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Rickets and osteomalacia
BONE DISORDERS
Rickets and osteomalacia
What’s new?
Michael P Whyte C
Identification of several phosphatonins e circulating factors that cause phosphaturia and hypophosphataemic rickets and osteomalacia
C
Fibroblast growth factor 23 (FGF23) concentrations are elevated in plasma of patients with oncogenous osteomalacia
C
Discovery of the gene defects that cause heritable forms of rickets and osteomalacia
Rajesh V Thakker
Abstract Rickets is the clinical consequence of impaired mineralization of bone matrix throughout the growing skeleton in children, whilst osteomalacia is the result of this disturbance after the growth plates have fused in adults. The three major causes of rickets and osteomalacia are vitamin D deficiency, renal tubular dysfunction, and abnormalities of chondrocyte, osteoblast or bone matrix function. Rickets and osteomalacia can occur as heritable disorders. The major clinical features of rickets and osteomalacia include bone pain and tenderness, skeletal deformity, muscle weakness and occasionally tetany due to hypocalcaemia. Hypocalcaemia, hypophosphataemia, and raised serum alkaline phosphatase activity are typically found together with radiographic abnormalities such as widening of growth plates in rickets and pseudofractures in osteomalacia. Serum 25-hydroxyvitamin D concentrations are low in states of vitamin D deficiency, but may be normal in chronic renal failure, hereditary forms of rickets and oncogenous osteomalacia; in these latter disorders, the serum 1,25-dihydroxy vitamin D concentrations are low or inappropriately in the normal range. Treatment with vitamin D, or its active metabolites, will generally provide relief of bone pain, improve mobility and prevent fractures, but must be carefully monitored.
Occasionally, renal tubule dysfunction results in urinary phosphate wasting, leading to hypophosphataemia, often associated with impaired bioactivation of vitamin D. Rarely, disturbances of chondrocytes and osteoblasts, defective bone matrix or other disruptions block calcium and phosphate entry into the skeleton. In rickets, there are defects in growth, shaping (modelling) and turnover remodelling of bone in accordance with metabolic, structural and repair requirements, and patients exhibit short stature (physeal disturbances). Osteomalacia is usually not deforming (unless fractures occur) because growth plates are fused and modelling has essentially ceased; only remodelling is deranged. Accordingly, impaired mineralization of skeletal matrix in osteomalacia is less apparent clinically and radiographically.
Vitamin D
Keywords bone; electrolytes; mineral; osteomalacia; renal; rickets; skeletal; vitamin D
Most of the vitamin D in healthy, active individuals is derived via a cutaneous synthesis pathway. In the skin, 7-dehydrocholesterol is converted to cholecalciferol (vitamin D3) by 290e310 nm ultraviolet light. Ergocalciferol (vitamin D2) is the product of ultraviolet irradiation of ergosterol extracted from animal or plant tissues, and is used as a supplement or as a pharmaceutical. Vitamin D should be regarded as a steroid hormone, not a nutrient, because it undergoes two bioactivation steps, circulates and then binds to a receptor, as follows. Vitamin D2 and vitamin D3 are prohormones transported by a high-affinity binding protein in the blood to muscle or fat for storage, or to the liver and then the kidney for bioactivation. Vitamin D is hydroxylated in hepatocyte mitochondria by the enzyme P450c25, forming the 25-hydroxyvitamin D metabolite, which is also called calcidiol. Regulated by circulating ionized calcium, inorganic phosphate and parathyroid hormone (PTH) levels, 25-hydroxyvitamin D is further hydroxylated in renal proximal convoluted tubule cells by the enzyme 25-hydroxyvitamin D, 1a-hydroxylase (1a-hydroxylase). The product is the potent 1,25-dihydroxyvitamin D metabolite, which is also called calcitriol. Calcitriol circulates to target organs, where it binds to the vitamin D receptor. The vitamin D receptor activates transcription of genes in enterocytes, kidney and bone to ensure adequate extracellular concentrations of minerals by increasing gut absorption of calcium, increasing urinary calcium reclamation by the kidneys and facilitating bone resorption.
Rickets is the clinical consequence of impaired mineralization of matrix throughout a growing skeleton. Infants, children and adolescents can be affected. Osteomalacia results from this disturbance after growth plates fuse (i.e. adulthood). There are three principal causes (Table 1) of rickets and osteomalacia. The most common explanation is deficiency of vitamin D, which may result from lack of exposure to sunlight leading to inadequate cutaneous biosynthesis, poor dietary intake or malabsorption as a result of hepatobiliary or gastrointestinal disease. This often leads to hypocalcaemia, secondary hyperparathyroidism and hypophosphataemia.
Michael P Whyte MD is Director of the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children, and Professor of Medicine, Pediatrics and Genetics at Washington University School of Medicine, St Louis, USA. Competing interests: none declared. Rajesh V Thakker MD FRCP FRCPath FMedSci is May Professor of Medicine and Head of the Academic Endocrine Unit at the University of Oxford, UK. Competing interests: none declared.
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BONE DISORDERS
rosary’). The pull of the diaphragm produces a groove in the rib cage (Harrison’s sulcus). In toddlers, rickets causes bow-leg deformities; knock-knees are characteristic in later childhood. Both occasionally occur together as ‘windswept’ legs. Rickets myopathy is part of the differential diagnosis of the ‘floppy baby’ and cardiac failure. If muscle weakness is sufficiently severe to prevent walking, it may limit deformity of the lower limbs. Short stature is common. Pathological fractures in the shafts of the long bones can occur in severe forms of rickets.
Causes of rickets and osteomalacia Primary (‘‘nutritional’’) vitamin D deficiency C
C C C
Classic vitamin D deficiency (e.g. in Asian children) e infants and puberty (‘late’ rickets) Immigrant adults in developed countries Elderly, housebound and institutionalized groups Food faddists
Secondary vitamin D deficiency Partial gastrectomy Small bowel malabsorption syndromes (e.g. coeliac disease) C Hepatobiliary disease C Pancreatic insufficiency Chronic renal failure Metabolic acidosis Drugs and toxins C
Osteomalacia Osteomalacia in adults may cause vague symptoms. Bone pain usually occurs in the axial skeleton (shoulders, spine, ribs and pelvis). Localized pain (e.g. in the groin) may result from an undisplaced femoral neck fracture or an underlying Looser’s zone (pseudofracture), which can be seen on radiography. Tenderness may be elicited by spinal percussion or by sternal and lateral rib compression; the most painful bones are generally those with the thinnest cortices. In severe osteomalacia, the vertebrae become compressed, and patients become immobilized and chair-bound. Osteomalacia myopathy has a characteristic proximal distribution. Gait should be assessed; it is commonly described as ‘waddling’. A simple test for myopathy is failure to rise from a sitting position unaided with the arms folded in front. However, it may be difficult clinically to detect myopathy if there is pain; even when it is undoubtedly present, electromyographic abnormalities are non-specific and can be absent. The nature of osteomalacia pain and muscle weakness is often vague and can lead to misdiagnosis. Hypocalcaemia may be suggested by a positive Chvostek’s and/or Trousseau’s sign.
