Osteoarticular and connective tissues

Published on 19/03/2015 by admin

Filed under Pathology

Last modified 19/03/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 4569 times

Chapter 25 Osteoarticular and connective tissues

Common clinical problems from osteoarticular and connective tissue disease 711
Pathological basis of clinical signs and symptoms of bone, joint and connective tissue diseases 711
BONE 712
Normal structure and function 712
Structure of bone
Development and growth of bones
Fractures and their healing 714

Causes of fractures
Fracture healing
Osteoporosis and metabolic bone disease 715

Normal calcium metabolism
Rickets and osteomalacia
Hyperparathyroidism and hypercalcaemia
Bone disease in renal failure (renal osteodystrophy)
Osteomyelitis 720
Paget’s disease 721
Miscellaneous bone disorders 723

Avascular necrosis of bone
Fibrous dysplasia
Hypertrophic osteoarthropathy
Osteogenesis imperfecta
Bone tumours 723

Incidence and aetiology
Benign tumours
Malignant tumours
Normal structure and function 726
Osteoarthritis (osteoarthrosis) 728
Rheumatoid disease 730

Aetiology and pathogenesis
Clinicopathological features
Laboratory investigations
Prognosis and complications
Rheumatoid disease in children
Spondyloarthropathies 734

Ankylosing spondylitis
Reiter’s disease
Psoriasis and arthritis
Arthritis and bowel disease
Degenerative disease of intervertebral discs 735
Infective arthritis 735

Uncommon forms of infective arthritis
Rheumatic fever 736
Gout 736
Pyrophosphate arthropathy 738
Joint involvement in systemic disease 738
Traumatic and degenerative conditions of connective tissues 739
Connective tissue diseases 739

Systemic lupus erythematosus
Polyarteritis nodosa
Polymyalgia rheumatica
Cranial arteritis
Polymyositis and dermatomyositis
Mixed connective tissue disease (MCTD)
Connective tissue tumours 745

Benign connective tissue tumours
Malignant connective tissue tumours (sarcomas)
Tumour-like lesions of connective tissues
Commonly confused conditions and entities relating to osteoarticular and connective tissue pathology 746

Common clinical problems from osteoarticular and connective tissue disease



Pathological basis of clinical signs and symptoms of bone, joint and connective tissue diseases

Sign or symptom Pathological basis
Bone disease
Pain Stimulation of nerve endings in bone by:

trauma (fracture)
pathological increased bone resorption (e.g. Paget’s disease)

Fracture after trivial injuryBone weakening due to:

congenital disorders of bone integrity
metabolic bone disease
erosion of bone by tumour

DeformityAbnormal bone growth/remodelling due to:

congenital disorders of bone integrity
metabolic bone disease
malunion of a fracture


Extensive bone erosion by tumour deposits
Secretion of parathyroid hormone (PTH) by parathyroid adenoma
Secretion of PTH-related peptide by visceral tumours, e.g. carcinoma of the bronchus

Joint disease PainStimulation of nerve endings in joint capsule and synovium by inflammation (arthritis) or abnormal load bearing/joint movementDeformityJoint swelling due to:

synovial inflammation
effusion into joint space
Erosion of articular surfaces
Abnormal remodelling of subchondral bone
Loss of alignment of joint surfaces by cartilage destruction and bone deformity

Restricted movement

Synovial swelling
Limited by pain

Systemic features (e.g.subcutaneous nodules,lymphadenopathy)Arthritis mediated by immune mechanismsConnective tissue diseases Swelling


Joint painSynovial oedema and inflammation with stimulation of nerves in joint capsuleIschaemic lesionsVasculitisRestricted mobility of tissuesFibrosis or increased tissue tension due to inflammation



Functions of bone

Bone has structural, protective and metabolic functions. The skeleton is divided into the axial (head, vertebral column, thoracic cage, shoulder and pelvic girdles) and the appendicular (limbs). The axial skeleton participates extensively in all three areas of function, whereas the appendicular skeleton has a primarily structural function. The structural functions of bone are to provide support and also insertion sites for muscles and ligaments. The skull and thoracic cage provide physical protection for the brain, thoracic and upper abdominal organs.

Bone has two major metabolic functions:

1. It provides a reservoir of essential minerals, most importantly calcium, phosphorus (in the form of phosphate) and magnesium. These minerals can be released from bone matrix through the process of bone resorption (see below) and are also constantly incorporated into bone matrix during the process of bone mineralisation.
2. The second metabolic function provided by bone is the support of haemopoiesis. This is a metabolic function rather than simply a structural function: the bone micro-environment provides growth factor support for haemopoietic precursors which, under normal circumstances, reside in no other tissue in the adult human body.

