Paediatrics and International Child Health

ISSN: 2046-9047 (Print) 2046-9055 (Online) Journal homepage: http://www.tandfonline.com/loi/ypch20

Nutritional rickets around the world: an update

Ana L. Creo, Tom D. Thacher, John M. Pettifor, Mark A. Strand & Philip R.
Fischer

To cite this article: Ana L. Creo, Tom D. Thacher, John M. Pettifor, Mark A. Strand & Philip R.
Fischer (2016): Nutritional rickets around the world: an update, Paediatrics and International
Child Health, DOI: 10.1080/20469047.2016.1248170

To link to this article: http://dx.doi.org/10.1080/20469047.2016.1248170

Published online: 06 Dec 2016.

Submit your article to this journal

Article views: 6

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ypch20

Download by: [New York University] Date: 09 December 2016, At: 05:14
Nutritional rickets around the world: an
update
Ana L. Creo1 , Tom D. Thacher2 , John M. Pettifor3, Mark A. Strand4,
Philip R. Fischer1
Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA, 2Department of Family
1

Medicine, Mayo Clinic, Rochester, MN, USA, 3Wits/SAMRC Developmental Pathways for Health Research Unit,
Department of Paediatrics, University of the Witwatersrand, Johannesburg, South Africa, 4Pharmacy Practice,
Department of Public Health, North Dakota State University, Fargo, ND, USA

Worldwide, nutritional rickets continues to be an evolving problem with several causes. This paper provides an
updated literature review characterising the prevalence, aetiology, pathophysiology and treatment of nutritional
rickets worldwide. A systematic review of articles on nutritional rickets from various geographical regions was
undertaken. For each region, key information was extracted, including prevalence, cause of rickets specific
to the region, methods of confirming the diagnosis and current treatment and preventive measures. Calcium
deficiency continues to be a major cause of rickets in Africa and Asia. Vitamin D deficiency rickets is perhaps
increasing in the Americas, Europe and parts of the Middle East. There continues to be a distinct presentation
of calcium-predominant versus vitamin D predominant rickets, although there are overlapping features. More
careful diagnosis of rickets and reporting of 25-OHD concentrations has improved accurate knowledge of rickets
prevalence and better delineated the cause. Nutritional rickets continues to be an evolving and multi-factorial
problem worldwide. It is on a spectrum, ranging from isolated vitamin D deficiency to isolated calcium deficiency.
Specific areas which require emphasis include a consistent community approach to screening and diagnosis,
vitamin D supplementation of infants and at-risk children, prevention of maternal vitamin D deficiency and the
provision of calcium in areas with low calcium diets.
Keywords: Rickets, Vitamin D, Calcium, Osteomalacia, Infants, Children, Global health

Introduction development of nutritional rickets, especially in low- and

Nutritional rickets is a disabling childhood condition of
impaired bone mineralisation at the growth plate and
bone-forming surfaces owing to inadequate availability
of calcium or phosphorus. While it is found globally,
the aetiology of nutritional rickets varies geographically
(Table 1). Nutritional rickets in temperate countries is
typically caused by vitamin D deficiency, having been
born to a vitamin D-deficient mother, being exclusively
breastfed without vitamin D supplementation, and/or
having poor vitamin D intake, insufficient sun exposure,
living in countries of high latitude, or practising customs
which prevent adequate exposure to the sun.1 Particular
groups of children, such as those with darker skin, mal-
absorptive disorders such as coeliac disease and cystic
fibrosis, or those with decreased synthesis or increased
degradation of vitamin D secondary to liver disease or
certain drugs, are at additional risk. Vitamin D deficiency
as a cause of nutritional rickets in children typically pre-
sents between 3 and 18months of age.2 Worldwide, die-
tary calcium deficiency plays a very important role in the
middle-income countries (LMIC) in Asia and Africa. In
children, this is typically related to a limited or absent
intake of dairy produce. Low-calcium diets also tend to
be higher in grains containing phytates, which may reduce
calcium bio-availability. Nutritional rickets owing to cal-
cium deficiency typically presents later than nutritional
rickets caused by vitamin D deficiency at 116years
of age.2 Ultimately, nutritional rickets is probably caused
by a range of factors which are regionally and culturally
determined.
The pathophysiology and global epidemiology of rick-
ets was reviewed in 2006.3 In view of subsequent scientific
advances, this article now provides an updated review.
Nutritional rickets is the most common cause of paediatric
bone disease globally.1 It is a major public health problem
which is increasingly recognised in LMIC and increas-
ingly prevalent in countries with latitudes>55.47 This
updated literature review characterises the prevalence,
aetiology, pathophysiology and treatment of nutritional
rickets worldwide.

