Category Archives: Rheumatology and bone disease

Other hereditary diseases

Osteopetrosis (marble bone disease)

This condition may be inherited in either an autosomal dominant or an autosomal recessive manner; the recessive type is severe and the dominant type is mild. In the severe form, bone density is increased throughout the skeleton but bones tend to fracture easily. Involvement of the bone marrow leads to a leucoerythroblastic anaemia. There is mental retardation and early death.
In the mild form there may only be X-ray changes, but fractures and infection can occur. The acid phosphatase level is raised.


This rare autosomal recessive condition is due to a deficiency of alkaline phosphatase and pyrophosphatase. It is not known where the primary defect lies, but it may be in the osteoblasts. It varies in severity from unrnineralized bones in utero resulting in death, to rickets in infancy or recurrent fractures in adults.

Further reading

Huskisson EC & Hart FD (1987) Joint Disease: All the Arthropathies, 4th edn. Bristol: John Wright. Kelley WN et al (eds) (1993) Textbook of Rheumatology, 4th edn. Philadelphia: WB Saunders. Maddison PJ et al (eds) (1993) Oxford Textbook of Rheumatology. Oxford: Oxford University Press. McCarty OJ & Koopman WJ (eds) (l993) Arthritis and Allied Conditions: A Textbook of Rheumatology, l2th edn. Philadelphia: Lea & Febiger. Bilezikian JP (ed) (1994) The Parathyroids: Basic and Clinical Concepts. New York: Raven Press. Nordin BC (1993) Metabolic Bone and Stone Disease, 3rd edn. Edinburgh: Churchill Livingstone. Smith R (ed) (l990) Osteoporosis 1990. London: Royal
College of Physicians.

Connective tissue

All connective tissues have a large proportion of extracellular matrix as well as cells. This matrix consists of extracellular macromolecules containing collagens, elastins, non-collagenous glycoproteins and proteoglycans.


These consist of three polypeptide chains (a chains) wound around one another in a triple helical confirmation. These a chains contain repeating sequences of Gly-X-Y triplets where X and Yare often prolyl and hydroxyprolyl residues. There is much genetic heterogeneity in collagen fibres and the gene for different chains is located on several chromosomes.

Functionally the tissue depends on the type of collagen. Thirteen distinct collagen types have been described so far, although the exact function of many remains undefined. For example, type I collagen fibres are seen in structures with a high tensile strength, e.g. tendons, type II collagen molecules form the cartilaginous structures and type III collagen is seen in more distensible tissues such as blood vessels.


Elastic fibres in the extracellular matrix consist of elastin and microfibrils. Elastin is an insoluble protein polymer and its gene has been characterized. Its precursor, tropoelastin,is synthesized by vascular smooth muscle cells and  skin fibroblasts. Elastin fibres are cross-linked with desmosine and isodesmosine which are specific to elastin.


Fibronectin is the major non-collagenous glycoprotein in the extracellular matrix. Its molecule contains a series of functional domains, or cell recognition sites, that bind ligands and are involved in cell adhesion. A synthetic peptide sequence (Arg-Gly-Asp), which mimics some of the functions of fibronectin, is also found in other adhesion proteins, e.g. vitronectin, laminin and collagen type VI.
Fibronectin plays a major role in tissue remodelling. It is stimulated by interferon-y and transforming growth factor-/ 3 and inhibited by tumor necrosis factor and interleukin-L


These are of different shapes and sizes. Their function isthat of a multipurpose glue in that they bind extra cellular  matrix together, mediate cell binding and inhibit soluble molecules. Osteogenesis imperfecta (fragilitas ossium, brittle bone syndrome) This rare group of inherited disorders is due to an abnormality of connective tissue. The major feature is very fragile and brittle bones; other collagen-containing tissues are also involved, such as tendons, the skin and the eyes. Osteogenesis imperfecta tarda is a mild, dominantly inherited condition with milder bony deformities, blue sclerae, defective dentine, early-onset deafness, hypermobility of joints, and heart valve disorders. More severe forms present with multiple fractures and gross deformities. Prognosis is variable, depending on the severity of the disease.


This is one of a group of heterogeneous disorders that affect the normal development of bone and cartilage. Achondroplasia (dwarfism) is diagnosed in the first years of life. The disease is inherited in an autosomal dominant manner. The trunk is of normal length but the limbs are very short and broad. The vault of the skull is enlarged, the face is small and the nose bridge is flat. Intelligence is normal.

Neoplastic bone disease

Malignant tumours of bone are shown. The most common tumours are metastases from the bronchus, breast and prostate. Metastases from kidney and thyroid are less common. Symptoms are usually related to the anatomical position of the tumour, with local bone pain over the area. Systemic symptoms including malaise and pyrexia, and aches and pains occur and are some times related to the hypercalcaemia . The diagnosis of metastases can often be made from the history and examination, particularly if the primary has already been diagnosed. Symptoms from bony metastases may, however, be the first presenting feature.

Malignant neoplasms of bone.

Malignant neoplasms of bone.


SKELETAL ISOTOPE SCANS can pick up bony metastases as ‘hot’ areas before radiological changes occur.
X – RAYS may show metastases as osteolytic areas with bony destruction. Osteosclerotic metastases are characteristic of prostatic metastases.
SERUM ALKALINE PHOSPHATASE (from the bone) is usually raised.
HYPERCALCAEMIA is seen in 10-20% of patients with malignancies. It is chiefly associated with metastases.
SERUM ACID PHOSPHATASE is raised in prostatic metastases.
PROSTATIC SPECIAL ANTIGEN (PSA) is also raised in prostatic metastases.


