PRIMER

Rickets
Thomas O. Carpenter1, Nick J. Shaw2,3, Anthony A. Portale4, Leanne M. Ward5,
Steven A. Abrams6 and John M. Pettifor7
Abstract | Rickets is a bone disease associated with abnormal serum calcium and phosphate levels.
The clinical presentation is heterogeneous and depends on the age of onset and pathogenesis but
includes bowing deformities of the legs, short stature and widening of joints. The disorder can be
caused by nutritional deficiencies or genetic defects. Mutations in genes encoding proteins involved in
vitamin D metabolism or action, fibroblast growth factor 23 (FGF23) production or degradation, renal
phosphate handling or bone mineralization have been identified. The prevalence of nutritional rickets
has substantially declined compared with the prevalence 200 years ago, but the condition has been
re-emerging even in some well-resourced countries; prematurely born infants or breastfed infants who
have dark skin types are particularly at risk. Diagnosis is usually established by medical history, physical
examination, biochemical tests and radiography. Prevention is possible only for nutritional rickets and
includes supplementation or food fortification with calcium and vitamin D either alone or in
combination with sunlight exposure. Treatment of typical nutritional rickets includes calcium and/or
vitamin D supplementation, although instances infrequently occur in which phosphate repletion may
be necessary. Management of heritable types of rickets associated with defects in vitamin D
metabolism or activation involves the administration of vitamin D metabolites. Oral phosphate
supplementation is usually indicated for FGF23‑independent phosphopenic rickets, whereas the
conventional treatment of FGF23‑dependent types of rickets includes a combination of phosphate and
activated vitamin D; an anti‑FGF23 antibody has shown promising results and is under further study.

1
Department of Pediatrics
(Endocrinology), School of
Medicine, Yale University,
PO Box 208064, New Haven,
Connecticut 06520–8064,
USA.
7
South African Medical
Research Council–Wits
Developmental Pathways
for Health Research Unit,
Department of Paediatrics,
Faculty of Health Sciences,
University of the
Witwatersrand,
7 York Road, Parktown,
Johannesburg 2194,
South Africa.
Correspondence to T.O.C.
and J.M.P.
thomas.carpenter@yale.edu;
john.pettifor@wits.ac.za
Article number: 17101
doi:10.1038/nrdp.2017.101
Published online 21 Dec 2017
Rickets is a bone disease that is associated with decreased
serum calcium and/or phosphate levels in the blood,
leading primarily to widening and delay of mineraliza-
tion of growth plates in bones1 (FIG. 1). Rickets is also
associated with osteomalacia, which is characterized by a
delay in the mineralization of bone matrix (FIG. 2). Rickets
can be caused by deficiencies of vitamin D, calcium or
phosphate attributable to nutritional or environmental
causes (that is, nutritional rickets) or by mutations in
genes encoding proteins involved in vitamin D activa-
tion and function, phosphate homeostasis and/or bone
mineralization (that is, heritable rickets); rickets can also
be the consequence of acquired defects in vitamin D
metabolism (such as in severe liver disease) or renal
tubular handling of minerals (which may occur with a
number of drugs). Nutritional rickets is the most com-
mon type of rickets globally 2. Although nutritional rick-
ets can rarely be caused by dietary phosphate deficiency,
this form of rickets is most often the consequence of an
inability to maintain serum calcium levels as a result of
inadequate dietary calcium intake, vitamin D deficiency
(either due to insufficient dietary intake or insufficient
sunlight exposure, which is required for the activation
of vitamin D) or a combination of both.
Rickets was almost universal among young children in
large towns and cities in Europe and North America in the
late 19th and early 20th centuries3,4. However, following
the discovery of the role of cod liver oil (which contains
high levels of vitamin D) and ultraviolet (UV) irradiation
(involved in the formation of vitamin D in the skin) in
the prevention and management of vitamin D deficiency,
nutritional rickets was almost eradicated in several
countries. Despite these early successes, the prevalence
of nutritional rickets has risen in at-risk communities
in Europe and North America over the past 40 years5,6.
A high prevalence of rickets has also been observed in
children in the Middle East7, the Indian subcontinent, the
northern provinces of China and in Mongolia8. A global
estimate of the risk of developing rickets is limited by
the paucity of basic data such as calcium and vitamin D
intake or serum 25‑hydroxyvitamin D (25(OH)D; an
inactive vitamin D metabolite) concentrations among
children in non-industrialized countries.
Although nutritional rickets remains the most com-
mon type of rickets globally, with the decline in its prev-
alence from the early 20th century, the heritable forms
of rickets have become comparatively more common.
The development of molecular genetic techniques has

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Author addresses
1
Department of Pediatrics (Endocrinology), School of Medicine, Yale University,
PO Box 208064, New Haven, Connecticut 06520–8064, USA.
2
Department of Endocrinology & Diabetes, Birmingham Children’s Hospital,
Birmingham, UK.
3
Institute of Metabolism and Systems Research, University of Birmingham,
Birmingham, UK.
4
Department of Pediatrics, University of California, San Francisco, California, USA.
5
Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
6
Department of Pediatrics, Dell Medical School at the University of Texas-Austin, Austin,
Texas, USA.
7
South African Medical Research Council–Wits Developmental Pathways for Health
Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the
Witwatersrand, 7 York Road, Parktown, Johannesburg 2194, South Africa.
made it possible to identify the genetic cause of many
of these uncommon types of rickets. Through these dis-
coveries, the past 40 years have seen a rapid expansion
in our understanding of the causes and pathogenesis of
rickets in children.
In this Primer, we highlight the epidemiology,
pathophysiology, diagnosis and management of ­rickets
with a focus on advances in the understanding of the
disease.
Epidemiology
Nutritional rickets
Rickets associated with vitamin D deficiency was wide-
spread 120–200 years ago9, with a prevalence of 25%
among infants and young children in parts of the United
States reported in 1870 (REF. 10). Definitive treatment of
nutritional rickets with cod liver oil became common
around the 1930s, and with vitamin D fortification in
milk, nutritional rickets in the United States was virtu-
ally eliminated by the 1950s. Nevertheless, the disorder
still occurs in the United States, Europe and many other
countries globally, as consistently evidenced by limited
case series. Case rate estimates of 2.9–27 per 100,000
individuals have been reported in the United States and
Europe, and dark-skinned infants who are breastfed for
>6 months are particularly at risk5. Nutritional rickets
seems to be less common in Australia and New Zealand,
the Americas and Europe than in the Indian subconti-
nent, Africa and the Middle East 2,11–14. The prevalence
in Turkey in 2008 was reported to be 100 per 100,000
individuals2,15. As recently as the late 1900s, the rates of
rickets in infants and young children were reported to
be extremely high in Tibet and Mongolia (>50%) and in
a few African and Middle Eastern countries (>10%)16.
Globally, the disorder predominantly affects infants
and preschool-aged children11–14. In well-resourced
countries, the prevalence is highest among immigrant
populations, those with dark skin and those with min-
imal sunshine exposure. Breastfed infants are particu-
larly at risk because of the high prevalence of vitamin D
deficiency in many mothers and the low content of
­vitamin D and its metabolites in breast milk17.
In the United States5 and the United Kingdom6,
reports indicate that nutritional rickets is becoming
more common. Incidence estimates of rickets were
24.1 per 100,000 children <3 years of age in the early
2000s compared with 0 per 100,000 in the early 1970s
and 2.2 per 100,000 in the early 1980s in Minnesota,
United States5. In the United Kingdom, 7.5 per 100,000
children <5 years of age were diagnosed with rick-
ets18. These observations have been attributed to an

a b
a c
Epiphysis

Resting zone
Growth Growth
plate Proliferating zone plate
Hypertrophic zone

Metaphysis

Figure 1 | Morphology of the growth plate in rickets. a,b | Morphology
of a healthy, human growth plate (physis). The growth plate is
characterized by maturation of chondrocytes (cartilage cells) occurring
progressively from the epiphysis to the metaphysis. The border between
the metaphysis and the growth plate is marked by a provisional zone of
calcification of the cartilage matrix (red-pink staining) that undergoes
resorption and replacement with mineralized bone (turquoise staining).
c | A rachitic growth plate showing the marked increase in longitudinal
width marked by the persistence of the zone of hypertrophic
chondrocytes that lose their columnar arrangement. The growth plate
abnormalities are the consequence of impaired chondrocyte apoptosis
and impaired mineralization of the cartilage matrix surrounding the
apoptotic chondrocytes. Apoptosis ofNature Reviews |chondrocytes
hypertrophic Disease Primers is
induced by extracellular phosphate via phosphorylation of
mitogen-activated protein kinase (MAPK) pathway intermediates and
downstream inhibition of the caspase 9‑dependent mitochondrial
apoptotic pathway43. Thus, reduction in ambient phosphate availability to
the chondrocyte, which is common to all forms of rickets, seems to be
central to the impaired apoptosis. The ligand 1,25‑dihydroxyvitamin D
(1,25(OH) 2D) and its receptor might be involved as well 194. Finally,
expansion of the hypertrophic chondrocyte zone can be induced by
impaired vascularization, influenced by vascular endothelial growth
factor, which is regulated by MAPK pathway intermediates195. Parts b and
c courtesy of F. H. Glorieux.