Correspondence to: Ana L. Creo, Department of Pediatric and Adolescent

Medicine, Rochester, MN, USA. Email: Creo.Ana@mayo.edu.

2016 Informa UK Limited, trading as Taylor & Francis Group

DOI 10.1080/20469047.2016.1248170 Paediatrics and International Child Health 2016 1
Creo et al. Nutritional rickets around the world

Table 1. Vitamin D vs calcium-predominant rickets.

Primary deficiency Vitamin D Calcium

Peak age 318months 116years
Risk factors Lack of supplementation for the breastfeeding Poverty, malnutrition
infant Calcium intake<300mg/day
Restricted diets Competing dietary phytate and oxalates
Insufficient sunshine exposure Extended breastfeeding without complementary
Darker skin pigmentation calcium-containing foods (extended breastfeed-
High latitude ing may be modestly protective if no other cal-
Full-body clothing cover cium food sources are available)
Maternal deficiency
Regions of highest prevalence North America, South America, Europe, parts of Africa, South-east Asia, parts of the Middle East
the Middle East
25(OH)D levels Very low [<31nmol/L (<12.5ng/mL)] Normal/low
1,25(OH)2D levels Low/normal/high Normal/high/very high
Prevention strategy (1)Infant vitamin D supplementation birth to (1)Adequate dietary calcium (200mg/day
12months, longer for children at risk 06m; 260mg/day 612m; 500mg/
(2)Vitamin D food fortification programmes day>12m)
(3)Sunshine exposure when appropriate (2)Staple food fortification, or supplementation if
diet insufficient
(3)Introduction of complementary foods

Methods levels at birth.16,17 Although women with darker skin in

PubMed and Medline were searched for studies on nutri-
tional rickets in English and Spanish within the past
10years (January 2006 to December 2015). The search
was performed using the MeSH terms nutritional rickets,
vitamin D deficiency and calcium deficiency and indi-
vidual continents. Additional articles were added from the
authors collections. Key information extracted for each
region included prevalence, cause of rickets specific to the
region, methods of confirming the diagnosis and current
treatment and preventive measures.
Results
Aetiology of nutritional rickets
Vitamin D
Worldwide, nutritional rickets is primarily caused by
vitamin D deficiency.8 A systematic review explored arti-
cles published in the past 10years to assess the global
vitamin D status in the paediatric age range and identify
at-risk groups.9 The review concluded that low vitamin
D status was indeed a global health concern, especially
in infants and children.9 Vitamin D supplementation and
fortified foods have been the main source of vitamin D in
regions with limited sunshine.10 While only a few coun-
tries, largely in North America and Europe, mandate food
fortification, many countries allow optional fortification
of food staples.11 Summary consensus now recommends
daily vitamin D intakes of 400IU in infants and 600IU
in older children.8,12,13
Over the past decade, it has been increasingly rec-
ognised that maternal vitamin D stores and duration of
breastfeeding are important determinants of an infants
vitamin D status. The peak age for nutritional rickets
related to vitamin D deficiency is the first 12 months
when exclusive or partial breastfeeding is prevalent.2
Many women of childbearing age are deficient in vitamin
D.14,15 Neonatal cord blood 25-hydroxyvitamin D [25(OH)
D] levels are directly related to but lower than maternal
extreme northern and southern latitudes are at increased
risk of severe deficiency, Caucasian women also tend to
be deficient.18,19
Currently recommended vitamin D supplementation
may not be adequate for pregnant and lactating women in
many parts of the world.20 Low maternal 25(OH)D serum
concentrations are strongly associated with poor vitamin
D status in breastfed infants. Currently, the consensus is
that women of childbearing age require a daily vitamin
D intake of at least 600IU. Breast-milk usually contains
inadequate amounts of vitamin D, with an estimated vita-
min D content of 2060IU/L.2022 Supplementing lactating
women with 400IU/day of vitamin D increased their serum
concentration of 25(OH)D levels by only 7nmol/L (2.8ng/
mL).23 Lactating women receiving 2000 and 4000IU daily
for 3months post-partum increased maternal and infant
serum 25(OH)D concentrations.24 Increasing a mothers
vitamin D status with high-dose supplementation may
enrich breast-milk with adequate amounts of vitamin D
for the infant to achieve vitamin D sufficiency and may be
preferable to mothers, although the long-term safety has
not been fully established.12,13,25,26 However, administration
of vitamin D to infants is not without a risk of toxicity
owing to dosing errors.27,28
Calcium
Calcium deficiency is also recognised as an important
cause of nutritional rickets across the world, particularly
in LMIC with abundant sunshine.2,29 Even in developed
countries, calcium deficiency is an important cause of
nutritional rickets.30 Dietary calcium intake to prevent
nutritional rickets has been categorised as sufficiency
(>500 mg/day), insufficiency (300500 mg/day) and
deficiency (<300mg/day).12,13 Children adapt to low die-
tary calcium intakes with reduced renal calcium excretion
and increased intestinal absorption.31 These adaptations
can only compensate for a relatively limited reduction