Treatment is usually symptomatic with analgesics and anti-inflammatory drugs like indomethacin. Local radiotherapy over bone metastases may be the best way of relieving pain. Depending on the tumour, cytotoxic chemotherapy is occasionally helpful. Some tumours are hormone-dependent and a remission can be obtained by hormonal therapy. Occasionally pathological fractures require internal fixation.
PRIMARY BONE TUMOURS are rare and usually seen in children and young adults.

Infections of bone


Staphylococcus is the organism responsible for 90% of cases of acute osteomyelitis . Other organisms include Haemophilus influenzae and Salmonella; infection with the latter may occur as a complication of sickle cell anaemia.

Osteomyelitis can be due either to metastatic haem atogenous spread (e.g. from a boil) or to local infection. Malnutrition, debilitating disease and decreased immunity may playa part in the pathogenesis.
Chronic osteomyelitis may follow an acute infection.
Another variety of chronic osteomyelitis is due to infection being localized to form a chronic abscess within the bone (Brodie’s abscess). Patients may be asymptomatic for months or years or may have intermittent local pain. Treatment of osteomyelitis is with immobilization and antibiotic therapy with flucloxacillin and fusidic acid.

Tuberculous osteomyelitis

This is usually due to haematogenous spread from a primary focus in the lungs or gastrointestinal tract. The disease starts in intra-articular bone. The spine is commonly involved (Pott’s disease), with damage to the bodies of two neighbouring vertebrae leading to vertebral collapse and later abscess formation (‘cold abscess’). Pus can track along tissue planes and discharge at a point far from the affected vertebrae. Symptoms consist of local pain and later swelling if pus has collected. Systemic symptoms of malaise, fever and night sweats occur. Treatment is as for pulmonary tuberculosis (see p. 686) together with immobilization.

Calcium disorders

Hypocalcaemia and hypoparathyroidism


Hypocalcaemia may be due to deficiencies of calcium homeostatic mechanisms, secondary to high phosphate levels or other causes of hypocalcaemia. Hypoparathyroidism is uncommon.

Paget's disease

Paget’s disease


1 Renal failure is the commonest cause of hypocalcaemia.
2 Immediately following thyroidectomy and parathyroidectomy, hypocalcaemia is usually transient.
3 Idiopathic hypoparathyroidism is one of the rarer autoimmune disorders. Vitiligo, cutaneous moniliasis and other autoimmune diseases are often seen.
4 The DiGeorge syndrome is a familial condition and associated with intellectual impairment, cataracts, calcified basal ganglia and occasionally with organ-specific autoimmune disease.
S Pseudohypoparathyroidism is a syndrome of endorgan resistance to PTH. It is associated with short stature, short metacarpals and intellectual impairment.

Pseudopseudohypoparathyroidism describes the phenotypic defects without the calcium abnormalities.

Causes of hypocalcaemia.

Causes of hypocalcaemia.


The symptoms are those of neuromuscular irritability and neuropsychiatric manifestations. Paraesthesiae, circumoral numbness, cramps, anxiety and tetany are followed by convulsions, laryngeal stridor, dystonia and psychosis. Two important signs of hypocalcaemia are Chvostek’s sign-gentle tapping over the facial nerve causes twitching of the facial muscles-and Trousseau’s sign, where inflation of the sphygmomanometer cuff above diastolic blood pressure for 3 min induces tetanic spasm of the fingers and wrist. Severe hypocalcaemia may cause papilloedema and a prolonged Q-T interval on the ECG.


The clinical picture is usually diagnostic and is confirmed by a low serum calcium. Additional tests include:

• Serum urea and creatinine
• High phosphate levels
• Absent or low PTH levels
• Parathyroid antibodies (not widely available)
• Vitamin D metabolite levels
• X-rays of metacarpals showing short fourth metacarpals, which occur in pseudo hypoparathyroidism


Urgency of treatment depends upon severity of symptoms and degree of hypocalcaemia. If severe, e.g. tetany, intravenous calcium (10 ml initially, then 10-40 ml of 10% calcium gluconate in I litre of 150 mmol litre ” saline over 4-8 hours) is given. Oral calcium supplements (2- 10 g daily, 40-200 mmol Ca2+) are rarely sufficient alone. l o-Hydroxylated derivatives of vitamin D are preferred for their shorter half-life. Usual daily maintenance doses are I J-Lgfor la(OH)D3 (alfacalcidol) and 1,25(OH)2D3 (calcitriol) and 0.25 mg of dihydrotachysterol. During treatment, plasma calcium must be monitored frequently to prevent hypercalcaemia.

Hyperparathyroidism and hypercalcaemia

Hypercalcaemia is much commoner than hypocalcaemia and is frequently detected incidentally with multichannel chemical analysers, Mild, asymptomatic hypercalcaemia occurs in about 1 in 1000 of the population, especially elderly females, and is usually due to primary hyperparathyroidism. True hypercalcaemia should always be confirmed on a carefully collected specimen.