C
Anticonvulsants Phosphate-binding antacids (e.g. aluminium hydroxide) C Bisphosphonate (etidronate) C Fluoride Miscellaneous forms C C
Calcium depletion Magnesium depletion C Primary hyperparathyroidism Oncogenic Hereditary forms C C
C C C C
C
Hypophosphataemia (X-linked and autosomal dominant) Vitamin D-dependent rickets type 1 and type 2 Proximal renal tubular disorders (Fanconi’s syndrome) Distal renal tubular disorders (renal rickets with nephrocalcinosis and dwarfism) Hypophosphatasia
Investigations Table 1
Biochemical investigations Hypocalcaemia is usually more severe in vitamin D-deficiency rickets than in osteomalacia, and sometimes paradoxically results in hyperphosphataemia by directly affecting renal tubules. Secondary hyperparathyroidism causes mild hyperchloraemic metabolic acidosis, reflecting increased renal excretion of bicarbonate. However, significant metabolic acidosis suggests Fanconi’s syndrome. Serum alkaline phosphatase (ALP) activity is elevated in almost all patients with rickets or osteomalacia; the exception is hypophosphatasia, which features hypophosphatasaemia. Levels of other markers of skeletal turnover can be disturbed, but need not be measured routinely. Quantification of circulating vitamin D levels directly assesses vitamin D status, but assays for these prohormones are not readily available, and measurement of serum 25-hydroxyvitamin D is a useful alternative.
Clinical findings The major features of rickets and osteomalacia are: bone pain and tenderness skeletal deformity and fractures muscle weakness occasionally, signs of tetany from associated hypocalcaemia. An underlying cause (Table 1) is often suggested by the medical history (e.g. bowel disturbance, positive family history). The features of specific types of rickets and osteomalacia are discussed below.
Rickets Rickets manifests during growth and the signs are most prominent in areas where bone growth is most rapid. Thus, the signs of rickets can vary with age. At birth, the skull is growing most rapidly. Neonatal rickets may therefore present as craniotabes, in which the cranial vault has the consistency of a ping-pong ball. In the first year of life, rickets swells metaphyses at the wrists and causes ‘beading’ of the costochondral junctions (‘rachitic
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Radiology In rickets, anteroposterior radiography of the knees and posteroanterior radiography of the wrists show widening of growth plates. Typically, the metaphyses are splayed, ragged and concave, and the epiphyses appear as though held within a cup.
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Vitamin D preparations Five sterols with vitamin D activity are currently available (Table 2). They differ in potency and biological half-life. Active metabolites of vitamin D can circumvent defective vitamin D bioactivation, are more potent than vitamin D itself and have a more rapid onset of action. However, these agents are expensive and have shorter biological half-lives, although toxicity can easily be corrected. Furthermore, they do not replenish deficient vitamin D stores and cessation of therapy leads rapidly to return of the disturbance of mineral homeostasis.
Radiographic signs of secondary hyperparathyroidism are seen best as subperiosteal erosions involving the radial border of the middle phalanx of the index finger, and erosion of the distal ends of the clavicles and symphysis pubis. The vertebrae may develop a ‘rugger-jersey’ appearance. Intervertebral discs may compress softened end-plates, causing biconcave (‘cod-fish’) vertebrae. In osteomalacia, pseudofractures can occur anywhere (except in the skull), and most often affect the pubic and ischial rami, the ribs, the scapulae and the medial cortex of the proximal femora. Bone scintigraphy is useful, but does not provide a diagnosis. Enhanced radioisotope uptake occurs when osteoidosis is present, hence rickets or osteomalacia can produce a ‘superscan’. Bone scanning is usually unnecessary in children with rickets. In adults, bone scanning helps to detect focal complications of osteomalacia such as fractures and pseudofractures.
Mineral supplementation Many calcium and phosphate preparations are available. Oral calcium carbonate is least expensive, but calcium citrate is better absorbed. Calcium gluconate is costly. For phosphate supplementation, tablets are more convenient than liquid preparations, taste better and seem less likely to cause diarrhoea. Preparations containing high levels of sodium should be avoided. Careful monitoring is required. The most useful biochemical parameters are serum calcium and phosphate, ALP activity and PTH levels. Depending on the aetiology and pathogenesis of the rickets or osteomalacia, serum 25-hydroxyvitamin D and 1,25dihydroxyvitamin D concentrations may also be helpful. Calcium excretion in 24-hour urine collections (corrected for creatinine content) guides therapy and helps monitor for impending toxicity. Because hypocalciuria characterizes most forms of rickets and osteomalacia, rising urinary calcium levels suggest effective therapy. Maintenance of normal urinary calcium levels typically indicates adequate treatment. Dose reductions may be necessary once healing is complete (maintenance therapy). Satiation of ‘hungry bones’ can abruptly increase urinary calcium excretion because the skeleton no longer acts as a sump for mineral deposition, and correction of previously abnormal biochemical findings heralds hypercalciuria. Unless there is advanced renal failure or fixed elevation of circulating PTH levels (reclaiming calcium from the glomerular filtrate), hypercalciuria generally precedes hypercalcaemia. Lower doses of vitamin D and mineral supplements may then be needed. Thus, 24-hour urine collections (not random specimens) assayed for calcium and creatinine are particularly important for follow-up.
Histopathology Biopsy showing defective mineralization of skeletal tissue is the definitive investigation. It is not required routinely in rickets, but is more useful in osteomalacia because radiographic studies are less helpful. A specimen of iliac crest obtained using a 5 mm internal diameter trephine is ideal. Both cortical and trabecular bone are sampled. Two 3-day courses of oxytetracycline or demeclocycline hydrochloride, 20 mg/kg/day in divided doses, are given (separated by a 2-week interval) for in vivo tetracycline labelling of bone tissue. The final dose is taken several days before the transiliac biopsy. In rickets and osteomalacia, nondecalcified stained sections reveal abundant osteoid covering bone surfaces, but fluorescence microscopy fails to show two discrete tetracycline ‘labels’ produced by ongoing mineralization. Instead, absent or indistinct fluorescence is seen.
Principles of management The aims of treatment are: reversal of short stature and deformity in rickets relief of bone pain and fracture prevention in osteomalacia. Ideally, the primary pathological process is corrected. This may not be possible, and vitamin D (or an active metabolite), often with mineral supplementation, is needed.
