19

Bone disease

Donncha O'Gradaigh, Richard Conway

Anatomy and Physiology of Bone

Bone is a specialized connective tissue serving three major functions:

Bone structure

Bone is comprised of cells and a matrix of organic protein and inorganic mineral. Long bones (femur, tibia, humerus) and flat bones (skull, scapula) have different embryological templates, with varying proportions of cortical and trabecular bone.

Bone cells
Osteoblasts

Derived from local mesenchymal stem cells, these cells synthesize matrix (osteoid) and regulate its mineralization. After bone form­ation, the majority of osteoblasts are removed by apoptosis (see p. 105), others remaining at the bone/marrow interface as lining cells or within the bone as osteocytes. Osteoblasts regulate bone resorption through the balance in expression of the stimulatory receptor activator of nuclear factor kappa B ligand (RANKL) and its antagonist, osteoprotegerin (OPG). Osteoblasts are rich in alkaline phosphatase and express receptors for parathyroid hormone (PTH), oestrogen, glucocorticoids, vitamin D, inflammatory cytokines and the transforming growth factor-beta (TGF-β) family, all of which may therefore influence bone remodelling.

Osteocytes

These small cells, derived from osteoblasts, are embedded in bone and interconnected with each other and with bone lining cells through cytoplasmic processes. They respond to mechanical strain by undergoing apoptosis or through altered cell signalling, which in turn activates bone formation with or without prior resorption. As osteocytes also express RANKL and OPG, the relative importance of osteocytes and osteoblasts in bone resorption function continues to be explored.

Osteoclasts

These cells have the unique capacity to resorb bone and are derived from haemopoietic precursors of the macrophage lineage. In response to RANKL, macrophage colony stimulating factor (M-CSF) and local adhesion factors (integrins), osteoclasts attach to bone, creating a ruffled border that forms a number of extracellular lysosomal compartments. Hydrogen ions are actively secreted into these spaces and the acid environment removes the mineral phase before specialized cysteine proteases (e.g. cathepsin K) resorb the collagen matrix.

Bone growth and remodelling

Longitudinal growth occurs at the epiphyseal growth plate, a cartilage structure between the epiphysis and metaphysis (Fig. 19.1). Cartilage production is tightly regulated, with subsequent mineralization and growth finally arrested at 18–21 years, when the epiphysis and metaphysis fuse.

image
Figure 19.1 A longitudinal section of a growing long bone. (From NICE guidelines: Osteoporosis – primary prevention. http://www.nice.org.uk/Guidance/TA160 (23 July 2012).)

In adults, bone is regularly remodelled to ensure repair of microdamage and turnover of calcium and phosphate for homeostasis. This remodelling cycle is carried out by the basic multicellular unit (BMU; Fig. 19.2 ). Signals initiating resorption include osteocyte apoptosis and altered signalling (sclerostin, prostaglandins, RANKL and other molecules), resulting in localized retraction of bone-lining cells and binding of multinucleate osteoclasts to the bone surface, followed by bone resorption. Bone formation involves reciprocal effects of wnt versus dickkopf (Dkk) and sclerostin on the LRP5/6-β-catenin pathway. The switch from resorption to formation may rely on osteocyte signalling or on release of signals from the bone matrix, such as TGF-β. Bone remodelling is said to be coupled when formation follows resorption, but may be unbalanced when the amount of bone removed is not replaced with an equal amount.

image
Figure 19.2 Bone is remodelled in response to alterations in two reciprocal systems. (a) Quiescent bone (centre) may experience reduced load in response, the osteocyte increases expression of sclerostin (SOST+), inhibiting the response to wnt via the LRP5/frizzled co-receptor complex (orange). (b) Microdamage causes osteocyte apoptosis, with direct osteoclast-generating effects via receptor activator of nuclear factor kappa B ligand (RANKL), and loss of the inhibitory effect of SOST on later bone formation (dashed line, SOST−). The osteoblastic lining cells retract from an area of bone, forming a bone remodelling unit, while increased expression of RANKL and reduced osteoprotegerin (OPG) activates the formation of bone-resorbing multinucleate osteoclasts from circulating precursors; the resorbed area is then replaced by new osteoid, formed by cuboidal osteoblasts. As new osteocytes are formed, SOST levels rise and the osteoblasts cease formation, the majority undergoing apoptosis. (c) If bone experiences loading without damage, sclerostin expression is reduced (SOST−), increasing signal response to wnt, activation of osteoblast bone formation, and increased OPG expression.