Major causes of hypercalcaemia are listed; primary hyperparathyroidism and malignant disease are the commonest.
Hyperparathyroidism may be primary, secondary or tertiary.
PRIMARY HYPERPARATHYROIDISM is caused by single (80%+) or multiple (5%) parathyroid adenomas or by hyperplasia (10%). Parathyroid carcinoma is rare (2%) though usually with severe hypercalcaemia.
SECONDARY HYPERPARATHYROIDISM is physiological compensatory hypertrophy of all four parathyroids due to hypocalcaemia (e.g. in renal failure or vitamin D deficiency). PTH levels are raised, but calcium levels are low or normal; PTH levels fall to normal after correction of the cause of hypocalcaemia.
TERTIARY HYPERPARATHYROIDISM is the development of apparently autonomous parathyroid hyperplasia after long-standing secondary hyperparathyroidism, most often in renal failure. Plasma calcium and PTH are both raised, the latter often grossly so. Parathyroidectomy is necessary at this stage.

Causes of hypercalcaemia.

Causes of hypercalcaemia.


The symptoms and signs of hypercalcaemia are now moreoften mild and general rather than the severe renal and  bone problems seen years ago:

GENERAL-malaise, depression.
RENAL- renal colic from stones, polyuria/nocturia, haematuria and hypertension. The polyuria results from the effect of hypercalcaemia on the renal tubules reducing concentrating ability, a form of nephrogenic diabetes insipidus.
BONEs-bone pain.
ABDOMINAL -abdominal pain, sometimes due to peptic ulceration.
Particular points of note are:
MALIGNANT DISEASE is usually advanced by the time hypercalcaemia occurs as a result of bony metastases. The common primary tumours are bronchus, breast, myeloma, oesophagus, thyroid, prostate, lymphoma and renal cell carcinoma. ‘Ectopic PTH secretion’ is very rare. There is evidence of a PTH-related protein, a 141 amino acid polypeptide, the sequence of which
shows an initial approximate homology with PTH. The biological action appears to lie in the first 34 amino acids. Local bone-resorbing cytokines and prostaglandins may be important locally where there are metastatic skeletal lesions leading to local mobilization of calcium by osteolysis with subsequent hypercalcaemia. They probably rarely cause hypercalcaemia by a generalized ‘hormonal’ action as previously thought. EVERE HYPERCALCAEMIA (>3 mmollitre-1) is usually associated with malignant disease, hyperparathyroidism, renal dialysis or vitamin D therapy.
CORNEAL CALCIFICATION is a marker of long-standing hypercalcaemia.
1:-< PRIMARY HYPERPARATHYROIDISM, only 5-10% have definite bony lesions and 20-40% renal involvement.



is common in primary hyperparathyroidism.
-ERUM PTH LEVELS should be measured. Detectable levels during hypercalcaemia are inappropriate and imply hyperparathyroidism.
ABDOMINAL X-RAYS may show renal calculi or nephrocalcinosis. Renal function must be measured.
HIGH-DEFINITION HAND X-RAYS may show subperiosteal erosions in the middle or terminal phalanges.
plasma calcium in hyperparathyroidism is resistant to suppression by steroids (10 days of hydrocortisone 40 mg three times daily); this also occurs with some malignancies. In sarcoidosis, vitamin D-mediated hypercalcaemia and some malignancies, suppression to normal or near-normal levels is seen.

PLASMA CHLORIDE is elevated and the bicarbonate reduced in primary hyperparathyroidism due to PTH which reduces renal tubular reabsorption of bicarbonate. If primary hyperparathyroidism is confirmed, the following may be helpful in localization, although adenomas are usually small:
ULTRASOUND, though insensitive to small tumours, is simple and safe.
CT SCAN, though very high resolution is needed. MRI may prove more sensitive. RADIOISOTOPE ‘SUBTRACTION’ SCANS: a picture of the parathyroid tissue is derived from the difference in uptake between thallium-201 (taken up by thyroid and parathyroid) and technetium-99m (thyroid only). Reports on its efficacy are conflicting. BARIUM SWALLOW may show indentation of the oesophagus by an adenoma.
VENOUS CATHETERIZATION of parathyroids to measure PTH. This is usually reserved for previous operative failures.



Indications for surgery in hyperparathyroidism remain controversial. All agree that with renal disease or bone involvent surgery is indicated, there being no longterm medical treatment. The situation in which the plasma calcium is mildly raised (2.65-3.0 mmol litre “) is disputed; most physicians feel that probable symptoms of hypercalcaemia, which may be mild and non- specific, should lead to parathyroidectomy. Those who are asymptomatic should receive careful follow-up; development of renal, bone or other symptoms then warrants surgery.


Parathyroid surgery should only be performed by experienced surgeons. Ninety per cent of these patients have adenomas rather than hyperplasia, but the minute glands may be very difficult to define. It is also very difficult to distinguish between an adenoma and normal parathyroid. If initial exploration is unsuccessful, venous catheteriz ation for PTH levels may be helpful if CT or MRI is not; a few parathyroids lie in ectopic sites elsewhere in the neck and upper mediastinum.

Treatment of acute hypercalcaemia.

Treatment of acute hypercalcaemia.

Postoperative care

The main danger postoperatively is hypocalcaemia :
CHVOSTEK AND TROUSSEAU SIGNS should be sought regularly.
MILD TRANSIENT HYPOPARATHYROIDISM often occurs for 1-2 weeks, possibly owing to suppression of other parathyroids. Depending on severity, oral or intravenous calcium should be given temporarily.


Treatment depends upon the primary pathology, although steroids are often useful. Emergency treatment is discussed below.