Pharmaceutical preparations of vitamin D and active metabolites Calciferol*
Dihydrotachysterol
Drug Form and preparation
Vitamin D3 or D2 C Capsules, 0.25 mg and 1.25 mg
DHT C Liquid, 0.25 mg/ml
Time to maximum effect Persistence of effect after cessation
4e10 weeks 6e30 weeks
2e4 weeks 2e8 weeks
Calcifediol
Calcitriol
Alfacalcidiol
25-hydroxyvitamin D3 Capsules, 20 and 50 mg
1,25(OH)2D3 C Capsules, 0.25 and 0.5 mg C Injection, 1 mg/ml
4e20 weeks 4e12 weeks
0.5e1 week 0.5e1 week
1a(OH)D3 C Capsules, 0.25, 0.50 and 1 mg C Liquid, 2 mg/ml C Injection, 2 mg/ml in propylene glycol 0.5e1 week 0.5e1 week
C
* Calciferol may contain cholecalciferol or ergocalciferol.
Table 2
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Surgery Consultation and follow-up with an orthopaedic surgeon can be an important aspect of the management of rickets. Leg-bracing, physeal stapling (epiphysiodesis) or rarely osteotomy may be helpful. Achievement of straight lower limbs when growth ceases, with the physes aligned parallel to the ground, may forestall osteoarthritis. Intramedullary rodding may be necessary to heal pseudofractures or prevent fractures in some patients with osteomalacia.
osteoporosis. Vitamin D deficiency can result from subclinical malabsorption (e.g. coeliac disease). These disturbances are complex, and vitamin D therapy and follow-up must be individualized. Serum 25-hydroxyvitamin D assays document vitamin D deficiency and are essential for monitoring progress. Despite malabsorption, sufficient doses of oral vitamin D, in the form of calciferol, should be effective and are relatively inexpensive. Vitamin D treatment repletes the stores and is readily converted to 25-hydroxyvitamin D by hepatocytes even with parenchymal liver disease.
Types of rickets and osteomalacia Low calcium Profound deficiency of dietary calcium despite intact stores of vitamin D can also impair skeletal mineralization. Inadequate calcium intake has caused so-called calciopenic rickets in premature infants and in children fed a cereal-based diet. Poor dietary calcium intake can also exacerbate vitamin D-deficiency rickets. Members of religious, ethnic and other groups that do not consume dairy products are at risk. Correcting the diet or using calcium supplements should readily reverse this disorder. In addition, hypophosphataemia from secondary hyperparathyroidism or primary renal phosphate wasting can cause defective matrix mineralization. Notably, some patients with hypocalcaemia alone from hypoparathyroidism or pseudohypoparathyroidism develop rickets or osteomalacia, despite raised serum phosphate levels.
Primary (‘‘nutritional’’) vitamin D deficiency The minimum daily requirement for vitamin D is 10 mg (400 IU) in children and 2.5 mg (100 IU) in adults. Primary (‘nutritional’) rickets or osteomalacia occurs as a result of social, economic and/or cultural factors that prevent sufficient exposure to sunlight (Table 1): about 20 minutes on the face and arms is required on several occasions each week. Various factors reduce cutaneous vitamin D biosynthesis, including ageing, pigmentation, extent of clothing, residence at latitudes at which only lowintensity UV exposure is possible and use of sunscreens that block the access of UV light to the skin. Institutionalized/ housebound individuals, the poor, the elderly, food faddists and some religious groups (because of diet and dress) are at risk. Infants who are breast-fed beyond 6 months of age or who drink non-fortified milk or formula are also susceptible if they are insufficiently exposed to sunlight. Low dietary calcium intake is an important exacerbating factor. Low serum 25-hydroxyvitamin D concentration confirms the diagnosis of vitamin D deficiency. Unless there is significant hypoproteinaemia, levels less than 20 ng/ml are diagnostic; and levels 21 to 29 ng/ml are considered insufficient. Patient/parent education and correction of adverse socioeconomic factors could help to prevent and treat vitamin D deficiency, but are often difficult to achieve. However, drug therapy is inexpensive, effective and works rapidly (Table 2). Vitamin D deficiency should be treated using vitamin D (i.e. calciferol preparations). 25-hydroxyvitamin D3, 1a-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 are more potent and act more rapidly, but all fail to correct depleted stores of vitamin D.
Drugs and toxins Anticonvulsants: rickets and osteomalacia have been reported in institutionalized individuals receiving anticonvulsants. Phenobarbital can alter hepatic vitamin D metabolism, predisposing patients to vitamin D depletion. Many such individuals also have primary vitamin D deficiency. Phosphate-binding antacids: osteomalacia can result from excessive use of phosphate-binding antacids (magnesium and aluminum hydroxides). Significant hypophosphataemia can occur. Urinary phosphate assays reveal low levels. Rickets has occurred when these preparations were added to infant formula to treat colic. Aluminium is also toxic to osteoblasts and directly inhibits skeletal mineralization. Conversely, these patients may hyperabsorb dietary calcium and become hypercalciuric because hypophosphataemia stimulates renal 1ahydroxylase activity. Rarely, kidney stones develop. Hypophosphataemia impairs skeletal mineralization, and elimination of antacid exposure rapidly corrects this. Dietary phosphate intake is quite variable, but sufficient for skeletal remineralization. Phosphate supplementation or vitamin D therapy is unnecessary. It may be several months before serum ALP activity returns to normal.
Secondary vitamin D deficiency Vitamin D deficiency can be due to malabsorption despite normal exposure to sunlight. Gastrointestinal, pancreatic or hepatobiliary disease may be responsible. The mechanism is often complex. Vitamin D is a fat-soluble secosterol and bile salts are necessary for its absorption. Additionally, there is enterohepatic circulation of vitamin D and its derivatives. Thus, hepatobiliary/pancreatic disease or short bowel syndrome causing deficiency of bile salts, steatorrhoea and malabsorption can lead to vitamin D depletion. Furthermore, the small bowel mediates dietary calcium uptake, and malabsorption of calcium exacerbates vitamin D deficiency. In secondary hyperparathyroidism, conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D is increased, and 25hydroxyvitamin D stores may be diminished by this mechanism. In some conditions in which osteomalacia might be anticipated (e.g. primary biliary cirrhosis), the associated osteopathy is often
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Ifosfamide can cause transient or permanent renal tubule damage, leading to urinary phosphate wasting and hypophosphataemic skeletal disease. Etidronate is a first-generation bisphosphonate used in Paget’s bone disease (see article on pp. 485e486) and hypercalcaemia of
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BONE DISORDERS
malignancy. Excessive or prolonged therapy can cause rickets or osteomalacia.