Examples of bone remodelling include:

Calcium homeostasis and its regulation

Calcium homeostasis is regulated by the effects of PTH and 1,25-dihydroxyvitamin D (1,25(OH)2D3) on gut, kidney and bone. Calcium-sensing receptors are present in the parathyroid glands, kidney and brain.

Calcium absorption and distribution

Daily calcium consumption (Fig. 19.3), primarily from dairy foods, is 20–25 mmol (800–1000 mg). The combined effect of calcium and vitamin D deficiency contributes to the bone fragility seen in some older persons. Intestinal absorption of calcium is reduced by vitamin D deficiency and in malabsorption states (see p. 204).

image
Figure 19.3 Calcium exchange in the normal human. The amounts are shown in mmol per day.
Vitamin D metabolism

The primary source of vitamin D (Fig. 19.4) in humans is photo­activation in the skin of 7-dehydrocholesterol to cholecalciferol, which is then converted first in the liver to 25-hydroxyvitamin D (25(OH)D3) and subsequently in the kidney (by the enzyme 1α-hydroxylase) to 1,25(OH)2D3. (This step can occur in lymphomatous and sarcoid tissue, resulting in hypercalcaemia.) Regulation of the latter step is by PTH, phosphate and feedback inhibition by 1,25(OH)2D3.

image
Figure 19.4 The metabolism and actions of vitamin D. 1,25-Dihydroxycholecalciferol (calcitriol) is the biologically active agent. It inhibits 1α-hydroxylase and stimulates 24-hydroxylase to produce 24,25-dihydroxy-D3, which is not biologically active. CYP, cytochrome P enzyme; FGF, fibroblast growth factor secreted mainly by osteocytes (see p. 171).
Parathyroid hormone

Parathyroid hormone (PTH), an 84-amino-acid hormone, is secreted from the chief cells of the parathyroid gland, which have calcium-sensing and vitamin D receptors. PTH increases renal phosphate excretion and increases plasma calcium by:

Hypomagnesaemia can suppress the normal PTH response to hypocalcaemia.

Clinical Approach to the Patient with Bone Disease

Investigation of bone and calcium disorders

(See Box 19.1.)

Diagnostic imaging

• Plain radiographs. These identify fractures, tumours and infections. Other specific features may be seen (see following sections).

• Radionucleotide imaging. The uptake of a 99mtechnetium-labelled bisphosphonate in bone reflects bone turnover and blood flow. Increased uptake is therefore seen in fractures, tumour and metastatic deposits, infection and Paget's disease of bone.

• Magnetic resonance imaging (MRI). This is the most sensitive and specific test for the diagnosis of osteomyelitis. It is also useful in the detection of stress fractures, which may not be demonstrated on plain radiographs. A technique to suppress the high signal associated with bone marrow (such as STIR sequences; see p. 651) allows highly sensitive recognition of ‘bone marrow oedema’, a non-specific feature of a number of bone disorders, including osteonecrosis.

• Bone biopsy (Fig. 19.5). A core of bone is removed, including both cortices of the iliac crest, using a trephine. The non-decalcified specimen is examined for static and dynamic (bone turnover) indices. An oral tetracycline is given to the patient prior to the biopsy, for 2 days on two occasions 10 days apart, allowing assessment of the rate of bone turnover and mineralization. Biopsy is most commonly used in the assessment of suspected renal bone disease and osteomalacia.

image
Figure 19.5 Computerized images of bone biopsies in osteoporosis. These images demonstrate changes in bone architecture over time. Upper pair: Without treatment, the bone cortex becomes thinner and numerous trabecular rods and plates are lost. Centre pair: In response to bisphosphonate treatment, resorption is reduced, with preservation of bone mineral and structure. Lower pair: In response to anabolic therapy, bone is increased at both trabecular and cortical sites. (From Jiang Y, Zhao JJ, Mitlak BH et al. Recombinant human parathyroid hormone (1–34) improves both cortical and cancellous bone structure. Journal of Bone and Mineral Research 2003; 18:1932–1941, with permission of the American Society for Bone and Mineral Research.)

• Bone densitometry measurements (see p. 712).

Osteoporosis

Osteoporosis is defined as ‘a disease characterized by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and an increase in fracture risk’.