Osteoporosis means thin bone and the term implies a reduction in bone mass including all components of bone and not just calcium. It is already a major problem; it is said that 40% of Caucasian women and 20% of men will suffer fractures as a result of osteoporosis. The risk in women will triple as a result of increasing life expectancy. One-third of women will have had a fracture by the age of 90 years.


Changes in bone mass with age are shown. Bone mass increases up to the age of puberty and remains stable until the menopause. After the menopause, there is a progressive reduction as a result of oestrogen deficiency. The rate of reduction in bone mass is much less in men. When bone mass falls below the fracture threshold, there is a risk of fracture, which is increased in the elderly by other factors such as failing eyesight, incoordination and falls.


Osteoporosis is not a disease but a condition which exists to a variable extent as a result of a number of different factors, shown. The most important risk factors are age and sex: osteoporosis has its biggest impact in postmenopausal women.


There are two types of osteoporosis: type 1 the typical postmenopausal osteoporosis and type 2 the more recently recognised senile osteoporosis which occurs in the over-seventies. Their features are summarized. Four factors are thought to be important in the pathogenesis of type 2 osteoporosis:

1 Less sunshine.
2 Lower calcium intake.
3 Less vitamin D-containing foods.
4 Less vitamin D synthesis in the skin.
Increased parathyroid activity is the result, leading to cortical bone resorption.

Risk factors and diseases associated with osteoporosis.

Risk factors and diseases associated with


Osteoporosis is not itself painful. The pain results from fractures and is usually therefore self-limiting although long-standing pain can result from structural problems, for example as a result of vertebral crush fractures. The typical history in osteoporosis of the spine is thus an episode of very severe pain in the dorsal spine which resolves lowly over the course of about 6 weeks. Fractures can also occur in the lumbar spine. The typical sites of fractures in osteoporosis are vertebrae, the distal radius (Colles fracture) and the neck of the femur. Other symptoms which result from vertebral osteoporosis are loss of height, increasing kyphosis and abdominal protruberance. Similar symptoms can occur in such conditions as multiple myeloma and metastatic deposits.

The two types of osteoporosis.

The two types of osteoporosis.


X-RAYS will demonstrate most fractures. Bone scans are sometimes useful to demonstrate a recent fracture and to distinguish an osteoporotic crush fracture from ametastatic lesion. These often appear identical on Xray  but metastatic lesions are likely to be associated with multiple lesions elsewhere. X-rays are however of limited value in diagnosing osteoporosis itself because the whiteness of the bone depends on the penetration of the film.
SERUM CALCIUM, PHOSPHATES AND ALKALINE PH0SPHATASE are usually normal. Osteoporosis is not a disorder of calcium metabolism.
HISTOLOGICAL EXAMINATION of a bone biopsy mayoccasionally be required to confirm the diagnosis.
BONE DENSITOMETRY (DEXA SCANNING) is of increasing importance in screening people at risk and in monitoring the effects of treatment.
ApPROPRIATE INVESTIGATIONS to exclude diseases that are associated with osteoporosis are shown.


Treatment of the established disease is unsatisfactory because bone mass has already been lost. Prophylaxis for high-risk individuals is, therefore, preferable. Elderly patients should be educated about the risks of falling.
FRACTURES should be treated by conventional orthopaedic means. Fresh fractures of the spine require short-term bed rest with adequate analgesia and, if necessary, muscle relaxants.


Prevention of osteoporosis IS Important, particularly in postmenopausal women and in the elderly. The following measures are used:
OESTROGEN THERAPY is of proven value and is being increasingly used as evidence accumulates that the potential side-effects (thrombosis, endometrial carcinoma, hypertension) are less than the benefits. Those with premature menopause or ovariectomy, those with high-risk factors, e.g. nullipara, the hypogonadal, those with family history of osteoporosis, should certainly be treated and many believe hormone replacement therapy (HRT) should be given to most postmenopausal women.
It is now clear that androgens should be given to hypogonadal men, though prostatic hypertrophy is a problem.
DIETARY CALCIUM should be increased to above 1.5 g daily (40 mmol Ca2+), especially for postmenopausal women, with or without vitamin D supplements. This gives a small benefit. Vitamin D is necessary for housebound elderly people.
COURSES OF DIPHOSPHONATES which inhibit bone resorption  may be used and seem to be safe.
MODERATE EXERCISES AGAINST GRAVITY, e.g. walking, running and competitive sports, also retard bone loss and should be encouraged.
FLUORIDE increases bone density but is difficult to use and is not recommended.
CALCITONIN AND PTH remain under investigation and the field is changing rapidly. Paget’s disease
Strictly this is a disorder of bone remodelling rather than a metabolic bone disease, although the metabolic changes are considerable. Recent evidence involving apparent viral inclusion bodies suggests a possible ‘slow viral’ aetiology, for which canine distemper virus is a prime candidate. The condition causes uncontrolled bone turnover with local excessive osteoclastic resorption followed by disorded osteoblastic activity leading to abundant new bone formation which is structurally abnormal and weak.


It is a common disorder, most often seen in Europe and particularly northern England, affecting up to 10% of adults by the age of 90 years, though rarely before the age of 40 years. It is relatively rare in North America, Africa and Asia. Probably less than 2% of those affected show any symptoms.



The commonest sites are the femur, pelvis, tibia, skull and lumbosacral spine, although any bone can be involved. Most cases are entirely asymptomatic, but features include:

• Bone pain, usually spine or pelvis
• Apparent joint pain, when involved bone is close to a joint
• Deformities, particularly bowed tibia and skull changes
• Complications, e.g. deafness due to nerve compression, a high-output cardiac state from shunting, fracture through abnormal bone and, rarely, osteogenic sarcoma.


