Osteoarticular and connective tissues

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 microenvironment provides growth factor support for haemopoietic precursors which, under normal circumstances, reside in no other tissue in the adult human body.

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. 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 mononucleated 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 Fig. 25.1 , forms the basis of bone metabolism.

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, postmenopausal 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 preexisting 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 cartilaginous 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 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 preexisting, 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.

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 ).

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 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 5 . The major causes of delayed fracture healing are:

• 1.

  Local factors:

  • excessive movement of fractured bone during healing

  • extensive damage to fractured bone, that is, bony necrosis in a comminuted fracture

  • a poor intrinsic blood supply, for example, lower tibia

  • severe local soft tissue injury or impaired blood supply

  • interruption of blood supply following fracture, for example, 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, for example, corticosteroids.

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.

Normal calcium metabolism

The two major hormones that regulate calcium metabolism are vitamin D and 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 D ₃ , and subsequently by the kidney to the active metabolite 1,25-dihydroxyvitamin D ₃ . 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 PTH 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 Fig. 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 D ₃ also have important direct effects on bone: PTH stimulates both bone resorption and formation; 1,25-dihydroxyvitamin D ₃ promotes bone matrix mineralisation.

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.

Osteoporosis

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 postmenopausal oestrogen withdrawal. Osteoporosis is a clinically silent disease until it is complicated by deformity or fractures.

Complications

The major complications of osteoporosis are:

• skeletal deformity

• bone pain (usually due to compression fractures)

• fracture.

The most common 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 ). 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.

Rickets and osteomalacia

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).

Diagnosis

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 nonmineralised osteoid ( Fig. 25.6 ).

Hyperparathyroidism and hypercalcaemia

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 PTHrP by malignant tumours

• sarcoidosis

• renal failure

• iatrogenic, for example, thiazide diuretics, hypervitaminosis D.

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

In hyperparathyroidism ( Ch. 17 ), increased secretion of PTH 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. These conditions are sometimes part of the multiple endocrine neoplasia syndromes MEN 1 and MEN 2A. 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 ).

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 or characteristic changes around the teeth. As the disease progresses, cystic bone lesions may develop — osteitis fibrosa cystica (von Recklinghausen disease of bone) . Solid brown-destroying masses sometimes referred to as ‘brown tumours’ can also form. 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.

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:

• osteosclerosis

• osteoporosis

• 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. 6 ).

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. Long-standing 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’).

Achondroplasia

Achondroplasia is a single-gene disorder transmitted as an autosomal dominant with almost complete penetrance; it occurs in approximately 1 in 25,000 births. The affected gene is fibroblast growth factor receptor type 3, which has an important function in endochondral ossification. The physical appearances of the patients are characteristic. The limbs are short, particularly the proximal portions of the arms, but the trunk is of normal length. There is a failure of proper ossification in bones that have developed from a cartilaginous template (endochondral ossification). In contrast, bones that develop from connective tissue (intramembranous ossification), such as the vault of the skull, are normal. Affected patients have normal intelligence and lifespan. There is a wide variety of other congenital skeletal dysplasias, many of which are lethal in utero. Achondroplasia is the most common nonlethal form.

Avascular necrosis of bone

This usually presents with pain and limitation of joint movement. For anatomical reasons, fractures of bones such as the neck of the femur ( Fig. 25.9 ) or the scaphoid deprive some areas of adjacent bone of their blood supply. Necrosis is then an inevitable consequence. Surgical treatment is therefore sometimes necessary to replace the fractured head of femur. The cause of other cases of avascular necrosis is less certain. Lesions occur in patients treated with corticosteroids, in sickle cell disease and other haemoglobinopathies. Similar lesions develop in divers and are probably the result of air embolism associated with decompression.

Fibrous dysplasia

In this benign disorder of children and young adults, lesions composed of fibrous and bony tissue develop, usually in the ribs, femur, tibia or skull. It is sometimes associated with precocious puberty (McCune–Albright syndrome). The cause is a mutation in the GNAS1 gene. Histologically, these lesions are composed of irregular masses of immature woven bone separated by a richly vascular fibrous stroma. Mature lamellar bone is not formed and this suggests that the lesion is a result of an arrest of bone maturation at the woven bone stage. Lesions do not usually enlarge after puberty, though some appear to be reactivated during pregnancy. Although the clinical and radiological findings are often diagnostic, lesions in long bones are often biopsied and the affected parts of ribs can be excised.

Hypertrophic osteoarthropathy

This is an uncommon reactive condition in which there is clubbing, pain and swelling of the wrist and ankle joints, and subperiosteal new bone formation in the distal part of long bones. In the vast majority of affected patients, there is an associated pulmonary carcinoma or a pleural mesothelioma. The underlying causes of both clubbing and hypertrophic osteoarthropathy are unknown, but in both cases, there is a marked increase in blood flow in the distal portions of the limbs. Occasional cases regress after surgical treatment of the primary tumour.

Osteogenesis imperfecta

Osteogenesis imperfecta is a clinical syndrome characterised by fractures occurring as a result of mild or minimal trauma. In its most severe form it is fatal in utero or in the perinatal period. Mild forms compatible with normal development also occur, but many patients are severely disabled. Many cases are associated with mutations of the genes encoding the chains of type I collagen. Inheritance is usually autosomal dominant, but many cases result from sporadic new mutations. The uveal pigment of the eye is visible through the thinned sclera, which therefore appear blue in some forms of the disease.