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 PRIMER

a b c

Figure 2 | Histological characteristics of osteomalacia. Goldner’s trichrome staining of undecalcified iliac

Nature Reviews crest bone
| Disease Primers
samples showing mineralized bone in turquoise and unmineralized bone matrix (osteoid) in red-pink. Compared with a
control sample (part a), a sample obtained from a child with X‑linked hypophosphataemic rickets (part b) shows a marked
increase in the amount and thickness of osteoid (arrows) covering mineralized bone in the bone cortex or outer shell (*) and
the trabecular area, which is a typical feature of osteomalacia. Part c depicts abnormal accumulation of osteoid surrounding
the osteocytes (the intercommunicating osteogenic lineage cells that are embedded throughout the bone matrix), which is
another characteristic of osteomalacia in patients with X‑linked hypophosphataemic rickets known as peri-osteocytic
lesions. Parts a and b courtesy of F. H. Glorieux. Part c is from REF. 128, Macmillan Publishers Limited.

increasing number of dark-skinned immigrants as Rickets in adolescents

well as an increase in the use of sunscreen and other
skin-protective barriers19.
Rickets in infants and young children
Currently, nutritional rickets in prepubertal children
is most common in prematurely born infants5,20 and
in infants who are breastfed for >6–12 months, have
dark skin and have inadequate vitamin D, calcium or,
rarely, phosphate intake21. Rickets associated with die-
tary calcium deficiency was first described in an infant
with suspected food allergies who had been placed on a
milk-free diet with very low calcium content 22. Rickets
has also been described in several infants who were fed
macrobiotic or vegan diets that were low in calcium23.
Preterm birth is associated with an increased risk of
developing rickets, especially when the birthweight is
<1,000 g. In premature infants, rickets is primarily caused
by insufficient calcium and phosphate intake, but not
vitamin D deficiency 24. Data on the prevalence of rick-
ets in preterm infants are limited. In one study, ~15% of
infants in the United States with a birthweight of <1,000 g
showed radiological evidence of rickets20. This number is
lower than estimates in the early 1980s, which revealed a
presence of rickets in up to 50% of preterm infants25; this
improvement reflects the introduction of modern nutri-
tional practices. In the United States, ~20,000 babies are
born each year weighing between 500 g and 1,000 g, and
6,000 babies are born weighing <500 g. Extrapolation of
these data based on the incidence estimate of rickets
of 15% and taking into account that some of these babies,
especially those born <500 g, will not survive suggests
that ~3,000 babies are at risk of developing rickets annu-
ally in the United States, which makes rickets an impor-
tant cause of neonatal morbidity 26. Extremely preterm
infants (born at <28 weeks gestation) are now surviving
with multiple complications and considerable treatment
requirements, some of which increase the risk of rickets,
for example, treatment with corticosteroids to quicken
lung maturation. Medical conditions such as necrotizing
enterocolitis, which is observed in 2–4% of infants with a
birthweight of <1,500 g, and other conditions might add
to the b
­ urden of rickets.
Most of the literature pertaining to the epidemiology
of rickets is focused on infants and young children
because rickets is identified most frequently in the first
few years of life2. Nevertheless, rickets will persist into
adolescence in those who are at risk of vitamin D defi-
ciency and in those with early-onset genetic forms, such
as X‑linked hypophosphataemia (XLH); genetic forms
rarely first come to medical attention during teenage
years27. Genetic forms of rickets are less common than
nutritional rickets. Indeed, XLH is the most common
heritable form of hypophosphataemia, but the incidence
is only 1 in 20,000 individuals28.
Nutritional rickets may also present during ado-
lescence. In such cases, the manifestations tend to be
different than those of infants and children, with iso-
lated bone pain and proximal muscle weakness being
common presenting features29,30. Regional reports of
nutritional rickets in adolescents suggest that the con-
dition is highly prevalent in several regions, including
the Middle East and north India, particularly among
girls. In one study, 25% of children aged 10–13 years
presenting to orthopaedic clinics in north India with a
myriad of musculoskeletal complaints had rickets, with
knee pain at night followed by leg deformity being the
most common complaints31. In Saudi Arabia, 40% of
adolescents with increased alkaline phosphatase levels
(a biochemical marker of rickets and osteomalacia)
were found to have nutritional rickets; of these, 39%
presented with bone pain, 18% with limb deformity,
14% with pathological fractures and 29% were asymp-
tomatic29. A female preponderance was reported both
in India and in Saudi Arabia29,31. Globally, girls in the
Middle East seem to have the highest rates of vitamin D
deficiency, an observation that has been attributed to
cultural dress codes combined with inadequate calcium
and vitamin D intake32–35. The sex difference is concern-
ing in light of the implications for future offspring. Risk
factors for vitamin D deficiency have been studied in
Ethiopian adolescents, almost half of whom were vita-
min D deficient, and included living in urban settings,
lower maternal socioeconomic and education status and
ownership of televisions or computers35.

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PRIMER

7-Dehydrocholesterol Dietary intake of vitamin D2 the mitochondrial enzyme 25‑­hydroxyvitamin D-1α‑­

(some plants and fortified foods) hydroxylase (further referred to as 1α‑hydroxylase;
7-Dehydrocholesterol encoded by CYP27B1). Activity of 1α‑hydroxylase in
reductase
the kidney is tightly regulated by PTH, calcium, phos-
Vitamin D3
phate, FGF23 and 1,25(OH)2D. Metabolic inactivation of
1,25(OH)2D and 25(OH)D occurs, primarily in the kidney
and intestine, via hydroxylation at the 24 position by the
Vitamin D
enzyme 25‑hydroxyvitamin D-24‑hydroxylase (further
referred to as 24‑hydroxylase; encoded by CYP24A1)36.
Classically, 1,25(OH)2D acts on the intestine to
stimulate calcium and phosphate absorption, thereby
25-Hydroxylase maintaining plasma concentrations of these ions at
levels sufficient for normal bone mineralization (FIG. 3).
25(OH)D
Such action depends on binding of 1,25(OH)2D to the
vitamin D receptor (VDR).

FGF23. FGF23 — a phosphaturic hormone produced by

1α-Hydroxylase PTH osteocytes — decreases the threshold for renal tubular
reabsorption of phosphate by decreasing the abundance
Degradation 1,25(OH)2D
24-Hydroxylase of the main renal phosphate transporters, sodium-­
dependent phosphate transport protein 2A (NPT2A;
also known as NaPi-IIa) and NPT2C (also known as
FGF23 ↑ Bone ↑ Calcium and ↑ Phosphate NaPi-IIc), on the apical surface of proximal renal tubular
resorption phosphate absorption excretion cells37,38 (FIG. 4). Thus, when FGF23 levels are increased,
serum phosphate is maintained at considerably lower
levels than normal.
In addition, FGF23 regulates vitamin D metabolism
by increasing the expression of CYP24A1 and down-
regulating the expression of CYP27B1 (FIGS 3,4). Thus,
Figure 3 | Regulation of calcium and phosphate homeostasis. Serum calcium abnormally increased FGF23 levels result in lower cir-
Nature Reviews | Diseaseand
Primers
phosphate levels are regulated by the concerted action of 1,25‑dihydroxyvitamin D culating levels of the 1,25(OH)2D metabolite than would
(1,25(OH)2D), fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) on the normally be expected given the hypophosphataemia39.
intestine, bone and kidney. 25(OH)D, 25‑hydroxyvitamin D. The relative deficiency of 1,25(OH)2D may contribute to
the low serum phosphate level, as intestinal phosphate
absorption is positively regulated by 1,25(OH)2D (FIG. 3)
Mechanisms/pathophysiology via NPT2B (also known as NaPi-IIb), which is expressed
Calcium and phosphate homeostasis in the intestine and mediates ~50% of intestinal phos-
Serum calcium and phosphate levels are regulated by phate transport 40. Indeed, intestinal phosphate absorp-
vitamin D, fibroblast growth factor 23 (FGF23) and tion is decreased in a mouse model of XLH (Hyp mice)
parathyroid hormone (PTH) through actions on the compared with control mice41. Nevertheless, the primary
intestine, kidney and bone (FIG. 3). The development disruption incurred by excessive FGF23 action must be
of rickets, which is associated with abnormal serum in renal phosphate reabsorption, as the tubule is unable
calcium and/or phosphate levels, is often associated to compensate for any limitations in intestinal phosphate
with abnormalities in vitamin D, PTH and FGF23 absorption, which would normally occur in primary
­metabolism or action. ­disorders of nutritional phosphate deprivation.

Vitamin D. Vitamin D, a biologically inactive prohor- Calciopenic rickets

mone, exists as either ergocalciferol (vitamin D2) pro-
duced by fungi and yeast or as cholecalciferol (vitamin D3)
produced by near-UV irradiation (290–315 nm) from
7‑dehydrocholesterol in human skin (FIG. 3). Vitamin D
is hydroxylated at the 25 position in the liver by one or
more enzymes, including the microsomal enzyme vita-
min D 25‑hydroxylase (further referred to as 25‑hydrox-
ylase; encoded by CYP2R1). The activity of hepatic
25‑­hydroxylase is not tightly controlled and, conse-
quently, circulating concentrations of 25(OH)D are deter-
mined primarily by dietary intake and skin ­synthesis of
vitamin D. Next, 25(OH)D undergoes ­1α‑­hydroxylation
(primarily in the kidney) to its hormonally active
form, 1,25‑dihydroxyvitamin  D (1,25(OH) 2D), by
Although various types of rickets have different causes
and pathogenetic mechanisms42, the characteristic
growth plate abnormalities of rickets are similar, inde-
pendent of the cause (FIG. 1). BOX 1 highlights the three
broad categories of the causes of rickets, which are
based on the primary defect in the pathogenesis of the
disease: calcium-related disorders (calciopenic rickets),
phosphate-related disorders (phosphopenic rickets) and
those disorders associated with the direct impairment
of mineralization. Although the terms ‘calciopenic’ and
‘phosphopenic’ refer to the initiating clinical insults
that eventually lead to rickets (that is, hypocalcaemia
or hypophosphataemia), both mineral deficits will gen-
erate hypophosphataemia either through secondary

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hyperparathyroidism in the case of calciopenic rickets
or through mechanisms unrelated to secondary hyper-
parathyroidism (that is, primary renal tubular defect
or elevated FGF23 levels) in the case of phosphopenic
rickets. Reduced ambient phosphate supply seems to
be the common pathway in the development of the
growth plate abnormalities observed in rickets, in both
­calciopenic and phosphopenic forms43.
Nutritional and environmental causes. The central
abnormality common to the two major causes of nutri-
tional rickets (that is, dietary calcium deficiency and
vitamin D deficiency) is an inability to absorb suffi-
cient dietary calcium to meet the requirements of the
growing skeleton44 (FIG. 5). In dietary calcium deficiency,
the poor calcium content or its limited bioavailability
in the diet prevents sufficient absorption to meet the
growing child’s needs even though fractional intestinal
calcium absorption may be maximized45 through ele-
vated 1,25(OH)2D levels46. In the case of vitamin D defi-
ciency, intestinal calcium absorption is impaired owing
to inadequate levels of 1,25(OH)2D as a consequence of
insufficient substrate (25(OH)D) (FIG. 5). The combina-
tion of low calcium intake and poor vitamin D status
exacerbates the development and severity of rickets47.
Phosphate
Urine
NPT2A
Proximal renal tubular cell
NHERF1 NPT2C
P ↓1,25(OH)2D
SGK1 ↑ CYP24A1
↓ CYP27B1
ERK1
ERK2
Lysosome Nucleus
In both forms of nutritional rickets, the absolute
intestinal calcium absorption is inadequate, leading to
a fall in ionized calcium levels and secondary hyper-
parathyroidism, with the consequent development of
increased renal phosphate loss and hypophosphataemia.
Biochemically, rickets associated with vitamin D defi-
ciency and dietary calcium deficiency differ from each
other, in that serum 25(OH)D values are typically higher
(>25–30 nmol per litre) and serum 1,25(OH)2D levels
are increased in dietary calcium deficiency compared
with vitamin D deficiency, which is associated with low
25(OH)D and variable 1,25(OH)2D levels48.
FGF23 might also play a part in rickets owing to low
dietary calcium intake. Indeed, an intriguing finding in
children with rachitic-like bone lesions and suspected
dietary calcium deficiency in the Gambia has been the
presence of markedly elevated plasma FGF23 levels,
which were inversely correlated with serum phosphate
levels49. A potential explanation could be that low serum
calcium levels lead to increased PTH and 1,25(OH)2D
levels, which in turn lead to increased FGF23 secretion
(FIG. 3). An inverse relationship between elevated FGF23
levels and haemoglobin values was also observed in this
study, which was marked in the children with rachitic-­
like bone deformities50. Whether FGF23 plays a part in
rickets associated with dietary calcium deficiency
in other communities will need further investigation.
Hereditary defects in vitamin D synthesis, degrad­
ation or action can also give rise to hypocalcaemia,
hypophosphataemia and rickets in children (BOX 1).
These types of rickets are rare, especially when com-
pared with nutritional rickets. The disorders now known
to be due to 1α‑hydroxylase deficiency and hereditary
1,25(OH)2D resistance were originally labelled ‘vita-
min D‑dependent’ rickets in reference to the obser-
vation that rickets recurred in these disorders when
pharmacologic doses of vitamin D were discontinued.
This finding contrasts with rickets caused by vitamin D
deficiency, in which disease recurrence can be prevented
with ­physiological doses of vitamin D.

