neuropathic pain is usually more severe
and has a time course that can last from a few months
to many years — and sometimes the rest of a person’s
life. Because of the complex aetiology and the lack of
knowledge of the underlying mechanisms, treatment is
challenging. In some cases pharmacological interventions,
particularly when used in combination, produce positive
outcomes for patients. However, for others, pain relief is
less satisfactory and specialised ongoing therapies are
required in an effort to alleviate the effects of neuropathic
pain. Forms of neuropathic pain are dealt with in more
detail later in this chapter.

Psychogenic pain
It is well recognised that some people report pain that may
be severe and persistent but for which there appears to be
no underlying pathology. The pain experienced by these
patients (typically headaches, abdominal pain, back pain)
is indistinguishable from that experienced by people with
identifiable injuries or disease. Such pain can be debilitating
and consequently interferes with their ability to function
normally. In the absence of any physical explanation for
the symptoms, despite exhaustive clinical examination and
testing, the assumption is made that the pain is the result

of a psychological disorder, so it is termed psychogenic
pain. It is very likely that some pain of neuropathic origin
was at one time incorrectly diagnosed as psychogenic pain
due to similarities in symptoms and the absence of any
visible cause. However, due to improvements in diagnosis
and more sophisticated medical imaging, diagnosis of
psychogenic pain is less common.10

FOCUS ON LEARNING

1 Describe what is meant by the sensory-discriminative
aspect of pain.

2 Describe what is meant by the affective-motivational
aspect of pain.

3 Differentiate between nociceptive, neuropathic and
psychogenic pain.

4 Describe some of the ways in which pain can facilitate
the healing process.

Pain terminology
Whereas some types of pain have a relatively short time
course, others last a very long time indeed. In order to
discriminate between these types of pain, the terms acute
pain and chronic pain are used. Acute pain refers to any
pain that lasts less than 3 months. In contrast, chronic
pain is any pain that lasts longer than 3 months. The
timelines outlined in the previous section suggest that
most neuropathic pain is chronic pain, and although
this is often the case, the two terms should not be used
interchangeably. The terms acute and chronic refer
exclusively to the time course of the pain, irrespective of
aetiology. For instance, neuropathic pain that resolves
within 3 months is considered acute, while cancer-related
nociceptive pain that persists for more than 3 months is
chronic. Approximately one-fifth of Australians suffer
from chronic pain11 and are about five times more likely to
use healthcare services than those without chronic pain.12
Therefore, patients with chronic pain are a concern in the
healthcare industry and you are likely to encounter them
in all areas of the health sector.

Another important aspect of pain is the location of the
pain. Typically, neuropathic pain feels like it is coming
from the part of the body that the affected nerve innervates.
For example, a compression injury of branches of the
sciatic nerve (shown in Figure 6-15) caused by damage
to a vertebral disc can result in pain in the leg or foot.
Interestingly, this disconnection between injury site and
pain location is not restricted to neuropathic pain, but also
occurs in some forms of nociceptive pain. For example, the
first symptom of appendicitis is usually tenderness in the
midline abdominal region, despite the inflamed appendix
being located in the right lower quadrant (see Chapter 27).
Similarly, one of the classical signs of myocardial infarction
(see Chapter 23) is a shooting pain referred to the left
shoulder or arm, when the tissue damage is actually
occurring in the heart (see Figure 7-2). We refer to this
type of pain as referred pain.

ch07-137-154-9780729541602.indd 140 18/09/14 9:26 AM

CHAPTER 7 PAIN 141

Following injury the affected tissue becomes very sensitive
to subsequent stimuli. Thus, we tend to protect a bruised heel
or burnt hand because any additional stimulation greatly
enhances the pain. The increased sensitivity that follows
peripheral tissue damage can be attributed to two factors:
there can be an amplified neural response to any subsequent
painful stimulus and/or a decrease in the threshold such
that previously non-painful stimuli now cause pain. To
accommodate these two different characteristics we use
the term hyperalgesia to describe the situation where the
original tissue damage augments the pain produced by
subsequent high-intensity (damaging) stimuli. The term
allodynia refers to a reduction in the threshold such that pain
is now produced by low-intensity (non-damaging) stimuli.
(See Box 7-1 for key pain terminology.) These changes in
sensitivity occur in nociceptive pain and many forms of
neuropathic pain. For example, individuals with trigeminal
neuralgia (an alteration to cranial nerve V causing episodes
of excruciating pain to the face) rarely wear high collars or
scarves because of mechanical allodynia, where even the
gentle touch of such clothing can elicit excruciating pain
referred to the face.13

The physiology of pain
Since pain is the conscious perception of a stimulus that
causes tissue damage, this means that the presence of
the stimulus has to be detected in the tissue and then
information about the tissue damage relayed to the
cerebral cortex, where it is consciously perceived as pain.
In order to enable this, small patches of each peripheral
tissue (skin, muscle and viscera) are connected to regions
of the cerebral cortex by a three-neuronal pain pathway
(see Figure 7-3). The first-order neuron in this path-
way carries the information from the periphery to the
spinal cord, where it synapses with the second-order
neuron. This second-order neuron relays the information
to a number of sites in the brain. Some of the brain sites
are involved in the autonomic nervous system reflex
responses to injury (such as increases in cardiac output or
ventilation rate). However, conscious perception of tissue

Heart

Liver

Small
intestine

Kidney

Ureter

A B

Lung and
diaphragm

Pancreas
Stomach

Ovary
Kidney

Colon

Bladder

Liver

Appendix

A B

FIGURE 7-2

Visceral referred pain.
Examples of some of the typical sites of referred pain from visceral
structures on A the anterior and B the posterior surface of the body.
(See also Box 7-2 later in this chapter.)

Acute pain Pain that lasts less than 3 months.
Allodynia Pain due to a stimulus that does not normally provoke pain.
Analgesia Absence of pain in response to a stimulus that would normally be painful.
Chronic pain Pain that lasts longer than 3 months.
Hyperalgesia An increased response to a stimulus that is normally painful.
Referred pain Pain perceived as occurring in a region of the body topographically distinct from the region in which the

actual source of pain is located.

BOX 7-1 Key pain terminology

FIGURE 7-3

Basic arrangement of the pain pathway.
Schematic diagram showing that the pain pathway consists of
three neurons, which connect peripheral tissues (skin, muscle and
viscera) with the cerebral cortex. Large numbers of these three
neuronal pathways are arranged in parallel to ensure that most
tissues in the body are connected to the cortex.

ch07-137-154-9780729541602.indd 141 18/09/14 9:26 AM

142 PART 2 ALTERATIONS TO REGULATION AND CONTROL

damage is transmitted from the thalamus via the third-
order neuron, which relays the information to the cerebral
cortex. It is here that the individual becomes aware of
the pain. Large numbers of these three-neuronal relays
are arranged in parallel to ensure that most tissues in the
body are connected to the cerebral cortex. The structure
and function of each of these three classes of neuron are
considered in more detail in the following section.

