NORMAL STRUCTURE AND FUNCTION

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:

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.

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. A greenstick fracture of the distal radius in a young child (arrowed). A displaced spiral fracture of the femur in a child. A comminuted fracture of the tibia. One fragment of bone has almost separated from the shaft. 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:

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:

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.

Osteoporosis

Reduction in total bone mass causing weakening

Common in the elderly, particularly females

Common predisposing cause of fractures, particularly neck of femur

Complication of steroid therapy and Cushing’s syndrome

Follows any form of immobility

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.

Complications

The major complications of osteoporosis are:

• skeletal deformity

• bone pain (usually due to compression fractures)

• fracture.

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. The lower thoracic vertebrae showing small protrusions of the intervertebral disc into the osteoporotic bone (arrowed). 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.

Rickets and osteomalacia

Inadequate mineralisation of organic bone matrix

Rickets occurs in children and is characterised by bone deformities

Osteomalacia occurs in adults, causing susceptibility to fracture but few deformities

Due to deficiency of active metabolites of vitamin D

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:

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 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.

Hyperparathyroidism and hypercalcaemia

Hyperparathyroidism causes increased osteoclastic breakdown of bone

Serum calcium is usually raised in primary hyperparathyroidism, but low or normal in secondary (reactive) hyperparathyroidism

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:

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

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:

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)

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’).