25‑Hydroxylase deficiency. Rickets associated with low

Blood α-KLOTHO
FGFR1
FGF23
Figure 4 | Regulation of renal phosphate transport and vitamin D metabolism by
FGF23. Fibroblast growth factor 23 (FGF23) specificallyNature Reviews
recognizes | Disease
the FGF Primers
receptor 1
(FGFR1) associated with the kidney-produced co-receptor α‑KLOTHO on the basolateral
surface of renal tubular cells196. Downstream signalling through extracellular-signal-­
regulated kinase 1 (ERK1), ERK2 and serine/threonine protein kinase SGK1 leads to
phosphorylation of sodium-hydrogen exchanger regulatory factor 1 (NHERF1) and
translocation of the sodium-dependent phosphate transport protein 2A (NPT2A)
and NPT2C from the apical membrane107. NPT2A is then degraded in the lysosomal
compartment, whereas NTP2C might be recycled to the membrane or degraded.
Furthermore, FGF23 has been shown to downregulate transcription of NTP2A, providing
another mechanism by which renal phosphate transport can be affected197. Parathyroid
hormone contributes to the regulation of renal tubular phosphate reabsorption by its
effect on NTP2A and NPT2C transporter removal from the apical membrane and may
interact with FGF23 in regulating membrane transporter abundance107,198. In addition
to regulation of renal phosphate transport, FGFR1 activation inhibits CYP27B1
expression (encoding 1α‑hydroxylase) and stimulates CYP24A1 expression (encoding
24‑hydroxylase), resulting in impaired production and increased degradation of
1,25‑dihydroxyvitamin D (1,25(OH)2D).
to undetectable 25(OH)D levels can be caused by inac-
tivating mutations in the hepatic microsomal enzyme
CYP2R1, the predominant 25‑hydroxylase in humans51,52
(FIG. 3). Individuals with 25‑hydroxylase deficiency pres-
ent in a manner similar to those with rickets associ-
ated with vitamin D deficiency. Two different CYP2R1
mutations were identified in Nigerian children with
familial rickets; both mutations dramatically reduced
25‑­hydroxylase activity in vitro53,54. Further, two Saudi
Arabian siblings with severe vitamin D deficiency were
found to be compound heterozygotes (presence of a dif-
ferent mutation in each allele) for CYP2R1 mutations that
are predicted to encode null alleles55. Response to treat-
ment differs between individuals who are homozygous
and those who are heterozygous for CYP2R1 mutations.
1α‑Hydroxylase deficiency. 1α‑Hydroxylase deficiency
causes rickets owing to loss‑of‑function mutations in
CYP27B1 (FIG. 3), which often manifests within the first

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Box 1 | Classification of rickets* 24 months of life. Rickets associated with 1­ α‑hydroxylase

Calciopenic rickets
Calciopenic rickets is the consequence of the inability to maintain serum calcium
concentrations in the normal range, leading to secondary hyperparathyroidism and
hypophosphataemia. The hypocalcaemia can be caused by vitamin D or dietary
calcium deficiencies, and abnormalities of vitamin D metabolism and action.
Vitamin D‑associated causes of rickets:
• Rickets associated with vitamin D deficiency due to insufficient vitamin D intake,
insufficient epidermal ultraviolet radiation exposure or intestinal malabsorption
syndromes (such as obstructive jaundice)
• 25‑Hydroxylase deficiency (also known as vitamin D‑dependent rickets type 1B):
impaired 25‑hydroxylation of vitamin D owing to mutations in CYP2R1
• 1α‑Hydroxylase deficiency (the inherited form also known as vitamin D‑dependent
rickets type 1A): impaired 1α‑hydroxylation of 25(OH)D owing to renal disease or
mutations in CYP27B1
• Hereditary 1,25(OH)2D-resistant rickets due to mutations in the VDR (also known as
vitamin D‑dependent rickets type 2) or to overexpression of a vitamin D response
element (VDRE)-binding ribonucleoprotein (also known as vitamin D‑dependent
rickets type 2b)
• Increased degradation of vitamin D due to use of anticonvulsants (such as
phenobarbital, carbamazepine and phenytoin) or antimicrobials (such as rifampicin)
Rickets as a consequence of dietary calcium deficiency due to insufficient dietary
calcium intake or gastrointestinal disorders resulting in calcium malabsorption
Phosphopenic rickets
Phosphopenic rickets results from a primary inability to maintain serum phosphate
concentrations in the normal range due to impaired renal phosphate reabsorption or
reduced gastrointestinal phosphate absorption.
Rickets as a consequence of dietary phosphate deficiency or impaired bioavailability:
• Breastfed very low birthweight infants
• Use of elemental or hypoallergenic formula diet or parental nutrition
• Excessive use of phosphate binders
• Gastrointestinal surgery or disorders
Rickets caused by increased renal phosphate loss:
• Fibroblast growth factor 23 (FGF23)‑dependent types of rickets are associated with
increased FGF23 levels owing to overproduction or reduced degradation of FGF23:
-- X‑Linked hypophosphataemia (XLH): associated with mutations in PHEX
-- Autosomal recessive hypophosphataemic rickets (ARHR): associated with mutations
in DMP1 (ARHR type 1) or ENPP1 (ARHR type 2)
-- Autosomal dominant hypophosphataemic rickets (ADHR): associated with
mutations in FGF23
-- Raine syndrome: associated with mutations in FAM20C
-- Others: tumour-induced osteomalacia or polyostotic fibrous dysplasia,
overexpression of α‑KLOTHO
• FGF23‑independent types of rickets:
-- Due to mutations in SLC34A1 (encoding sodium-dependent phosphate transport
protein 2A (NPT2A))
-- Due to mutations in SLC34A3 (encoding NTP2C), causing hereditary
hypophosphataemic rickets with hypercalciuria
-- Due to mutations in NHERF1
-- Due to disorders such as Fanconi syndrome or distal renal tubular acidosis
Rickets associated with a direct inhibition of mineralization
Direct impairment of the process of mineralization at the growth plate
• Hereditary hypophosphatasia
• Treatment with etidronate (first-generation bisphosphonate)
• Fluoride excess
• Aluminium excess
*This classification provides a rational division of the numerous causes of rickets into three
major categories based on pathogenesis, biochemical abnormalities and methods of treatment
and, consequently, provides a straightforward approach to diagnosis and management.
Please note that this list is incomplete, as rare causes of rickets have been omitted.
deficiency is also known as vitamin  D‑dependent
­r ickets type  1, hereditary pseudo-vitamin  D defi-
ciency ­r ­­ickets type 1 or vitamin D dependency 56,57.
In patients with 1α‑hydroxylase deficiency, serum con-
centrations of 25(OH)D are not decreased, which dis-
tinguishes patients with 1α‑hydroxylase deficiency from
those with nutritional vitamin D deficiency in whom
serum 25(OH)D is reduced. Levels of 1,25(OH)2D are
­consistently very low in 1α‑hydroxylase deficiency.
Although 1α‑hydroxylase deficiency is rare in most
populations, it is particularly common among French
Canadians, with an apparent carrier rate of 1 per 26 indi-
viduals58; inheritance is autosomal recessive. As of 2017,
~60 different CYP27B1 mutations have been identified
in >100 patients since the first described mutations in
1997 (REF. 59). All the described frameshift and nonsense
(premature translation arrest) mutations eliminate the
haeme-binding site of the 1α‑hydroxylase, resulting in a
protein devoid of enzymatic activity. Of the many mis-
sense mutations reported, the majority 60,61 also eliminate
enzyme activity when assayed in vitro. Some patients
with mild clinical manifestations have CYP27B1 muta-
tions that result in a 1α‑hydroxylase protein with partial
enzyme activity 60,61.
Hereditary 1,25(OH)2D-resistant rickets. Hereditary
1,25(OH)2D-resistant rickets, which is caused by end-
organ resistance to the action of 1,25(OH)2D usually
due to mutations in VDR, was first described in 1978
by Brooks et al.62 and is characterized by hypocalcaemia,
hyperparathyroidism, normal serum concentrations of
25(OH)D and substantially increased (3‑fold to 30‑fold)
serum 1,25(OH)2D levels. This disorder, initially termed
vitamin D‑dependent rickets type 2, is also known as
pseudo-vitamin D deficiency type 2, calcitriol-resistant
rickets, hypocalcaemic vitamin D‑resistant rickets and
hereditary 1,25(OH)2D-resistant rickets. Although most
of the clinical, laboratory and radiographic findings in
patients with hereditary 1,25(OH)2D-resistant rickets62–65
are similar to those in patients with 1α‑hydroxylase
deficiency or nutritional vitamin D deficiency, a strik-
ing difference is the finding of either sparse body hair
or total alopecia in the majority of affected patients64–68.
Patients with alopecia, which can be present at birth
or develop within the first year of life, seem to have
an earlier age of onset of rickets and greater resistance
to 1,25(OH)2D treatment than those with hereditary
1,25(OH)2D‑resistant rickets without alopecia68.
The VDR is a member of the family of nuclear
transcription factors69 and is composed of an amino-­
terminal DNA binding domain and a carboxy-­terminal
ligand-binding domain. The VDR heterodimerizes
preferentially with the retinoid‑X receptor (RXR),
enabling optimal binding to vitamin D response ele-
ments (VDREs), DNA motifs that are critical for VDR-
dependent gene regulation. Approximately 50 different
mutations in VDR have been described70; they have been
categorized into those that affect the ligand-­binding
domain, which interrupt binding of 1,25(OH)2D to
VDR, and those that affect the DNA-binding domain,