2 Paediatrics and International Child Health 2016


in calcium intake, and low dietary calcium intakes (usu-
ally200mg/day) may still result in nutritional rickets,
especially if there is concurrent vitamin D deficiency.32 A
current hypothesis is that dietary calcium deficiency and
low serum calcium lead to reduced 25(OH)D concentra-
tions through secondary hyperparathyroidism. Increased
secretion of parathyroid hormone (PTH) decreases
25(OH)D through increased conversion to 1,25(OH)2D
by CYP27B1 and through increased degradation by
CYP24A1, induced by 1,25(OH)2D.3335 Increased degra-
dation of 25(OH)D may explain why calcium deficiency
can increase a growing childs vitamin D requirement.36
Another effect of increased PTH is increased phosphorus
excretion by the kidneys, decreasing the phosphorus avail-
able for bone mineralisation. New evidence suggests that
ethnicity affects urinary calcium and phosphorus excre-
tion in the setting of high PTH concentrations, but further
studies are needed.37
In infants, extended breastfeeding may contribute to
poorer calcium status by displacing other dietary sources
of calcium. Introducing calcium-rich complementary foods
from 26weeks of life is now recommended.12,13 Although
calcium in human breast-milk is more bio-available than
that in cows milk, it contains only ~25% of the calcium in
cows milk and the content declines as breastfeeding con-
tinues,38,39 beginning as early as 4months post-partum and
despite maternal high-dose (2000 and 4000IU) vitamin
D supplementation.24 The calcium content of the breast-
milk of African mothers who previously had children with
nutritional rickets has been compared to that of lactating
women at the same stage of lactation who did not have
children with nutritional rickets.38,40 The calcium content
of breast-milk in the mothers of children with previous
nutritional rickets was significantly lower than that in con-
trol mothers. Furthermore, studies indicate that lactating
African women have lower breast-milk calcium than their
Caucasian counterparts, and it was not influenced by cal-
cium supplementation.40
Factors influencing the calcium status of older children
include both low intake and possibly higher dietary phytate
or oxalate intakes, which can bind to calcium and impair
its absorption. The oxalate content is a critical variable
in the bio-availability of calcium in vegetables. It is an
especially important consideration for Asian children who
obtain much of their calcium from vegetables and soy.41
Spinach and broccoli are rich in calcium, but spinach-de-
rived calcium is only 5.1% bio-available compared with
40.9% for broccoli.41 Soy products are variably useful for
their calcium content. Soy itself contains sufficient oxa-
lates and phytates to limit calcium bio-availability; soy
milk supplemented with calcium provides a bio-availabil-
ity similar to that of cows milk calcium.42 Tofu (coagu-
lated soy milk) might be a good source of calcium, but its
calcium content varies with each manufacturer.42
Phytate concentrations are particularly high in grains,
legumes, nuts and seeds; oxalates tend to be higher in
 Paediatrics and International Child Health2016
Creo et al. Nutritional rickets around the world
spinach, sweet potatoes and beans. Foods high in phytates
and oxalates comprise a large portion of a childs diet in
many African regions where nutritional rickets is related to
low calcium intakes.33 Previous studies suggest that higher
phytate intakes inhibit intestinal calcium absorption.4345
Methods such as fermentation have not been very effective
in removing phytates, and newer methods of enzymatic
dephytinisation and phytase treatment have not been suc-
cessful either in increasing calcium absorption.46 Calcium
absorption with a high-phytate meal did not differ between
children with and without calcium deficiency rickets.33,46
Updated physiology other factors
In addition to vitamin D and calcium, newer studies have
examined other factors which might modulate the risk of
developing nutritional rickets. It has been suggested that
there is an association between increased meat intake and