Characteristic changes are seen most often in the pelvis, skull or spine involving resorption fronts, osteolytic lesions, sclerosis and thickening of bone trabeculae, long bones and vertebrae. Bone scans will show the extent of skeletal involvement, often including unsuspected areas, but may be difficult to distinguish from metastatic carcinoma, sometimes a major clinical differential diagnosis.


The hallmark of Paget’s disease is an increased serum alkaline phosphatase with normal serum calcium and phosphate, reflecting the increased bone turnover . The serum alkaline phosphatase levels may exceed 1000 mU litre.”. The levels are normal only when bone involvement is limited. Mild hypercalcaemia only follows immobilization. Bone turnover can also be monitored by 24 hour urinary hydroxyproline excretion, which is frequently increased.


When asymptomatic, Paget’s disease requires no therapy. Pain is the usual indication for treatment: SIMPLE ANALGESICS OR NSAIDs are sometimes adequate.
DIPHOSPHONATES, most often disodium etidronate 5 mg kg:’ daily over 3-12 months, will reduce osteoclastic activity and frequently induce remissions of up to 2 years. Diphosphonates are pyrophosphate analogues which are resistant to enzymatic hydrolysis. Serum alkaline phosphatase activity frequently falls, reflecting the effect of the drug. Disodium etidronate must be given away from meals as absorption is erratic, and higher doses may lead to osteomalacia. CALCITONIN (salmon or porcine) 50IU three times weekly to 160 IU daily inhibits bone resorption and turnover, but is extremely expensive and the sideeffects of flushing and nausea are frequent problems. Antibody formation is a further difficulty.
SEVERE CASES may benefit from courses of intravenous diphosphonates under specialist supervision.
MITHRAMYCIN is very occasionally used in severe cases.
The dose is 10-15 JLgkg:’ i.v. and requires monitoring of platelets and liver biochemistry.

Metabolic bone disease



This results from inadequate mineralization of the osteoid framework, leading to soft bones. It is thus usually caused by a defect in vitamin 0 availability or metabolism. The effect on bone is shown.



• Dietary plus inadequate sunlight exposure often seen in Asian immigrant females in Western countries. increased melanin in skin decreases vitamin 03 formantion  and as many Asians are vegans they do not benefit from the small amounts of dietary vitamin D.
• ElderIy people who are immobile and not exposed to right.
• Malabsorption: patients after gastric surgery, those with coeliac disease and those with deficient bile salt production.
• Renal disease leading to inadequate conversion of 25(OH)03 to 1,25(OH)203.

Diagrammatic representation of the effects of osteoporosis

Diagrammatic representation of the effects of

Less common causes are hepatic failure (reduced 25(OH)03 causes) and phenytoin or barbiturate therapy (which induce the mixed function oxidase system and affect vitamin 0 metabolism). Vitamin O-resistant rickets (familial hypophosphataemia) is an X-linked disorder with hypophosphataemia, phosphaturia and rickets:


Childhood rickets usually presents with bony deformity or failure of adequate growth. In the adult, osteomalacia may produce bone and muscle pain and tenderness, often due to subclinical fractures. There is often a marked proximal myopathy, with a characteristic ‘waddling’ gait, but a high degree of clinical suspicion is needed.


Certain diagnosis can only be made by bone biopsy with demonstration of increased unmineralized bone; undecalcified
bone must be used. The procedure is uncomfortable and clinically rarely necessary.
The biochemical  and radiological findings are characteristic:
• low serum phosphate
• increased serum alkaline phosphatase
• low or low-normal plasma calcium, corrected for albumin
• a low phosphate-calcium product is a useful screening test, but use the local laboratory normal ranges
• X-rays show defective mineralization, especially in the pelvis, long bones and ribs, often with Looser’s zone (linear areas of low density)


The simplest treatments are exposure to sunlight and oral vitamin O2 supplements (calciferol); 250/kg daily will cure rickets and osteomalacia and should be given until the serum alkaline phosphatase returns to normal. An adequate calcium intake is necessary. Vitamin D 1 mg (40000 units) daily should be given as a supplement to patients with chronic fat malabsorption. la-Hydroxycholecalciferol (alfacalcidol) (1 J.Lg daily) is the usual treatment for vitamin D deficiency in renal disease and other conditions. 1,25(OH)2D, (calcitriol) is also available for anephric patients.

Serum biochemical findings in some bone diseases.

Serum biochemical findings in some bone diseases.

A whole-life strategy to prevent osteoporosis.

A whole-life strategy to
prevent osteoporosis.

All patients receiving pharmacological doses of vitamin D should have their serum calcium measured regularly. Hypervitaminosis D presents with nausea and vomiting and other features of hypercalcaemia. REVENTION. Education to ensure a balanced diet,
exposure to sunlight and the taking of vitamin D supplements when necessary will prevent both rickets and osteomalacia.

Physiology, structure and formation of bone

Bone is subdivided into cortical and cancellous bone. In an adult long bone, cortical bone forms the diaphyseal shaft within which is the medullary cavity containing bone marrow. Cancellous bone consists of a network of interconnecting trabecular plates and rods, and is found within the medullary cavity at the epiphyses. Bone remodelling takes place at four bone surfaces: the periosteum, the Haversian systems, at the endosteum of cortical bone and the cancellous bone surface, which is continuous with the endosteal surface. In normal adult bones, 80% of surfaces are quiescent. The rest are remodelled by a coupling process, resorption by osteoclasts being followed in sequence by bone matrix synthesis and mineralization by osteoblasts. This process takes 4 months with no net change in bone mass. Bone metabolism and mineralization is thus dependent on:
• Collagen synthesis
• Absorption and availability of calcium, affected by vitamin D
• Bone resorption and deposition, largely under hormonal control with local factors affecting bone resorption and remodelling.