Using bone densitometry at the hip or spine measured by dual X-ray absorptiometry (DXA), the World Health Organization (WHO) also defines osteoporosis as a bone density of 2.5 standard deviations (SDs) below the young healthy adult mean value (T-score ≤−2.5) or lower. Values between −1 and −2.5 SDs below the young adult mean are termed ‘osteopenia’. The rationale for this definition is the inverse relationship between bone mineral density (BMD) and fracture risk in postmenopausal women and older men. However, this definition should not be applied to younger populations.

Fractures due to osteoporosis are a major cause of morbidity and mortality in elderly populations, with osteoporotic fractures of the spine causing acute pain or deformity and postural back pain. One in two women and one in five men aged 50 years will have an osteoporotic fracture during their remaining lifetime. Caucasian and Asian races are particularly at risk. As the risk of fracture increases exponentially with age, changing population demographics will increase the burden of disease.

image Pathogenesis

Osteoporosis results from increased bone breakdown by osteoclasts and decreased bone formation by osteoblasts, leading to loss of bone mass.

Bone mass decreases with age (Fig. 19.6) but will depend on the ‘peak’ mass attained in adult life and on the rate of loss in later life. Genetic factors are the single most significant influence on peak bone mass. Multiple genes are involved, including collagen type 1A1, vitamin D receptor and oestrogen receptor genes. Nutritional factors, sex hormone status and physical activity also affect peak mass. Not all causes of osteoporosis affect bone remodelling and architecture in the same way.

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Figure 19.6 Lifetime changes in bone mineral density (BMD). Peak bone mass is achieved between 20 and 30 years of age (gain), and consolidated up to around the age of 40 years. Then, age-related bone loss occurs in both men and women, with an accelerated loss in women starting around the time of menopause, which lasts between 5 and 10 years.

Oestrogen deficiency results in increased numbers of remodelling units, premature arrest of osteoblastic synthetic activity and perforation of trabeculae, with a loss of resistance to fracture that is not fully reflected in the bone density measurement.

Glucocorticoids induce a high-turnover state initially, with increased fracture risk evident within 3 months of starting therapy. More prolonged use leads to a reduced-turnover state but with a net loss due to reduced synthesis (through increased inhibition of the wnt-LRP5/6 axis).

Ageing results in increased turnover at the bone/vascular interface within cortical bone, resulting in a weak structure for the stresses occurring in this area of long bones (trabecularization of cortical bone).

image Risk factors

Risk factors for fracture may exert their effect through reducing BMD, or they may increase risk over that attributable to BMD, meaning that they are BMD-independent (Box 19.2). Oestrogen deficiency is a major factor in the pathogenesis of accelerated bone loss due to a normal or premature menopause or amenorrhoea in anorexia and in athletes. In the elderly, vitamin D insufficiency and consequent hyperparathyroidism reduce BMD. However, previous fracture, increasing age, glucocorticoid therapy, smoking and falls increase the risk of fracture at any given BMD. For instance, 10% of women who are 65 years old and have a T-score of −2 at the hip would be expected to sustain a fracture over the next 10 years; if similar women had a Colles' fracture, smoked and had prolonged exposure to steroids, their risk would be closer to 26% in the same period.

Treatment depends on the type of risk factors: if they are recognized as ‘BMD-dependent’, they respond to bone-directed treatment; if classed as ‘BMD-independent’, they require additional intervention (e.g. reduction of falls risk).

image Investigations

Plain radiographs (Fig. 19.7) usually show a fracture and may reveal previously asymptomatic vertebral deformities. Such clinically silent fractures may also be detected during DXA scanning with an additional analysis (called lateral vertebral assessment, carried out with a much lower radiation dose than conventional imaging).

image
Figure 19.7 Vertebral fracture as seen on lateral vertebral assessment (LVA) and plain radiograph. A. The LVA image shows a vertebra with reduced height at T12 (arrow). B. The radiograph shows a typical wedge compression fracture.
Selection of individuals for treatment: risk assessment

The purpose of treatment in osteoporosis is to reduce the risk of fractures (Box 19.3). Thus, assessment of absolute fracture risk should be made in every case. All patients with a history of fragility fracture should be reviewed for treatment. In those aged over 75 years, DXA is often not necessary prior to treatment, but in those under 75 years of age, DXA is useful in guiding treatment decisions (Box 19.4 and Fig. 19.9 ). Although age and BMD measurements in the spine and proximal femur are the most useful data for assessing fracture risk, it is vital to recognize that the majority of fragility fractures occur in women with a T-score better than −2.5. Therefore, factors that are known to increase fracture risk independently of BMD should be taken into account when assessing an individual's risk of fracture, for example, using risk calculators such as FRAX®. The threshold for recommending treatment will be determined by the cost-effectiveness of treatment in a particular healthcare setting and by clinical judgement.

image Box 19.3

Management of osteoporosis: summary

Treatment is guided by risk of fracture, not BMD alone.

