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Bones and soft tissue


Bone266

25.2 Joints270
25.3 Connective tissue diseases274
25.4 Soft tissue tumours276

Self-assessment: questions277
Self-assessment: answers279

Chapter overview
Within the osteoarticular system, the bones provide structural support for the body and have
an important role in mineral homeostasis and haematopoiesis, and the joints permit
movement. Disorders of the osteoarticular system can, therefore, cause significant disability
and deformity. Most of the more common disorders such as osteoarthritis, osteoporosis and
rheumatoid arthritis are chronic and progressive, causing significant morbidity among the
general population, especially the elderly. Bone tumours affect all age groups, show marked
diversity in their behaviour and different types target particular age groups and anatomic sites.
Connective tissue diseases form an important group of multisystem disorders, and they are
presented here because a feature common to most of them is their propensity to involve the
joints and soft tissues. ‘Soft tissue tumours’ form a highly heterogeneous group of neoplasms
that are important because benign tumours are relatively frequent and sarcomas are often
highly aggressive.

25.1. Bone
Learning objectives
You should:

• know the structure and function of bones


• know the major bone diseases, their pathogenesis and clinicopathological features
• know the major types of bone tumour.

Structure and function


The skeletal system is composed of 206 bones, and has a number of functions:

• Structural support.
• Protective. The skull and the vertebral column protect the brain and spinal cord respectively.
The ribs protect the thoracic and upper abdominal organs to a lesser degree.
• Mineral homeostasis. Bone is a reservoir for the body’s calcium, phosphorus and
magnesium.
• Haematopoiesis. Under normal conditions in the adult, bone is the sole site of haematopoietic
marrow.
Bone is a special type of connective tissue, which is mineralised, and therefore has an organic
and inorganic component. The organic component is the connective tissue matrix composed
predominantly of type I collagen. The organic matrix undergoes mineralisation by the
deposition of the mineral calcium hydroxyapatite. This mineral is the inorganic component of
bone. Mineralisation gives bone its strength and hardness. Unmineralised bone is called
osteoid. Bone formation, maintenance and remodelling is performed by the bone cells, of
which there are three main types:
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• Osteoblasts – these cells are responsible for bone formation. They synthesise the type I
collagen that forms osteoid, and also initiate the process of mineralisation.
• Osteoclasts – these are multinucleate cells responsible for bone resorption.
• Osteocytes – evidence suggests that these cells have an important role in the control of the
daily fluctuations in serum calcium and phosphorus levels and the maintenance of bone.
Bone can be formed quickly or slowly. When bone is formed quickly, such as in fracture repair
or fetal development, the osteoblasts deposit the collagen in a random weave arrangement.
This type of bone is called woven bone. Woven bone is replaced by lamellar bone, which is
formed much more slowly.
In lamellar bone, the collagen is arranged in parallel sheets. Lamellar bone can also form
without a woven bone framework. There are two types of mature lamellar bone:

• Cortical (compact) bone – this is composed of numerous units called haversian systems. In
each haversian system the lamellar bone is arranged concentrically around a central canal
called the haversian canal, through which arteries and veins run.
• Cancellous (spongy) bone – this consists of lamellar bone arranged in a meshwork of bone
trabeculae.
Most bones are tubular, hollow structures that consist of a shaft, called the diaphysis,
expanded end regions, called the epiphyses, and a region between the diaphysis and each
epiphysis, called the metaphysis (Figure 69). The sleeve-like tube (or cortex) of each bone is
composed of compact sheets of cortical bone. The inner portion of bone is not quite hollow
and is called the medulla. The medulla contains cancellous bone, connective tissue, nerves,
blood vessels, fat, and haematopoietic tissue. All bones are covered by a periosteum
composed of connective tissue.

Figure 69

Parts of a bone.

