BONE DISORDERS

Rickets and osteomalacia

Whats new ?
Identification of phosphatonins circulating factors
that cause phosphaturia and hypophosphataemic
rickets and osteomalacia

Michael P Whyte
Rajesh V Thakker

Discovery of the gene defects that cause heritable

forms of rickets and osteomalacia

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, 1-hydroxylase (1-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
bone, kidney, and enterocytes to ensure adequate extracellular
concentrations of minerals by increasing gut absorption of calcium,
suppressing PTH synthesis, 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 (Figure 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.
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 of bone in accordance with metabolic, structural,
and repair requirements (remodelling), 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.

Clinical features
The major features of rickets and osteomalacia are:
bone pain and tenderness
skeletal deformity
muscle weakness
occasionally, signs of tetany from associated hypocalcaemia.
An underlying cause (Figure 1) is often suggested by the history
(e.g. bowel disturbance, positive family history). The features of
specific types of rickets and osteomalacia are discussed below.
Rickets manifests during growth, and the signs are most prominent in areas where bone growth is most rapid. Thus, the signs of
rickets 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 epiphyses at the wrists
and causes beading of the costochondral junctions (rachitic
rosary). The pull of the diaphragm produces a groove in the rib
cage (Harrisons sulcus).
In toddlers, rickets causes bow-leg deformities; knock-knees
are characteristic in later childhood. Both occasionally occur as
windswept legs.
Rickets myopathy is part of the differential diagnosis of the
floppy baby. 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.

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 290310 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.

Michael P Whyte 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. Conflicts of interest: none declared.
Rajesh V Thakker is May Professor of Medicine and Head of the Academic
Endocrine Unit at the University of Oxford, UK. Conflicts of interest: none
declared.

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Causes of rickets and osteomalacia

Investigations
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 Fanconis 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.
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.
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.
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.

Primary (nutritional) vitamin D deficiency

Classic vitamin D deficiency (e.g. in Asian children)
infants and puberty (late rickets)
Immigrant adults in developed countries
Elderly, housebound and other institutionalized groups
Food faddists
Secondary vitamin D deficiency
Partial gastrectomy
Small bowel malabsorption syndromes (e.g. coeliac disease)
Hepatobiliary disease
Pancreatic insufficiency
Chronic renal failure
Metabolic acidosis
Drugs and toxins
Anticonvulsants
Phosphate-binding antacids (e.g. aluminium hydroxide)
Bisphosphonates
Fluoride
Miscellaneous forms
Phosphate depletion (intestinal phosphate binders)
Calcium depletion
Magnesium depletion
Primary hyperparathyroidism
Oncogenic
Hereditary forms
Hypophosphataemia (X-linked and autosomal dominant)
Vitamin D-dependent rickets type 1 and type 2
Proximal renal tubular disorders (Fanconis syndrome)
Distal renal tubular disorders (renal rickets with
nephrocalcinosis and dwarfism)
Hypophosphatasia

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 Loosers 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 nonspecific 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 Chvosteks
and/or Trousseaus sign.

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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
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not be possible, and vitamin D (or an active metabolite), often

with mineral supplementation, is needed.
Vitamin D preparations (Figure 2) five sterols with vitamin D
activity are currently available. 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, though
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.
Mineral supplementation many calcium and phosphate
preparations are available. Oral calcium carbonate is least expensive, but calcium citrate is better absorbed. Calcium gluconate
is expensive. 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 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 followup.
Surgery consultation and follow-up with an orthopaedic surgeon is often an important aspect of the management of rickets.
Leg-bracing, physeal stapling (epiphysiodesis) or 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.

Types of rickets and osteomalacia

Primary (nutritional) vitamin D deficiency the minimum
daily requirement for vitamin D is 10 g (400 IU) in children and
2.5 g (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 (Figure 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 low-intensity 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 about 8 ng/ml (normal 1050 ng/ml)
are diagnostic.
Patient/parent education and correction of adverse socioeconomic
factors could help to prevent and treat vitamin D deficiency, but

Pharmaceutical preparations of vitamin D and active metabolites

Drug

Dihydrotachysterol
Calciferol1
Vitamin D3 or D2
DHT
Capsules, 0.25 mg
Liquid, 0.25 mg/ml
and 1.25 mg
Injection, 7.5 mg/ml
i.m. in oil2

Time to maximum
410 weeks
effect
Persistence of effect 630 weeks
after cessation

Calcifediol
25-hydroxyvitamin D3
Capsules, 20 and
50 g

Calcitriol
1,25(OH)2D3
Capsules, 0.25 and
0.5 g
Injection, 1 g/ml

24 weeks

420 weeks

0.51 week

Alfacalcidiol
1(OH)D3
Capsules, 0.25,
0.50 and 1 g
Liquid, 2 g/ml
Injection, 2 g/ml
in propylene
glycol
0.51 week

28 weeks

412 weeks

0.51 week

0.51 week

Calciferol may contain cholecalciferol or ergocalciferol. 2Prolonged effect.