If there is an intermediate risk from clinical factors, request a DXA scan (see http://www.shef.ac.uk/FRAX or other risk calculator until familiar with assessments).

Do not under-estimate the risk from steroids or previous fracture.

Many guidelines (e.g. NICE) recommend bisphosphonate as first-line drugs in most cases. Other options include:

BMD monitoring is required in:

BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry; NICE, National Institute for Health and Care Excellence.

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Figure 19.9 Graph illustrating the combined effects of age (x-axis) and reduced bone mass (expressed as T-scores on the z-axis) on the 10-year probability of fracture (y-axis) in a population of women. Reduced bone mass osteopenia, T-scores between −1 and −2.5. Osteoporotic bone (T-scores <−2.5) is shown in pale green. Note that the risk of fracture may be greater in an older woman with osteopenia than in a young woman with osteoporosis. (Data from Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359:1929–1936.)

image Prevention and management

Pharmacological intervention

Most interventions (see Fig. 19.5 ) act by inhibiting bone resorption (anti-resorptives), the exception being PTH peptides, which stimulate bone formation. The impression from bone turnover markers that strontium ranelate may have both anti-resorptive and stimulatory effects remains poorly understood.

The evidence base for the anti-fracture efficacy of interventions varies. Some interventions have been shown to reduce fracture at vertebral and non-vertebral sites, including the hip, whereas others have not been demonstrated to be effective at all sites (Box 19.5). Since a fracture at one site increases the risk of subsequent fracture at any site, treatments with efficacy at all major fracture sites (particularly spine and hip) are preferable. Hence, the bisphosphonates and denosumab are generally regarded as first-line options in the majority of postmenopausal women with osteoporosis.

Bisphosphonates

Synthetic analogues of bone pyrophosphate, bisphosphonates adhere to hydroxyapatite and inhibit osteoclasts. Alendronate and risedronate are given as once-weekly doses, zoledronate as a once-yearly infusion, and ibandronate usually as a once-monthly oral therapy (a 3-monthly intravenous injection is rarely used).

Oral bisphosphonates should be taken fasting, with a large drink of water, while standing or sitting upright. The patient should then remain upright and avoid food and drink for at least 30 minutes.

Bisphosphonates are generally well tolerated but may be associated with upper gastrointestinal side-effects such as oesophag­itis, particularly if the dosing instructions are not closely followed. Bisphosphonates should be used with careful monitoring in patients who have chronic kidney disease (stage 4 or 5). Osteonecrosis of the jaw is rarely seen following high-dose intravenous bisphosphonates in patients who have malignant disease. It is associated with poor dental hygiene. As prolonged suppression of bone turnover is linked with atypical femoral fractures, it is currently advised to reassess bisphosphonate treatment after 5 years. Only those with vertebral fractures and a T-score at the neck of femur of <−2.5 at this 5-year scan appear to have a reduced risk of fracture with continued treatment.

Denosumab

Denosumab is a fully human monoclonal antibody to RANKL and is administered as a single subcutaneous injection every 6 months. It is an anti-resorptive agent that increases BMD and reduces fractures at the spine, hip and other non-vertebral sites. Fracture risk reduction at the spine is equivalent to that with most bisphosphonates, and risk reduction at the hip is superior (with the exception of zoledronic acid). Adverse effects are infrequent: most commonly dysuria, rarely cellulitis. Osteonecrosis of the jaw and atypical femoral fractures have also occurred but estimating the true frequency of these rare adverse events is not possible with current data.

Strontium ranelate

This is used only when no alternative exists because of its adverse cardiovascular effects. It has weak anti-resorptive activity whilst maintaining bone formation. It reduces the risk of vertebral fractures in postmenopausal women with osteoporosis, and the risk of hip and other non-vertebral fractures in high-risk subgroups (women with previous fracture and T-scores at the hip of −2.4 or less). Nausea, diarrhoea and headaches are infrequent side-effects.