Nociceptors
Nociceptors are the first-order neurons in the pain path way.
They are a subpopulation of the primary sensory neurons
that collectively are responsible for the detection of all
sensations, such as touch, temperature, muscle length and
joint position (see Chapter 6). Like other primary sensory
neurons, they have a cell body located in the posterior root
ganglia, just outside the spinal cord, and an axon that runs
from the peripheral tissue through a peripheral nerve and
terminates within the superficial layers of the posterior
horn of the spinal cord (see Figure 7-4).

The important thing about nociceptors is that they are
selectively activated by high-intensity stimuli that have
the potential to cause tissue damage. Thus, they are not
activated by low-intensity (innocuous) stimuli, and only
respond when the stimulus is of sufficient intensity to
threaten the integrity of the tissue they innervate.

In addition, tissue damage leads to the release of
substances that produce pain. These substances are
intricately involved in the inflammation process (see
Chapter 13 for more detail) and often cause a cascade of
inflammatory events, such as vasodilation, local swelling
and stimulation of nociceptors. The most recognised
substances are bradykinin, histamine and prostaglandin.
Some substances are released by cells that migrate to
the injured site, such as mast cells and white blood
cells, while other substances are released by the tissues
themselves. These substances flood the injured site during
the inflammatory process and have been referred to as an
‘inflammatory soup’ (see Figure 7-5). Collectively, they
stimulate nociceptors, which transmit the pain signals to

FIGURE 7-4

Detailed arrangement of the pain pathway.
The relationship between nociceptors (red), spinothalamic tract
neurons (blue) and thalamocortical neurons (green) as they course
through the peripheral and central nervous systems.

FIGURE 7-5

Tissue damage leading to inflammation and stimulation of
nociceptors.
In this example, tissue damage has occurred to the skin causing
the release of a ‘soup’ of substances, namely bradykinin, serotonin,
potassium and prostaglandin, which stimulate nociceptors. Mast
cells degranulate (release the contents of) histamine when triggered
by tissue damage, which stimulates the nerve ending but also
causes the blood vessels to allow fluid to leak into the extracellular
space, causing swelling and more pain stimulation.

ch07-137-154-9780729541602.indd 142 18/09/14 9:26 AM

CHAPTER 7 PAIN 143

the brain and then the individual becomes aware of the
injured tissue.

Not surprisingly, nociceptors have been identified in
virtually every peripheral tissue from which we experience
pain. However, a lot more is known about the properties of
the nociceptors responsible for sensations that arise from
the skin than from other structures. Therefore, we begin by
examining the properties of these cutaneous nociceptors
before considering what is known about the neurons
responsible for detecting tissue damage in deeper tissues
such as muscle and viscera.

Cutaneous nociceptors
It is well established that there are two distinct pain
sensations — sharp pain and burning pain — that differ in
their timing and quality. These can be clearly demonstrated
by a mechanical injury such as that produced by a paper
cut or pin-prick. Very shortly after a mechanical injury we
experience a pain that has a ‘sharp’ quality. A few seconds
later we experience a second pain sensation that is usually
described as ‘burning’. The burning pain can also be elicited
by exposure to high temperatures and by the application of
pain-producing chemicals such as acid. Underlying these
two sensations are two classes of nociceptor in the skin that
are quite distinct in structural and functional properties:
high-threshold mechanoreceptors and polymodal noci-
ceptors (see Table 7-1).

High threshold mechanoreceptors
Structurally, high threshold mechanoreceptors have small
diameter myelinated axons in which action potentials
travel along their length at about 5–15 m/sec. The axons
terminate within the dermis of the skin as simple ‘free
nerve endings’ with none of the specialised structures
associated with low threshold mechanoreceptors (such as
touch receptors).

As the name suggests, high threshold mechanoreceptors
are activated by high intensity mechanical stimuli such as a
pin-prick, cutting or pinching the skin. They are completely
unresponsive to low-threshold stimuli (touch, vibration,
warmth) or to painful thermal or chemical stimuli.

Clearly this class of cutaneous nociceptor is very well-
suited to detecting mechanical injury of the skin as they
are activated only by mechanical stimuli at intensities high
enough to cause damage. In addition, because these neurons
have myelinated axons they are able to relay information
about a mechanical injury to the spinal cord rapidly.
For these reasons, high threshold mechanoreceptors are
responsible for detecting the fast-sharp pain that follows a
mechanical injury of the skin.

Polymodal nociceptors
Like high threshold mechanoreceptors, cutaneous
polymodal nociceptors have free nerve endings in the
dermis, with some projecting into the epidermis. Therefore,
they are well positioned to detect stimuli affecting the skin.
They have small-diameter axons but no myelin sheath
and consequently action potentials travel along these

unmyelinated axons relatively slowly (0.5–2.5 m/sec)
compared to high-threshold mechanoreceptors.

As their name suggests, this class of nociceptors
respond to multiple modalities of high intensity stimuli.
They respond to the same high intensity mechanical
stimuli that activate high-threshold mechanoreceptors
but in addition are activated by high temperatures (above
45°C) and a range of chemicals (such as acid). This is
important, because these intense thermal and chemical
stimuli will cause pain when exposed to the skin. Thus, this
class of nociceptor is truly polymodal in that they respond
to mechanical, thermal and chemical stimuli of sufficient
intensity to cause damage to the skin. As polymodal
nociceptors are activated by high intensity mechanical
stimuli, but have unmyelinated axons and hence a slow
conduction velocity, they are responsible for the slow-
burning pain that follows mechanical injury of the skin.
In addition, the burning sensation that is characteristic
of heat or chemical injury to the skin is relayed by these
receptors.

A mechanical injury such as a cut will, of course,
activate both high threshold mechanoreceptors and
poly modal nociceptors in the skin at exactly the same
time. However, because action potentials travel along
myelinated axons much more quickly than along unmye-
linated axons, the information carried by the high
threshold mechanoreceptors reaches the spinal cord before
that carried by the polymodal nociceptors. Because this
time difference is maintained all the way through to the
cerebral cortex the first sensation we perceive is mediated
by the high threshold mechanoreceptors and has a sharp
quality (fast-sharp pain) and this is followed a couple of
seconds later by a burning sensation because of the activity
of polymodal nociceptors (slow-burning pain).