decreased risk of developing nutritional rickets, even after
controlling for confounding variables.47 The mechanism
remains unclear but could be owing to displacement of
other, higher phytate and calcium-binding foods in the
diet. Another theory is that meat itself may alter vitamin D
absorption or modify calcium and phosphorus absorption
and renal excretion.
Environmental factors interplay with the development
of nutritional rickets. Exposure to the suns ultraviolet-B
(UVB) radiation is an important predictor of vitamin D
status for infants worldwide.48 Increasing air pollution in
urban areas can account for reduced UVB exposure.49,50
Use of sunscreen also limits childrens UVB exposure.
Globally, the ozone layer is continually changing and
probably contributes to varying levels of UVB radiation,
although the effects are much less apparent at higher
altitudes where ozone continues to be at a greater con-
centration.49 High altitude independently increases UVB
exposure with an increase of 7% for every km of altitude.51
The time of year also impacts the UVB radiation via the
change in solar zenith angle (season and latitude). At lower
solar zenith angles photons have more absorption and scat-
ter, decreasing UVB radiation. Even cloudy weather can
decrease UVB radiation by 99%.51
Finally, the presence of certain vitamin D-receptor
(VDR) genotypes may affect individual physiology and
genetic susceptibility to vitamin D deficiency rickets. In
24 children with nutritional rickets in Turkey, having the
Apa 1 allele was significantly more common in cases
than in controls.52 There were no significant differences
in the fok 1 and Taq 1 alleles between cases and controls.
Another multi-centre prospective study in Turkey and
Egypt explored VDR genotypes in 98 rachitic children
and 50 control children. The fok 1 allele was significantly
more frequently seen in rachitic Turkish children while
the Bsm 1 allele was associated with lower 25(OH)D lev-
els and increased severity of rickets in both Turkish and
Egyptian groups.53 This is in contrast with previous work
in Nigerian children where the fok 1 allele was associated
3
Creo et al. Nutritional rickets around the world
with rickets.54 In Asian children, 12 single nucleotide
polymorphism (SNPs) of vitamin D metabolism-related
genes in relation to the presence of rickets were analysed
through linear regression. The presence of specific GC and
CYP2R1 alleles was associated with an increased risk of
developing rickets.55
In some familial cases of rickets in Nigerian children,
mutations of the CYP2R1 (25-hydroxylase) gene have
been related to rickets.56 Further studies are needed to
identify the contribution of genetic susceptibility to the
development of rickets.
Diagnosis of nutritional rickets
Clinical features of nutritional rickets
Identifying key clinical features is integral to the diagnosis
and detection of active rickets in children. In Nigerian
children with suspected calcium-deficient nutritional
rickets, wrist and costochondral enlargement had the best
sensitivity and specificity.57 Other studies also support the
presence of a rachitic rosary and widening of the wrists as
correlating to biochemical and radiological evidence.5658
In countries with a high prevalence of nutritional rick-
ets and limited resources, visual inspection for a double
malleoli sign, referring to the presence of two distinct
medial bony prominences at the ankle of a rachitic child,
may offer quick, economical screening.59 However, in
Nigerian children, ankle enlargement was much less sen-
sitive than wrist enlargement for detecting active rickets.
Fractures may occur in mobile children with severe rickets,
but are not generally seen in children with milder disease.60
Updated radiological and biochemical markers
of nutritional rickets
Nutritional rickets should be diagnosed on the basis of
radiological findings of axial widening of the growth plate
with evidence of impaired mineralisation. The radiological
changes are most severe at the growth plates of rapidly
growing long bones which demonstrate the typical fraying