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Vitamin D deficiency Dietary calcium deficiency

↓ Conversion to vitamin D3 in the skin (UV) Inadequate dietary calcium intake

↓ Dietary intake of vitamin D2 or vitamin D3

Inadequate intestinal ↑ Fractional intestinal

↓ Serum 1,25(OH)2D calcium absorption calcium absorption
VDR

↓ Serum calcium
25-Hydroxylase
↑ Serum PTH

1α-Hydroxylase ↓ Serum phosphate ↑ Serum 1,25(OH)2D

↓ Chondrocyte apoptosis
↓ Serum 25(OH)D ↑ Delayed endochondral calcification

Rickets Impaired
Osteomalacia mineralization

Figure 5 | The pathogenesis of rickets associated with nutritional vitamin D or dietary calcium
Nature deficiency.
Reviews | Disease Primers
Vitamin D deficiency (left panel) leads to a fall in 25‑hydroxyvitamin D (25(OH)D) levels, resulting in a reduction in
1,25‑dihydroxyvitamin D (1,25(OH)2D) levels and consequent impairment of intestinal calcium absorption and fall in serum
calcium. Secondary hyperparathyroidism results in an increase in renal phosphate excretion and hypophosphataemia and
stimulation of 1α‑hydroxylase activity that fails to increase 1,25(OH)2D levels owing to a lack of substrate (25(OH)D). The
resultant hypophosphataemia is primarily responsible for the development of osteomalacia and rickets. Low dietary
calcium intake (right panel) results in a fall in serum calcium levels and an increase in parathyroid hormone (PTH) levels,
which promotes renal phosphate loss and increases 1α‑hydroxylase activity. The consequent increase of 1,25(OH)2D levels
increases the fractional intestinal calcium absorption, which might partially correct serum calcium levels with slightly
elevated PTH levels and mild hypophosphataemia. However, if calcium intake decreases further or calcium demand
increases, intestinal calcium transport can no longer compensate and normocalcaemia cannot be maintained; secondary
hyperparathyroidism, elevated 1,25(OH)2D levels and hypophosphataemia are established with consequent development
of rickets and osteomalacia. UV, ultraviolet; VDR, vitamin D receptor.

which interfere with binding of the 1,25(OH)2D–VDR
complex to the VDREs in DNA. Of interest, alopecia is
observed in patients with mutations in the DNA-binding
domain or in regions that inhibit hetero­dimerization
with RXR or in those with mutations that cause trun-
cation of the VDR. By contrast, patients with muta-
tions in the ligand-binding domain or co-activator
binding regions without defective heterodimerization
do not develop alopecia71–73. Studies in Vdr-null mice
have helped to establish the critical role of the VDR
in hair follicle development 74–76, which presumably
involves WNT signalling via β‑catenin and Hedgehog
signalling pathways77.
Several patients with apparent resistance to
1,25(OH)2D but with no identified VDR mutation have
been described. One such individual, with the biochem-
ical and clinical hallmarks of hereditary 1,25(OH)2D-
resistant rickets including alopecia, has been found to
overexpress a heterogenous nuclear ribonucleoprotein
that competes with VDR for VDRE binding, illustrative
of yet another mechanism for vitamin D resistance78.
calcium deficiency or vitamin D deficiency. However, in
premature infants, phosphate deficiency can dominate
the clinical picture of rickets, particularly in breastfed
preterm infants; these infants may require high levels of
phosphate supplementation via oral or parenteral routes
to meet requirements80,81. A recent report has identified
that the use of amino acid-based elemental formulas,
such as Neocate (Nutricia), can result in hypophospha-
taemic rickets, particularly in infants with coexistent
gastrointestinal diseases. Although such formulas have
appropriate phosphate content, the bioavailability seems
to be impaired in certain clinical settings82. Similarly,
excessive use of antacids that bind dietary phosphate can
result in symptomatic hypophosphataemia and bone dis-
ease83, a complication that has been reported in all ages.
Parenteral nutrition and gastrointestinal surgery may
also limit adequate phosphate delivery to infants or older
patients. In these cases, phosphate supplementation gen-
erally corrects the problem. Finally, congenital impair-
ment of combined intestinal phosphate malabsorption
and renal reabsorption has been reported84.

Phosphopenic rickets FGF23‑mediated causes. This group of disorders is

Nutritional cause. Phosphate is required together with
calcium for mineralization of bones. Thus, severe phos-
phate deficiency can lead to osteomalacia and rickets79.
However, phosphate-deficient diets are rare, and the clin-
ical picture of nutritional rickets is usually that of dietary
caused by either overproduction of FGF23 or reduced
degradation of intact FGF23, thereby leading to excess
FGF23 levels and hypophosphataemia (BOX 1; FIG. 3).
As shown in FIG. 6a, excess circulating FGF23 ­levels may
result from abnormalities in genes encoding proteins

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PRIMER

a Physiological b Fibrous dysplasia

regulators
• ↑ Phosphate
Osteocyte • ↑ 1,25(OH)2D
• ↓ Iron Gain-of-function
Genetic regulators • ↑ α-KLOTHO mutations in GNAS
Loss-of-function
mutation in:
• PHEX
• DMP1 ↑ Protein kinase A
• ENPP1 signalling
• FAM20C

↑ FGF23
Gain of function
of FGFR1 ↑ FGF23

c Tumour cell associated with d Epidermal nevus

tumour-induced osteomalacia syndrome

Fusion proteins
(FN1–FGFR1 or
FN1–FGF1 fusions) Gain-of-function
mutations in:
• HRAS
• NRAS
Increased FGFR1
signalling

↑ FGF23 ↑ FGF23

Figure 6 | FGF23: tissue sources and mechanisms of regulation. a | The regulation of the production or secretion of
fibroblast growth factor 23 (FGF23) in osteocytes is not completely understood, but phosphate Natureitself and | Disease Primers
Reviews
1,25‑dihydroxyvitamin D (1,25(OH)2D) stimulate production of FGF23 (REF. 199). Iron deficiency results in increased FGF23
secretion200 and, paradoxically, administration of certain iron salts (that is, ferric carboxymaltose) will increase FGF23
levels in humans201,202. As evidenced by the presence of rickets associated with loss of function of PHEX, DMP1 and ENPP1,
proteins encoded by these genes regulate FGF23 production, but the mechanisms are unknown201–203. Furthermore, FGF23
production and secretion by osteocytes depends on the FGF receptor 1 (FGFR1). b–d | Excessive production of FGF23
occurs in various pathological conditions, such as the skeletal fibrous dysplasia in McCune–Albright syndrome (part b),
which is due to activating mutations in GNAS. Signalling through FGFR1 can stimulate FGF23 production, a process
thought to be amplified by somatic mutations resulting in FGFR1 fusion proteins in tumours associated with
tumour-induced osteomalacia (part c). Finally, activating mutations in HRAS and NRAS cause epidermal nevus syndrome,
which is associated with increased FGF23 levels owing to unknown mechanisms. FN, fibronectin.

involved in the regulation of FGF23 expression or
abnormalities in regulators of FGF23 metabolism85.
XLH is caused by mutations in PHEX and autosomal
recessive hypophosphataemic rickets (ARHR) is caused
by mutations in DMP1 or ENPP1. All these mutations
are associated with increased FGF23 levels, but the exact
mechanisms are unknown. FGF23 is active as a full-
length molecule and is enzymatically cleaved into inac-
tive amino-terminal and carboxy-terminal fragments86.
The prototype disorder of defective degradation of intact
FGF23, autosomal dominant hypophosphataemic rick-
ets (ADHR), results from specific missense mutations
resulting in amino acid substitutions at residues 176–179,
a protease recognition site. Such mutations disrupt the
RXXR motif of this recognition site, thereby rendering
the molecule resistant to proteolytic cleavage, resulting in
excess accumulation of active, intact FGF23 (REF. 87).
In addition, loss‑of‑function mutations of the extracellu-
lar serine/threonine protein kinase FAM20C, as observed
in Raine syndrome, can interfere with phosphorylation
of FGF23, which, in turn, enables increased glycosylation
at nearby critical residues in FGF23, such that cleavage of
FGF23 is limited88,89. Ultimately, the mutation can result
in FGF23‑mediated hypophosphataemia with variable
occurrence of rickets or osteomalacia90.
Other mechanisms by which FGF23 secretion seems
to be regulated include activation of the protein kinase A
pathway through activating mutations in GNAS, as
occurs in the fibrous dysplasia lesions observed in
McCune–Albright syndrome91, and exposure to high lev-
els of circulating α-KLOTHO92,93 (FIG. 6a,b). Excess FGF23
secretion in the pathological setting of tumour-induced
osteomalacia has been speculated to result from a
somatic rearrangement, resulting in a fusion protein
consisting of the amino terminus of fibronectin and
the FGF receptor 1 (FGFR1) in a substantial proportion
of tumours causing this syndrome (FIG. 6c). Germline
mutations in FGFR1 have been identified as causing
osteoglophonic dysplasia, a particular skeletal dysplasia
with FGF23‑mediated hypophosphataemia, pronounced