Musculoskeletal and visceral nociceptors
Studies of nociceptors in deeper tissues (muscles, joints
and visceral organs) suggest that the vast majority have
unmyelinated axons and therefore relatively slow conduction

TABLE 7-1 Comparison of the structural and functional
properties of cutaneous nociceptors

HIGH-THRESHOLD POLYMODAL
FEATURE MECHANORECEPTORS NOCICEPTORS

Axon diameter Small Small
Myelin sheath Yes No

Conduction velocity 5–15 m/sec 0.5–2.5 m/sec
Activated by low-
threshold stimulus

No No

Activated by
mechanical injury

Yes Yes

Activated by thermal
injury

No Yes

Activated by
damaging chemicals

No Yes

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144 PART 2 ALTERATIONS TO REGULATION AND CONTROL

velocities.14–16 Some of these are activated by high-intensity
mechanical stimuli as well as a variety of pain-producing
chemicals. Although the temperature sensitivity of these
neurons can be difficult to test, many of them respond to
high temperatures, suggesting that they are like polymodal
nociceptors. As these neurons are not activated by low-
intensity stimuli they are very well-suited at detecting the
twisting of joints, the distension of visceral organs and
ischaemia, which often causes pain in deeper tissues.

A new class of nociceptor has been identified in joints,
muscle and visceral organs that is completely insensitive
to stimulation in normal healthy tissue. These nociceptors
cannot be activated by either low intensity or high intensity
stimulation and are called silent (or ‘sleeping’) nociceptors.16
However, if the peripheral tissue these neurons innervate
becomes inflamed, they are activated and may even begin to
respond to relatively low-threshold stimuli — that is, stimuli
that would not cause pain in healthy tissue. Interestingly,
these neurons do not appear to have any physiological role
but instead are responsible for the sometimes debilitating
pain that is often associated with tissues that become
inflamed because of damage or disease.

in the thalamus. The thalamus is a large, oval-shaped
structure located deep within the forebrain underneath the
cerebral hemispheres and lateral to the third ventricle (see
Figure 7-4). It is a major component of the diencephalon,
and receives information from all the senses (except smell)
and passes this on to the cerebral cortex. The thalamus is
made up of a large number of nuclei, named according to
their anatomical position. Spinothalamic tract neurons
terminate in two structurally distinct regions of the
thalamus. Some neurons terminate in a group of nuclei
in the posterolateral (back and to the side location) part
of the thalamus, while another population synapse in the
medial (towards the midline) region (see Figure 7-4).
These two different termination sites form the basis for
projections from the thalamus to the

cerebral cortex.

Thalamocortical neurons
The third-order neurons of the pain pathway collect the
information relayed to the thalamus by spinothalamic tract
neurons and relay this to the cerebral cortex, and so are
referred to as thalamocortical neurons. As there are two
thalamic sites that receive information about peripheral
tissue damage from the spinothalamic tract, there are two
distinct populations of thalamocortical neurons:
• Thalamocortical neurons with their cell bodies in

the posterolateral parts of the thalamus are activated
by high-intensity stimulation of small, well-defined
regions in the periphery and relay this information
in a highly ordered fashion to the somatosensory
cortex of the parietal lobe and the adjacent insular
cortex. The insula is the lobe of the cerebral cortex
hidden behind the parietal and temporal lobes, and
the region where these lateral thalamocortical neurons
terminate is referred to as the interoceptive cortex
(see Figure 7-4) as it receives sensory information
about the physiological condition of the whole
body.

• Thalamocortical neurons that are located in the
medial thalamus tend to be activated by painful
stimulation of large areas of the body — for instance,
a whole limb — and relay this information to the
anterior cingulate cortex of the frontal lobe (see
Figure 7-4).

Cortical representation of pain
There are three known cortical regions that are responsible
for the perception of pain: the lateral pain pathway
that terminates in the parietal and insular lobes, and a
medial pain pathway that terminates in the frontal lobe.
Functional brain imaging and analyses of patients with
damage to these different cortical areas suggest that
they are responsible for different aspects of the pain
experience.

Brain imaging analyses of both somatosensory and
interoreceptive cortices have revealed that they are
activated by painful peripheral stimuli.17 In addition,
electrical stimulation of the interoreceptive cortex in
conscious humans has shown that the pain is located in

FOCUS ON LEARNING

1 Discuss why a paper cut causes two sensations that
have different qualities and delays.

2 Describe the anatomy of nociceptor cell bodies and
axon terminals.

3 Provide an explanation of the type of nociceptor
responsible for the pain associated with myocardial
infarction (heart attack).

Spinothalamic tract neurons
The nociceptors that relay action potentials intersect with
the spinal cord. The ascending pathway connects the
spinal cord with the thalamus and consequently is referred
to as the spinothalamic tract (refer to Figure 6-19).
Spinothalamic tract neurons are second-order neurons
in the pain pathway and they receive information about
peripheral tissue damage from nociceptors and relay it to
the thalamus.

Spinothalamic tract neurons have their cell bodies
located in the superficial layers of the grey matter of
the posterior horn of the spinal cord (see Figure 7-4).
Therefore, they are well positioned to receive the inputs
from the nociceptors that terminate there. The axons of
spinothalamic tract neurons cross the midline of the spinal
cord underneath the central canal and then ascend along
the length of the spinal cord in the white matter on the
opposite side. The axons of spinothalamic tract neurons
from different parts of the body appear to run together
in a white matter tract (the funiculus, which translates
as ‘slender cord’), which is located between the anterior
funiculus and lateral funiculus and is known as the
anterolateral funiculus (see Figure 7-4).

The axons of spinothalamic tract neurons project out
of the spinal cord, through the brainstem and terminate

ch07-137-154-9780729541602.indd 144 18/09/14 9:26 AM

CHAPTER 7 PAIN 145

well-defined peripheral tissues.18 This is supported by the
observation that damage to this part of the cortex interferes
with pain perception.19 These observations have led to the
suggestion that the lateral pain pathway is responsible for
the sensory-discriminative aspect of pain (i.e. the position,
intensity and modality of the tissue damage).

Analysis of the anterior cingulate cortex with functional

imaging has revealed that it is activated by peripheral
tissue damage and that these responses can be alleviated
by hypnosis.20,21 Furthermore, patients who have damage
in this region can still feel pain but are less troubled
by it.22 Therefore, it is believed that the medial pain
pathway is involved in the affective-motivational aspect
of pain.

Interneuron

Pain
receptors

(afferent pathway)

To thalamusInterneuron

Excitatory impulse
(afferent pathway)

Impulse from brain
(efferent pathway)

Dorsal root
ganglion

Narcotic

Opiate
receptor

Pain
transmission
blocked by
release of
endorphins

To
th

ala
mu

FIGURE 7-6

Descending pathway and endorphin release.
Endorphin receptors are located close to the known pain receptors in the peripheral tissues and pain pathways in the spinal cord.