Calcium absorption and distribution

Normal Western adult calcium consumption is approximately (20-25 mmol Ca2+) (800-1000 mg) daily, though it is much lower in some less affluent countries. Calcium deficiency does not appear to be a significant cause of bone disease, probably because calcium absorption increases in states of dietary calcium deficiency. Absorption is, however, sometimes reduced by generalized malabsorption.
Calcium fluxes between gut, plasma, bone and kidney are shown in Fig. 8.24. The circulating pool of calcium (about 12 mmol in total) is tiny compared with the bOD\” reservoir and small compared with the daily fluxes. Regulation

Vitamin D metabolism

The metabolism and actions of vitamin D are shown . Vitamin D is produced in the skin as cholecalciferol (vitamin D3) by photoactivation of 7-dehydrocholesterol. This, rather than dietary vitamin D, is the chi – source of vitamin D metabolites in humans and poor nutrition is of only small importance in producing vitamin D deficiency. These metabolites are transported in the circulation bound to vitamin D-binding protein.
the liver cholecalciferol is hydroxylated to 25-hydroxycholecalciferol (25(OH)D3) and the measurement of this in the blood is a good indicator of vitamin D bioavailability. The next step in the metabolism occurs in the kidn where, in the tubules, the enzyme l o-hydroxylase is CODcentrated and the highly biologically active 1,25-dihydroxycholecalciferol (l,25(OH)2D3) is produced. The kidneyalso produces a second metabolite, 24,25(OH)2D3′ well as 1,25(OH)2D3 if vitamin D supplies are adequate.. The production of 1,25(OH)2D3 is strictly regulated parathyroid hormone (PTH), phosphate and by a feedback inhibition by 1,25(OH2)D3 itself. Hypocalcae also stimulates 1,25(OH2)D3 production probably \ PTH.
Extra-renal sources of 1,25(OH)2D3 production are small under normal conditions but it can be produced – lymphomatous and sarcoid tissue. The mode of action is similar to that of other stero hormones, i.e. interaction with a specific receptor in target cell (Fig. 8.26): 1,25(OH)2D3 attaches non-coxently to an intracellular receptor protein; this complex is transported through the nuclear membrane into the nucleus, where it interacts with 0 A to initiate or suppress the synthesis of RNA-encoding proteins. The control of this is regulated by several factors; for example, interleukin, interferons and C-MYC down-regulate, and prolactin and fibronectin up-regulate. The biological potencies of the D3 metabolites influence their ligand affinities for the receptor proteins. Bone, gut, kidney and the parathyroid gland are the prime target organs, but many other tissues respond to 1,25(OH)2D3′ e.g. the skin, activated lymphocytes and cancer cells. This suggests a much wider role, e.g. immunoregulation and cellular differentiation, for vitamin D.

Calcium exchange in the normal human. The fluxes are shown in mmols per day.

Calcium exchange in the normal human. The fluxes are shown in mmols per day.

The metabolism and actions of vitamin 0. PTH, parathyroid hormone.

The metabolism and actions of vitamin 0. PTH, parathyroid hormone.

Parathyroid hormone

PTH levels rise as plasma calcium falls. The effects of PTH, secreted by the four parathyroid glands, are several, all serving to raise plasma calcium:

• Increased tubular reabsorption of calcium
• Increased excretion of phosphate
• Increased osteoclastic resorption of bone
• Increased intestinal absorption of calcium
• Increased synthesis of 1,25(OH)2D3
The effects are mediated at membrane receptors on the target cells, with resultant increased adenyl cyclase activity.
While the parathyroids are usually situated posterior to the upper and lower lobes of the thyroid, additional local ones are sometimes seen and they may also occasionally be found elsewhere in the neck or in the mediastinum.

Suggested mode of action of l,25(OH),D. (DO) on target cells (see text).

Suggested mode of action of l,25(OH),D. (DO) on
target cells (see text).

Other regulatory factors

CALCITONIN. This 32 amino acid polypeptide is produced by thyroid C-cells. Its physiological importance in man as a hypocalcaemic hormone remains uncertain. Plasma levels rise with increasing plasma calcium, and it is known to inhibit osteoclastic bone resorption and increased renal excretion of calcium and phosphate. However, total thyroidectomy (absent calcitonin) and medullary carcinoma (excess calcitonin) have few skeletal or other noticeable clinical effects. It is, however, used in the treatment of Paget’s disease and, rarely, in hypercalcaemia.