Genes in hereditary rickets
Uraemic patients who are exposed excessively to aluminiumcontaining antacids or to contaminated dialysis fluid or parenteral feeds have developed osteomalacia. With increasing use of sevelamer hydrochloride and other pharmaceuticals for phosphate-binding and corrected dialysate and parenteral nutrition, this disorder is now rare. Excessive fluoride intake (well water, industrial exposure, treatment for osteoporosis) can cause osteomalacia. Bone mineralization responds gradually to calcium supplementation and cessation of fluoride poisoning. Metabolic acidosis Metabolic acidosis can cause rickets or osteomalacia. The pathogenesis is poorly understood, but the skeletal disease responds well to vitamin D and alkali therapy. Calcium and potassium supplementation may be necessary at initiation of alkali therapy to prevent hypocalcaemia and hypokalaemia. Vitamin D, 50,000 IU thrice weekly p.o., can be used in adults, with careful followup until healing occurs. Alkali therapy should be continued after the mineralization defect is corrected. Urinary calcium levels must be monitored frequently because metabolic acidosis per se causes hypercalciuria.
Chromosomal Gene location
X-linked dominant hypophosphataemia X-linked recessive hypophosphataemia Autosomal dominant hypophosphataemia Lowe’s syndrome (Fanconi’s syndrome) Vitamin D-dependent type 1 Vitamin D-dependent type 2 Hypophosphatasia
Xp22.1 Xp11.22 12p13 Xq25eq26 12q14 12q12eq14 1p34e1p36.1
PHEX CLCN5 FGF23 OCRL 1aOHase VDR TNSALP
PHEX, phosphate-regulating gene with homologies to endopeptidases on the X chromosome; CLCN5, voltage-gated chloride channel 5 gene, mutations of which cause Dent’s disease; FGF23, fibroblast growth factor 23; OCRL, oculocerebrorenal syndrome of Lowe, encoding an inositol polyphosphate phosphatase; 1aOHase, the renal 1a-hydroxylase gene; VDR, 1,25-dihydroxyvitamin D3 receptor gene; TNSALP, tissue nonspecific alkaline phosphatase.
Table 3
occasionally presents with knock-knees. Affected children can seem clumsy but are otherwise well. The skull is often dolichocephalic (long and narrow), but the chest and upper extremities are not deformed. Contrary to almost all other forms of rickets, muscle weakness does not occur. Fractures during childhood are uncommon. Serum calcium levels are low-normal, but usually not distinctly reduced. Bioactivated forms of vitamin D (e.g. calcitriol), together with oral phosphate supplements, are used in treatment. XLH is caused by inactivating mutations of the PHEX gene, which encodes a putative endopeptidase (Table 3).
Renal failure In uraemia, skeletal disease usually reflects secondary or tertiary hyperparathyroidism, leading to rapid bone remodelling (osteitis fibrosa cystica) or excessive pharmacological suppression of bone turnover. However, some patients exhibit defective mineralization of the skeletal matrix. Several causes have been documented, and excessive use of aluminium-containing antacids is to be avoided and substituted with other phosphate binders.
Autosomal dominant hypophosphataemia, an especially rare form of renal phosphate wasting, features mild rickets that appears during adolescence. It is caused by gain-of-function mutation of FGF23.
Oncogenic osteomalacia (or rickets) Oncogenic osteomalacia (or rickets) is a rare disorder typically caused by a benign mesenchymal tumour in soft tissues. Patients are profoundly weak and hypophosphataemic with low (or undetectable) plasma 1,25-dihydroxyvitamin D concentrations. Extirpation of the tumour cures the condition. Some tumours have been shown to produce fibroblast growth factor 23 (FGF23) and plasma FGF23 concentrations are usually elevated. In fact, activating mutations in the gene encoding FGF23 are associated with autosomal dominant hypophosphataemia (see below). These tumours may also produce other putative phosphaturic ‘phosphatonins’.
Fanconi’s syndrome features renal phosphate wasting and other manifestations of proximal renal tubule dysfunction, causing low serum phosphate, potassium, bicarbonate and uric acid, and aminoaciduria. Causes include cystinosis, tyrosinaemia and Lowe’s syndrome. Treatment with 1,25-dihydroxyvitamin D3 and phosphate supplementation is helpful, but urinary calcium levels must be monitored carefully because hypercalciuria can occur. McCuneeAlbright syndrome, due to activating mutation of the a subunit of the G-protein, can cause hypophosphataemic rickets. Treatment with 1,25-dihydroxyvitamin D3 and phosphate controls the rickets, but efficacy may be difficult to assess because of premature closure of growth plates and the underlying fibrodysplastic skeletal disease. Bone biopsy interpretation may be difficult because of widespread fibrous dysplasia.
Heritable rickets and osteomalacia Several genetic disorders cause rickets or osteomalacia (Table 3). Some feature renal phosphate wasting, some reflect disturbances in the bioactivation or action of vitamin D. A few are inborn errors of metabolism caused by enzyme deficiencies. X-linked hypophosphataemia (XLH) is the most common heritable form of rickets (‘vitamin D-resistant rickets’) and osteomalacia. The prevalence is about 1/20,000 live births. All races are affected. XLH causes short stature and bowing of the lower limbs in toddlers as they begin to bear weight. Skeletal disease
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Disease
Vitamin D-dependent rickets types I and II are rare, autosomal recessive disorders that mimic vitamin D-deficiency rickets by reduced biosynthesis of, and target tissue resistance to, 1,25dihydroxyvitamin D, respectively.
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Ruppe MD, Jan de Beur SM. Disorders of phosphate homeostasis. In: Rosen CJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 7th edn. Washington, DC: American Society for Bone and Mineral Research, 2008. White KE, Econs MJ. Fibroblast growth factor-23. In: Rosen CJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 7th edn. Washington, DC: American Society for Bone and Mineral Research, 2008. Whyte MP. Approach to the patient with metabolic bone disease. In: Feldmann D, Glorieux FH, Pike JW, eds. Vitamin D. 2nd edn. San Diego: Academic Press, 2005. Whyte MP. Rickets and osteomalacia (acquired and heritable forms). In: Wass JAH, Shalet SM, eds. Oxford textbook of endocrinology and diabetes. Oxford: Oxford University Press, 2002. Whyte MP. Hypophosphatasia: Nature’s window on alkaline phosphatase function in humans. In: Bilezikian J, Raisz L, Martin TJ, eds. Principles of bone biology. 3rd edn. San Diego: Academic Press, 2008.
Hypophosphatasia is a rare, heritable form of rickets featuring deficient activity of the tissue-non-specific isoenzyme of ALP. The severity is remarkably variable, ranging from premature loss of teeth only, to intrauterine death from profound skeletal hypomineralization. Approximately 200 different mutations have been discovered in the gene that encodes the ALP expressed in bone. A
FURTHER READING Glorieux FH. Rickets. New York: Raven Press, 1991. Hollick MF. Vitamin deficiency. N Engl J Med 2007; 357: 266e81. Parfitt AM. Vitamin D and the pathogenesis of rickets and osteomalacia. In: Feldmann D, Glorieux FH, Pike JW, eds. Vitamin D. 2nd edn. San Diego: Academic Press, 2005.