Although the origin of cutaneous and musculoskeletal pain is usually fairly well-defined (that is, we can determine the origin
of the pain fairly well), visceral pain can be a little more difficult to localise. For example, pain from the heart is often referred
to the left shoulder and arm. It is thought that when many nociceptors from different peripheral tissues merge onto the same
spinothalamic tract neurons, the pain will be referred. So, a population of spinothalamic tract neurons may receive input from
nociceptors in the left arm as well as the heart. Typically, they are activated by injury of the skin or muscles of the left arm,
and the cerebral cortex associates activity in these neurons with arm pain. However, the cerebral cortex cannot distinguish
between this and activation of the same neurons by nociceptors in the heart, so the angina pain is referred to the left arm.
The exact reason for this is not known.

Endorphins (endogenous opioids produced by the body) inhibit transmission of pain impulses in the spinal cord and brain
by binding to opioid receptors. These are receptors in the central nervous system that block pain transmission. You may be
familiar with the term endorphins as they are released during exercise and produce the ‘runner’s high’ that gives the exercising
individual a sense of euphoria, despite being physically drained and experiencing pain. It is thought that endorphins attach
to the limbic and prefrontal areas of the brain (involved in emotion), which alters the individual’s mood. Beta-endorphin is
a potent substance, released from the hypothalamus and pituitary gland, which results in analgesic effects. It may also be
responsible for general sensations of wellbeing. Encephalin, found in the neurons of the brain and spinal cord, is a weaker
analgesic than other endorphins but is more potent and longer lasting than morphine.

All endorphins attach to opioid receptors on the cell membrane of the afferent neuron (see Figure 7-6) and inhibit the
release of excitatory neurotransmitters. Opioid analgesics relieve pain by attaching to the opioid receptors and enhancing the
natural endorphin response. Stress, excessive physical exertion, acupuncture, sexual intercourse and other factors increase the
levels of circulating endorphins, serotonin, noradrenaline and other neurotransmitters, thereby raising the pain threshold.

BOX 7-2 Mechanisms of referred pain

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146 PART 2 ALTERATIONS TO REGULATION AND CONTROL

Neuromodulation of pain
As well as the neural pathways, several substances are
capable of altering the pain pathways. Collectively, these
are referred to as neuromodulators. They are found in
the pathways that control information about painful
stimuli throughout the nervous system. Neuromodulators
are substances, other than neurotransmitters, which are
released by neurons and transmit signals to other
neurons that change the activities of these neurons. It is
thought that neuromodulators are released in response
to tissue injury (such as prostaglandins, bradykinin) and
chronic inflammatory changes (cytokines; see Chapter 12).
Excitatory neuromodulators (ones that propagate the action
potential that excites the neuron) include substances
such as glutamate, substance P, somatostatin and vaso-
active intestinal polypeptide. Inhibitory neuromodulators
(ones that delay or stop nerve transmission) include
gamma-aminobutyric acid (GABA), 5-hydroxytryptamine
(serotonin), noradrenaline and endorphins.

well as sweating, when experiencing pain, especially acute
surgical pain. However, these clinical signs are not universal
in all individuals who are experiencing pain. When there
is damage to the internal organs, this can also result in
activation of the sympathetic nervous system, causing an
elevation in cardiovascular and respiratory responses.

Evaluation and treatment
The evaluation of pain is often difficult. Nurses are usually
the primary clinicians responsible for assessing a patient’s
pain. Foremost in the evaluation of pain is to listen to,
and believe, what the patient says about their level of
pain. There is no single test that assesses an individual’s
level of pain and, despite numerous measures to provide
an objective measure of pain, the most useful is asking
the patient to relate the location, type and duration of the
pain, as well as any therapies previously used to effectively
alleviate pain.

As well as receiving information from the patient about
their pain, there are numerous pain measurement tools
that the clinician can use to obtain more information about
the patient’s pain (see Figure 7-7). These can be used to
assess changes in the patient’s level of pain and response
to therapies. In addition, facial pain scales can be used for
individuals who may not be able to vocalise their feelings of
pain or who cannot speak (see ‘Paediatrics and pain’ below).

The management of pain can be divided into
pharmacological and non-pharmacological therapies, or
a combination of both. The principal management aim
should be to treat the cause of pain, if possible. Second,
choose appropriate therapies that target the type of pain.
For instance, opioids and NSAIDs target nociceptive pain.
If using pharmacological agents, provide doses regularly
and prevent pain from arising, such as postsurgical
pain. The administration route also becomes important
when deciding the severity of the pain. While originally
developed for the management of cancer pain, the World
Health Organization (WHO) analgesic ladder provides
a simple scale for the determination of pharmacological
agents in pain management (see Figure 7-8). The effect
of different types of analgesic agents on pain pathways is
illustrated in Figure 7-9.

If the pain is bilateral, then more effective relief can
be produced by a midline myelotomy (see Figure 7-10).
The objective of this procedure is to cut the axons of the
spinothalamic tract neurons as they cross the midline
underneath the central canal. A midline myelotomy
is a complicated procedure as it usually requires a
laminectomy to access the posterior surface of the spinal
cord and special care to ensure that the lesion is made
at the correct level in order to target the axons of the
appropriate spinothalamic tract neurons. However,
the advantage of the procedure is that it cuts the axons
of the spinothalamic tract neurons crossing the midline
from both sides of the spinal cord and so produces
bilateral analgesia, which is particularly beneficial when
the pain is of visceral origin. (See also Box 7-3.)

FOCUS ON LEARNING

1 Discuss why a cut in the right thalamus might interfere
with the ability to feel pain on the left side of the body.

2 Outline which cortical sites are thought to be involved in
the conscious perception of pain.

3 Describe how neuromodulators of pain alter pain signal
transmission.

Clinical manifestations of pain
Pain is complex and highly subjective, meaning that no two
people are likely to experience the same level of pain for a
given painful stimulus. Pain tolerance is the amount of time
or the intensity of pain that an individual will endure before
initiating overt pain responses. Pain tolerance varies greatly
among individuals, as well as in the same individual over
time, because of the body’s ability to respond differently
to noxious stimuli. It is influenced by cultural perceptions,
expectations, role behaviours, gender and physical and
mental health.23 It generally decreases with repeated
exposure to pain, fatigue, anger, boredom, apprehension and
sleep deprivation; and may increase with increased alcohol
consumption, medication, hypnosis, warmth, distracting
activities and strong beliefs or faith.

The pain threshold is the lowest intensity at which a
stimulus is perceived as pain and may be influenced by
genetics.24 Intense pain at one location may increase the
threshold in another location. For example, a person with
severe pain in one knee is less likely to experience chronic
back pain that is less intense. Therefore, an individual
with many painful sites may report only the most painful
one. Then, when the dominant pain is diminished, the
individual identifies other painful areas.