Development and growth of the skeleton


During fetal development, bone can be formed either directly in mesenchyme, as in the case of
the skull and clavicles (intramembranous ossification), or on pre-existing cartilage
(endochondral ossification). In intramembranous ossification, bone is laid down as woven bone
that eventually matures into lamellar bone. In endochondral ossification, the cartilaginous
template undergoes ossification at particular sites along the bone known as ossification
centres. In long bones, the cartilage at the epiphysis persists until after puberty, allowing
growth. This area of persisting cartilage is called the growth plate.
Once the bones are fully formed, further growth occurs by the laying down of further bone onto
the pre-existing bone. The coordinated actions of the osteoblasts and osteoclasts are
paramount in bone development andMedicine
Master maintenance. Inand
General bone development,
Systematic the action of
Pathology
osteoblasts predominates. When the skeleton has reached maturity, the bones are continually
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renewed and remodelled, which requires the actions of the osteoblasts and osteoclasts to be
in equilibrium. By the third decade, osteoclastic resorption begins to predominate, with a
resultant steady decrease in skeletal mass.

Developmental disorders
Achondroplasia

Achondroplasia is a major cause of dwarfism, and is due to mutation of a single gene. The
condition can be familial, with autosomal dominant inheritance, or sporadic. The defective
gene leads to abnormal ossification at the growth plates of bones formed by endochondral
ossification. Intramembranous ossification is unaffected. Affected individuals have a
characteristic appearance, with shortening of the proximal extremities, a relatively normal-
sized trunk, and a disproportionately large head with typical bulging of the forehead and
depression of the nasal bridge.

Osteogenesis imperfecta (‘brittle bone’ disease)

This is a rare group of genetic disorders that have in common the abnormal synthesis of type I
collagen. In addition to bone, the other tissues rich in type I collagen are tendons, ligaments,
skin, dentine and sclera. Affected individuals have brittle bones and spontaneous fractures
may occur. The sclera appears blue because it is so thin that the underlying uveal pigment
becomes visible. Some variants of osteogenesis imperfecta are fatal early in life while others
are associated with survival.

Acquired disorders
Osteoporosis

Osteoporosis is characterised by reduced bone mass, making bone vulnerable to fracture.


Trabecular bone is affected before cortical bone. Trabecular bone is found in the greatest
amounts in the vertebral bodies and pelvis, and cortical bone is found in the greatest amounts
in the long bones.

Aetiology and pathogenesis

Osteoporosis may be primary or secondary. Primary osteoporosis refers to senile osteoporosis


and post-menopausal osteoporosis. Secondary osteoporosis is due to conditions other than
age or menopause, such as reduced mobility (e.g. after fracture or associated with rheumatoid
arthritis), smoking and alcohol consumption, endocrine disorders (e.g. Cushing’s syndrome,
hyperthyroidism, diabetes) and corticosteroid therapy. Obesity and exercise appear to be
protective against osteoporosis.
Senile osteoporosis There is a normal progressive loss of bone mass after around the age of
30years, and so all elderly people will have some degree of osteoporosis. Bone loss rarely
exceeds 1% per year. The higher the initial bone density, the lower the risk of significant
osteoporosis. Women are at higher risk than men, and white people are at higher risk than
black people.
Post-menopausal osteoporosis Post-menopausal osteoporosis is characterised by
hormone-dependent acceleration of bone loss. Post-menopausal women may lose up to 2% of
cortical bone per year and up to 9% of trabecular bone per year for 8–10years, declining to the
normal rate of bone loss after that. Oestrogen deficiency is thought to have a major role, and
oestrogen replacement at the beginning of the menopause reduces the rate of bone loss.

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The major complication of osteoporosis is bone fracture. The sites most commonly affected
are the vertebral bodies, the distal radius (Colles’ fracture) and the hips. Fractures of the
vertebral bodies can be of the ‘crush’ variety leading to progressive loss of height and
considerable pain, or of the ‘wedge’ variety causing deformity of the spine (kyphosis). Hip
fractures are important because they cause major disability and lead to hospital admission.
Secondary complications such as pneumonia and pulmonary thromboembolism are common
with hip fractures, and account for the high mortality rate associated with hip fractures.

Treatment

Women who take hormone replacement therapy have a reduced risk of developing post-
menopausal osteoporosis. Also, oral bisphosphonates and vitamin D may be effective.

Metabolic bone disease

Rickets and osteomalacia

Osteomalacia is characterised by defective mineralisation of the osteoid matrix, and is


associated with lack of vitamin D. When the condition occurs in the growing skeleton (children)
it is called rickets. Vitamin D is important in the maintenance of adequate serum calcium and
phosphorus levels, and deficiency impairs normal mineralisation of osteoid laid down in the
remodelling of bone. The result is osteomalacia. In children, lack of vitamin D leads to
inadequate mineralisation of the epiphyseal cartilage as well as the osteoid, resulting in
rickets.