The main clinical manifestations of bone disease are:

disturbances of mineral homeostasis (usually hypercalcaemia).

Structure of bone

Bone is characterised by its hard matrix. This matrix consists of two components, matrix proteins and mineral. The main structural protein in bone matrix is type I collagen. This protein provides the framework of the overall structure of bone. Within the collagen framework there is a mixture of many other proteins, some of which are thought to aid mineralisation; others mediate cell attachment. Another major group of proteins present in bone matrix are growth factors, such as the bone morphogenetic proteins and transforming growth factor beta (TGF-beta). These appear to be important in mediating the cellular events of bone remodelling. Proteoglycans are also present in bone matrix, but do not have the same major structural role in bone as they do in cartilage. The mineral component of bone matrix provides its structural resilience. Most of the mineral deposited in bone is in the form of a calcium phosphate complex known as hydroxyapatite. The precise mechanism by which bone mineral forms is unclear. The enzyme alkaline phosphatase, a major product of osteoblasts, and vitamin D metabolites are thought to be important in this process.

Despite its lifeless appearance, bone is a highly complex and dynamic cellular tissue. Bone contains two distinct types of cell, osteoclasts and the osteoblast family. Osteoclasts, the bone-resorbing cells, are mono- or multinucleated cells that are specialised members of the monocyte–macrophage lineage. These short-lived cells are recruited to the bone surface at sites of remodelling and destroy bone matrix by secreting hydrogen ions and proteolytic enzymes into a sealed space beneath the cell. The osteoblast family consists of: osteoblasts, which are bone forming cells; osteocytes, which form an interconnecting network throughout bone matrix; and lining cells, which cover metabolically inactive bone surfaces. Osteocytes are thought to be mechanosensory cells. The cells of the osteoblast family are unrelated to osteoclasts, being related more closely to fibroblasts, chondrocytes and adipocytes.

Osteoclasts and osteoblasts act together to control bone growth and metabolism through the bone remodelling cycle. This cycle, illustrated in Figure 25.1, forms the basis of bone metabolism.


Fig. 25.1 The bone remodelling cycle. The bone remodelling cycle consists of resorption by osteoclasts (arrowheads in left-hand plate) which results in the removal of an area of bone matrix and is inevitably followed at the same site by resynthesis of bone matrix by osteoblasts (right-hand plate). Many osteoblasts become incorporated into the matrix they synthesise to become osteocytes (arrowed). Osteocytes are connected by a complex network of cytoplasmic processes not visible on these haematoxylin and eosin-stained sections.

Each remodelling cycle takes several weeks to complete. Approximately one million remodelling cycles are occurring within the adult human skeleton at any one time. These cycles are asynchronous, some being in resorption, some in formation. This continual process of remodelling renews the adult human skeleton approximately every 7 years. The functions of the remodelling cycle are to:

continually release minerals to maintain appropriate levels in the circulation
maintain structural integrity of bone
allow changes in bone structure in response to the requirements of growth or changes in load bearing.

In the normal bone remodelling cycle, resorption and formation are coupled, with the same quantity of bone being formed as had been resorbed, except where extra bone matrix is called for by the requirements of growth. In pathological situations, the two processes can become uncoupled; for example, osteoporosis can result from uncoupled increases in bone resorption or decreases in bone formation resulting in a net loss of bone. All diseases of bone are associated with changes in bone remodelling of some type.

There are two types of mature bone, cortical and trabecular (sometimes known as cancellous bone). Cortical bone has a predominantly structural load-bearing function. It is the dense bone that forms the diaphyses (shafts) of long bones such as the femur and the outer surfaces of predominantly trabecular bones such as the vertebral bodies. Trabecular bone has some structural function, but contributes to the metabolic functions of bone far more than cortical bone. Because it is metabolically more active, it is far more prone to diseases involving or resulting from increased bone remodelling than cortical bone. For example, post-menopausal osteoporosis affects trabecular bone before it affects cortical bone, and deposits of metastatic carcinoma are far more common in sites occupied by trabecular bone.

Development and growth of bones

Most tissues and organs grow as a result of a general increase in the number of their constituent cells. Because the proteinaceous matrix is so heavily calcified, a similar process is not possible in bone. Thus the process of remodelling described above is essential for bone growth.

During development, bone is formed either directly in connective tissue, as in the skull (intramembranous ossification), or on pre-existing cartilage, as in the limb bones (endochondral ossification).

During intramembranous ossification the first bone that is laid down has a loose and rather haphazard arrangement. This ‘woven bone’ gradually matures into more organised and compact ‘lamellar’ bone.