GLUCOCORTICOIDS. Steroids have complex actions on bone, essentially leading to excessive bone resorption and osteoporosis.
SEX HORMONES. Androgens and/or oestrogens have several effects on the skeleton:
• In puberty they induce the growth spurt and subsequent epiphyseal closure
• Both influence skeletal calcium content, especially postmenopausal oestrogen deficiency, which leads to progressive bone loss
GROWTH HORMONE. Acting via IGF-1 (insulin-like growth factor-I or somatomedin C, see p. 797) growth hormone stimulates growth of cartilage.
THYROID HORMONES. Excess thyroxine (T.) and triiodothyronine (T3) cause increased bone turnover, while hypothyroidism leads to growth delay.
THE ROLE OF MAGNESIUM. Total body magnesium is about 25 g. Plasma magnesium ranges between 0.7 and 1.1 mmol litre “, and generally follows plasma calcium. Magnesium deficiency prevents the release of PTH; the level should be measured when there are signs and symptoms of hypocalcaemia unresponsive to calcium administration.
THE ROLE OF PHOSPHATE. Phosphate forms an essential part of most biochemical systems from nucleic acids downwards. About 80% of all body phosphorus is within bone, plasma phosphate normally ranging from 0.80 to 1.40 mmollitre-I. Phosphate reabsorption from the kidney is decreased by PTH, thus hyperparathyroidism is associated with low plasma levels of phosphate. High levels are found in hypoparathyroidism and in renal failure when normal excretion does not occur.

Measurement of plasma calcium, phosphate and PTH

Total plasma calcium is normally 2.2-2.6 mmollitre-I (8.5-10.5 mg dl””). Usually only 40% of total plasma calcium is ionized and physiologically relevant; the remainder is protein bound or complexed and thus unavailable to the tissues. Ionized calcium is difficult to measure, but is very dependent upon protein, in particular albumin, concentration. An approximate correction for plasma calcium is to add or subtract 0.02 mmol litre ” for every gram per Litre by which the simultaneous albumin lies below or above a standard figure (normally 40 or 47 g litre-I). Thus, a total calcium of 2.22 mmollitre-I with an albumin of 35 g litre-I will become 2.32 mmollitre-I (corrected to 40 g litre-I).
For critical measurements, samples should be taken in the fasting state without use of a cuff, as this affects protein concentration.
Improved two-site immunoradiometric assays for PTH are now available that only measure the intact molecule and not fragments; interpretation requires simultaneous plasma calcium and phosphate measurements.



Bone forms 25% of the weight of a normal adult; its major mineral constituents are calcium, phosphate and, to a much lesser extent, magnesium. While obviously there is major growth in childhood, bone is not a static framework in the adult. There is a continuous process of bone remodelling with bone formation by osteoblasts and resorption by osteoclasts. While exchange of calcium between bone and plasma is only 10—15mmol daily, over 1 year 20% of total bone calcium is exchanged; minor imbalances of control of the remodelling processes can therefore lead to substantial changes in bone mass or mineralization over the years.

Soft-tissue rheumatism

Soft-tissue rheumatism is a convenient term for a number of conditions with similar features . They cause musculoskeletal or joint pain that arises, not from the joint itself, but from surrounding structures such as the tendon sheaths and bursae. These conditions are benign and in most cases self-limiting. They are often regarded as trivial except by those who have them. Many are best treated by local corticosteroid injection rather than by anti-inflammatory drugs. It is also important to remove aetiological factors whenever possible; mechanical factors such as overuse and repetitive strain are probably particularly important. Common soft-tissue rheumatic syndromes are shown.


There are numerous bursae around the body and any of these can become inflamed; olecranon bursitis (student’s elbow) and prepatellar bursitis (housemaid’s knee) are two examples. Bursitis may appear for no obvious reason or it can be secondary to trauma, repetitive injury or an arthritis such as RA or gout. Occasionally, bursitis is due to infection, when aspiration will be necessary. In many cases no treatment is required other than protection of the inflamed site. Injection of corticosteroid may be useful and, very occasionally, large and troublesome bursae may require excision. Ischial bursitis causes pain over the ischial tuberosity and makes sitting difficult. A ring cushion is usually helpful.

Mechanisms of soft-tissue rheumatism.

Mechanisms of soft-tissue rheumatism.

Common soft-tissue rheumatic syndromes.

Common soft-tissue rheumatic


Tenosynovitis can occur in any tendon sheath. The flexor tendons of the fingers are often affected and cause the condition known as trigger finger. Patients characteristically wake with one finger fixed in flexion. Some force is needed to extend the finger and this produces pain. There is a palpable nodule in the flexor tendon. Injection of this nodule with a corticosteroid preparation usually provides relief.
De Quervain’s tenosynovitis gives rise to pain in the anatomical snuff box and may be mistaken for OA of the first carpometacarpal joint. The point of maximum tenderness should be injected with a combination of corticosteroid and local anaesthetic.


The enthesis is the specialized area at the junction of tendons or ligaments and bone. Inflammation of the junction of the common extensor origin of the muscles of the forearm and the lateral humeral epicondyle results in ‘tennis elbow’. This condition is seldom due to tennis, more often it is caused by housework or some repetitive manual occupation. Often there is no obvious cause. There is pain in the elbow, but it is not clearly localized. However, on examination, the joint is normal and there is an area of exquisite tenderness over the lateral epicondyle. It is usually treated by injecting this tender area with a combination of corticosteroid and local anaesthetic. Since the condition resolves within a year or two whatever is done, in mild cases it may be best ignored.
Golfer’s elbow is a similar problem at the junction of the origin of the flexor muscles of the forearm and the medial humeral epicondyle. Another common site is the greater trochanter of the femur (trochanteric syndrome). In plantar fasciitis, the inflammation arises on the undersurface of the heel at the origin of the plantar fascia. This common condition is best treated with an injection of corticosteroid and a protective heel pad; it normally resolves within a year or two.