and splaying of the metaphyses and widening of the phy-
ses. A ten-point radiological scoring method of assessing
the severity of nutritional rickets has been evaluated pro-
spectively in children with nutritional rickets at the time
of diagnosis and throughout treatment61,62; it was found to
be useful and accurately predicted the time of radiologi-
cal resolution using a linear regression model.62 Reduced
fore-arm areal bone mineral density has also been demon-
strated, and this is more pronounced in the diaphyseal than
metaphyseal regions of the radius and ulna.63
Vitamin D deficiency rickets is associated with low
levels (<31nmol/L or 12.5ng/mL) of 25(OH)D, impaired
calcium intestinal absorption and secondary hyperparath-
yroidism.64 Biomarkers of vitamin D status include serum
25(OH)D and, to an extent, D binding protein (DBP).
Markers of function include free and bound 1,25(OH)2D
and PTH. Other metabolites of vitamin D such as
24,25(OH)2D correlate well with 25(OH)D concentrations
4 Paediatrics and International Child Health 2016
(vitamin D status) in children with and without nutritional
rickets.64 Serum 25(OH)D continues to be the optimal
marker of vitamin D status because its long half-life.18
The best marker of vitamin D function has not yet been
fully elucidated. An increase in 1,25(OH)2D in response to
vitamin D administration appears to be a functional indica-
tor of vitamin D deficiency.64 It is thought that 1,25(OH)2D
elicits the majority of biological actions of vitamin D and
interacts with tissue via vitamin D receptors (VDRs). For
the multi-factor and calcium-deficient types of nutritional
rickets, PTH is still used as a biomarker of vitamin D
function and perturbations of calcium homeostasis, but
appears to have inconsistent elevations in dietary calci-
um-deficient rickets.65 In a small group of children who
developed rickets after prolonged breastfeeding without
vitamin D supplementation, the use of an alkaline phos-
phatase (ALP) cut-off value of 552 U/L as a screening
test for nutritional rickets resulted in 97.4% specificity
for detecting nutritional rickets.66 However, because of
variations in the assay and temperature requirements, each
laboratory will need to establish its own cut-off value. New
studies have identified urinary levels of candidate metab-
olites as a non-invasive way to diagnose nutritional rick-
ets.67 In 200 children with and without nutritional rickets,
the combination of urinary phosphate and urinary sebacic
acid had 94% sensitivity and 71% specificity, but these
findings need to be confirmed.67
The role of fibroblast growth factor 23 (FGF23) in bone
metabolism has been investigated as a potential biomarker.
Osteocytes secrete FGF23, which is possibly an additional
regulatory hormone of 1,25(OH)2D.6870 FGF23 plays a
role in renal phosphate re-absorption and the modifica-
tion of 1,25-(OH)2D degradation.7174 While some work
has linked FGF23 expression to iron status, ALP and
phosphorus levels, more evidence is needed to clarify the
association.19,7578 This relationship between FGF23 and
iron deficiency may explain the relationship between meat
consumption and nutritional rickets.47
Management of nutritional rickets
Experts now agree on the treatment of nutritional rickets
(Table 2).12,13 The use of oral vitamin D, either D2 or D3,
is preferred to intramuscular injection, and many concen-
trations and dosing schedules have been explored.12,13,79,80
Children with nutritional rickets were treated with either
600 000IU of vitamin D intramuscularly once or 60 000IU
orally once a week for 10weeks and, over 3months, all
tolerated the treatment and showed similar improvements
in serum calcium, ALP and radiological scores.81
Ideally, nutritional rickets should be treated with
calcium and vitamin D. Recent evidence indicates that
calcium, 1000mg/day, may be the optimal dose.12,13,82
Exploring sources of calcium supplementation, a recent
trial randomised Nigerian children with active rickets to
receive calcium as powdered limestone (920mg elemen-
tal calcium) or ground fish (952mg) for 24weeks.83 Of