Selective oestrogen-receptor modulators

Selective oestrogen-receptor modulators (SERMs) include raloxifene and bazedoxifene. They have no stimulatory effect on the endometrium but activate oestrogen receptors in bone. Both prevent BMD loss at the spine and hip in postmenopausal women, but have been found to reduce only vertebral fracture rates. Leg cramps and flushing may occur and the risk of thromboembolic complications is also increased to a degree similar to that seen with hormone replacement therapy (HRT; see pp. 1296–1297 and Box 29.1). The use of SERMs is associated with a small increase in the risk of stroke.

Recombinant human parathyroid hormone

Recombinant human PTH peptide 1–34 (teriparatide) and recombinant human PTH 1–84 are anabolic agents that stimulate bone formation. Teriparatide reduces vertebral and non-vertebral fractures in postmenopausal women with established osteoporosis, although data on hip fracture are not available. It is given by daily subcutaneous injection for 24 months. Recombinant human PTH 1–84 is also administered by once-daily subcutaneous injection but has been shown to reduce only vertebral fractures. An anti-resorptive drug, such as denosumab, should be given on completion of PTH peptide therapy to maintain the increase in BMD. Non-osteoporotic bone diseases, such as osteomalacia, should be excluded prior to treatment. PTH peptide therapy is indicated mainly in severe cases of vertebral osteoporosis or in women who fail to respond to other therapies. Teriparatide may cause mild transient hypercalcaemia but routine monitoring is not required. Nausea and headache may occur. Recombinant human PTH 1–84 is associated with a higher incidence of hypercalcaemia and hypercalciuria, and routine monitoring is advised. Neither agent should be used in people with skeletal metastases or osteosarcoma.

Hormone replacement therapy

Because of its adverse effects on breast cancer and cardiovascular disease risk, HRT is not indicated for osteoporosis except in early postmenopausal women who also have significant perimenopausal symptoms.

Calcitriol (1,25-(OH)2D3) and calcitonin

These may reduce vertebral fracture rate, although the data are inconsistent.

Combination therapies

Combination therapies, either with two anti-resorptive agents, or an anti-resorptive and an anabolic agent, often produce larger increases in BMD than monotherapy but have not been shown to result in greater fracture reduction.

Surgery

This is required to stabilize vertebral fractures. Percutaneous vertebroplasty and balloon kyphoplasty are discussed on page 659. Hip fractures are dealt with by hip replacements or stabilization with pins.

Treatment of specific conditions
Glucocorticoid-induced osteoporosis

Individuals requiring continuous oral glucocorticoid therapy for 3 months or more (at any dose) should be assessed for coexisting risk factors (age, previous fracture, hormone status). Postmenopausal women, men aged over 50 years and any individuals who have sustained a fragility fracture should receive treatment without waiting for DXA scanning. DXA results and fracture risk assessment guide treatment for other patients (see Box 19.4 ). For these individuals, bisphosphonates and teriparatide are the approved agents. Denosumab is likely to be equally effective; though it is not yet formally approved for this indication, its mode of delivery may be advantageous in some settings.

Osteoporosis in men

Alendronate, risedronate and denosumab increase BMD and reduce vertebral fractures in men with osteoporosis. Teriparatide is also approved for use in this setting. In men with osteoporosis who have clinical and biochemical evidence of hypogonadism, testosterone replacement is also used.

Further reading

Coughlan T, Dockery F. Osteoporosis and fracture risk in older people. Clin Med 2014; 14:187–191.

Cummings SR, Martin J, McClung MR et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361:756–757.

Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med 2010; 363:2027–2035.

Gourley ML, Fine JP, Preisser JS et al. Bone-density testing interval and transition to osteoporosis in older women. N Engl J Med 2012; 366:225–233.

Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011; 377:1276–1287.

Weinstein RS. Glucocorticoid-induced bone disease. N Engl J Med 2011; 365:62–70.

http://www.nhsgrampian.org Sample calcium intake questionnaire.

http://www.nof.org/ National Osteoporosis Foundation clinical guidelines.

http://www.shef.ac.uk/FRAX FRAX tool for 10-year probability of hip fracture and 10-year probability of major osteoporotic fracture.

Osteonecrosis

This is also known as aseptic, avascular or ischaemic necrosis of bone. There are a multitude of risk factors but over 80% of cases are attributed to glucocorticoid treatment or alcohol excess. Less frequent causes include sickle cell disease, systemic lupus erythematosus (SLE), deep-sea diving (Caisson's disease), endocrine disorders (e.g. Cushing's, diabetes mellitus), trauma, human immunodeficiency virus (HIV) infection and irradiation.