Endochondral ossification is a much more complicated process during which a cartilagenous template is converted into a bony structure with capacity for further growth. In each bone, ossification occurs at particular sites or centres of ossification situated in the shaft (diaphyseal centres) or towards the ends of the bone (epiphyseal centres) (Fig. 25.2). Ossification proceeds at different, but predictable, rates in each particular bone. In long bones, a plate of epiphyseal cartilage persists into adolescent or early adult life; this allows a continual increase in bone length. Skeletal growth through the growth plates is controlled by growth hormone and sex steroids with parathyroid hormone-related peptide (PTHrP) and insulin-like growth factor-1 (IGF-1) acting as paracrine (locally produced) growth factors. The overall shape and size of bone changes during growth and, to some extent, in adult life. This involves both osteoclastic bone resorption and enlargement of pre-existing, or the formation of new, bony trabeculae. Cortical bone grows in an analogous way through remodelling occurring at the periosteal and endosteal surfaces and within Haversian canals.


Fig. 25.2 Structure of a long bone.


image Types of fracture: simple (clean break); comminuted (multiple bone fragments); compound (breaking through overlying skin); complicated (involving adjacent structures—blood vessels, nerves, etc.); stress fractures (small linear fractures)
image Pathological fracture: fracture of bone weakened by disease (e.g. tumours, osteoporosis, osteomalacia, Paget’s disease)
image Healing requires immobilisation of approximated bone ends
image Healing may be impaired by movement, poor blood supply, interposition of soft tissue, infection, poor nutrition, steroid therapy

Causes of fractures

Fractures in normal bone are the result of substantial trauma, such as direct violence or a sudden unexpected fall. The precise site of fracture, the nature and direction of the fracture line, and the speed of the subsequent repair process depend very much on the age of the patient, the particular bone involved and the precise pattern of injury (Fig. 25.3).


Fig. 25.3 Fracture types and fracture healing. image A greenstick fracture of the distal radius in a young child (arrowed). image A displaced spiral fracture of the femur in a child. image A comminuted fracture of the tibia. One fragment of bone has almost separated from the shaft. image A healing fracture of the ulna. The site of the break is just visible and is surrounded by callus (arrowed).

Repeated episodes of minor trauma, for example after marching, marathon running or training for sport, can produce small but often painful stress fractures. These usually occur in the long bones of the lower limbs but have also been described in the metatarsals, the upper limb, pelvis and spine. They usually heal satisfactorily after a short period of rest. Even professional athletes can develop these fractures.

Fractures occur more easily in bone that is structurally abnormal. They may occur after a trivial injury or minor fall or even spontaneously during normal activity. This is particularly common in patients with osteoporosis but also occurs in most forms of metabolic bone disease (e.g. in osteomalacia and rickets), in Paget’s disease and in bone infiltrated by malignant tumours. Fractures of this type are called pathological fractures.

Fracture healing

The first stage in fracture healing is the formation of a bony bridge between the separated fragments. When this is formed, and some rigidity has been regained, remodelling and restructuring gradually restore the normal contours of the fractured bone. This process and the factors that can interfere with it are described in Chapter 6.

The major causes of delayed fracture healing are:

1. Local factors:

excessive movement of fractured bone during healing
extensive damage to fractured bone, i.e. bony necrosis in a comminuted fracture
a poor intrinsic blood supply, e.g. lower tibia
severe local soft tissue injury or impaired blood supply
interruption of blood supply following fracture, e.g. head of femur, scaphoid
infection—only if overlying skin surface is broken, as in compound fracture
interposition of soft tissue in fracture gap, or wide separation of fracture ends.
2. General factors:

elderly patients
poor general health
drug therapy, e.g. corticosteroids.

All of these are well recognised by orthopaedic surgeons, who modify the treatment in individual cases in line with the particular pattern of injury, and the age and general health of the patient. For example, a fracture through the neck of the femur usually deprives the head of its normal blood supply and satisfactory fracture healing is unlikely to occur. Surgical treatment, such as excision of the head and replacement by a metallic prosthesis, is therefore essential. Fractures in which the overlying skin surface is broken (compound fractures) are liable to infection, whereas this is extremely uncommon in closed fractures. Healing will be substantially delayed if a wound infection develops.

In many fractures, healing can be accelerated by prompt and appropriate surgical treatment using internal fixation by nails, plates and screws or external fixator devices to hold the fractured fragments in an appropriate position; this often allows early mobilisation. Primary callus does form but is reduced in amount. Small gaps are filled by new woven bone. Dead bone is gradually revascularised and new Haversian bone grows in.