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 PRIMER

short stature and characteristic facial features94. More
recently, another rearrangement generating a fibronectin
and FGF1 fusion protein has been described95. Another
unusual disorder, epidermal nevus syndrome, also
known as cutaneous skeletal hypophosphataemia syn-
drome, is characterized by somatic activating mutations
in HRAS or NRAS in both skin and bone and can lead to
excess FGF23 production by unknown mechanisms96,97
(FIG. 6d). Finally, FGF23 can be stimulated by adminis-
tration of specific iron products, such as ferric carboxy­
maltose that is used to treat refractory iron deficiency,
resulting in considerable hypophosphataemia that may
masqerade as tumour-induced osteomalacia98.
FGF23‑independent causes. Hypophosphataemia disor-
ders with renal phosphate wasting attributable to primary
renal defects may be genetic or acquired. The genetic
causes are most often due to mutations in genes encoding
NPT2A (that is, SLC34A1) or NPT2C (that is, SLC34A3).
Homozygous, loss‑of‑function mutations in SLC34A1
were identified in two adult siblings from a consanguin-
eous family with a form of hypophosphataemic rickets
and Fanconi syndrome (a syndrome of impaired renal
solute reabsorption in the proximal tubules caused by
diseases or toxicity) inherited in an autosomal recessive
pattern99. As children, both siblings had hypophospha-
taemic rickets, severe bone deformities, fractures and
stunted growth100, Fanconi syndrome without metabolic
acidosis, high serum levels of 1,25(OH)2D and hyper-
calciuria. As adults, the hypophosphataemia persisted,
but serum 25(OH)D and 1,25(OH)2D levels were low,
plasma FGF23 levels were low to normal and glomerular
filtration rate was reduced99. The mutant NPT2A protein,
when expressed in Xenopus laevis oocytes and opossum
kidney cells, failed to transport phosphate owing to fail-
ure of the transporter to reach the plasma membrane99.
Mutations in SLC34A1 were also identified in 16 patients
with a form of idiopathic infantile hypercalcaemia with-
out mutations in CYP24A1 (REF. 101). These patients,
four from consanguineous families and twelve unrelated,
presented in early infancy with hypophosphataemia due
to renal phosphate wasting, failure to thrive, polyuria,
symptomatic hypercalcaemia, high serum concentrations
of 1,25(OH)2D and medullary nephrocalcinosis (renal
parenchymal calcification). The clinical phenotype is
attributed to hypophosphataemia owing to primary renal
phosphate wasting and suppression of FGF23 expression,
leading to inappropriate activation of 1,25(OH)2D with
subsequent hypercalcaemia and hypercalciuria.
Inactivating mutations of SLC34A3, which encodes
NPT2C, give rise to the autosomal recessive disorder
hereditary hypophosphataemic rickets with hyper­
calciuria (HHRH)102–104. HHRH is characterized by
early childhood onset of hypophosphataemia second-
ary to renal phosphate wasting, rickets or osteomala-
cia, lower limb deformities, muscle weakness and bone
pain. In contrast to XLH, serum levels of 1,25(OH)2D in
HHRH are elevated and, presumably as a consequence,
intestinal calcium absorption is increased, resulting in a
compensatory increase in calcium excretion in the urine.
Circulating PTH102,103 and FGF23 (REF. 104) levels are
normal to low. Long-term oral administration of neutral
phosphate salts alone is associated with improvements
in the hypophosphataemia, bone pain, muscle strength,
growth rate and healing of rickets. Hypophosphataemia
and rickets also can occur in children as part of renal
Fanconi syndrome associated with, for example, nephro-
pathic cystinosis, oculocerebrorenal syndrome (also
known as Lowe syndrome) or Dent disease.
Mutations in the gene encoding the sodium-­hydrogen
regulatory factor 1 (NHERF1) have been identified in
patients with hypophosphataemia due to renal phosphate
wasting; these patients can also present with nephrolithia-
sis (renal stone formation), osteomalacia and normal cir-
culating levels of PTH105,106. Interaction of NHERF1 with
NPT2A is important for proper expression of NPT2A
at the plasma membrane (FIG. 4). In addition, NHERF1
is involved in PTH signalling by modulating the PTH-
induced generation of cAMP107. Mutations located in the
PDZ2 domain or the inter-region between PDZ1 and
PDZ2 of NHERF1 had no effect on phosphate uptake
when expressed in vitro but rather stimulated PTH-
induced generation of cAMP and, consequently, exac-
erbated the inhibition of phosphate transport by PTH105.
By contrast, mutations in the PDZ1 domain were asso-
ciated with reduced abundance of NPT2A at the plasma
membrane but had no effect on PTH-induced cAMP
production106. It seems that the PTH-dependent pathway
that stimulates NPT2A movement from the plasma mem-
brane converges with the FGF23‑dependent pathway at
NHERF1; activation of either pathway can lead to inhibi-
tion ­of phosphate transport through NHERF1 (REF. 107).
Direct inhibition of mineralization
Although ambient hypophosphataemia is considered
the major cause of rickets in XLH, other factors likely
contribute to the bone abnormalities. Indeed, transgenic
mouse models designed to rescue XLH by overexpressing
PHEX in osteoblasts of Hyp mice do not entirely remedi-
ate the underlying osteomalacic bone disease of the Hyp
mice108–110. In humans and in mouse models, phosphate
supplementation does not entirely correct the bone dis-
ease111,112. Whether the inability to completely rescue the
phenotype of Hyp mice can be overcome with more-­
sustained physiological exposure to phosphate or with
inhibition of FGF23 remains to be seen.
Although a number of explanations might exist for
these observations, it is possible that FGF23 or the PHEX
mutation itself have direct effects on mineralization inde-
pendent of phosphate. Along those lines, the presence of
α-KLOTHO has recently been identified in bone cells,
albeit at relatively low levels, which potentially allows for
a targeted role for FGF23 in bone113. Pyrophosphate, a
mineralization inhibitor, has been shown to accumulate
in the bone matrix of Hyp mice114. Finally, fragments of
the family of small integrin-binding ligand, N‑linked
glycoprotein (SIBLING) proteins, that is, acidic serine
aspartate-rich MEPE-associated motif (ASARM) pep-
tides115,116, have been shown to directly inhibit minerali-
zation in vitro and to accumulate in the absence of PHEX.
Other causes of direct inhibition of mineralization are
mentioned in BOX 1.

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PRIMER

a b of the anterior fontanelle, craniosynostosis (premature

closure of the skull sutures) and delayed eruption of the
teeth with enamel hypoplasia. In XLH, dental abscesses
associated with defects in the consolidated mineraliza-
tion of globular dentin may come to the attention of the
family before overt evidence of skeletal disease. Chest
deformities include a rachitic rosary (expansion of the
costochondral junctions) and Harrison sulcus (groove
in the lower thoracic cage in which the diaphragmatic
attachments pull the softened bone inward). Associated
features that may occur in rarer forms of rickets include
features of McCune–Albright syndrome, early-onset hear-
ing loss120 and melanocytic nevi (pigmented mole-like
lesions)96. Complications of XLH that present in adult-
hood include enthesopathy (mineralizing abnormalities
of tendon and ligament insertion sites), osteophytes and
arthritic-like degeneration of joints, none of which are
well understood121.

Figure 7 | Clinical manifestations of rickets. a | A childNature
with X‑linked
Reviews | Disease Primers
hypophosphataemia with a windswept deformity of the legs characterized by a
valgus deformity (genu valgus) of the left leg (inward bowing of the knee) and a
mild varus deformity (genu varus) of the right leg (an outward bowing of the knee).
b | The typical widened wrist in active rickets. This bone deformity is frequently more
apparent visually than on palpation and involves abnormalities in the distal metaphyses
and growth plates of the radius and ulna. The deformity may take some time to resolve
after appropriate treatment of the rickets. In severe rickets, widening may also occur at
the knees and distal tibias.
Diagnosis, screening and prevention
Clinical presentation
The clinical presentation of rickets is heterogeneous,
involves skeletal and non-skeletal manifestations and
depends on the age of presentation. Many children who
present with rickets in early childhood will have progres-
sive bowing deformities of the legs (genu varum) (FIG. 7a)
often associated with a characteristic waddling gait.
In children who develop rickets in the first year of life, the
ability to walk is typically delayed (>18 months of age).
When rickets develops in older children (aged >3 years),
a knock-knee deformity (genu valgum) or a combina-
tion of both genu varum and genu valgum is common117
(FIG. 7a). The age dependency of the presentation as genu
varum or genu valgum reflects the normal growth pat-
tern of the lower limb in the second year of life when the
tibio-femoral angle changes from varus to valgus. Older
children with rickets may complain of bone pain and
fatigue. Fractures may be a presenting feature in a child
with nutritional rickets but only in the presence of clear
radiological features of rickets15. Loss of height and short
stature might occur as a consequence of the progressive
leg deformities. Infants with rickets associated with vita-
min D deficiency or abnormalities of vitamin D metabo-
lism may also develop seizures owing to hypocalcaemia118
and life-threatening cardiomyopathy 119; the presence of
vitamin D deficiency rickets should always be investigated
when children present with these conditions.
Additional clinical signs seen in an infant with rickets
include craniotabes (softening of the skull bones), widen-
ing of the wrists (FIG. 7b), frontal bossing, delayed closure
Investigations
The diagnosis of rickets is made on the basis of medical
history, physical examination and biochemical testing
and is confirmed by radiography. The use of molecular
genetic techniques enables identification of the mutations
causing heritable types of rickets. Management of the dif-
ferent types of rickets differs markedly; thus, a specific
diagnosis for each patient with rickets is imperative not
only to inform parents of a possible genetic aetiology but
also to provide appropriate information on prevention,
prognosis and management.
Medical history. Important enquiries when taking the
medical history of a child suspected to have rickets include
environmental risk factors for nutritional rickets (BOX 2), an
assessment of dietary calcium intake and a family history,
which might suggest an inherited form of rickets. A sim-
ple food intake assessment can be used to provide relia-
ble information on dietary calcium intake122. An intake
of <300 mg of calcium per day in a child aged >12 months
is consistent with dietary calcium deficiency, whereas
infants aged 0–6 months and 6–12 months should have a
daily dietary intake of 200 mg and 260 mg, respectively 15.
Biochemical investigations. The typical biochemical pic-
ture of a child with calciopenic rickets is low or normal
serum calcium levels with increased serum PTH levels
leading to decreased renal tubular reabsorption of phos-
phate and low serum phosphate levels. By contrast, in
typical phosphopenic rickets, normal serum calcium,
low serum phosphate and normal serum levels of PTH
and 25(OH)D are observed. Serum alkaline phosphatase
levels are usually markedly raised in calciopenic rickets
owing to the high PTH causing increased bone turno-
ver but are often only modestly raised in phosphopenic
­rickets (especially in XLH) (TABLE 1).
Measurement of serum PTH is essential to distinguish
between calciopenic and phosphopenic rickets. In calcio­
penic rickets, serum PTH levels will be considerably
increased, whereas serum PTH levels are often in the
normal range or only slightly increased in phosphopenic
rickets.