Table 2. Treatment doses of vitamin D and calcium for nutritional rickets*.
Vitamin D
Age Daily dose for 90days, IU
<3m 2000
312m 2000
>12m to 12 y 30006000
>12 y 6000
*
Revised from Munns et al.12,13
calcium doses for the treatment of calcium-deficiency rickets have not been studied in detail in children<12months of age.
the children who completed the treatment, 66 and 55%
in the fish and limestone groups, respectively, achieved
radiological healing within 6months. In the same popu-
lation, vitamin D supplementation increased 1,25(OH)2D
levels but with no further improvement in intestinal cal-
cium absorption, which was already high.31,33,84 Rickets in
children heals more rapidly when treated with combined
calcium and vitamin D rather than either one alone. In
India, 67 children aged between 6 months and 5 years
were randomised to receive 600 000IU of vitamin D intra-
muscularly, 75mg/kg/day of elemental calcium orally or
both for 12weeks.85 Using a defined endpoint of normal
ALP, complete radiological healing was observed in 11.5,
15.7 and 50% of subjects in the calcium, vitamin D and
combination groups, respectively. The benefit of treatment
with combined calcium and vitamin D has been replicated
in African groups also.86
While global strategies focusing on preventing nutri-
tional rickets are beyond the scope of this paper, recent
consensus guidelines recommend national supplementa-
tion or programmes of fortification with calcium, vitamin
D or both.12,13 At least 400IU vitamin D should be given
to all infants until 12months of age, and 600IU vitamin
D should be given to pregnant women, toddlers and chil-
dren at high risk of vitamin D deficiency and rickets. In
a double-blinded randomised clinical trial supplementing
infants with 400, 800, 1200 or 1600IU/day vitamin D,
all doses resulted in 25(OH)D concentrations>50nmol/L
(20ng/mL) in 97% of infants at 3months of age, with sus-
tained levels in 98% at 12months. The 1600IU/day dose
was discontinued early because of elevated 25(OH)D con-
centrations above 250nmol/L (100ng/mL).87 Other inter-
ventions during pregnancy to improve maternal 25(OH)
D levels to the benefit of the foetal/neonatal population
have been investigated.88 Adherence to and effectiveness
of supplementation might be challenging in older children.
In adolescents, daily supplementation with 400IU did not
significantly increase 25(OH)D levels compared with edu-
cation on environmental factors which influence exposure
to the sun.89 Continuing efforts are needed to integrate and
fund public health programmes on these interventions?90
Geography of nutritional rickets
Asia
In South Korea, 35 cases of rickets diagnosed by radiology
were reported in young children over a 2year period.91
 Paediatrics and International Child Health2016
Creo et al. Nutritional rickets around the world
Vitamin D Vitamin D Calcium
Single dose, IU Daily maintenance dose, IU mg/day
N/A 400 500
50 000 400 500
150 000 600 1000
300 000 600 1000
The majority had a mean age of 7.5 months and were
breastfed; interestingly, only 51% had vitamin D defi-
ciency, defined as 25(OH)D <38 nmol/L (<15 ng/mL).
Another study found vitamin D deficiency to be common:
58.6% of 1212 children aged 415years had a 25(OH)D
level of<50nmol/L (20ng/mL) and 38.5% had levels of
5075nmol/L (2030ng/mL).92 The proportion of children
with levels of<50nmol/L (20ng/mL) increased with age:
77% of those aged 1315years had levels of<50nmol/L
(20ng/mL). Additionally, low levels were more common
in overweight children. Despite the high prevalence of low
25(OH)D levels, only 2.4% had elevated PTH levels and
none had developed rickets. In a study of mothers and their
infants, breastfed infants had a higher PTH at 6months
and lower bone mineral density at 12months than their
formula-fed counterparts even with 200IU vitamin D sup-
plementation.93 Additionally, baseline maternal 25(OH)D
levels were marginal (60.261.5nmol/L or 24.124.8ng/
mL) and baseline neonatal 25(OH)D levels were low
(42.544.5nmol/L or 17.018.1ng/mL) in both groups.
In Japan, nutritional rickets may be increasing and is
related to prolonged breastfeeding, lack of sunlight or
severe dietary restriction.7 On the basis of data from 84
major paediatric departments, the prevalence of nutritional
rickets in children has been estimated to be 9/100 000. All
patients were infants and toddlers, and all were breast-
fed. There was a history of malnutrition or severe dietary
restriction in a third of them. Another case series reported
a similar pattern.94 All children presented before 2years of
age and all were associated either with prolonged breast-
feeding or a poor diet without supplementation or with
lack of sunlight.
In China, particularly in rural areas, rickets remains
a major public health problem. In rural areas, rates of
nutritional rickets ranging from 15.9 to 26.7 have been
reported on the basis of clinical signs only, but these rates
were much lower when radiology confirmed the diag-
nosis.54,58 In one study of 250 toddlers aged between 12
and 24months, the rickets prevalence was estimated to
be 41.6% using clinical signs alone. When clinical signs
were combined with radiographs and ALP levels, the prev-
alence of active nutritional rickets was estimated to be
only 3.7%.58 The authors reported that the five clinical
signs of active nutritional rickets were wrist-widening,
frontal bossing, a rachitic rosary, Harrisons sulcus, and
leg-bowing.
5
Creo et al. Nutritional rickets around the world
Similarly high rates of nutritional rickets have been
reported from rural central Tibet, where 30% of children
aged 05years had at least one sign of nutritional rickets
on clinical examination.95 The older the child, the more
frequently at least one sign of rickets was found, with