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are often difficult to achieve. However, drug therapy is inexpensive, effective and works rapidly (Figure 2). Vitamin D deficiency
should be treated using vitamin D (i.e. calciferol preparations).
25-hydroxyvitamin D3, 1-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3 and dihydrotachysterol are more potent and act more
rapidly, but all fail to correct depleted stores of vitamin D.
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 fatsoluble 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, steatorrhea 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 25-hydroxyvitamin
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 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.
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.
Drugs and toxins
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.
Osteomalacia can result from excessive use of phosphatebinding 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

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renal 1-hydroxylase 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.
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
Pagets bone disease (see page 66) and hypercalcaemia of
malignancy. Excessive or prolonged therapy can cause rickets or
osteomalacia.
Uraemic patients who are exposed excessively to aluminiumcontaining antacids or to contaminated dialysis fluid or parenteral
feeds have developed osteomalacia. With increasing use of calcium
carbonate 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 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
follow-up 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.
Renal failure in uraemia, skeletal disease usually reflects
secondary or tertiary hyperparathyroidism leading to rapid bone
remodelling (osteitis fibrosa cystica). However, some patients
exhibit defective mineralization of the skeletal matrix. Several
causes have been documented, and excessive use of aluminiumcontaining antacids is to be avoided and substituted with calcium
carbonate or other phosphate binders.
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 and other
putative phosphatonins. In fact, activating mutations in the
gene encoding FGF23 are associated with autosomal dominant
hypophosphataemia (see below).
Heritable rickets and osteomalacia several heritable disorders
can cause rickets or osteomalacia (Figure 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. Affected
children can seem clumsy but otherwise well. The skull is often
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Genes in hereditary rickets

Disease
X-linked dominant
hypophosphataemia
X-linked recessive
hypophosphataemia
Autosomal dominant
hypophosphataemia
Lowes syndrome
(Fanconis syndrome)
Vitamin D-dependent type 1
Vitamin D-dependent type 2
Hypophosphatasia

Chromosomal location
Xp22.1

Gene
PHEX

Xp11.22

CLCN5

12p13

FGF23

Xq25q26

OCRL

12q14
12q12q14
1p341p36.1

1OHase
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 Dents disease;
FGF23, fibroblast growth factor 23; OCRL, oculocerebrorenal syndrome of Lowe, encoding
an inositol polyphosphate phosphatase; 1OHase, the renal 1-hydroxylase gene;
VDR, 1,25-dihydroxyvitamin D3 receptor gene; TNSALP, tissue nonspecific alkaline
phosphatase
3

teeth to intrauterine death from profound skeletal hypomineralization, and 100160 different mutations have been discovered in the
gene that encodes ALP expressed in bone.

dolichocephalic, but the chest and upper extremities are not

deformed. Contrary to almost all other forms of rickets, muscle
weakness does not occur. Fractures are uncommon. Skeletal
disease occasionally presents with knock-knees. 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 (Figure 3).
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.
Fanconis 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
Lowes syndrome. Treatment with 1,25-dihydroxyvitamin D3 and
phosphate supplementation is helpful, but urinary calcium levels
must be monitored carefully, because hypercalciuria can occur.
McCuneAlbright syndrome, due to activating mutation of the
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
disease. Bone biopsy interpretation may be difficult because of
widespread fibrous dysplasia.
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.
Hypophosphatasia is a rare, heritable form of rickets featuring
deficient activity of the tissue-nonspecific isoenzyme of ALP. The
severity is remarkably variable, ranging from premature loss of

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FURTHER READING
Glorieux F H. Rickets. New York: Raven Press, 1991.
Glorieux F H, St-Arnaud R. Vitamin D pseudodeficiency. In: Feldman D,
Glorieux F H, Pike J W, eds. Vitamin D. 2nd ed. San Diego: Academic
Press, 2005: 1097205.
Parfitt A M. Vitamin D and the pathogenesis of rickets and osteomalacia.
In: Feldmann D, Glorieux F H, Pike J W, eds. Vitamin D. 2nd ed.
San Diego: Academic Press, 2005: 102948.
Schiavi S C, Kumar R. The phosphatonin pathway: new insights in
phosphate homeostasis. Kidney Int 2004; 65: 114.
Whyte M P. Approach to the patient with metabolic bone disease.
In: Feldman D, Glorieux F H, Pike J W, eds. Vitamin D. 2nd ed.
San Diego: Academic Press, 2005: 91329.
Whyte M P. Heritable rickets and osteomalacia. In: Royce P M,
Steinmann B, eds. Connective tissue and its heritable disorders:
medical, genetic, and molecular aspects. 2nd ed. New York:
Wiley-Liss, 2002: 76587.
Whyte M P. Rickets and osteomalacia (acquired and heritable forms).
In: Wass J A H, Shalet S M, eds. Oxford textbook of endocrinology and
diabetes. Oxford: Oxford University Press, 2002: 697715.
Whyte M P. Hypophosphatasia. In: Scriver C R, Beaudet A L, Sly W S et al.,
eds. The metabolic and molecular bases of inherited disease. 8th ed.
New York: McGraw-Hill, 2001: 531329.

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