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Serum phosphate levels should be interpreted with
care as reference phosphate values are higher in young
children and infants (1.3–2.1 mmol per litre) than in
adults (0.7–1.3 mmol per litre). Thus, it is important to
ensure that a reference range for adults is not quoted for
serum phosphate levels in children; a serum phosphate
level of <1.0 mmol per litre is always abnormal in a child.
Although serum 25(OH)D concentrations are con-
sidered to reflect vitamin D nutritional status, the serum
level below which the clinical consequences of vitamin D
deficiency occur has been difficult to define and remains
a contentious issue. The US Institute of Medicine (IOM)
has defined vitamin D deficiency as serum 25(OH)D
levels of <30 nmol per litre; this cut-off reflects the level
below which the risk of developing rickets and meta-
bolic bone disease increases123. However, a task group of
the Endocrine Society defined vitamin D deficiency as
serum 25(OH)D levels of <50 nmol per litre124, although
the criteria used to define vitamin D deficiency were
different from those used by the IOM. More recently,
a report from a scientific panel in the United Kingdom
suggested that the risk of rickets increases at serum
25(OH)D levels <25 nmol per litre125. Several factors
likely influence whether or not clinical or biochemical
abnormalities occur at low levels of 25(OH)D; among
these are the severity and duration of low 25(OH)D lev-
els, habitual dietary calcium intake and its bioavailability,
the rate of bone growth and mineralization and genetic
polymorphisms that might influence the total levels of
25(OH)D and its circulating available component 126.
It is worth collecting an additional serum sample
before starting any treatment for subsequent analysis for
1,25(OH)2D or FGF23 if the diagnosis is not explained
by the initial investigations. A urine sample, ideally in
the fasting state, is an important additional investigation
to assess renal excretion of calcium and phosphate and to
Box 2 | Environmental risk factors for nutritional rickets
Certain environmental risk factors can predispose a child to develop nutritional rickets
and should be taken into account when rickets is suspected. The relative importance of
these factors will vary among different childhood populations around the world15.
Vitamin D deficiency
• Dark skin pigmentation
• Living at a high latitude during winter or spring with lack of ultraviolet B radiation
exposure as a consequence
• Restricted sun exposure, for example, due to cultural skin covering or pollution
• Lack of vitamin D supplementation during infancy
• Prolonged exclusive breastfeeding
• Maternal vitamin D deficiency
Dietary calcium deficiency
• Limited dairy product intake, for example, due to cow milk intolerance or lack of
access to milk
• Unusual diets, for example, veganism in infants
• Malabsorption, for example, cholestatic liver disease*
Heritable forms of rickets are more likely to occur if there is a known family history (for example,
X‑linked hypophosphataemic rickets) or in children born to consanguineous parents (for
example, 1α‑hydroxylase deficiency). *Cholestatic liver disease is also associated with impaired
absorption of vitamin D.
exclude more generalized tubular defects by measuring,
for example, pH or glucose and protein levels. Calcium
excretion is measured as a ratio of urine calcium to urine
creatinine levels (careful note of the units used to meas-
ure the concentrations needs to be taken to interpret the
results correctly), whereas assessment of renal excretion
of phosphate is best performed by calculating the tubular
reabsorption of phosphate and the tubular maximum
for phosphate reabsorption127 using an equation that
includes serum phosphate and creatinine.
Radiography. Radiographs of the wrist and knee enable
the diagnosis of rickets (FIG. 8). Typical changes seen in
the metaphyseal region are cupping, fraying and lateral
widening with expansion of the growth plate. Bones
with metaphyseal abnormalities may show evidence of
osteopenia in calciopenic rickets owing to bone dem-
ineralization as a consequence of the high PTH levels.
By contrast, in XLH, the bones may become somewhat
sclerotic by adulthood, and dense vertebrae can be a
particular feature of ARHR type 1, even in childhood.
XLH and ARHR type 1 can be further distinguished
from other forms of hypophosphataemia by the pres-
ence of characteristic peri-osteocytic lesions on bone
biopsy samples128,129 (FIG. 2c). Other forms of hypophos-
phataemic rickets may be associated with severe loss of
trabecular and cortical bone, which is well described in
HHRH and tumour-induced osteomalacia. Occasionally,
fractures of long bones may be seen in both calciopenic
and phosphopenic (excluding XLH) forms of rick-
ets in conjunction with osteopenic bone and typical
metaphyseal changes.
Differential diagnosis
A number of conditions exist of which radiographic and
clinical features can be mistaken for rickets. In meta-
physeal chondrodysplasia (typically Schmid type), meta­
physeal changes are seen on radiographs in conjunction
with short stature and a waddling gait130 (FIG. 9). However,
serum biochemistry is normal in this condition. Jansen
type metaphyseal chondrodysplasia due to an activating
mutation of PTHR1 (encoding the PTH1 receptor) can
also have a radiographic appearance similar to that of
rickets131. Bone turnover is increased with an increased
serum alkaline phosphatase level, and the serum calcium
level is often raised with PTH levels suppressed.
Infants with osteopetrosis (a condition in which
bones become dense and brittle) due to a defect in
osteo­clastic bone resorption can have metaphyseal
changes that resemble rickets termed osteopetro­
rickets (REF. 132). However, the long bones are strikingly
dense in this condition. Hypocalcaemia and secondary
­hyperparathyroidism may be evident in severe cases.
Another important but rare condition is the infantile
form of hereditary hypophosphatasia, in which the radio­
graphic appearance may resemble rickets133. This condi-
tion, due to inactivating mutations in TNSALP (encoding
tissue-nonspecific alkaline phosphatase), may present
in the perinatal period to the first 6 months of life with
poor feeding and failure to thrive due to hypercalcaemia.
Respiratory insufficiency due to the small and poorly

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mineralized ribcage is often evident. The key biochemi-
cal marker that distinguishes infantile hypo­phosphatasia
from true rickets is a low, rather than increased, serum
alkaline phosphatase level. Additional investigations,
such as the measurement of the urinary phospho­
ethanolamine to creatinine ratio and plasma pyridoxal
phosphate, will help to confirm the diagnosis as they
are typically increased in children with infantile hypo­
phosphatasia. Early diagnosis of this condition, which
has a high mortality rate, is important as treatment with
recombinant alkaline phosphatase is now available and
can heal skeletal manifestations and improve survival134.
Prevention
Prevention is possible only for nutritional rickets, not
for heritable forms. Adequate dietary calcium intake is
necessary to prevent nutritional rickets due to calcium
deficiency, with a recommended intake of 500 mg daily
in children aged 1–3 years. In communities in which die-
tary calcium intakes are habitually low, calcium intakes
can be increased effectively with calcium fortification
of, for example, cereals or laddus (an Indian sweet ball
made with flour, ghee and sugar)135. In Nigeria, both
powdered limestone and ground dried fish have been
used to increase dietary calcium intakes by their addition
to porridge136.
To ensure an adequate vitamin D status, three strat-
egies have been proposed that can be used alone or
together: vitamin D supplementation, food fortification
and sunlight exposure. Vitamin D supplementation,
particularly of infants, has been the main method used
to prevent nutritional rickets, with varying evidence of
success. Current consensus opinion, supported by a ran-
domized clinical trial involving different vitamin D doses
in breastfed infants137, is that a daily dose of 400 interna-
tional units (IU) of vitamin D given to all infants from
birth to 12 months of age, regardless of mode of feeding,
is adequate to prevent rickets15. Examples of successful
public health strategies using 400 IU vitamin D daily exist
that have reduced the incidence of rickets and sympto-
matic vitamin D deficiency 138,139. However, ensuring
adequate daily supplementation to infants is difficult 140.
For example, the annual rate of vitamin D supplement
use was only 17.9% despite a policy of free vitamin D
supplements for all breastfed infants141. Alternative strat­
egies to increase effective use of vitamin D supplements
need to be considered. A randomized clinical trial of
daily vitamin D (400 IU) versus a bolus dose of 50,000
IU of vitamin D3 in babies born to vitamin D‑deficient
mothers in Melbourne, Australia, demonstrated that the
bolus dose could safely achieve similar 25(OH)D levels
at 3–4 months as the daily dose142. Maternal supplemen-
tation with high doses of vitamin D (such as 6,400 IU
per day)143 was safe and effective at maintaining suffi-
cient 25(OH)D levels, but some concerns have been
expressed about the possible risk of complications related
to the high dose of vitamin D given to the mother, which
passes to the infant in breastmilk. Caution about its rou-
tine acceptance has been raised until more large-scale
clinical trials have been conducted15.

Table 1 | Serum and urinary biochemistry associated with different types of rickets
Condition Associated gene sCa sP sPTH s25(OH)D s1,25(OH)2D sALP sFGF23 uP uCa
mutation
Calciopenic rickets
Dietary calcium NA = or ↓ ↓ ↑ = ↑ ↑ ? Variable ↓
deficiency
Vitamin D NA = or ↓ ↓ ↑ ↓ Variable ↑ = Variable ↓
deficiency
25‑Hydroxylase CYP2R1 = or ↓ ↓ ↑ ↓ ↓ ↑ ? Variable ↓
deficiency
1α‑Hydroxylase CYP27B1 ↓ ↓ ↑ = ↓ ↑ ? Variable ↓
deficiency
Hereditary VDR ↓ ↓ ↑ = ↑ ↑ ? Variable ↓
1,25(OH)2D-
resistant rickets
Phosphopenic rickets
Phosphate NA = or ↑ ↓ = = ↑ or = ↑ ↓ or = ↓ ?
deficiency
XLH PHEX = ↓ = = ↓ or = ↑ ↑ ↑ ↓ or =
ADHR FGF23 = ↓ = = ↓ ↑ ↑ ↑ ?
ARHR type 1 DMP1 = ↓ = = ↓ ↑ ↑ ↑ ?
ARHR type 2 ENPP1 = ↓ = = ↓ ↑ ↑ ↑ ?
HHRH SLC34A3 = ↓ = = ↑ or = ↑ ↓ or = ↑ ↑
25(OH)D, 25‑hydroxyvitamin D; 1,25(OH)2D, 1,25‑dihydroxyvitamin D; ADHR, autosomal dominant hypophosphataemic rickets; ALP, alkaline phosphatase;
ARHR, autosomal recessive hypophosphataemic rickets; Ca, calcium; FGF23, fibroblast growth factor 23; HHRH, hypophosphataemic rickets with hypercalciuria;
NA, not applicable; P, phosphate; PTH, parathyroid hormone; s, serum; u, urinary; XLH, X‑linked hypophosphataemia; ↑, increased levels; ↓, decreased levels;
=, normal levels; ?, not known.

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a b between sunlight exposure and 25(OH)D levels149,150,

Femur but these studies have usually been performed in light-
skinned children and may not be appropriate for those
with darker skin types. A study in adults using whole-
body irradiation chambers to simulate summer sunlight
exposure showed that 30 minutes of sunlight three times
per week for 6 weeks would achieve a 25(OH)D level of
>50 nmol per litre in >90% of white adults151. However,
no south Asian adult exposed to the same level of UV
radiation could achieve such a concentration. A dose–
response study in south Asian adults demonstrated that
exposures equivalent to 45 minutes of sunlight three
times per week would achieve 25(OH)D concentrations
of >25 nmol per litre in 94% of individuals, but only 12%
could achieve levels >50 nmol per litre152.