Surgical treatment is sometimes necessary for fractures in which the healing process has been delayed. The object is to ‘restart’ the primary callus response. This can sometimes be achieved by lifting flaps of periosteum close to the fracture site. In addition, local ‘grafting’ with the patient’s own bone or devitalised bone from another donor can promote bone healing, presumably through the action of bone morphogenetic proteins and other growth factors present in the graft matrix.


Normal calcium metabolism

The two major hormones that regulate calcium metabolism are vitamin D and parathyroid hormone (PTH). Vitamin D is not a vitamin in the strict sense of an essential dietary requirement, as it can also be synthesised photochemically in the skin. In reality, vitamin D is more like a steroid hormone precursor that can be derived from the diet. Its active metabolites function in a similar way to conventional hormones. Vitamin D must be metabolised by the liver to 25-hydroxyvitamin D3, and subsequently by the kidney to the active metabolite 1,25-dihydroxyvitamin D3. Receptors for vitamin D are present in a variety of cell types in the body; the physiological role of this vitamin may be much wider than is currently known. Expression of the receptors is subject to genetic variation within the population and may contribute to the individual differences in risk of developing metabolic bone disease. The combined effects of vitamin D and parathyroid hormone are:

to stimulate bone calcium mobilisation
to increase renal reabsorption of calcium in the distal tubule (chiefly PTH, but also vitamin D)
to stimulate intestinal calcium and phosphate absorption (vitamin D).

These functions are complex and are demonstrated in Figure 25.4. This area of metabolism is still incompletely understood. There is evidence to suggest that there may be another pathway regulating phosphate transport involving fibroblast growth factor 23. PTH and 1,25-dihydroxyvitamin D3 also have important direct effects on bone: PTH stimulates both bone resorption and formation; 1,25-dihydroxyvitamin D3 promotes bone matrix mineralisation.


Fig. 25.4 Regulation of calcium metabolism. Calcium levels are maintained in the extracellular fluid within a narrow range of concentrations by absorption from the gut and excretion via the kidney with bone acting as a buffering reservoir. PTH raises calcium levels by increasing renal tubular calcium reabsorption, increasing release of calcium from bone matrix through osteoclastic resorption and indirectly increasing calcium absorption from the gut by increasing the metabolism of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (the active form) in the kidney.

In contrast to PTH, calcitonin, a peptide hormone, appears to lower serum calcium, but usually only when it is pathologically elevated. The stimulus to its secretion is an increase in the serum calcium concentration; it is produced in specialised parafollicular cells (C-cells) of the thyroid. Its exact physiological action is uncertain but it has an inhibitory effect on osteoclasts.

Although vitamin D, PTH and, possibly, calcitonin are the most important factors controlling calcium and phosphate concentrations, and therefore normal bone integrity, several other factors are also involved. Glucocorticoids have a role in the regulation of skeletal growth but prolonged corticosteroid therapy often induces osteoporosis. Thyroid hormone deficiency, as in cretinism, is associated with several skeletal abnormalities. Sex steroids accelerate the closure of epiphyses, and growth hormone has an effect on the development and maturation of cartilage.


image Reduction in total bone mass causing weakening
image Common in the elderly, particularly females
image Common predisposing cause of fractures, particularly neck of femur
image Complication of steroid therapy and Cushing’s syndrome
image Follows any form of immobility
image Associated with alcoholism, diabetes, liver disease and smoking

Osteoporosis is a disease in which there is a reduction in bone mass in the presence of normal mineralisation. It is diagnosed by radiological assessment of bone mineral density (generally measured by dual photon absorptiometry). The usual definition of osteoporosis is a bone mineral density measurement two standard deviations below the mean value for young adults of the same sex. Clinically, osteoporosis may present as a fragility fracture, loss of height, or stooping deformity (kyphosis or ‘dowager’s hump’) due to wedge fractures of the vertebral bodies. Sometimes osteoporosis is diagnosed, when clinically silent, by screening individuals thought to be at risk.

Clinically significant osteoporosis most often results from a combination of age-related bone loss and additional bone loss from another cause; by far the most common such cause is post-menopausal oestrogen withdrawal. Osteoporosis is a clinically silent disease until it is complicated by deformity or fractures.


Osteoporosis is caused by a loss of coupling in the bone remodelling process. This can be due to increased bone resorption, decreased bone formation, or both. The loss of coupling results in a net loss of bone volume. In contrast to osteomalacia (see below), mineralisation of bone is normal. Because of its greater metabolic activity, trabecular bone is usually affected more severely than cortical bone. This is particularly the case when increased bone resorption is the main pathogenetic mechanism.