While pain is a subjective sensation, it may result
in changes in the level of autonomic nervous system
activation. Patients often experience an increase in heart
rate, blood pressure, ventilation, nausea and vomiting, as

ch07-137-154-9780729541602.indd 146 18/09/14 9:26 AM

CHAPTER 7 PAIN 147

Pain intensity scale

No
pain

Mild
pain

Moderate
pain

Severe
pain

Worst
possible

pain

Pain distress scale

None Annoying Uncomfortable Bad Dreadful Agonising,
unbearable

0 1 2 3 4 5 6 7 8 9 10

0–10 numerical pain intensity scale

Simple descriptive pain distress scale

0
NO HURT

1
HURTS

LITTLE BIT

0 2 4 6 8 10

2
HURTS

LITTLE MORE

3
HURTS

EVEN MORE

4
HURTS

WHOLE LOT

5
HURTS
WORST

FIGURE 7-7

Scales for rating the intensity of pain.
The numerical and facial scales can be used by patients to self-rate their pain. A Pain intensity scale. B Pain distress scale. C Facial pain scale

for children. D Facial pain scale for adults, used in multiple languages.

Due to their well-characterised anatomical location, the axons of spinothalamic tract neurons are sometimes targeted in surgical
approaches for the treatment of severe chronic pain in patients whose pain is inadequately controlled by analgesics.25,26 Because
of the importance of these neurons in the onward transmission of the pain signal, cutting the axons should result in abolition of
the pain.

In an anterolateral cordotomy (-otomy refers to surgical cutting) the objective is to cut the axons of the spinothalamic tract
as they course through the anterolateral funiculus. At one time this involved exposing the lateral surface of the spinal cord with
an operation called a laminectomy, so that the cordotomy could be performed under direct visual control. Today, it is performed
percutaneously (through the skin) and involves the insertion of an electrode into the anterolateral funiculus of the upper cervical
segments of the spinal cord, which is visualised using computed tomography (CT) scanning. The cut is made by heating the tip
of the electrode. Anterolateral cordotomy is particularly useful when the pain is unilateral, as the lesion only affects the axons of
the spinothalamic tract on one side of the body (see Figure 7-10A).

BOX 7-3 Surgical treatment of chronic pain

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148 PART 2 ALTERATIONS TO REGULATION AND CONTROL

Pathophysiology of pain
So far we have considered pain from a physiological
perspective and have identified it as both having a protective
function (warning us about environments that can cause
us harm) and acting as a stimulus to adopt behaviours
that enhance healing. However, when the nervous system
components that are responsible for detecting pain are
themselves affected by injury or disease, the consequences
can be severe and persistent neuropathic pain. It has
been estimated that chronic pain affects about 3.2 million
Aust ralians and that the total cost of chronic pain on
the Australian economy is about $34.3 billion per year
— that is, more than $10,000 per person with chronic
pain.27 Healthcare costs are estimated to comprise 20%
of these costs (about $7 billion per year), mainly due to
inpatient, outpatient and out-of-hospital medical costs.27
The different types of peripheral pathophysiological pain
are summarised in Table 7-3.

Peripheral neuropathic pain
Peripheral neuropathic pain results from damage to
the peripheral nervous system including the cranial
nerves, spinal nerves and any of the peripheral nerves
that branch from these. Typically the pain feels like it
is coming from the parts of the body that the affected
nerves innervate — that is, referred pain — and the
pain often has a characteristic quality (e.g. burning or
shooting). The term mononeuropathy is used where only

Mild pain

Moderate pain

Severe pain

Opioid + non-opioid

Non-opioid

± Adjuvant

± Adjuvant
Paracetamol

NSAID

Codeine
Tramadol

Oxycodone

Morphine
Oxycodone

Hydromorphone
Methadone

Fentanyl

Step 1

Step 2

Step 3

Advance up the ladder if pain persists

FIGURE 7-8

Strategy for pharmacological management of pain using the
World Health Organization analgesic ladder.
Multiagent therapy is usually required for optimal pain
management. Patients with mild pain should be started on a
non-opioid analgesic, and those with moderate pain on a step 2
opioid. Many patients can benefit from the addition of a non-opioid
to the opioid (e.g. for bone pain) or an adjuvant agent to the opioid
(e.g. for neuropathic pain). If this combination does not produce
adequate relief or the patient presents with severe pain, step 3
opioids should be begun initially.

Perception
Cortex

Thalamo-
cortical

projections

Systemic
opioids

Spinothalamic
tract Primary afferent

nociceptor

Thalamus

Noxious stimulus

Local anaesthetics
Transmission

Transduction

Epidural and
local anaesthetics

FIGURE 7-9

Schematic diagram outlining the nociceptive pathway for
transmission of painful stimuli.
Interventions that prevent nociceptive transmission are shown
at the points in the pathway that are thought to be their sites of
action. Agents that block the transduction of pain actually prevent
the generation of pain action potentials. In contrast, agents that
block transmission actually stop the relay of action potentials to the
cerebral cortex.

FIGURE 7-10

Surgical approaches to pain relief.
Two approaches to the surgical alleviation of pain that target the
axons of spinothalamic tract neurons as they project through
the anterolateral funiculus, A, and cross the midline underneath the
central canal, B.

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CHAPTER 7 PAIN 149

There is now compelling evidence to suggest that
newborn children have the neural apparatus necessary
to perceive pain. Despite this pain in young children
is very poorly managed with analgesics administered
infrequently or sometimes not at all. The evaluation
of pain in infants and young children represents a
significant challenge as they are unable to effectively
communicate what they feel and may therefore receive
inadequate pain control following traumatic injury or
during painful medical procedures (Table 7-2). A number
of behavioural assessment tools have been developed to

allow carers to obtain a quantitative estimate of pain in
preverbal children. The most popular of these for both
procedural and postoperative pain is the Face Legs
Activity Cry Consolability (FLACC) scale. The presence
of pain-related behaviours associated with each of these
five components is scored from 0 to 2 giving an overall
rating of 0 (no pain) through to 10 (severe pain). This
scale has been used successfully in the assessment of pain
in neonates through to teenagers where it is particularly
useful in the assessment of individuals with impaired
cognitive function.