Radius Ulna Tibia
Figure 8 | Radiographic characteristics of rickets. TheNature
radiographic
Reviews changes of rickets
| Disease Primers
are most evident at the rapidly growing ends of long bones. Thus, the most appropriate
sites for radiography when rickets is suspected are the distal radius and ulna at the wrist
(part a) and the distal femur and proximal tibia at the knee (part b). Typical radiographic
changes in nutritional rickets are widening of the growth plates (arrows), loss of the
provisional zone of calcification at the distal metaphyses with fraying of the junction
between the growth plate and the metaphysis and splaying of the metaphyses. The
metaphyses of the long bones typically show coarsening of the trabecular pattern with
apparent increase in radiolucency. Note that identifying osteopenia or low bone mineral
content is difficult and subjective, as it is dependent on the quality and contrast of the
radiograph. Typically, mineralization of the carpal bones and development of epiphyses
are delayed.
Fortification of staple foods with vitamin D is another
preventive strategy that has been used to v­ arying degrees
around the world. A systematic review and meta-­analysis
of trials in adults showed that food fortification can safely
reduce the prevalence of vitamin D deficiency 144. A ran­
domized controlled trial of vitamin D fortification of milk
in Indian schoolchildren showed that those consuming
milk that contained vitamin D were able to achieve
satisfactory 25(OH)D levels of >50 nmol per litre145.
Fortification of milk and margarine in Finland was estim­
ated to increase daily vitamin D intakes from 176 IU
to 360 IU and to raise 25(OH)D levels by 10 nmol per
litre146. There is considerable variation worldwide in food
fortification practice, with cow milk and some fruit juices
being fortified with vitamin D in the United States and
Canada but with fortification limited to margarine, some
breakfast cereals and yoghurts in the United Kingdom147.
In considering the fortification of staple foods within a
country, careful attention must be paid to the variation in
staple food consumption across targeted communities to
ensure the widest possible consumption, while ­preventing
toxic effects in some members of a community.
To provide consistent simple advice regarding sun-
light exposure to prevent rickets in children of different
ages, geographical locations and skin types is impossible.
In fact, achieving satisfactory vitamin D status should
not depend on sunlight exposure alone148. The concept
of ‘safe sunlight exposure’ is often provided in vita-
min D guidelines but is rarely precisely defined. Some
studies have provided information on the relationship
Management
Calciopenic rickets
Nutritional rickets. If dietary calcium deficiency is con-
sidered the primary cause of rickets, calcium supplements
of ≥1,000 mg per day are recommended, as they ensure a
more rapid biochemical and radiographic response than
500 mg per day 153. Calcium supplements in children with
dietary calcium deficiency rickets may need to be contin-
ued for >6 months to ensure radiographic healing of the
growth plate153. Nutritional rickets associated primarily
with vitamin D deficiency is managed by correcting defi-
ciencies in both vitamin D and calcium; thus, recommen-
dations include both vitamin D supplementation (TABLE 2)
and ensuring an adequate diet­ary calcium intake15. The
vitamin D and calcium status of children with nutritional
rickets should be maintained after treatment by ensur-
ing sufficient vitamin D and calcium intake and/or by
increasing sunshine exposure.
Vitamin D supplements may be given as a single bolus
dose or as daily therapy, as outlined in TABLE 2. There is
no evidence of the clinical superiority of supplemen-
tation with vitamin D3 over vitamin D2 when admin-
istered daily 154, but when administered as bolus doses,
vitamin D3 is more effective than D2 in raising 25(OH)
D levels154. Single-day high-dose vitamin D therapy
(stoss therapy) of up to 600,000 IU has been suggested,
but owing to the risk of hypercalcaemia155,156, an inter-
national consensus group recommends more prudent
doses that have been shown to be as effective in healing
rickets without the risk of vitamin D toxicity 15. Although
daily therapy provides a more stable 25(OH)D level
during the supplementation period than stoss therapy,
non-adherence to the treatment regimen may result in a
failure of or delay in radiographic healing of the growth
plate. Therapy should be continued for 8–12 weeks but
may need to be continued longer if radio­graphic healing
is not complete or serum ­biochemistry has not returned
completely to normal157.
25‑Hydroxylase deficiency. The optimal dose of vita-
min D supplementation seems to vary in patients with
25‑hydroxylase deficiency depending on whether one or
both alleles of CYP2R1 are affected by loss‑of‑function
mutations, although these observations are based on
few patients54,55,158,159. Patients who are heterozygous are

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oral administration of physiological replacement doses

of 1,25(OH)2D (10–400 ng kg–1 per day) or alfacalcidol
(80–100 ng kg–1 per day)161. Response to 1,25(OH)2D
or alfacalcidol is rapid, with healing of rickets and nor-
malization of the biochemistry within 7–9 weeks162. The
maintenance dose is lower than that needed to initiate
healing of rickets, but therapy is lifelong and adherence
might be an issue163,164. Monitoring of serum calcium
and PTH levels and urinary calcium levels is required
regularly to ensure that values are maintained within the
normal range. The disease shows an autosomal recessive
inheritance, and thus genetic counselling of the parents
and the offspring needs to be undertaken.

Hereditary 1,25(OH)2D-resistant rickets. Success of

Figure 9 | Radiograph of metaphyseal
Nature Reviewschondrodysplasia.
| Disease Primers
Radiograph of the femur of a child with metaphyseal
chondrodysplasia, a rare genetic condition; these
abnormalities resemble those of rickets.
able to increase circulating 25(OH)D levels in response
to a vitamin D bolus, but the achieved levels are lower
than those achieved in controls. Patients who are homo­
zygous for mutations in CYP2R1 show a very limited or
no increase in 25(OH)D levels in response to the same
vitamin D bolus54. Consequently, clinical, biochemical
and radiographic changes might normalize in patients
who are heterozygous when receiving 5,000–10,000 IU
of vitamin D per day, whereas a homozygous patient
might need a 600,000 IU dose every 3 months. It is of
interest that affected children can respond radiograph-
ically to calcium supplements alone, despite very little
change in the perturbed biochemistry 54. Studies using
25(OH)D in the management of this genetic disorder
have not been reported.
1α‑Hydroxylase deficiency. Symptoms and signs of
1α‑hydroxylase deficiency generally appear in the second
6 months of life160. A high index of suspicion should be
raised if an infant with features of vitamin D deficiency
does not respond rapidly to vitamin D therapy. Before
starting definitive therapy with activated vitamin D
(that is, 1,25(OH)2D or the monohydroxylated analogue
alfacalcidol (1α(OH)D)), diagnosis of 1α‑hydroxylase
deficiency should be confirmed by measuring serum
levels of 25(OH)D and 1,25(OH)2D (TABLE 1). Currently
recommended therapy for 1α‑hydroxylase deficiency is
the management of autosomal recessive hereditary
1,25(OH)2D-resistant rickets varies depending on the
VDR mutation165. Mutations in the DNA binding domain
cause almost total 1,25(OH)2D resistance and alope-
cia, whereas mutations in the ligand-binding domain
cause variable resistance to 1,25(OH)2D. Patients who
have mutations that interfere with heterodimerization
of the VDR also have alopecia. Patients without alo-
pecia are generally more responsive to treatment than
patients with alopecia68. Some patients without alopecia
responded to treatment with 25(OH)D3 in doses rang-
ing from 20 to 200 μg per day and 1,25(OH)2D in doses
of 17–20 μg per day 63; the latter dose is approximately
20‑fold that needed to reverse hypocalcaemia in patients
with 1α‑hydroxylase deficiency. For patients who are
refractory to treatment with activated vitamin D, intra-
venous administration of large amounts of elemental
calcium (400–1400 mg/m2 per day) for periods of up to
3.8 years was associated with resolution of bone pain,
normalization of biochemical findings of rickets166–170,
radiographic and histologic healing of skeletal lesions166
and increased growth velocity 166,167. Oral administration
of calcium also has been effective in such patients171,172.
The alopecia, if present, does not respond to treatment
with calcium or vitamin D metabolites.
Phosphopenic rickets
The primary goal of therapy is to improve rickets.
Initially, improvement of growth plate abnormal-
ities should be aimed for, which will set the stage for
the chronic correction of bow deformities of the bone
and growth enhancement. Conventional treatment of
FGF23‑dependent types of rickets includes a combina-
tion of phosphate and activated vitamin D. As XLH is
the most frequent type of FGF23‑dependent rickets, we
focus on this condition. In phosphopenic rickets inde-
pendent of FGF23, 1,25(OH)2D production is usually
not impaired owing to primary defects specific to renal
phosphate reabsorption, and treatment usually does not
include activated forms of vitamin D.
Children with XLH. Current management of XLH
involves the combination of phosphate supplements
and active vitamin D. Although this approach has been
a mainstay for the treatment of XLH since the early
1980s, it is cumbersome, does not completely correct the