Aetiology

There are two main sources of vitamin D – dietary and endogenous. Consequently, there are
four main causes of osteomalacia:

• Dietary deficiency of vitamin D – this used to be a common cause of rickets and


osteomalacia. Improvements in diet and the addition of vitamin D to foodstuffs has drastically
reduced the incidence of osteomalacia due to nutritional deficiency.
• Intestinal malabsorption – this is now the commonest cause of osteomalacia. Vitamin D is
fat soluble. Any condition that causes malabsorption or poor absorption of fat (steatorrhoea)
can cause osteomalacia. Causes include coeliac disease and Crohn’s disease.
• Deficiency of endogenous vitamin D due to defective synthesis in the skin – more than
90% of circulating vitamin D is photochemically synthesised in the skin. A steroid molecule
precursor found in the epidermis is converted to vitamin D by UV light from the sun. Decreased
exposure to sunlight or increased skin pigmentation hinders synthesis of vitamin D.
• Renal or liver disease – newly synthesised vitamin D is biologically inactive. A number of
metabolic steps are required to convert vitamin D into its active form. The first of these steps is
carried out by hepatocytes. The resulting compound is converted to the active form of vitamin
D (1,25-dihydroxycalciferol) in the kidney. Hence, renal disease and, to a lesser extent, liver
disease can lead to a deficiency in the active form of vitamin D.

Clinicopathological features

The basic abnormality is deficient mineralisation of the organic matrix of the skeleton. In
children, the skeleton becomes deformed because there is reduced structural rigidity and
inadequate ossification at the growth plates. In pre-ambulatory infants, there is flattening of the
occipital bones, and in ambulatory children, bowing of the legs and lumbar lordosis are
characteristic. A pigeon breast deformity may develop due to the forces incurred on the
weakened bones of the chest during normal respiration. Excess osteoid may cause frontal
bossing of the head. Inadequate calcification of the epiphyseal cartilage in long bones leads to
Masterplates,
cartilaginous overgrowth at the growth Medicine General
resulting and Systematic
in localised Pathology
enlargement, which is seen
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especially at the wrists, knees and ankles. Overgrowth of the cartilage at the costochondral
junctions of the chest results in an appearance that is referred to as a ‘rachitic rosary’.
In adults, the osteoid that is laid down in the remodelling of bone is inadequately mineralised.
The shape of the bone is usually not affected, but the bone becomes vulnerable to
spontaneous fractures. Looser zones (pseudofractures) are the hallmark of osteomalacia, and
they appear on X-rays as transverse linear lucencies perpendicular to the bone surface.
Persistent inadequate mineralisation may eventually lead to generalised osteopenia.

Hyperparathyroidism and renal osteodystrophy


These are discussed in Chapter 19.

Paget’s disease (osteitis deformans)

The aetiology of Paget’s disease is uncertain. There is an initial phase of osteoclastic


resorption of bone followed by a ‘reparative phase’ in which there is intense osteoblastic
activity and overproduction of disordered and architecturally abnormal bone. Bones may
become larger than normal, and are composed of structurally unsound cortical bone and
thickened trabeculae with numerous prominent cement lines, which give the bone its
characteristic ‘mosaic pattern’ on microscopy. Later, bone may become ivory hard (‘sclerosis’).
The abnormal bone is vulnerable to fracture.

Clinical features and complications

The clinical features and complications of Paget’s disease are:

• bone pain
• fractures
• neuropathies
• deformities
• deafness
• high-output heart failure
• osteosarcoma and other bone tumours.
The usual presenting features are bone pain, deformities and fractures. The axial skeleton,
skull and proximal femur are involved in the vast majority of cases. Pain is a common problem,
and is localised to the affected bone. Deformities are most common when the skull is involved,
resulting in enlargement of the head with protuberance of the frontal lobes and lion-like
(leonine) facies. When the long bones of the lower extremities are involved, weight-bearing
leads to anterior bowing of the legs. Fractures occur most commonly in the long bones of the
legs, and ‘crush’ fractures of the spine may lead to spinal cord injury and kyphosis.
The spinal cord and nerve roots are also at risk of compression due to enlargement of the
vertebral bodies. Distortion of the middle ear cavity and VIIIth nerve compression may lead to
deafness. Other cranial nerves may be affected by compression. The bones in Paget’s disease
are extremely vascular, and the subsequent increased blood flow can (rarely) lead to high-
output heart failure. Paget’s disease may be complicated by the development of bone tumours,
the most sinister being osteosarcoma.