PAEDIATRICS AND PAIN

TABLE 7-2 Pain perception in infants, children and the elderly

INFANTS CHILDREN THE ELDERLY

Pain threshold Painful neonatal experiences increase pain sensitivity Lower or the same as
adults

No increase compared with
middle age

Physiological
symptoms

Increased heart rate, blood pressure and ventilatory
rate; flushing or pallor, sweating and decreased
oxygen saturation

Same as infants;
nausea and vomiting

Same as infants and children;
nausea and vomiting

Behavioural
responses

Changes in facial expression, crying and body
movements, with lowered brows drawn together;
vertical bulge and furrows in the forehead between
the brows; broadened nasal root; tightly closed
eyes; angular, square-shaped mouth, chin quiver;
withdrawal of affected limbs, rigidity, flailing

Individual responses
vary

Individual responses vary and
may be influenced by the
presence of painful chronic
diseases

TABLE 7-3 Clinical features and likely pathophysiology of peripheral neuropathies

PAIN SYNDROME PATHOPHYSIOLOGY CLINICAL FEATURES

Complex regional pain
syndrome (type II)

Traumatic injury of peripheral nerves causing
spontaneous action potentials to be generated in
both damaged and intact nociceptors

Ongoing pain, allodynia, hyperalgesia,
oedema, cutaneous blood flow and sweating
abnormalities

Painful diabetic neuropathy Hyperglycaemia leading to degeneration of
unmyelinated sensory neurons

Loss of sensation and burning pain in feet and
hands

Postherpetic neuralgia Infection of peripheral nerves with varicella zoster
virus leading to sensory neuron loss

Loss of sensation, pain and allodynia in
dermatome of infected nerve

Lumbosacral radicular pain Herniated intervertebral disc, resulting in
compression injury of spinal nerve causing
spontaneous activity in nociceptors

Lancinating (stabbing, piercing sensation) pain
in the thigh or lower leg

Phantom limb pain Spontaneous activation of nociceptors in
neuroma and sensitisation of central neurons as a
result of nerve transection during amputation

Ongoing cramping or aching pain referred to
amputated limb

Trigeminal neuralgia
(Tic douloureux)

Compression of the trigeminal nerve (sometimes
by an atypical blood vessel) as it enters the brain

Episodes of severe, sharp, piercing pain
referred to the facial region sometimes
triggered by light touch

Chemotherapy-induced
peripheral neuropathy

Chemotherapy-induced neurotoxicity of
myelinated primary sensory neurons

Loss of sensation and spontaneous burning
pain

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150 PART 2 ALTERATIONS TO REGULATION AND CONTROL

a single nerve is involved and polyneuropathy is used
where multiple nerves are affected. The nerve damage
that causes the pain can be the result of a range of factors,
including physical injury, disease, infection or poisoning
(e.g. chemotherapy).

One of the most common causes of painful peripheral
neuropathies is where a peripheral nerve is damaged
by a traumatic injury. The damage can be caused by a
variety of mechanical insults such as nerve compression
(following a crush injury) or transection (as the result
of a penetrating injury or surgical procedure). The
resultant pain is severe, often has a burning quality and
is characterised by both hyperalgesia and allodynia.
These types of pain used to be referred to as causalgias
but are now known as complex regional pain syndromes
(CRPSs).28

Painful diabetic neuropathy is an example of a
neuropathic pain caused by either type 1 or type 2
diabetes mellitus. Unfortunately, it occurs in more
than 50% of individuals with long-standing diabetes.
Painful diabetic neuropathy appears to be due to
hyperglycaemia, as the pain can be reduced in severity
and delayed in onset by careful control of blood
glucose levels.29 The longer the length of the axons, the
more susceptible the neurons are to hyperglycaemia,
which is why painful diabetic neuropathy is usually
characterised by numbness and burning pain in the distal
extremities (a ‘stocking and glove’ type distribution)
(see Figure 7-11) that gradually spreads proximally
and becomes more severe.30 The lack of sensation in
the affected areas may result in the formation of ulcers,
which may require limb amputation if they become
gangrenous. The major cause of the painful neuropathy
appears to be degeneration of unmyelinated axons caused
directly by hyperglycaemia, as well as ischaemia caused

by hyperglycaemia-induced damage to the blood vessels
supplying the peripheral nerves. Further descriptions of
diabetes are in Chapter 35.

Infections of the peripheral nerves can also result
in neuropathic pain. About 20% of Australians will
experience shingles (herpes zoster) during their lifetime.
In shingles, the virus responsible for chickenpox (varicella)
can lie dormant in the sensory nerves for years and then
spontaneously erupt to cause a rash and painful blisters
in the skin innervated by the infected nerves. Although
the rash and blisters usually heal, in some sufferers
the pain persists and is referred to as postherpetic
neuralgia.

Given the diversity of causes of these peripheral
neuropathies, it is perhaps not surprising that the
mechanisms that underlie them differ and indeed in
many cases remain poorly understood. Probably one
of the better understood pathologies is that following a
traumatic injury of a peripheral nerve responsible for
CRPS. Where the nerve is completely transected (cut)
or crushed, the portions of the axons distal to the injury
typically degenerate because they are separated from
their supporting cell bodies in the posterior root ganglia.
This results in sensory loss due to the denervation of the
peripheral tissue innervated by the affected nerve, as well
as the formation of a neuroma at the site of the nerve
damage. A neuroma consists of a disorganised array of
scar tissue, neuroglial cells and inflammatory cells, as
well as the axons of neurons attempting to regenerate
along the damaged nerve and reinnervate the peripheral
tissues. The regenerating axons within the neuroma itself
appear to be highly sensitive and this is partly responsible
for some of the symptoms associated with this type of
injury. Action potentials appear to arise spontaneously
from the neuroma, which may partly explain the pain in
the absence of any peripheral stimuli. The structure itself
is also very sensitive to mechanical stimuli, with gentle
tapping of the skin overlying the neuroma or movement
of the affected limb enough to elicit action potentials and
produce pain.31

In some patients, the sympathetic nervous system also
appears to play a role in CRPSs, because local anaesthetic
blockade of sympathetic ganglia (or pharmacological
block of adrenergic receptors) alleviates the pain. This
pain appears to be a consequence of intact nociceptors
in tissues that have been denervated by the nerve injury,
that then become sensitive to noradrenaline released from
sympathetic postganglionic neurons nearby.32 These intact
nociceptors (which have axons in nerves not affected
by the peripheral nerve injury) become sensitised and
exhibit spontaneous activity and augmented responses to
peripheral stimuli.

In addition to these changes in the properties of primary
sensory neurons brought about by damage to the nerve,
there is evidence to suggest that changes in the properties
of neurons within the central nervous system may also
contribute to neuropathic pain. Second-order neurons in
the parts of the spinal cord receiving input from damaged

FIGURE 7-11

Painful diabetic neuropathy.
In poorly controlled diabetes, hyperglycaemia affects the longest
sensory neurons first. A Normal intact nervous system.
B Diabetes-affected nervous system with degeneration of axons in
the distal extremities, resulting in C diabetic neuropathy with the
characteristic ‘stocking and glove’ distribution.