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Rickets and osteomalacia
What’s new?
Michael P Whyte C
Identification of several phosphatonins e circulating factors that cause phosphaturia and hypophosphataemic rickets and osteomalacia
C
Fibroblast growth factor 23 (FGF23) concentrations are elevated in plasma of patients with oncogenous osteomalacia
C
Discovery of the gene defects that cause heritable forms of rickets and osteomalacia
Rajesh V Thakker
Abstract Rickets is the clinical consequence of impaired mineralization of bone matrix throughout the growing skeleton in children, whilst osteomalacia is the result of this disturbance after the growth plates have fused in adults. The three major causes of rickets and osteomalacia are vitamin D deficiency, renal tubular dysfunction, and abnormalities of chondrocyte, osteoblast or bone matrix function. Rickets and osteomalacia can occur as heritable disorders. The major clinical features of rickets and osteomalacia include bone pain and tenderness, skeletal deformity, muscle weakness and occasionally tetany due to hypocalcaemia. Hypocalcaemia, hypophosphataemia, and raised serum alkaline phosphatase activity are typically found together with radiographic abnormalities such as widening of growth plates in rickets and pseudofractures in osteomalacia. Serum 25-hydroxyvitamin D concentrations are low in states of vitamin D deficiency, but may be normal in chronic renal failure, hereditary forms of rickets and oncogenous osteomalacia; in these latter disorders, the serum 1,25-dihydroxy vitamin D concentrations are low or inappropriately in the normal range. Treatment with vitamin D, or its active metabolites, will generally provide relief of bone pain, improve mobility and prevent fractures, but must be carefully monitored.
Occasionally, renal tubule dysfunction results in urinary phosphate wasting, leading to hypophosphataemia, often associated with impaired bioactivation of vitamin D. Rarely, disturbances of chondrocytes and osteoblasts, defective bone matrix or other disruptions block calcium and phosphate entry into the skeleton. In rickets, there are defects in growth, shaping (modelling) and turnover remodelling of bone in accordance with metabolic, structural and repair requirements, and patients exhibit short stature (physeal disturbances). Osteomalacia is usually not deforming (unless fractures occur) because growth plates are fused and modelling has essentially ceased; only remodelling is deranged. Accordingly, impaired mineralization of skeletal matrix in osteomalacia is less apparent clinically and radiographically.
Vitamin D
Keywords bone; electrolytes; mineral; osteomalacia; renal; rickets; skeletal; vitamin D
Most of the vitamin D in healthy, active individuals is derived via a cutaneous synthesis pathway. In the skin, 7-dehydrocholesterol is converted to cholecalciferol (vitamin D3) by 290e310 nm ultraviolet light. Ergocalciferol (vitamin D2) is the product of ultraviolet irradiation of ergosterol extracted from animal or plant tissues, and is used as a supplement or as a pharmaceutical. Vitamin D should be regarded as a steroid hormone, not a nutrient, because it undergoes two bioactivation steps, circulates and then binds to a receptor, as follows. Vitamin D2 and vitamin D3 are prohormones transported by a high-affinity binding protein in the blood to muscle or fat for storage, or to the liver and then the kidney for bioactivation. Vitamin D is hydroxylated in hepatocyte mitochondria by the enzyme P450c25, forming the 25-hydroxyvitamin D metabolite, which is also called calcidiol. Regulated by circulating ionized calcium, inorganic phosphate and parathyroid hormone (PTH) levels, 25-hydroxyvitamin D is further hydroxylated in renal proximal convoluted tubule cells by the enzyme 25-hydroxyvitamin D, 1a-hydroxylase (1a-hydroxylase). The product is the potent 1,25-dihydroxyvitamin D metabolite, which is also called calcitriol. Calcitriol circulates to target organs, where it binds to the vitamin D receptor. The vitamin D receptor activates transcription of genes in enterocytes, kidney and bone to ensure adequate extracellular concentrations of minerals by increasing gut absorption of calcium, increasing urinary calcium reclamation by the kidneys and facilitating bone resorption.
Rickets is the clinical consequence of impaired mineralization of matrix throughout a growing skeleton. Infants, children and adolescents can be affected. Osteomalacia results from this disturbance after growth plates fuse (i.e. adulthood). There are three principal causes (Table 1) of rickets and osteomalacia. The most common explanation is deficiency of vitamin D, which may result from lack of exposure to sunlight leading to inadequate cutaneous biosynthesis, poor dietary intake or malabsorption as a result of hepatobiliary or gastrointestinal disease. This often leads to hypocalcaemia, secondary hyperparathyroidism and hypophosphataemia.
Michael P Whyte MD is Director of the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children, and Professor of Medicine, Pediatrics and Genetics at Washington University School of Medicine, St Louis, USA. Competing interests: none declared. Rajesh V Thakker MD FRCP FRCPath FMedSci is May Professor of Medicine and Head of the Academic Endocrine Unit at the University of Oxford, UK. Competing interests: none declared.
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rosary’). The pull of the diaphragm produces a groove in the rib cage (Harrison’s sulcus). In toddlers, rickets causes bow-leg deformities; knock-knees are characteristic in later childhood. Both occasionally occur together as ‘windswept’ legs. Rickets myopathy is part of the differential diagnosis of the ‘floppy baby’ and cardiac failure. If muscle weakness is sufficiently severe to prevent walking, it may limit deformity of the lower limbs. Short stature is common. Pathological fractures in the shafts of the long bones can occur in severe forms of rickets.
Causes of rickets and osteomalacia Primary (‘‘nutritional’’) vitamin D deficiency C
C C C
Classic vitamin D deficiency (e.g. in Asian children) e infants and puberty (‘late’ rickets) Immigrant adults in developed countries Elderly, housebound and institutionalized groups Food faddists
Secondary vitamin D deficiency Partial gastrectomy Small bowel malabsorption syndromes (e.g. coeliac disease) C Hepatobiliary disease C Pancreatic insufficiency Chronic renal failure Metabolic acidosis Drugs and toxins C
Osteomalacia Osteomalacia in adults may cause vague symptoms. Bone pain usually occurs in the axial skeleton (shoulders, spine, ribs and pelvis). Localized pain (e.g. in the groin) may result from an undisplaced femoral neck fracture or an underlying Looser’s zone (pseudofracture), which can be seen on radiography. Tenderness may be elicited by spinal percussion or by sternal and lateral rib compression; the most painful bones are generally those with the thinnest cortices. In severe osteomalacia, the vertebrae become compressed, and patients become immobilized and chair-bound. Osteomalacia myopathy has a characteristic proximal distribution. Gait should be assessed; it is commonly described as ‘waddling’. A simple test for myopathy is failure to rise from a sitting position unaided with the arms folded in front. However, it may be difficult clinically to detect myopathy if there is pain; even when it is undoubtedly present, electromyographic abnormalities are non-specific and can be absent. The nature of osteomalacia pain and muscle weakness is often vague and can lead to misdiagnosis. Hypocalcaemia may be suggested by a positive Chvostek’s and/or Trousseau’s sign.