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skeletal abnormalities and is associated with considerable
toxicity 173. Even with optimal dosage of phosphate and
activated vitamin D, many patients require orthopaedic
surgical intervention, and an experienced p ­ aediatric
orthopaedic surgeon is invaluable to the care team.
The primary goal of XLH therapy is to improve skele­
tal abnormalities and growth, not serum phosphate
levels. Moreover, it is not necessary to increase serum
phosphorus levels into the normal range to ensure
healing of rickets; to do so requires administration of
large doses of phosphate, increasing the risk of hyper­
parathyroidism and nephrocalcinosis and m ­ ineralization
of other soft tissues.
Typical dosages of 1,25(OH)2D are 20–30 ng kg–1 per
day given in 2–3 individual doses together with phos-
phate (20–40 mg kg–1 per day)173. The two medications
must be administered at balanced dosages and moni-
tored carefully; relative excess of 1,25(OH)2D may lead
to hypercalcaemia and hypercalciuria, whereas relative
excess of phosphate may result in secondary hyper-
parathyroidism or, if persistent, in parathyroid gland
hyperplasia. Dose adjustments are needed when these
abnormalities are encountered. Consequently, hyper-
calcaemia or hypercalciuria are indications to reduce
the 1,25(OH)2D dose. Increased PTH levels may be
corrected by either increasing the 1,25(OH)2D dose or
reducing the phosphate dose. The optimal dosages of
phosphate and 1,25(OH)2D are determined by monitor­
ing treatment effectiveness. Height, degree of skeletal
deformity and radiographic healing of the growth plate
regions necessitate periodic adjustments in the dose.
Radiographs of the distal femurs and proximal tibias
should be performed at least every 2 years. Renal ultra-
sonography may be intermittently performed to moni-
tor the development or progression of nephrocalcinosis,
which would warrant decreasing treatment dosages.
If persistent hyperparathyroidism is not success­fully
managed with careful adjustments of the dosing regi­
men, the phosphate or both, medications may need
to be discontinued. Further approaches have included
the administration of cinacalcet (a calcimimetic) after
discontinuation of 1,25(OH) 2D and phosphate 174.
Cinacalcet has been variably tolerated in our experience,
and rebound hyperparathyroidism following discontinu-
ation of the drug may occur. We have also used paricalci-
tol (a 1,25(OH)2D analogue) in the setting of intolerance
or unresponsiveness to cinacalcet with monitoring of
Table 2 | Treatment doses of vitamin D for nutritional rickets
Age Daily dose for Single dose (IU) Maintenance
90 days (IU)* daily dose (IU)
<3 months 2,000 NA 400
3–12 months 2,000 50,000 400
1–12 years 3,000–6,000 150,000 600
>12 years 6,000 300,000 600
IU, international units; NA; not available. Ensure a daily calcium intake of at least 500 mg.
*Reassess to verify decreasing serum alkaline phosphatase level and/or radiographic evidence
of healing rickets after 90 days, as further treatment may be required. Republished with
permission of the Endocrine Society, from Munns, C. F. et al. J. Clin. Endocrinol. Metab. 101,
394–415 (2016).
serum and urinary calcium175. Parathyroidectomy may
be required if hyper­parathyroidism with hypercalcaemia
is persistent and unresponsive to medical therapy.
Surgery is indicated for severe bowing or tibial tor-
sion unlikely to improve with medical management
alone176. Corrective osteotomies (a surgical procedure
in which a bone is cut to straighten it) are not usually
performed in children aged <6 years, as medical therapy
often improves bow deformities at this age. Osteotomies
are generally performed when growth has nearly ceased,
but severe deformities may require earlier intervention.
Less-invasive approaches include epiphysiodesis, a pro-
cedure that induces corrective differential growth of the
growth plate177. Many children are prone to recurrent
dental abscesses178. Frequent brushing and regular ­dental
hygienist visits are recommended.
Adults with XLH. Symptomatic adults with XLH may
benefit from therapy; the primary goal of treatment is
reducing pain. Patients are selected for treatment on
the basis of the presence of spontaneous insufficiency
fractures, disabling skeletal pain and/or biochemical
evidence of osteomalacia (such as increased serum
alkaline phosphatase levels). Therapy in adulthood
also uses oral phosphate salts and activated vitamin D
metabolites. The therapy does not seem to influence
(for better or worse) the commonly occurring entheso­
pathy (disorder involving the mineralization of the
attachments of tendons or ligaments to bone) or osteo­
phyte formation (bony spurs or outgrowths localized on
the joint margins)179. Doses of 1,25(OH)2D are usually
started at 0.75–1 μg per day administered once or twice
daily. Phosphate salts are added with gradual increase to
approximately 750–1,000 mg of elemental phosphorus
daily given in 3–4 doses. As with children, doses may
change abruptly during the course of therapy. Patients
must be agreeable to follow‑up evaluations and moni­
tored for toxicity. Orthopaedic surgery is likely to
more effectively heal when the skeleton is optimally
mineral­ized than in the presence of osteomalacia. Thus,
planning for elective orthopaedic procedures should
include the consideration of an ~6‑month window of
medical treatment before surgery. Further details of this
­treatment strategy are described elsewhere173.
Emerging strategies. The identification of excess FGF23
as the cause of renal phosphate wasting in XLH has prov­
ided a sound basis for novel therapeutic strategies aimed
at lowering FGF23 levels180. Monthly injections of an
anti‑FGF23 monoclonal antibody (burosumab) in adults
with XLH effectively restore serum phosphate and
1,25(OH)2D levels181, and biweekly injections in children
have induced similar biochemical findings, improved
radiographic parameters of rickets and a favourable safety
profile182. A randomized placebo-controlled study (pre-
sented as a meeting abstract) in adults with XLH has con-
firmed the effects on serum phosphate and 1,25(OH)2D
levels with improved rates of fracture healing evident in
the burosumab-treated group compared with placebo183.
At the time of this writing, ­burosumab is not yet approved
for widespread clinical use.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 17101 | 15

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PRIMER

Other FGF23‑dependent types of hypophosphataemic
rickets. FGF23‑dependent types of rickets other than
XLH (BOX 1) are generally treated in a manner similar
to that for XLH. An important consideration has arisen
in the context of ADHR184. As iron deficiency stimu-
lates FGF23 production185, individuals with ADHR are
susceptible to worsening disease in the setting of iron
deficiency owing to their inherent limitation to degrade
FGF23. Thus, identifying and correcting iron defi-
ciency in patients with ADHR are important manage­
ment considerations. Tumour-induced osteomalacia
best responds to removal of the tumour if it can be
approached surgically; if surgery cannot be performed,
therapy with phosphate and activated vitamin D is rec-
ommended. Recent studies have also indicated that
burosumab may be an alternative strategy for those
with inoperable or non-localized tumours186, although
it is currently available only as an investigational agent.
In epidermal nevus syndrome, skin resection of affected
lesions has had variable transient results, but burosumab
may also be useful in this condition, as well as activated
vitamin D and phosphate. Curiously, hypophospha­
taemia seems to wane somewhat during early adulthood
in patients with epidermal nevus syndrome.
FGF23‑independent types of hypophosphataemic rickets.
­HHRH is treated with phosphate alone, in view of the
normal‑to‑high serum levels of 1,25(OH)2D in this
condition103. Treatment with phosphate is targeted at
decreasing the 1,25(OH)2D levels to effect a reduction
in intestinal calcium absorption and hypercalciuria
while also improving skeletal mineralization. To further
decrease the risk of nephrocalcinosis and nephrolithiasis,
generous oral hydration to lower urine calcium concen-
tration is recommended and diets with a high sodium
content should be avoided. In phosphopenic rickets sec-
ondary to tubulopathies, Fanconi syndrome, Dent dis-
ease or other systemic diseases, specific treatment of the
underlying disease, in addition to cautious phosphate and
active vitamin D supplementation, is important.
Quality of life
Limb deformities and pain can considerably impair
quality of life (QOL) of children with rickets and adults
with osteomalacia. Ultimately, rickets has the poten-
tial to impede activities of daily living owing to bone
pain, muscle weakness and, in the case of phosphopenic
rickets, pain and reduction of physical function due to
enthesopathy, arthritis and spinal stenosis187. Bone pain
is typically the worst in those with profound lower limb
deformity. Dental abnormalities can also negatively
affect QOL187. The burden to the individual and soci-
ety remains greatest in developing countries, where the
incidence of nutritional rickets remains particularly high
and where fewer social networks exist to support those
who struggle with physical disabilities2.
There are limited studies that have specifically
quanti­fied the impact of rickets on QOL beyond reports
of the typical clinical manifestations of the disease.
Those that have done so arise from studies in adults with
XLH188,189. In one study that used validated QOL scoring
methods, 84% of adults with XLH were found to have
impaired QOL188. Increasing age, the presence of struc-
tural lesions (for example, enthesopathy, osteo­arthritis
or insufficiency fractures) and dental defects were the
strongest predictors of reduced QOL. Interestingly,
QOL was more significantly affected in women than in
men with XLH, which is an X‑linked dominant condi-
tion, a finding that was not specifically explored in this
study. Treatment with phosphate supplementation and
activated vitamin D was significantly associated with
improved mental health but not physical functioning
scores188. Compared with patients with axial spondylo­
arthritis, who also have structural bone lesions, those
with XLH had lower QOL scores, likely because 75%
of the patients with axial spondyloarthritis received
­effective treatment for their disorder 188.
The current standard of care (phosphate and activated
vitamin D therapy) only partially improves XLH190, but
data from clinical trials suggest that burosumab180,181
might improve QOL in XLH. Following a monthly
dose of burosumab for 4 months, the patients reported
improved perception of their chronic functional impair-
ments related to poor physical health, physical function-
ing and stiffness scores189. Controlled trials investigating
the long-term effects of burosumab on QOL are ongoing.
The ultimate proof of treatment efficacy in any setting
is improved QOL; as such, these preliminary data for
patients with XLH are encouraging and serve as a model
for studying QOL outcomes in other types of rickets.
Outlook
Nutritional deficiencies of vitamin D and dietary cal-
cium are the most common causes of rickets worldwide.
These disorders still account for considerable morbid-
ity, particularly in poorly resourced countries, where the
disease often presents late with established deformities
unlikely to be reversed by therapy. Thus, effective ways
to implement preventive strategies are key. With increas-
ing use of prepackaged food, dietary fortification holds
great promise in many countries and should be an inter-
national priority. However, the diversity of staple foods
between different countries makes it difficult to establish
universal recommendations.
At the same time, the chronic nature of heritable types
of rickets requires attention. Lifelong management should
be optimized, as relapse often results in consider­able
morbidity. Discovery of the mutations causing herit­able
types of rickets has led to detailed understanding of the
mechanisms of these disorders and continues to provide
a basis for the development of new therapies. A number
of issues remain poorly understood, including the mech-
anisms by which loss of function of PHEX (in XLH) gives
rise to excess production of FGF23 by osteocytes. It is
not known whether the mineralization defect in XLH is
due primarily to FGF23‑mediated hypophosphataemia
and suppression of 1,25(OH)2D production or whether
accumu­lation of ASARM peptides, pyrophosphate or
other factors have a critical role. In addition, the basis for
the development of many musculoskeletal complications
of XLH, such as enthesopathy, osteophyte formation and
arthritis, remains poorly understood.

16 | ARTICLE NUMBER 17101 | VOLUME 4 www.nature.com/nrdp

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 PRIMER

With the understanding that excess FGF23 is the
humoral basis for renal phosphate wasting in FGF23‑
dependent types of rickets, attention has focused
on newer strategies that directly inhibit the renal
actions of FGF23, such as a recombinant human mono­
clonal antibody that binds to FGF23, thereby block-
ing its biological activity. Other potential approaches
explored in mouse models include inhibition of down-
stream FGFR signalling 191, acceleration of FGF23
degradation192 and use of the carboxy-­terminal FGF23
fragment to inhibit binding of the active full-length
molecule193. As our understanding of the pathogenesis
of rickets and osteomalacia in the hypophospha­taemic
syndromes increases, more appropriate therapies
will likely become available. However, as with the
nutritional deficiencies, it is important that these
therapies be available globally, including in poorly
resourced countries.

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Author contributions
Introduction (T.O.C. and J.M.P.); Epidemiology (L.M.W. and
S.A.A.); Mechanisms/pathophysiology (T.O.C., J.M.P., A.A.P.
and S.A.A.); Diagnosis, screening and prevention (N.J.S.);
Management (T.O.C. and J.M.P.); Quality of life (L.M.W.);
Outlook (A.A.P.); Overview of Primer (T.O.C. and J.M.P.).
Competing interests
T.O.C. is a consultant for and is participating in clinical trials
of burosumab with Ultragenyx Pharmaceutical and has
served as a consultant for Alexion. A.A.P. has received hono-
raria from and is participating in a clinical trial of burosumab
with Ultragenyx Pharmaceutical. L.M.W. has received hono-
raria from and is participating in a clinical trial of burosumab
with Ultragenyx Pharmaceutical and has been a consultant
to Alexion. J.M.P. is a consultant for Biomedical Systems
Corporation. N.J.S. and S.A.A. declare no competing
interests.
How to cite this article
Carpenter, T. O. et al. Rickets. Nat. Rev. Dis. Primers. 3,
17101 (2017).
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

20 | ARTICLE NUMBER 17101 | VOLUME 4 www.nature.com/nrdp

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