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CHAPTER 7 PAIN 151

nerves exhibit higher rates of spontaneous activity, show
greatly enhanced responses to nociceptive stimuli applied
to the periphery and become sensitive to low-intensity
stimuli. The enhanced responsiveness of these neurons
in the central nervous system is referred to as central
sensitisation and appears to be a consequence of changes
in the excitability of the second-order neurons themselves,
as well as a reduction in the ongoing inhibitory influence
exerted on these neurons by endogenous pain control
circuits (disinhibition). Together with the peripheral
mechanisms detailed above, these central changes are
thought to be responsible for the spontaneous pain,
hyperalgesia and allodynia associated with some forms of
neuropathic pain.

Central pain syndromes
Forms of pain caused by damage to the central nervous
system are known as central pain syndromes. Such
forms of pain are typically very intense, aching, shooting
pains that feel like they are due to damage to peripheral
tissues but where clinical examination fails to identify
any peripheral tissue damage or peripheral nervous
system pathology. The causes of central pain syndromes
were first identified by postmortem examination of
the brains of individuals with CRPSs, which revealed
damage in parts of the brain and/or spinal cord
known to be involved in the processing of pain.33 The
damage may be the result of a number of factors,
including traumatic injury, tumour, stroke or even
the side effects of neurosurgery (see Table 7-4). Because
the cause of the pain is not visible, such pain can be
partic ularly frustrating for patients and diagnosis can
sometimes be a long and challenging process.

TABLE 7-4 Causes of central pain syndromes

Vascular lesions (infarction, haemorrhage)
Traumatic brain injury
Neurosurgery
Brain tumours
Multiple sclerosis
Spinal cord injury
Epilepsy

FOCUS ON LEARNING

1 Explain the difference between mononeuropathy and
polyneuropathy.

2 List some of the factors that can result in peripheral
neuropathic pain.

3 List some of the causes of central pain.
4 Discuss the neural mechanism thought to be responsible

for painful diabetic neuropathy.

AGEING AND PAIN

The elderly typically experience a higher incidence of pain
compared to other adults and as the population ages it is
estimated that chronic pain is likely to affect about 5 million
Australians by 2050. The impact of pain in older people can
have particularly devastating consequences on their quality
of life when it impacts upon their mobility and ability to
socialise.
The assessment of pain in the elderly can be challeng-
ing as some perceive it as an inevitable consequence of
ageing or fear the financial burden they perceive may
be associated with it. The fact that the pain may also
present with co-morbidities, including cognitive decline,
makes the diagnosis and effective management of pain
in older Australians a complex and time-consuming task
(Table 7-2).

Given the difficulties associated with assessment of pain in
the elderly it is perhaps not surprising that the treatment
of pain in older adults is also problematic. Some patients
simply don’t believe that their pain can be alleviated, while
others are reluctant to take opioid analgesics because
of their euphoric side effects or fear of addiction. This is
unfortunate as employment of opioid analgesics may be
more appropriate given the adverse effects of NSAIDs
particularly in individuals with impaired liver or kidney
function. Interestingly complementary and alternative
medicine approaches seem to be widely accepted by the
elderly as alternatives to drugs.

The mechanisms responsible for central pain syndromes
are not well understood, but it is likely that damage to
spinothalamic tract neurons and thalamocortical neurons
by the original insult is responsible for triggering ongoing
activity in neurons at subsequent levels of the pain pathway.
It has been postulated that this activity may be a response
to the loss of normal input to these neurons (caused by
the damage earlier in the pathway) or the loss of normal
inhibitory influences that normally suppress their activity.

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152 PART 1 ALTERATIONS TO BODY MAINTENANCE152 PART 1 ALTERATIONS TO BODY MAINTENANCEchapter SUMMARY

The definition of pain
• Pain is clinically important as it encourages patients to

seek medical help and adopt behaviours that enhance
healing.

• Pain has an important physiological role as it teaches us
to avoid environmental stimuli that cause harm.

• Individuals born with a congenital insensitivity to pain
suffer horrendous injuries because they are unaware of
the damage they are experiencing.

• Pain is a subjective sensation that is affected by a large
number of variables and consequently can be difficult to
define.

• The International Association for the Society of Pain’s
definition of pain highlights most of the key elements of
pain.

• Pain is invariably unpleasant (it is a negative experience)
and is therefore something we avoid.

• The ability to locate a painful stimulus and determine
its intensity and quality is referred to as the sensory-
discriminative aspect of pain.

• Pain produces changes in both mental state (affect) and
behaviour (motivation), which are referred to as the
affective-motivational aspect of pain.

• Pain is usually the result of tissue damage but can be
caused by stimuli that would cause tissue damage if
sustained.

• The threshold for pain is lower than the threshold for
tissue damage.

• The intensity of the pain experience can be modified by
behaviour, cognitive factors and clinical intervention.

Types of pain
• Nociceptive pain due to external damage is relatively

mild and has a comparatively short time frame.
• Nociceptive pain due to internal damage is less common,

is usually more severe and has a longer time frame.
• Neuropathic pain is caused by injury or disease of the

nervous system and can be both severe and persistent.
• Psychogenic pain is the result of a psychological disorder,

but for the patient it can be just as severe and debilitating
as nociceptive pain or neuropathic pain.

Pain terminology
• Pain is described as either acute or chronic and these

classifications are independent of aetiology.
• Chronic pain affects about 20% of Australians.
• Referred pain is perceived as originating from a part of

the body distinct from the site of tissue damage.
• Hyperalgesia is where there is increased pain in response

to a stimulus that is normally painful.
• Allodynia is where pain results from a stimulus that does

not normally produce pain.
• The conscious perception of tissue damage occurs in the

cerebral cortex.

The physiology of pain
• A three-neuronal pathway relays information about

peripheral tissue damage from the periphery to the
cerebral cortex Nociceptors are the first-order neurons in
the pain pathway.

• There are two classes of cutaneous nociceptor: high-
threshold mechanoreceptors and polymodal nociceptors.

• Joints, muscle and viscera appear to be innervated by
neurons with properties similar to cutaneous polymodal
nociceptors.

• Joints, muscle and viscera also appear to be innervated
by silent (or ‘sleeping’) nociceptors that only become
active when these tissues become inflamed as the result
of damage or disease.

• Although there are a number of neural pathways relaying
information about tissue damage between the spinal
cord and brain, the most important in terms of the
conscious perception of pain is the spinothalamic tract.

• Spinothalamic tract neurons are the second-order
neurons in the pain pathway and they collect the
information delivered to the spinal cord by nociceptors
and relay this to the thalamus.

• The axons of spinothalamic tract neurons are sometimes
targeted in surgical approaches to the treatment of
severe chronic pain through a midline myelotomy or
anterolateral cordotomy.

• Spinothalamic tract neurons terminate in two structurally
distinct regions of the thalamus.