Osteonecrosis usually presents with joint pain, the shoulder or hip being most commonly affected, but can be asymptomatic, particularly on the opposite side in the same person. It may only be recognized when it results in collapse of the articular bone.

MRI best confirms the diagnosis by showing bone marrow oedema. If advanced, it can be seen on plain X-rays.

Management is mainly symptomatic. Surgical options include drilling through the bone cortex (decompression), vascularized bone grafts, or rotation of the affected bone away from the load-bearing area; however, joint replacement is often required. Bisphosphonates may reduce pain, and progression has been reduced with statin therapy in steroid-associated osteonecrosis.

Paget's Disease of Bone

Paget's disease of bone is a focal disorder of bone remodelling. Increased osteoclastic bone resorption is followed by a compensatory increase in new bone formation, increased local bone blood flow and fibrous tissue in adjacent bone marrow. Ultimately, formation exceeds resorption but the new woven bone is weaker than normal bone, which leads to deformity and increased fracture risk. Paget's disease does not spread, but can become symptomatic at previously silent sites.

Epidemiological studies are difficult because most affected individuals are asymptomatic. Paget's disease is most often seen in Europe and particularly in northern England. It affects men and women (2:3) over the age of 40 years. The incidence approximately doubles per decade thereafter, with up to 10% of individuals radiologically affected by the age of 90. For unknown reasons, the incidence and severity of Paget's disease have decreased in recent years.

image Aetiology and pathogenesis

Genetic factors are implicated in Paget's disease. A positive family history is noted in about 15%. Mutations in SQSTM1, which encodes the osteoclast mediator protein p62, have been reported in up to 10% of cases. Intracellular inclusions in the osteoclasts in pagetic lesions are believed to be paramyxovirus nucleocapsid (e.g. canine distemper virus, measles or respiratory syncytial virus). However, similar inclusions are seen in other bone disorders, and theories of a viral aetiology in Paget's remain contentious. Altered expression of c-fos (an oncogene) is one suggested mechanism linking viral infection with the pathogenic changes in osteoclasts, which are more numerous and contain an increased number of nuclei (up to 100).

image Clinical features (see Fig. 19.10A)

Between 60% and 80% of people with radiologically identified Paget's disease are asymptomatic. Diagnosis often follows the finding of an asymptomatic elevation of serum alkaline phosphatase, or a plain X-ray performed for other indications. The disease may involve one bone (monostotic, in 15%) or many (polyostotic). The most common sites, in order of frequency, are pelvis, femur, lumbar spine, skull and tibia (see Fig. 19.10C ). Small bones of the feet and hands are rarely involved.

image
Figure 19.10 Paget's disease. A. Clinical features. B. X-ray appearance of the pelvis, showing osteolytic (thin arrow) and osteosclerotic (thick arrow) lesions. C. Legs showing bowing of the tibia caused by increased bone growth. Note the erythema ab igne on the medial aspect of the thigh.

Symptoms and complications include:

image Management

Bisphosphonates are the mainstay of treatment. New bone formed after treatment is lamellar, not woven (reflecting normalization of bone turnover rather than a direct effect on osteoblasts). Treatment is interrupted and repeat courses are guided by symptoms and by recurrence in elevation of alkaline phosphatase. In addition to treatment of symptomatic patients, treatment of asymptomatic lesions is appropriate if there is a significant risk of potential complications, such as fracture in weight-bearing long bones or the spine, nerve entrapment or deafness with skull involvement, and before orthopaedic procedures in involved bone (to reduce vascularity).

Rickets and Osteomalacia

Osteomalacia is defective mineralization of newly formed bone matrix or osteoid. Rickets is defective mineralization at the epiphyseal growth plate and is found in association with osteomalacia in children.

image Aetiology

Many factors can result in defective mineralization of the osteoid. For normal mineralization, adequate levels of vitamin D, calcium and phosphate, adequate activity of alkaline phosphatase, a normal pH at the osteoid surface and normal osteoid composition are all necessary (Box 19.6).

The most common cause of osteomalacia is hypophosphataemia due to hyperparathyroidism secondary to vitamin D deficiency. The most common cause of vitamin D deficiency worldwide is dietary deficiency. Bread, milk and cereals in high-income countries are now fortified with vitamin D. This has led to a much-reduced incidence of osteomalacia and rickets.