C
Anticonvulsants Phosphate-binding antacids (e.g. aluminium hydroxide) C Bisphosphonate (etidronate) C Fluoride Miscellaneous forms C C
Calcium depletion Magnesium depletion C Primary hyperparathyroidism Oncogenic Hereditary forms C C
C C C C
C
Hypophosphataemia (X-linked and autosomal dominant) Vitamin D-dependent rickets type 1 and type 2 Proximal renal tubular disorders (Fanconi’s syndrome) Distal renal tubular disorders (renal rickets with nephrocalcinosis and dwarfism) Hypophosphatasia
Investigations Table 1
Biochemical investigations Hypocalcaemia is usually more severe in vitamin D-deficiency rickets than in osteomalacia, and sometimes paradoxically results in hyperphosphataemia by directly affecting renal tubules. Secondary hyperparathyroidism causes mild hyperchloraemic metabolic acidosis, reflecting increased renal excretion of bicarbonate. However, significant metabolic acidosis suggests Fanconi’s syndrome. Serum alkaline phosphatase (ALP) activity is elevated in almost all patients with rickets or osteomalacia; the exception is hypophosphatasia, which features hypophosphatasaemia. Levels of other markers of skeletal turnover can be disturbed, but need not be measured routinely. Quantification of circulating vitamin D levels directly assesses vitamin D status, but assays for these prohormones are not readily available, and measurement of serum 25-hydroxyvitamin D is a useful alternative.
Clinical findings The major features of rickets and osteomalacia are: bone pain and tenderness skeletal deformity and fractures muscle weakness occasionally, signs of tetany from associated hypocalcaemia. An underlying cause (Table 1) is often suggested by the medical history (e.g. bowel disturbance, positive family history). The features of specific types of rickets and osteomalacia are discussed below.
Rickets Rickets manifests during growth and the signs are most prominent in areas where bone growth is most rapid. Thus, the signs of rickets can vary with age. At birth, the skull is growing most rapidly. Neonatal rickets may therefore present as craniotabes, in which the cranial vault has the consistency of a ping-pong ball. In the first year of life, rickets swells metaphyses at the wrists and causes ‘beading’ of the costochondral junctions (‘rachitic
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Radiology In rickets, anteroposterior radiography of the knees and posteroanterior radiography of the wrists show widening of growth plates. Typically, the metaphyses are splayed, ragged and concave, and the epiphyses appear as though held within a cup.
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Vitamin D preparations Five sterols with vitamin D activity are currently available (Table 2). They differ in potency and biological half-life. Active metabolites of vitamin D can circumvent defective vitamin D bioactivation, are more potent than vitamin D itself and have a more rapid onset of action. However, these agents are expensive and have shorter biological half-lives, although toxicity can easily be corrected. Furthermore, they do not replenish deficient vitamin D stores and cessation of therapy leads rapidly to return of the disturbance of mineral homeostasis.
Radiographic signs of secondary hyperparathyroidism are seen best as subperiosteal erosions involving the radial border of the middle phalanx of the index finger, and erosion of the distal ends of the clavicles and symphysis pubis. The vertebrae may develop a ‘rugger-jersey’ appearance. Intervertebral discs may compress softened end-plates, causing biconcave (‘cod-fish’) vertebrae. In osteomalacia, pseudofractures can occur anywhere (except in the skull), and most often affect the pubic and ischial rami, the ribs, the scapulae and the medial cortex of the proximal femora. Bone scintigraphy is useful, but does not provide a diagnosis. Enhanced radioisotope uptake occurs when osteoidosis is present, hence rickets or osteomalacia can produce a ‘superscan’. Bone scanning is usually unnecessary in children with rickets. In adults, bone scanning helps to detect focal complications of osteomalacia such as fractures and pseudofractures.
Mineral supplementation Many calcium and phosphate preparations are available. Oral calcium carbonate is least expensive, but calcium citrate is better absorbed. Calcium gluconate is costly. For phosphate supplementation, tablets are more convenient than liquid preparations, taste better and seem less likely to cause diarrhoea. Preparations containing high levels of sodium should be avoided. Careful monitoring is required. The most useful biochemical parameters are serum calcium and phosphate, ALP activity and PTH levels. Depending on the aetiology and pathogenesis of the rickets or osteomalacia, serum 25-hydroxyvitamin D and 1,25dihydroxyvitamin D concentrations may also be helpful. Calcium excretion in 24-hour urine collections (corrected for creatinine content) guides therapy and helps monitor for impending toxicity. Because hypocalciuria characterizes most forms of rickets and osteomalacia, rising urinary calcium levels suggest effective therapy. Maintenance of normal urinary calcium levels typically indicates adequate treatment. Dose reductions may be necessary once healing is complete (maintenance therapy). Satiation of ‘hungry bones’ can abruptly increase urinary calcium excretion because the skeleton no longer acts as a sump for mineral deposition, and correction of previously abnormal biochemical findings heralds hypercalciuria. Unless there is advanced renal failure or fixed elevation of circulating PTH levels (reclaiming calcium from the glomerular filtrate), hypercalciuria generally precedes hypercalcaemia. Lower doses of vitamin D and mineral supplements may then be needed. Thus, 24-hour urine collections (not random specimens) assayed for calcium and creatinine are particularly important for follow-up.
Histopathology Biopsy showing defective mineralization of skeletal tissue is the definitive investigation. It is not required routinely in rickets, but is more useful in osteomalacia because radiographic studies are less helpful. A specimen of iliac crest obtained using a 5 mm internal diameter trephine is ideal. Both cortical and trabecular bone are sampled. Two 3-day courses of oxytetracycline or demeclocycline hydrochloride, 20 mg/kg/day in divided doses, are given (separated by a 2-week interval) for in vivo tetracycline labelling of bone tissue. The final dose is taken several days before the transiliac biopsy. In rickets and osteomalacia, nondecalcified stained sections reveal abundant osteoid covering bone surfaces, but fluorescence microscopy fails to show two discrete tetracycline ‘labels’ produced by ongoing mineralization. Instead, absent or indistinct fluorescence is seen.
Principles of management The aims of treatment are: reversal of short stature and deformity in rickets relief of bone pain and fracture prevention in osteomalacia. Ideally, the primary pathological process is corrected. This may not be possible, and vitamin D (or an active metabolite), often with mineral supplementation, is needed.