• Thalamocortical neurons with their cell bodies in the
posterolateral parts of the thalamus relay information
about tissue damage to the somatosensory cortex and
interoreceptive cortex.

• Thalamocortical neurons located in the medial thalamus
relay information about peripheral tissue damage to the
anterior cingulate cortex.

• Through the information that they receive from the
posterolateral parts of the thalamus, the somatosensory
and interoreceptive cortices are thought to be
responsible for the sensory-discriminative aspect of pain.

• The medial thalamic projection to the anterior cingulate
cortex is thought to be responsible for the affective-
motivational aspect of pain.

• Neuropathic pain affects up to 7% of the population
and contributes significantly to the cost of healthcare in
developed countries.

• Modulators of pain include substances that stimulate
pain receptors (i.e. prostaglandins, bradykinins,
substance P, glutamate) and substances that suppress
pain (i.e. endorphins, gamma-aminobutyric acid (GABA),
serotonin).

• Endorphins are endogenous opioids that attach to opioid
receptors and inhibit transmission of pain impulses.
Encephalins are other opioid peptides.

• They are present in varying concentrations in the neurons
of the brain, spinal cord, and gastrointestinal tract.

ch07-137-154-9780729541602.indd 152 18/09/14 9:26 AM

A D U L T
Peter was a 59-year-old shearer whose best friend was a blue
heeler called Red. After noticing blood in his stools Peter visited
his local general practitioner and was subsequently diagnosed
with carcinoma of the colon. A colon resection was performed
and he underwent a complete course of radiotherapy and
chemotherapy. Six months later, Peter started to experience
abdominal pain. On investigation it was revealed that the
malignancy had spread into his urinary bladder and urethra.
Peter was readmitted to hospital and in subsequent weeks
his pain increased progressively until eventually it could
only be controlled with high doses of intravenous morphine.

Twelve months after the onset of the pain, Peter had a midline
myelotomy in the mid-thoracic region of the spinal cord. Ten
days following this operation, he was able to leave hospital
and lived pain-free until his death 5 years later.
1 Explain the physiology of Peter’s abdominal pain.
2 Discuss how morphine controls acute pain.
3 Explain why Peter was likely to experience ongoing pain

that was responsive only to high-dose morphine.
4 Outline the aim of a midline myelotomy.
5 Explain why you think a midline myelotomy might

provide a better outcome for pain of visceral origin.

Clinical manifestations of pain
• Pain tolerance is the duration of time or the intensity of

pain that an individual will endure before initiating overt
pain response.

• Pain threshold is the point at which pain is perceived.
• Pain is a subjective symptom but can result in activation

of the autonomic nervous system activation, which
causes an increase in heart rate, blood pressure and
ventilation, nausea and vomiting as well as sweating.

Evaluation and treatment
• Evaluation of pain is often difficult; the patients’

experiences and objective measures guide therapies.
• Treating the original cause of pain should be

addressed first, followed by pharmacological and non-
pharmacological therapies.

Paediatrics and ageing and pain
• Newborns and young children have the anatomical and

functional ability to perceive pain. Older individuals
tend to have a slightly higher pain threshold, probably
because of changes in the thickness of the skin and
peripheral neuropathies.

Pathophysiology of pain
• Peripheral neuropathic pain results from damage to the

peripheral nervous system.

• Peripheral neuropathic pain can be the result of physical
injury, disease, infection or toxicity.

• Mononeuropathy is where only a single nerve is involved
and polyneuropathy is where multiple nerves are
affected.

• The neural mechanisms responsible for painful peripheral
neuropathies are complex and in many cases remain
poorly understood.

• Following a traumatic injury of a peripheral nerve the
portions of the axons distal to the injury sometimes
degenerate and a neuroma may form at the site of the
nerve damage.

• Action potentials can occur spontaneously in the
neuroma and it may be very sensitive to mechanical
stimuli, resulting in pain if it is touched or disturbed by
movement.

• In some cases noradrenaline released from sympathetic
postganglionic neurons appears to exacerbate the pain
produced by nerve injury.

• Central sensitisation of spinothalamic tract neurons is
also thought to contribute to peripheral neuropathic
pain.

• Central pain syndromes are characterised by very severe
persistent pain caused by traumatic injury, tumour,
cerebrovascular incidents or brain surgery.

CASE STUDY

A G E I N G
Cecil, an 86-year-old man, who worked as a tradesman until
his retirement 16 years ago presents to the doctor with lower
back pain. He is generally active, playing lawn bowls twice
a week, and walking three times per week for 30 minutes
each time but his lower back pain is starting to restrict these
activities.

Upon questioning, Cecil related that the lower pain had
affected him for the last 10 years of his working life and had
gradually become more severe during retirement. When he
was physically examined, there was acute tenderness over
L2–L4, but Cecil only rated the pain as 3 out of 10. There were
no obvious signs detected. The doctor was unsure of the
origin of the lower back pain and Cecil was instructed to have

imaging studies using magnetic resonance imaging (MRI) and
prescribed a non-steroidal anti-inflammatory medication to
be taken when he experiences pain.
1 Explain the likely physiology of Cecil’s lower back pain.
2 Based on the lack of signs and symptoms experienced

by Cecil, is the MRI scan likely to identify an anatomical
reason for the lower back pain?

3 What is the significance of acute tenderness over L2–L4?
4 Discuss the effectiveness of NSAIDS for pain management

in older people.
5 Provide reasons why Cecil may perceive his pain at a

lower level than expected.

CASE STUDY

CHAPTER 7 PAIN 153

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154 PART 2 ALTERATIONS TO REGULATION AND CONTROL

1 Outline the features of the pain experience that are
included in the sensory-discriminative aspect of pain.

2 Explain why it is useful for the threshold for pain
sensation to be lower than the threshold for tissue
damage.

3 Discuss the difference between hyperalgesia and
allodynia.

4 Compare and contrast the properties of cutaneous high-
threshold mechanoreceptors and polymodal nociceptors.

5 Explain why a skin laceration often causes two pain
sensations separated in time.

6 Discuss why a painful stimulus applied to the right side
of the body results in activation of the cerebral cortex on
the left side of the body.

7 Explain the difference between a midline myelotomy and
an anterolateral cordotomy.

8 Which cortical sites are thought to be involved in the
conscious perception of pain? In which lobes of the
cerebral cortex are they located, and what is their
postulated function?

9 Outline some of the pathophysiological mechanisms
thought to underlie the neuropathic pain that may arise
from a peripheral nerve transection.

10 What is responsible for the nerve damage arising from
painful diabetic neuropathy?

R E V I E W Q U E S T I O N S

ch07-137-154-9780729541602.indd 154 18/09/14 9:26 AM

WSU Copyright PartVB Electronic Notice
Understanding pathophysiology CH 7 – Pain

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