The total bone mass of an individual is influenced by factors such as body build, race, gender, physical activity and general nutrition. Osteoporosis is more common in females than in males and is less common in blacks, who have a greater skeletal mass than whites or Asians. Osteoporosis can be assessed radiologically or by techniques based on the ability of bone to absorb photons released by a gamma-emitting isotope. These demonstrate a progressive loss of bone of 0.75–1% per annum in normal adults of both sexes from as early as 30 years of age. More importantly, there is an accelerated phase of bone loss of up to 1–3% per year in females in the 5–10 years following the menopause.

Localised osteoporosis is inevitable after immobilisation of any part of the skeleton. Even young, healthy males confined to bed after a limb fracture show substantial bone loss. Painful joints in patients with rheumatoid arthritis restrict movement, and osteoporosis often develops in adjacent bones, although this may also be the result of increased bone resorption due to inflammatory mediators produced in affected joints.


The major complications of osteoporosis are:

skeletal deformity
bone pain (usually due to compression fractures)

The commonest clinical feature of osteoporosis is the progressive loss of height that occurs with age. This is a direct result of compression of vertebrae. Sudden collapse or unequal compression of individual vertebral bodies can cause severe localised back pain and deformities such as kyphosis or scoliosis (Fig. 25.5).


Fig. 25.5 Vertebral osteoporosis. image The lower thoracic vertebrae showing small protrusions of the intervertebral disc into the osteoporotic bone (arrowed). image The lumbar spine. The vertebral body in the centre has collapsed and has a typical biconcave shape.

Wrist and hip fractures are common in elderly patients with osteoporosis. Although osteoporosis is the major underlying cause, other factors such as an increased tendency to fall and a loss of ‘protective neuromuscular reflexes’ (the ability to fall over safely) are also important. Hip fractures account for numerous hospital admissions and are a major source of disability and a frequent cause of death in the elderly.

Prevention and treatment

Osteoporosis is a major social and economic problem in the elderly, and preventive measures should begin in the middle-aged. Vertebral osteoporosis is reduced in women treated with oestrogens (hormone replacement therapy—HRT). Bisphosphonate drugs, which inhibit bone resorption, are more effective in preventing osteoporotic hip fractures. Regular exercise and an increased dietary intake of calcium also have beneficial effects.

Rickets and osteomalacia

image Inadequate mineralisation of organic bone matrix
image Rickets occurs in children and is characterised by bone deformities
image Osteomalacia occurs in adults, causing susceptibility to fracture but few deformities
image Due to deficiency of active metabolites of vitamin D
image Causes include nutritional deficiency of vitamin D, lack of sunlight, intestinal malabsorption, renal and liver disease

Osteomalacia is characterised by deficient mineralisation of the organic matrix of the skeleton. Rickets is the name given to osteomalacia affecting the growing skeleton of children; it results in characteristic deformities. Causes of osteomalacia, or rickets, include:

dietary deficiency of vitamin D
intestinal malabsorption
failure to metabolise vitamin D (renal disease, congenital enzyme deficiencies).


In the past, nutritional deficiency of vitamin D was a common cause of rickets in children and, occasionally, of osteomalacia in adults. In most communities, this has been eliminated by improvements in diet and by the addition of vitamin D to foodstuffs. The disease still occurs in some Asian communities in the UK; skin pigmentation impairs photochemical synthesis of vitamin D, and a constituent of chapatti flour interferes with calcium and phosphate absorption in the gut. As dietary rickets is becoming less common in Western countries, an increasing proportion of cases of rickets are due to congenital abnormalities in vitamin D metabolism. Disorders of this type are referred to as ‘vitamin D-resistant rickets’ because vitamin D supplements fail to generate active vitamin D metabolites.

Malabsorption of calcium and phosphate from the intestine is the commonest cause of osteomalacia in adults. The underlying cause is often coeliac disease, but occasional cases result from Crohn’s disease or extensive surgical resection of the small intestine. As the liver and kidney have important roles in the metabolism of vitamin D, renal and hepatic disorders may cause osteomalacia. This is uncommon in liver disease, but a complex pattern of bone disease that includes osteomalacia is seen in renal failure. Occasional patients treated with anticonvulsants, such as phenytoin, develop osteomalacia. These drugs induce liver enzymes that degrade vitamin D to inactive metabolites.


The characteristic clinical deformities of rickets include:

bowing of the long bones of the leg
pronounced swelling at the costochondral junctions
flattening or ‘bossing’ of the skull.