45% of children older than 2years displaying at least one
sign suggestive of rickets, most commonly Harrisons
sulcus. Only 13% of the children had three or more signs
of nutritional rickets. Decreased linear growth and head
circumference were also significantly more common in the
group with at least one sign of nutritional rickets.
As in China, studies from Mongolia continue to report
high prevalence rates of nutritional rickets; a national sur-
vey found that 21.8% of children under the age of 5years
had severe vitamin D deficiency [<18 nmol/L (7.2 ng/
mL)] and an additional 20.6% had levels of 1823nmol/L
(7.29.2ng/mL) with only 27% of those under 2years hav-
ing received supplementation.96 Based on clinical signs,
over 50% of children with 25(OH)D levels<23nmol/L
(<9.2ng/mL) had clinical rickets.
Despite the Indian subcontinents temperate and sub-
tropical climates, nutritional rickets caused by vitamin D
deficiency and low dietary calcium remains a public health
problem. Bangladeshi children<10years old were esti-
mated to have an 8% prevalence of nutritional rickets.97 In
these children, insufficient dietary calcium is thought to be
the underlying cause of nutritional rickets and daily treat-
ment with 50500mg of elemental calcium is curative.98
Bangladeshi children also remain vitamin D-deficient: an
estimated 28% of infants aged 16months have a 25(OH)
D level of<25nmol/L (<10ng/mL).99 In this population,
the extent to which vitamin D status contributes to the
development of nutritional rickets remains unknown. Most
cases of nutritional rickets appear correctable with calcium
administration alone or even nutritional advice about cal-
cium intake.100
Children in India have high rates of vitamin D defi-
ciency and nutritional rickets.101,102 Despite the latitude,
various factors including air pollution and hours work-
ing indoors have significantly decreased the vitamin D
stores of many children.103 A study of children in Pune
(latitude 18N) demonstrated the prevalence of vitamin D
deficiency [30nmol/L (<12ng/mL)] to be 77 and 16.4%
of those who were vitamin D-deficient had nutritional
rickets.104 Other case series in India also link nutritional
rickets to exclusively breastfed infants.105 Low-birthweight
(LBW) neonates at term had a similarly low vitamin sta-
tus [38 nmol/L (<15 ng/mL)] compared with infants of
normal birthweight (87.3 vs. 88.6%, respectively), but the
LBW group had a higher prevalence of nutritional rickets
by clinical diagnosis at 14-week follow-up than infants
of normal weight (13.4 vs. 4.9%).106 It is possible that a
higher prevalence of craniotabes in the LBW group might
have accounted for the increased diagnosis of clinical rick-
ets in the LBW group than in the appropriate-for-gesta-
tional-age group.
6 Paediatrics and International Child Health 2016
Reports from northern India suggest that vitamin D
deficiency and rickets are not uncommon in older children
and adolescents, particularly in females. Children aged
1013years who presented to an orthopaedic clinic were
screened for nutritional rickets using clinical, radiological
and biochemical evidence.107 The most common symp-
toms of nutritional rickets were knee pain at night (65%)
followed by lower limb deformity (37%). Approximately
25% of the screened patients had rickets.
In India, there is greater awareness of low calcium
intake as a cause of nutritional rickets.108 A case-control
study of 67 children with nutritional rickets matched
with controls was undertaken: in the children with nutri-
tional rickets, calcium intake was significantly decreased
(204mg/day), a lower proportion of calcium intake was
from dairy sources (42% vs. 89%) and there was an
increased phytate intake.109 Mean 25(OH)D levels were
34.048.5nmol/L (13.719.4ng/mL), with similar levels
in the nutritional rickets and control groups.
Nutritional rickets continues to be a significant health
problem in Asia. It seems to be linked to prolonged breast-
feeding and unusual dietary restrictions. The prevalence
is higher in rural and underprivileged areas, as is the
inadequacy of dietary calcium intake. Documented prev-
alence rates are variable in these regions and may be partly
explained by the use of different clinical, biochemical and
radiological definitions. Additionally, dietary calcium may
play a role in both the development and treatment of nutri-
tional rickets in many parts of Asia.
Middle East
The prevalence of vitamin D deficiency and rickets con-
tinues to be highlighted in a number of publications from
the region. In Turkey, however, there has been notable
success in reducing rickets in infants through programmes
aimed at increasing awareness and routine supplementa-
tion with vitamin D during the first year of life. Prior to the
programmes introduction, 946 children with nutritional
rickets were identified using a combination of biochem-
ical and clinical or radiological evidence over 5years at
one major medical centre.110 The peak age of rickets was
the first 2years of life and it was largely thought to be
related to vitamin D deficiency.104 Commencing in 2005,
the Turkish Ministry of Health provided free vitamin D
for all infants, and, subsequently, the incidence of nutri-
tional rickets decreased from 6% in 1998 to 0.1% in 2008
in children<3years of age.4,111114 Approximately 71% of
rachitic children had microcytic anaemia and 23% were
thought to have severe malnutrition.
Few studies have documented vitamin D status in Israeli
children. However, in a recent study from Jerusalem, 28%
of children aged 1.56years attending health clinics were
vitamin D-deficient [<50 nmol/L (<20 ng/mL)], but no
case of rickets was reported.115 Over three-quarters of the
study sample were from ultra-orthodox families and so
the results might not represent the general population of