Diagnosis and treatment

Paget’s disease may be detected incidentally on X-ray or become manifest through the
development of typical clinical features. Intense osteoblastic activity means that affected
individuals have raised serum alkaline phosphatase levels. Treatment is with calcitonin and
bisphosphonates.

Osteomyelitis
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Osteomyelitis refers to inflammation of the bone and marrow, and is usually the result of
infection.

Aetiology

Organisms may gain access to the bone by bloodstream spread from a distant infected site, by
contiguous spread from neighbouring tissues, or by direct access via a penetrating injury.
Almost any organism can cause osteomyelitis, but those most frequently implicated are
bacteria. Staphylococcus aureus is responsible for many cases. Patients with sickle cell
disease are predisposed to Salmonella osteomyelitis. Mycobacterium tuberculosis is
sometimes implicated.

Pathogenesis

The location of the lesions within a particular bone depends on the intraosseous vascular
circulation, which varies with age. In infants less than a year old, the epiphysis is usually
affected. In children the metaphysis is usually affected, and in adults the diaphysis is most
commonly affected.
In acute osteomyelitis, once the infection has become localised in bone, an intense acute
inflammatory process begins. The release of numerous mediators into the haversian canals
leads to compression of the arteries and veins, resulting in localised bone death
(osteonecrosis). The bacteria and inflammation spread via the haversian systems to reach the
periosteum. Subperiosteal abscess formation and lifting of the periosteum further impairs the
blood supply to the bone, resulting in further necrosis. The dead piece of bone is called the
sequestrum. Rupture of the periosteum leads to formation of drainage sinuses, which drain
pus onto the skin. If osteomyelitis becomes chronic, a rind of viable new bone is formed
around the sequestrum and below the periosteum. This new bone is called an involucrum. An
intraosseous abscess, called a Brodie abscess, may form.

Clinical features and treatment

Acute osteomyelitis presents with localised bone pain and soft tissue swelling. If there is
systemic infection, patients may present with an acute systemic illness. Presentation may be
extremely subtle in children and infants, who may present only with pyrexia (pyrexia of
unknown origin, PUO). Characteristic X-ray changes consist of a lytic focus of bone
surrounded by a zone of sclerosis. Treatment requires aggressive antibiotic therapy.
Inadequate treatment of acute osteomyelitis may lead to chronic osteomyelitis, which is
notoriously difficult to manage. Surgical removal of bony tissue may be required.

Avascular necrosis

This is necrosis of bone due to ischaemia. Ischaemia may result if the blood supply to a bone
is interrupted, which may occur if there is a fracture particularly in areas where blood supply is
suboptimal (e.g. the scaphoid and the femoral neck). Most other cases of avascular necrosis
are either idiopathic or follow corticosteroid administration.

Bone tumours
Primary bone tumours are uncommon. They can generally be classified according to whether
they are cartilage-forming or bone-forming.

Benign cartilage-forming tumours

Osteochondroma (exostosis)
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Osteochondromas are cartilage-capped bony outgrowths, which most frequently occur near
the metaphysis of long bones. Affected individuals are usually less than 20years of age.
Exostoses are usually solitary. Malignant change is very rare.

Chondroma (enchondroma)

Chondromas are cartilaginous tumours that usually arise within the medullary cavity of the
bones of the hands and feet. They occur most frequently in the third to fifth decades of life.
The lesions can sometimes cause localised pain, swelling, tenderness or pathological fracture.
X-rays show the characteristic ‘O-ring’ sign – oval-shaped radiolucent cartilage surrounded by
a dense rim of bone. Most chondromas are solitary. Malignant change is extremely rare.
Other rare benign cartilage-forming tumours are chondroblastomas and chondromyxoid
fibromas.