Inadequate mineralisation of bone reduces its normal strength and allows deformities to develop, for example from pressure on the skull while lying in a cot, or on the limbs as they begin to bear weight. Calcification of epiphyseal cartilage is an essential step in the normal process of ossification in long bone. When the levels of vitamin D metabolites are low, calcification cannot occur and cartilaginous proliferation continues. This accounts for the enlargement of long bones and the ribs at growth plates.

The characteristic pathological feature in adults with osteomalacia is spontaneous incomplete fractures (‘Looser’s zones’), often in the long bones or pelvis. The main symptoms are bone pain and tenderness, and weakness of proximal limb muscles. Serum calcium levels may be reduced and serum alkaline phosphatase is increased (these biochemical abnormalities are usually absent in osteoporosis). A bone biopsy will demonstrate an increase in non-mineralised osteoid (Fig. 25.6).


Fig. 25.6 Osteomalacia. This transiliac crest undecalcified bone biopsy, stained by the Goldner’s trichrome technique, was taken from a patient on renal dialysis suffering from osteomalacia due to a combination of low 1,25-dihydroxyvitamin D levels (a common consequence of renal failure) and aluminium toxicity (an iatrogenic complication of dialysis). Mineralised bone matrix is stained green and unmineralised matrix (osteoid) is stained red. The amount of osteoid present is approximately 20 times greater than normal.

Treatment and prevention

Uncomplicated rickets or osteomalacia will respond promptly to vitamin D treatment. Increased calcium intake may also be required to compensate for the flux of calcium into unmineralised bone matrix that occurs in response to vitamin D treatment. Intramuscular injection can overcome problems associated with malabsorption, and underlying disorders such as coeliac disease should be treated appropriately. A normal balanced diet will prevent rickets or osteomalacia, but many foodstuffs are now artificially supplemented with vitamin D.

Hyperparathyroidism and hypercalcaemia

image Hyperparathyroidism causes increased osteoclastic breakdown of bone
image Serum calcium is usually raised in primary hyperparathyroidism, but low or normal in secondary (reactive) hyperparathyroidism
image Bone lesions may be cystic and haemorrhagic (‘brown tumours’)

Persistent elevation of fasting blood calcium, after correction has been made for the serum albumin concentration, is an important indication for further investigation. The major pathological causes are:

primary hyperparathyroidism
bone destruction by metastatic carcinoma or myeloma
inappropriate secretion of parathyroid hormone-related peptide (PTHrP) by malignant tumours
renal failure
iatrogenic, e.g. thiazide diuretics, hypervitaminosis D.

By far the commonest causes of hypercalcaemia are primary hyperparathyroidism and hypercalcaemia of malignancy.

In hyperparathyroidism (Ch. 17), increased secretion of parathyroid hormone stimulates calcium absorption in the intestine, reabsorption in the kidney and osteoclastic breakdown of bone.

In primary hyperparathyroidism the usual cause is a parathyroid adenoma or, occasionally, diffuse hyperplasia of the parathyroid glands. In contrast, in secondary hyperparathyroidism, prolonged hypocalcaemia stimulates parathyroid hyperplasia and eventually produces parathyroid enlargement. This is usually the result of renal failure or malabsorption secondary to coeliac disease. In occasional patients, secondary hyperparathyroidism is associated with hypercalcaemia. This has been called tertiary hyperparathyroidism and usually results from inappropriately high secretion of PTH by an adenoma arising in secondary hyperparathyroidism.

When obvious causes, such as malignant disease, sarcoidosis or drug therapy, have been excluded, it must be suspected that an otherwise fit patient with hypercalcaemia has primary hyperparathyroidism (Table 25.1).

Table 25.1 causes of hypercalcaemia

Cause Pathophysiology
Primary hyperparathyroidism Abnormal PTH secretion from adenoma, hyperplasia or carcinoma of parathyroid glands
Malignant disease
Secondary deposits producing bone destruction and calcium release
Inappropriate PTHrP secretion, usually squamous carcinoma of bronchus or carcinoma of breast
Uncoupled bone resorption due to myeloma

SarcoidosisProbable secretion of vitamin D metabolites from granulomas

Miscellaneous causes:

Drugs, e.g. thiazide diuretics
Renal failure (tertiary hyperparathyroidism)
Hypervitaminosis D

The advanced bone pathology associated with hyperparathyroidism is now rare. In the early stages there are subtle radiological changes such as subperiosteal resorption of phalangeal bone (Fig. 25.7) or characteristic changes around the teeth. As the disease progresses, cystic bone lesions may develop—osteitis fibrosa cystica (von Recklinghausen’s disease of bone). These are sometimes referred to as ‘brown tumours’, although they are not neoplasms. The brown appearance is the result of haemorrhage and there is often a marked associated osteoclastic reaction. Because PTH has anabolic as well as catabolic effects in bone, hyperparathyroidism does not usually cause generalised osteoporosis.