Vitamin D is produced in the skin through the action of sunlight on 7-dehydrocholesterol (see Fig. 19.4 ). Lack of sun exposure can lead to vitamin D deficiency, especially in individuals living in temperate regions who keep large parts of the skin covered throughout the year.

Vitamin D is a fat-soluble vitamin, so gastrointestinal disease can result in malabsorption. Gastrectomy, cystic fibrosis, coeliac disease, Crohn's disease and primary biliary cirrhosis are well-recognized causes.

Due to the intimate involvement of the kidney in phosphate balance, a number of causes of osteomalacia are mediated by the kidney (see p. 779). Primary renal phosphate wasting occurs in tumour-induced osteomalacia, multiple myeloma and Fanconi syndrome. Proximal (type 2) renal tubular acidosis can cause osteomalacia due to both renal phosphate wasting and abnormal osteoid pH secondary to metabolic acidosis.

image Clinical features

Osteomalacia may be asymptomatic and identified incidentally on routine investigations following a fragility fracture. When symptomatic, it characteristically causes muscle weakness and widespread bone pain. Muscle weakness is due to a multifactorial proximal myopathy, with low vitamin D, hypophosphataemia and high PTH levels all contributing. It results in a characteristic waddling gait with difficulty climbing stairs and getting out of a chair. Generalized bone pain and tenderness are thought to be caused by hydration of the demineralized matrix, resulting in peri­osteal distension. The pain is typically a dull ache that is worse on weight-bearing and walking. It can be reproduced by pressure on the sternum or tibia. Insufficiency fractures can occur when the quality of the bone is insufficient to handle the stress of weight-bearing.

At birth, neonatal rickets may present as craniotabes (a thin, deformed skull). In the first few years of life, there may be widened epiphyses at the wrists and beading at the costochondral junctions, producing the ‘rickety rosary’, or a groove in the rib cage (Harrison's sulcus). In older children, lower limb deformities are seen. A myopathy may also occur. Hypocalcaemic tetany may occur in severe cases.

Bone Infections

Neoplastic Disease Of Bone

Bone pain may be due to multiple myeloma, lymphoma, a primary tumour of bone or secondary deposits. The pain is typically unremitting and worse at night, and there are other clinical clues such as weight loss or ill-health.

Malignant tumours of bone are shown in Box 19.7. The most common tumours are metastases from the bronchus, breast and prostate. Metastases from kidney and thyroid are less common. Primary bone tumours are rare and usually seen only in children and young adults.

Symptoms are usually related to the anatomical position of the tumour, with local bone pain. Systemic symptoms (e.g. malaise and pyrexia) and aches and pains occur and are occasionally related to hypercalcaemia. The diagnosis of metastases can often be made from the history and examination, particularly if the primary tumour has already been diagnosed. Symptoms from bony metastases may, however, be the first presenting feature.

Other Bone Disorders

image Osteopetrosis (marble bone disease)

This condition may be inherited in either an autosomal dominant or a typically severe, autosomal recessive pattern. Another recessive form associated with renal tubular acidosis is due to carbonic anhydrase II deficiency.

The severe form is caused by a mutation in the gene encoding a chloride channel necessary for osteoclast activity. Bone density is increased throughout the skeleton but bones tend to fracture easily. Encroachment on the marrow space leads to a leucoerythroblastic anaemia. There is mental retardation and early death. In the mild form, there may be only X-ray changes, but fractures and infection can occur. The acid phosphatase level may be raised. Stem cell transplantation has been successful.

image Scheuermann's disease

This disease predominantly occurs in adolescent boys. The main feature is a progressive dorsal kyphosis of the thoracic spine. Pain may or may not be present. The cause is unknown. A genetic predisposition, exacerbated by excessive exercise prior to epiphyseal fusion, is one suggested explanation. Older patients with kyphosis may be referred with suspected osteoporotic fractures but found to have long-standing kyphosis due to Scheuermann's. Management is focused on postural exercises and avoidance of precipitants. Surgery may be undertaken to correct kyphosis in severe cases.

Significant websites

http://nof.org National Osteoporosis Foundation – useful clinicians' guide.

http://www.iscd.org International Society for Clinical Densitometry – guidelines on DXA scanning.

http://www.nos.org.uk/ UK National Osteoporosis Society – useful information and reviews of ongoing research.