Pharmaceutical preparations of vitamin D and active metabolites Calciferol*
Dihydrotachysterol
Drug Form and preparation
Vitamin D3 or D2 C Capsules, 0.25 mg and 1.25 mg
DHT C Liquid, 0.25 mg/ml
Time to maximum effect Persistence of effect after cessation
4e10 weeks 6e30 weeks
2e4 weeks 2e8 weeks
Calcifediol
Calcitriol
Alfacalcidiol
25-hydroxyvitamin D3 Capsules, 20 and 50 mg
1,25(OH)2D3 C Capsules, 0.25 and 0.5 mg C Injection, 1 mg/ml
4e20 weeks 4e12 weeks
0.5e1 week 0.5e1 week
1a(OH)D3 C Capsules, 0.25, 0.50 and 1 mg C Liquid, 2 mg/ml C Injection, 2 mg/ml in propylene glycol 0.5e1 week 0.5e1 week
C
* Calciferol may contain cholecalciferol or ergocalciferol.
Table 2
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Surgery Consultation and follow-up with an orthopaedic surgeon can be an important aspect of the management of rickets. Leg-bracing, physeal stapling (epiphysiodesis) or rarely osteotomy may be helpful. Achievement of straight lower limbs when growth ceases, with the physes aligned parallel to the ground, may forestall osteoarthritis. Intramedullary rodding may be necessary to heal pseudofractures or prevent fractures in some patients with osteomalacia.
osteoporosis. Vitamin D deficiency can result from subclinical malabsorption (e.g. coeliac disease). These disturbances are complex, and vitamin D therapy and follow-up must be individualized. Serum 25-hydroxyvitamin D assays document vitamin D deficiency and are essential for monitoring progress. Despite malabsorption, sufficient doses of oral vitamin D, in the form of calciferol, should be effective and are relatively inexpensive. Vitamin D treatment repletes the stores and is readily converted to 25-hydroxyvitamin D by hepatocytes even with parenchymal liver disease.
Types of rickets and osteomalacia Low calcium Profound deficiency of dietary calcium despite intact stores of vitamin D can also impair skeletal mineralization. Inadequate calcium intake has caused so-called calciopenic rickets in premature infants and in children fed a cereal-based diet. Poor dietary calcium intake can also exacerbate vitamin D-deficiency rickets. Members of religious, ethnic and other groups that do not consume dairy products are at risk. Correcting the diet or using calcium supplements should readily reverse this disorder. In addition, hypophosphataemia from secondary hyperparathyroidism or primary renal phosphate wasting can cause defective matrix mineralization. Notably, some patients with hypocalcaemia alone from hypoparathyroidism or pseudohypoparathyroidism develop rickets or osteomalacia, despite raised serum phosphate levels.
Primary (‘‘nutritional’’) vitamin D deficiency The minimum daily requirement for vitamin D is 10 mg (400 IU) in children and 2.5 mg (100 IU) in adults. Primary (‘nutritional’) rickets or osteomalacia occurs as a result of social, economic and/or cultural factors that prevent sufficient exposure to sunlight (Table 1): about 20 minutes on the face and arms is required on several occasions each week. Various factors reduce cutaneous vitamin D biosynthesis, including ageing, pigmentation, extent of clothing, residence at latitudes at which only lowintensity UV exposure is possible and use of sunscreens that block the access of UV light to the skin. Institutionalized/ housebound individuals, the poor, the elderly, food faddists and some religious groups (because of diet and dress) are at risk. Infants who are breast-fed beyond 6 months of age or who drink non-fortified milk or formula are also susceptible if they are insufficiently exposed to sunlight. Low dietary calcium intake is an important exacerbating factor. Low serum 25-hydroxyvitamin D concentration confirms the diagnosis of vitamin D deficiency. Unless there is significant hypoproteinaemia, levels less than 20 ng/ml are diagnostic; and levels 21 to 29 ng/ml are considered insufficient. Patient/parent education and correction of adverse socioeconomic factors could help to prevent and treat vitamin D deficiency, but are often difficult to achieve. However, drug therapy is inexpensive, effective and works rapidly (Table 2). Vitamin D deficiency should be treated using vitamin D (i.e. calciferol preparations). 25-hydroxyvitamin D3, 1a-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 are more potent and act more rapidly, but all fail to correct depleted stores of vitamin D.
Drugs and toxins Anticonvulsants: rickets and osteomalacia have been reported in institutionalized individuals receiving anticonvulsants. Phenobarbital can alter hepatic vitamin D metabolism, predisposing patients to vitamin D depletion. Many such individuals also have primary vitamin D deficiency. Phosphate-binding antacids: osteomalacia can result from excessive use of phosphate-binding antacids (magnesium and aluminum hydroxides). Significant hypophosphataemia can occur. Urinary phosphate assays reveal low levels. Rickets has occurred when these preparations were added to infant formula to treat colic. Aluminium is also toxic to osteoblasts and directly inhibits skeletal mineralization. Conversely, these patients may hyperabsorb dietary calcium and become hypercalciuric because hypophosphataemia stimulates renal 1ahydroxylase activity. Rarely, kidney stones develop. Hypophosphataemia impairs skeletal mineralization, and elimination of antacid exposure rapidly corrects this. Dietary phosphate intake is quite variable, but sufficient for skeletal remineralization. Phosphate supplementation or vitamin D therapy is unnecessary. It may be several months before serum ALP activity returns to normal.
Secondary vitamin D deficiency Vitamin D deficiency can be due to malabsorption despite normal exposure to sunlight. Gastrointestinal, pancreatic or hepatobiliary disease may be responsible. The mechanism is often complex. Vitamin D is a fat-soluble secosterol and bile salts are necessary for its absorption. Additionally, there is enterohepatic circulation of vitamin D and its derivatives. Thus, hepatobiliary/pancreatic disease or short bowel syndrome causing deficiency of bile salts, steatorrhoea and malabsorption can lead to vitamin D depletion. Furthermore, the small bowel mediates dietary calcium uptake, and malabsorption of calcium exacerbates vitamin D deficiency. In secondary hyperparathyroidism, conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D is increased, and 25hydroxyvitamin D stores may be diminished by this mechanism. In some conditions in which osteomalacia might be anticipated (e.g. primary biliary cirrhosis), the associated osteopathy is often
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Ifosfamide can cause transient or permanent renal tubule damage, leading to urinary phosphate wasting and hypophosphataemic skeletal disease. Etidronate is a first-generation bisphosphonate used in Paget’s bone disease (see article on pp. 485e486) and hypercalcaemia of
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malignancy. Excessive or prolonged therapy can cause rickets or osteomalacia.