Fig. 25.7 X-ray of finger in primary hyperparathyroidism (left) and a normal patient (right). The irregular outlines of the phalanges are the result of resorption of bone.

Bone disease in renal failure (renal osteodystrophy)

Most patients with chronic renal failure have clinical, radiological or pathological evidence of bone disease. There is no single bone disease that occurs in renal failure; in most patients it is a combination of osteomalacia with a variable degree of hyperparathyroidism. Other features include:

bone necrosis
soft tissue calcification
aluminium-induced osteomalacia.

The most important pathophysiological changes in renal bone disease are summarised in Table 25.2. Several mechanisms have been suggested to account for the osteomalacia. In all forms of renal failure there is a decrease in the amount of functional renal tissue, and this may be directly responsible for the inadequate production of active vitamin D metabolites. An increased blood phosphate level (hyperphosphataemia) is frequent in renal failure, and this may directly inhibit enzymes responsible for vitamin D metabolism in the kidneys. In the past, haemodialysis fluids rich in aluminium were associated with aluminium deposition in organs such as brain and bone. In bone, aluminium inhibits the calcification of osteoid and contributes to osteomalacia in renal failure (Ch. 7).

Table 25.2 Mechanisms of renal bone disease (renal osteodystrophy)

Feature of renal failure Pathological effect in bone
Inadequate renal tissue Impaired conversion of 25(OH)D3 to 1,25(OH)2D3 → Osteomalacia
High serum phosphate
1. Inhibition of renal enzymes catalysing formation of 1,25(OH)2D3
2. Decrease in ionised Ca2+ in serum → Hyperparathyroidism

Prolonged haemodialysisInhibition of calcification of osteoid → OsteomalaciaSteroid therapy (e.g. for chronic glomerulonephritis)Osteoporosis Avascular necrosis of bone

Patients with chronic renal failure may have a low serum calcium. This is partly the result of impaired vitamin D metabolism, as vitamin D metabolites are essential for the proper absorption of calcium from the small intestine. The high serum phosphate also reduces the ionised fraction of plasma calcium. This acts as a stimulus to PTH production, and a degree of hyperparathyroidism is inevitable in severe renal failure. Patients with some forms of glomerulonephritis are treated with steroids and this may induce osteoporosis or, occasionally, areas of bone necrosis. Calcification of the soft tissues, or of blood vessel walls, is a further feature of chronic renal failure, particularly after prolonged haemodialysis. Longstanding disordered bone remodelling due to the combination of secondary hyperparathyroidism and osteomalacia can lead to alternating areas of thickened bone (osteosclerosis) and osteoporosis. This has a characteristic appearance (‘rugger jersey spine’).


image Inflammatory lesion due to bacterial infection of bone
image Bacteria enter bone either from blood (septicaemia) or directly through skin wound over a compound fracture
image Necrotic bone forms inner sequestrum; reactive new bone forms outer involucrum
image Most common in children, where Staphylococcus aureus is the usual cause
image A complication of advanced tuberculosis
image May complicate the use of internal fracture fixation devices


Osteomyelitis is the result of a bacterial infection of bone. The typical patient is a young child who presents with pain in a long bone, sometimes with a misleading history of recent trauma. In the majority of cases the lesion develops in the metaphysis, the part of the shaft immediately adjacent to the epiphyseal plate. The rich capillary network and large venous channels in this area may favour the deposition of circulating micro-organisms and their subsequent growth. In children and adolescents, osteomyelitis is usually the result of Staphylococcus aureus bacteraemia, often secondary to a boil or other skin infections. Sometimes, the underlying cause of bacteraemia is not apparent. Osteomyelitis is also increasingly seen in elderly patients.

Before the introduction of antibiotics, tuberculous and even syphilitic osteomyelitis were common. Children with haemoglobinopathies, especially sickle cell disease, have an increased risk of osteomyelitis; unusual organisms, such as Salmonella, are sometimes responsible.

Osteomyelitis is a well-recognised complication of compound fractures, particularly if the wound in the overlying skin is extensive and there are necrotic bone splinters at the fracture ends. Osteomyelitis is not a complication of closed fractures.


The classical sequence of changes in osteomyelitis is as follows:

1. transient bacteraemia, e.g. Staphylococcus aureus
2. focus of acute inflammation in metaphysis of long bone
3. necrosis of bone fragments, forming the sequestrum
4. reactive new bone forms, the involucrum (Fig. 25.8)
5. if untreated, sinuses form, draining pus to the skin surface via cloacae.