Malignant cartilage-forming tumours

Chondrosarcoma

Chondrosarcoma is the second most common primary tumour of bone, being half as frequent
as osteosarcoma. Chondrosarcomas occur most frequently in the trunk bones (ribs, spine and
pelvis). A few develop within pre-existing osteochondromas, chondroblastomas, or bones
affected by Paget’s disease. They present as painful enlarging masses, and their nodular
growth pattern gives them a scalloped appearance on X-ray. Most chondrosarcomas are low
grade, and therefore pursue a relatively indolent course. However, high-grade tumours
metastasise in 70% of cases, usually to other parts of the skeleton or the lungs.

Benign bone-forming tumours

Osteoma

These are bosselated tumours of bone, which most frequently occur in the skull and facial
bones. Symptoms depend on the site at which they occur, e.g. symptoms due to obstruction of
paranasal sinuses, symptoms related to impingement on the brain.

Osteoid osteoma

These round tumours consist of a small central area (called the ‘nidus’) surrounded by dense
sclerotic bone. Affected individuals are usually less than 25years old. The lesions are
characteristically painful.

Malignant bone-forming tumours

Osteosarcomas

These are the commonest primary malignant tumour of bone, and they usually affect young
adults. The metaphysis of long bones are the most frequently affected sites, particularly the
distal femur. They present as painful enlarging masses. The tumours usually penetrate the
bone cortex, causing elevation of the periosteum. This produces the characteristic triangular
shadow (Codman triangle) seen on X-ray, formed by the bone cortex and the elevated ends of
the periosteum. Patients with hereditary retinoblastoma are at significantly increased risk of
developing osteosarcomas. Mutations in the p53 gene have also been implicated in some
cases. A few cases are secondary to Paget’s disease or previous radiation. These aggressive
tumours can metastasise widely, especially to the lungs, but due to advances in treatment, the
5-year survival has improved to around 50%.
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Miscellaneous bone tumours

Ewing’s sarcoma

This tumour is composed of small, round, darkly staining cells, which are now believed to be
neuroectodermal in origin. The tumour affects children and adolescents, the average age at
presentation being 10–15years. The pelvis and the diaphysis of long bones are the most
frequently affected sites. The tumour presents as a painful enlarging mass, and some patients
may have systemic features such as a fever, raised white cell count, or raised erythrocyte
sedimentation rate (ESR). Treatment with radiotherapy and chemotherapy has drastically
improved survival rates.

Fibroblastic tumours

Although fibroblastic tumours such as malignant fibrous histiocytomas and fibrosarcomas more
frequently arise within soft tissues, they can also occur in bones. A quarter of cases are
secondary to pre-existing conditions such as Paget’s disease, radiation, or bone infarct. The
prognosis for high-grade tumours is poor.

Secondary bone tumours

The commonest malignant tumours of bone are secondary deposits from other sites. Most
skeletal secondary deposits originate from malignancies at the following sites:

• lung
• breast
• thyroid
• kidney
• prostate.
These deposits cause osteolytic lesions to the bone, with the exception of secondaries
originating from prostate tumours, which cause osteosclerotic lesions.

25.2. Joints
Learning objectives
You should:

• know the structure and function of joints


• know the major joint diseases, their pathogenesis and clinicopathological features.

Structure and function


Joints are of two types:

• Solid joints – these joints are fixed and rigid, and allow only minimal movement. Examples
of solid joints include the skull sutures (where the skull bones are bridged by fibrous tissue)
and the symphysis pubis (where the bones are joined by cartilage).
• Synovial joints – these joints have a joint space, which allows a wide range of movement.
The articular cartilage in synovial joints is a specialised hyaline cartilage, which is an excellent
shock absorber. The synovial membrane secretes synovial fluid into the joint space. Synovial
fluid acts as a lubricant and provides nutrients for the articular hyaline cartilage (Figure 70).

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Figure 70

A synovial joint.

Osteoarthritis (degenerative joint disease)


This is the most common type of joint disease, and is characterised by the progressive erosion
of articular cartilage in weight-bearing joints. The incidence increases with age. Osteoarthritis
can be primary or secondary to other bone or joint diseases, systemic diseases such as
diabetes, a congenital or developmental deformity of a joint, or previous trauma including
repetitive trauma.

Pathology and pathogenesis

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