Genes in hereditary rickets
Uraemic patients who are exposed excessively to aluminiumcontaining antacids or to contaminated dialysis fluid or parenteral feeds have developed osteomalacia. With increasing use of sevelamer hydrochloride and other pharmaceuticals for phosphate-binding and corrected dialysate and parenteral nutrition, this disorder is now rare. Excessive fluoride intake (well water, industrial exposure, treatment for osteoporosis) can cause osteomalacia. Bone mineralization responds gradually to calcium supplementation and cessation of fluoride poisoning. Metabolic acidosis Metabolic acidosis can cause rickets or osteomalacia. The pathogenesis is poorly understood, but the skeletal disease responds well to vitamin D and alkali therapy. Calcium and potassium supplementation may be necessary at initiation of alkali therapy to prevent hypocalcaemia and hypokalaemia. Vitamin D, 50,000 IU thrice weekly p.o., can be used in adults, with careful followup until healing occurs. Alkali therapy should be continued after the mineralization defect is corrected. Urinary calcium levels must be monitored frequently because metabolic acidosis per se causes hypercalciuria.
Chromosomal Gene location
X-linked dominant hypophosphataemia X-linked recessive hypophosphataemia Autosomal dominant hypophosphataemia Lowe’s syndrome (Fanconi’s syndrome) Vitamin D-dependent type 1 Vitamin D-dependent type 2 Hypophosphatasia
Xp22.1 Xp11.22 12p13 Xq25eq26 12q14 12q12eq14 1p34e1p36.1
PHEX CLCN5 FGF23 OCRL 1aOHase VDR TNSALP
PHEX, phosphate-regulating gene with homologies to endopeptidases on the X chromosome; CLCN5, voltage-gated chloride channel 5 gene, mutations of which cause Dent’s disease; FGF23, fibroblast growth factor 23; OCRL, oculocerebrorenal syndrome of Lowe, encoding an inositol polyphosphate phosphatase; 1aOHase, the renal 1a-hydroxylase gene; VDR, 1,25-dihydroxyvitamin D3 receptor gene; TNSALP, tissue nonspecific alkaline phosphatase.
Table 3
occasionally presents with knock-knees. Affected children can seem clumsy but are otherwise well. The skull is often dolichocephalic (long and narrow), but the chest and upper extremities are not deformed. Contrary to almost all other forms of rickets, muscle weakness does not occur. Fractures during childhood are uncommon. Serum calcium levels are low-normal, but usually not distinctly reduced. Bioactivated forms of vitamin D (e.g. calcitriol), together with oral phosphate supplements, are used in treatment. XLH is caused by inactivating mutations of the PHEX gene, which encodes a putative endopeptidase (Table 3).
Renal failure In uraemia, skeletal disease usually reflects secondary or tertiary hyperparathyroidism, leading to rapid bone remodelling (osteitis fibrosa cystica) or excessive pharmacological suppression of bone turnover. However, some patients exhibit defective mineralization of the skeletal matrix. Several causes have been documented, and excessive use of aluminium-containing antacids is to be avoided and substituted with other phosphate binders.
Autosomal dominant hypophosphataemia, an especially rare form of renal phosphate wasting, features mild rickets that appears during adolescence. It is caused by gain-of-function mutation of FGF23.
Oncogenic osteomalacia (or rickets) Oncogenic osteomalacia (or rickets) is a rare disorder typically caused by a benign mesenchymal tumour in soft tissues. Patients are profoundly weak and hypophosphataemic with low (or undetectable) plasma 1,25-dihydroxyvitamin D concentrations. Extirpation of the tumour cures the condition. Some tumours have been shown to produce fibroblast growth factor 23 (FGF23) and plasma FGF23 concentrations are usually elevated. In fact, activating mutations in the gene encoding FGF23 are associated with autosomal dominant hypophosphataemia (see below). These tumours may also produce other putative phosphaturic ‘phosphatonins’.
Fanconi’s syndrome features renal phosphate wasting and other manifestations of proximal renal tubule dysfunction, causing low serum phosphate, potassium, bicarbonate and uric acid, and aminoaciduria. Causes include cystinosis, tyrosinaemia and Lowe’s syndrome. Treatment with 1,25-dihydroxyvitamin D3 and phosphate supplementation is helpful, but urinary calcium levels must be monitored carefully because hypercalciuria can occur. McCuneeAlbright syndrome, due to activating mutation of the a subunit of the G-protein, can cause hypophosphataemic rickets. Treatment with 1,25-dihydroxyvitamin D3 and phosphate controls the rickets, but efficacy may be difficult to assess because of premature closure of growth plates and the underlying fibrodysplastic skeletal disease. Bone biopsy interpretation may be difficult because of widespread fibrous dysplasia.
Heritable rickets and osteomalacia Several genetic disorders cause rickets or osteomalacia (Table 3). Some feature renal phosphate wasting, some reflect disturbances in the bioactivation or action of vitamin D. A few are inborn errors of metabolism caused by enzyme deficiencies. X-linked hypophosphataemia (XLH) is the most common heritable form of rickets (‘vitamin D-resistant rickets’) and osteomalacia. The prevalence is about 1/20,000 live births. All races are affected. XLH causes short stature and bowing of the lower limbs in toddlers as they begin to bear weight. Skeletal disease
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Disease
Vitamin D-dependent rickets types I and II are rare, autosomal recessive disorders that mimic vitamin D-deficiency rickets by reduced biosynthesis of, and target tissue resistance to, 1,25dihydroxyvitamin D, respectively.
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Ruppe MD, Jan de Beur SM. Disorders of phosphate homeostasis. In: Rosen CJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 7th edn. Washington, DC: American Society for Bone and Mineral Research, 2008. White KE, Econs MJ. Fibroblast growth factor-23. In: Rosen CJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 7th edn. Washington, DC: American Society for Bone and Mineral Research, 2008. Whyte MP. Approach to the patient with metabolic bone disease. In: Feldmann D, Glorieux FH, Pike JW, eds. Vitamin D. 2nd edn. San Diego: Academic Press, 2005. Whyte MP. Rickets and osteomalacia (acquired and heritable forms). In: Wass JAH, Shalet SM, eds. Oxford textbook of endocrinology and diabetes. Oxford: Oxford University Press, 2002. Whyte MP. Hypophosphatasia: Nature’s window on alkaline phosphatase function in humans. In: Bilezikian J, Raisz L, Martin TJ, eds. Principles of bone biology. 3rd edn. San Diego: Academic Press, 2008.
Hypophosphatasia is a rare, heritable form of rickets featuring deficient activity of the tissue-non-specific isoenzyme of ALP. The severity is remarkably variable, ranging from premature loss of teeth only, to intrauterine death from profound skeletal hypomineralization. Approximately 200 different mutations have been discovered in the gene that encodes the ALP expressed in bone. A
FURTHER READING Glorieux FH. Rickets. New York: Raven Press, 1991. Hollick MF. Vitamin deficiency. N Engl J Med 2007; 357: 266e81. Parfitt AM. Vitamin D and the pathogenesis of rickets and osteomalacia. In: Feldmann D, Glorieux FH, Pike JW, eds. Vitamin D. 2nd edn. San Diego: Academic Press, 2005.
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