Fig. 25.8 Chronic osteomyelitis. image The radius and ulna of an 18th-century sailor. The ‘granular bone’ is the involucrum and the circular defects are ‘cloacae’ through which pus drained. image The cut surface of the femur of a 78-year-old male who received a shrapnel wound to his thigh in World War I. The pus drained through a sinus for the next 50 years! A thick bony involucrum surrounds a chronic inflammatory abscess in the marrow cavity.

The development of a sequestrum is due to necrosis of bone caused by compression of blood vessels by the inflammatory process within the Haversian canals of the cortical bone. This event rarely occurs if antibiotic treatment is initiated early in the course of the disease. However, infections in bone can be difficult to eradicate, particularly if foreign material is present, for example following a penetrating injury. Commonly encountered ‘foreign materials’ in bone are joint prostheses, internal fracture fixation devices and other pieces of orthopaedic hardware. Bone infections associated with orthopaedic surgery are more common than primary osteomyelitis in many countries.

Brodie’s abscess is a distinctive clinical form of subacute pyogenic osteomyelitis. The lesion is solitary and, as in typical acute osteomyelitis, localised to the metaphysis.

Clinical features, laboratory investigations and treatment

Most patients with acute osteomyelitis present with localised bone pain and some tissue swelling. A dull continuous back pain, which increases on straining, is typical of vertebral osteomyelitis. The radiological changes are usually characteristic. Blood cultures are positive in some patients, but open biopsy of the lesion may be needed to ensure accurate bacteriological diagnosis. The commonest organisms are Staphylococcus aureus, Mycobacterium tuberculosis, Escherichia coli, pneumococcus or group A streptococcus. Wherever possible a precise bacteriological diagnosis must be made and treatment continued for several weeks.


image Common disorder of unknown aetiology in which there is a localised increase in bone turnover
image May affect part of one bone, an entire bone, or many bones
image Most affected individuals have few symptoms
image Complicated by pain, deformities, fractures, nerve compression, deafness, osteosarcoma and (rarely) heart failure

Incidence and epidemiology

Paget’s disease is a disorder in which there is disorderly bone remodelling. There is considerable variation in its incidence both within and between different countries and racial groups. Despite intensive study, little is known of the cause of Paget’s disease and it is not regularly associated with any other common disorder. Electron microscopic studies have demonstrated probable viral inclusions in the nuclei of osteoclasts, possibly derived from measles or canine distemper virus, but no definite proof has been obtained. Paget’s disease has a distinctive epidemiology. It is most common in western Europe and those parts of the world to which western Europeans have emigrated. For unknown reasons, it is far more common in Lancashire (UK) than anywhere else in the world.

Clinicopathological features

The usual presenting complaints of patients with Paget’s disease are bone pain, deformities or fractures. Although the pelvis and spine are most frequently affected, deformities are most obvious in the long bones such as the tibia, which is characteristically bowed, and in the skull.

Serum calcium concentration is usually normal, but the alkaline phosphatase is markedly elevated, reflecting the osteoblastic activity. The histological changes of Paget’s disease consist of irregular trabecular bone, much of which is woven rather than lamellar, and areas of osteolysis with abnormally large osteoclasts. These changes reflect grossly disordered bone remodelling (Fig. 25.9).


Fig. 25.9 Paget’s disease. In normal trabecular bone (left) viewed by polarised light, note the regular lamellar pattern. In bone affected by Paget’s disease (right) the lamellar pattern is largely replaced by irregular woven bone. Bone of this type is associated with deformity and poor mechanical function.


The complications of Paget’s disease are:

bone pain
nerve or spinal cord compression
osteosarcoma, occasionally other bone tumours
heart failure.

In many patients, Paget’s disease is completely asymptomatic and is unlikely to be diagnosed unless discovered as an incidental finding on X-ray. The commonest complications are deformities (Fig. 25.10) and bone pain. In some cases, the pain is the result of osteoarthritic degeneration of a related joint. The cause of the pain is uncertain, but interestingly responds well to treatments that inhibit bone resorption. Pagetoid bone is particularly susceptible to fracturing in the initial lytic phase. Enlargement in the sclerotic stage can lead to nerve or spinal cord compression. Deafness is the result of both VIIIth cranial nerve compression and distortion of the middle ear cavity. Occasional patients develop other cranial nerve palsies and, in advanced cases, paraplegia can result.


Fig. 25.10 Paget’s disease. This affected femur shows characteristic thickening and deformity.

Buy Membership for Pathology Category to continue reading. Learn more here