Nerve compression syndromes

Carpal tunnel syndrome is described. A similar condition in the foot, tarsal tunnel syndrome, gives rise to burning pain with pins and needles in the sole of the foot and toes. As in carpal tunnel syndrome, the pain is often worse at night and may wake the patient from sleep. In cases of diagnostic difficulty, nerve conduction studies will show a block at the appropriate level. In Morton’s metatarsalgia, pain arises from a digital nerve in the foot, usually between the third and fourth metatarsal heads. It is due either to a neuroma or to compression by a bursa. There is pain in the forefoot that radiates into the toes. It is usually aggravated by wearing shoes and relieved by removing them. Manual compression of the forefoot reproduces the symptoms. The condition sometimes responds to local injection and to the use of a metatarsal pad. If not, surgical exploration and excision of the bursa or digital nerve is required.

Frozen shoulder

This is a convenient term for a group of soft-tissue syndromes that produce the same clinical picture-a painful stiff shoulder. Some people reserve the term for the later stage of the disease when the glenohumeral joint is comletely immobile. Many other terms, such as periarthritis or capsulitis, are used to describe this condition, but without much pathological justification. In some cases, 10cal tenderness points to a lesion such as supraspinatus rendinitis, bicipital tendinitis or subacromial bursitis. In st cases, however, it is not possible to identify a specific cause and differentiation makes little difference the outcome or treatment.

Frozen shoulder is a common condition occurring in aduIts at any age. It is usually but not always unilateral. there is pain in the shoulder that may radiate to the arm and is usually most troublesome at night. In most cases the condition appears without obvious cause but it may occasionally be related to overuse or injury. A similar clinical picture is produced by acute calcific periarthritis . Examination shows restriction of glenohumeral movement. Analgesics and exercises to prevent stiffness are sufficient treatment in mild cases. If there is restriction of movement, intra-articular injection of corticosteroid is required, followed by exercises to mobilize the joint. The response is variable but the condition usually resolves eventually.

Shoulder-hand syndrome

Shoulder-hand syndrome is a rare condition in which a frezen shoulder is followed by sympathetic nervous system mediated abnormalities in the corresponding hand, defuse swelling, warmth and erythema. It may be idiobut pathic but also occurs after strokes and head injuries. Untreated, hand involvement may progress to atrophy and constractures. ACTH is usually very effective, combined with an exercise programme to restore function.


This is used to describe a functional condition of voluntary muscle that gives rise to widespread pains arising from muscles and their insertions. In some cases there is a large psychogenic component and in this respect the condition has a lot in common with irritable bowel syndrome, with which it is often associated. It begins in early adult life, with females being particularly affected. Widespread aches and pains are characteristic, moving from place to place, varying in severity and often aggravated by cold and stress. Patients have a characteristic sleep disturbance, lacking non-rapid eye movement (REM, 6) sleep, waking unrefreshed and feeling tired. Interruption of sleep in normal volunteers will reproduce the syndrome. The characteristic physical sign in fibromyalgia is multiple areas of localized soft-tissue tenderness known as trigger points. They are particularly found around the dorsal spine in the interscapular region, around the base of the neck, over both sacroiliac joints, over the lateral epicondyles of the elbows (resembling tennis elbows), and over the medial sides of the knees. In some patients, crops of nodules appear in the muscles, but these have no consistent pathological basis and are believed to be part of the functional abnormality. Blood tests and X-rays are normal.
The condition is chronic or recurrent but entirely benign. Treatment measures include:
AN EXERCISE PROGRAMME. The rationale for this is the observation that it is difficult to induce fibromyalgia experimentally in trained athletes.
MEASURES TO IMPROVE SLEEP. Amitriptyline at night is particularly useful.
HEAT, MASSAGE AND LOCAL OINTMENTS to relieve pain. Analgesic and anti-inflammatory drugs are seldom helpful.
LOCAL INJECTION of trigger points.

Chest pain

Musculoskeletal conditions are sometimes a cause of chest pain. An example is Tietze’s disease. In this condition, pain arises from the costosternal junctions. It is usually unilateral and affects one, two or three joints. There is local tenderness, which helps to make the diagnosis. The condition is benign and self-limiting. It often responds well to anti-inflammatory drugs, or may be treated with local injections of corticosteroid and local anaesthetic.

Compartment syndromes

The muscles of the lower leg are enclosed in a compartment of fascia, with little room for expansion to occur. Compartment syndromes may be acute (anterior tibial syndrome), e.g. following exercise, or chronic. The former sometimes requires immediate surgical decompression to prevent muscle necrosis. Chronic compartment syndromes produce pain in the lower leg that is aggravated by exercise and may therefore be mistaken for a vascular or neurological disorder.

Repetitive strain syndrome

This term describes a muscular condition which arises as a result of excessive repetitive activity, usually involving the hands in occupations such as keyboard workers and those who work on assembly lines. Although overuse is the fundamental cause, the condition is more likely to arise in stressful circumstances and when other workers are affected. It presents with pain in the hands and forearms together with various other symptoms such as weakness, cramps, sensory disturbances and a feeling of swelling. There are usually no objective abnormalities. It is important to distinguish this condition from others like te nnis elbow, tenosynovitis and carpal tunnel syndrome which can also arise from repetitive manual work. Treatment involves remaining at work but stopping or reducing the activity which caused the problem, exercise and physiotherapy. The condition recovers with time but in severe cases this takes years. Prevention is therefore most important and involves ensuring a good ergonomic position at work, taking regular breaks and recognizing problems quickly if they occur.