children. As in other parts of the world, younger children
(<3 years) were more likely to have higher 25(OH)D
concentrations than older ones (36years). There are no
recent studies of the indigenous population of Bedouins
or dark-skinned immigrant populations (e.g. Ethiopians).
In Qatar and other countries of the Arabian Peninsula
region, vitamin D deficiency and nutritional rickets remain
public health problems owing to a lack of routine vita-
min D supplementation, a lack of exposure to the sun and
a high prevalence of vitamin D deficiency in women of
child-bearing age.116 Several cross-sectional studies report
a higher than expected prevalence of vitamin D deficiency,
particularly in females.117119
Vitamin D deficiency and nutritional rickets have been
reported in young children and adolescents in the United
Arab Emirates.120 Children with rickets were separated
into those with presumed calcium deficiency and those
with vitamin D deficiency [25(OH)D<25nmol/L (<10ng/
mL)]: the calcium-deficient children were more likely to
be older but did not have significantly different PTH or
ALP values than the children with presumed vitamin D
deficiency.
In Saudi Arabia, a survey of adolescents with ALP lev-
els>500IU/L found that 40% had nutritional rickets, 56%
of whom were female.120 At diagnosis, 38% had bone pain,
17% had visible deformity of the extremities, and 14%
had fractures. Interestingly, in identifying a cause, only
4% of patients were deemed to have rare sun exposure
(less than twice per week), while another 26% had a diet
of fast food and soft drinks with little dairy produce. The
causes in other patients were not documented.
A cross-sectional survey in Egypt found a low prev-
alence (11.5%) of 25(OH)D levels [<50nmol/L (20ng/
mL)] in school children aged 911years; little sun expo-
sure, low physical activity, and low milk intake were
considered to be the predisposing factors.121 In pregnant
Egyptian women, 54% were vitamin D-deficient, defined
as<50nmol/L (20ng/mL).122 In a survey of neonates and
mothers thought to be at risk of vitamin D deficiency on
the basis of cultural customs, the average 25(OH)D in
the mothers was 41.5 nmol/L (16.8 ng/mL), and in the
infants it was 7.5nmol/L (3.2ng/mL).123 Another Egyptian
study reported that 40% of mothers had a 25(OH)D level
of<50nmol/L (20ng/mL), although the maternal mean
level remained higher at 81.5nmol/L (32.6ng/mL) because
some had very high levels. The infants mean level was
41.4nmol/L (16.7ng/mL).124
Throughout the Middle East, there has been a special
focus on adolescent females. Of all paediatric groups glob-
ally, girls in the Middle East appear to have the highest
rates of vitamin D deficiency, although not obvious nutri-
tional rickets.9,125 An epidemiological survey in Iran esti-
mated a 10.6% prevalence rate of asymptomatic nutritional
rickets in 414 adolescent girls, defined by biochemical
findings: 38 had elevated ALP (>1000 IU/L) with only
15 being vitamin D-deficient [<23nmol/L (10ng/mL)],
 Paediatrics and International Child Health2016
Creo et al. Nutritional rickets around the world
despite low self-reported intake of vitamin D and limited
sun exposure.126 They received calcium (2000mg/day)
supplementation for 20days, during which time alka-
line phosphatase levels fell to just over 600 IU/L.127,128
In Jordan, women who wore a hijab or niqab were 1.6
and 1.87 times more likely to be vitamin D-deficient than
women who did not.129 The overall prevalence of vitamin
D deficiency [<30nmol/L (12ng/mL)] was 60.3%, which
is likely to contribute to lower neonatal levels in this part
of the world.
Vitamin D deficiency continues to be prevalent through-
out the Middle East, causing a high prevalence of nutri-
tional rickets in many regions.130 In parts of the Middle
East such as Saudi Arabia and United Arab Emirates, there
may be several causes of calcium and vitamin D-deficient
nutritional rickets such as poor sunlight exposure, an
unbalanced diet and poor maternal stores of vitamin D.
Adolescent females and women of child-bearing age at
risk of significant vitamin D deficiency and thus a poorer
supply to the developing infant require special attention.
Africa
Rickets remains a significant health problem in Africa,
particularly West Africa.131 The role of low dietary calcium
intakes in the pathogenesis of nutritional rickets has been
extensively investigated in sunny African countries.38
In Nigeria, calcium deficiency rather than vitamin D
deficiency is the cause of most cases of nutritional rick-
ets.3638 The effect of dietary calcium supplementation in
preventing nutritional rickets in toddlers and young chil-
dren has been studied in a community-based trial in central
Nigeria.132,133 Despite an increase in forearm bone min-
eral density in children in the two communities receiving
calcium through supplements or dried fish, there was no
effect on the incidence of rickets over 18months compared
with the children who did not receive calcium, probably
because the study was underpowered owing to the low
incidence of rickets in all groups.132,133 The incidence of
rickets per year was 6.4/1000 children aged 13years.
Unlike in India109 and South Africa134 where dietary
calcium intakes were significantly lower in patients with
suspected dietary calcium deficiency rickets than in
controls, no difference was found between patients and
controls in Nigeria (both had very low intakes of approx-
imately 200mg/day).38 The possibility that the calcium
content of the diet prior to weaning might play a role is
suggested by a study of breast-milk collected during a
subsequent lactation episode from 35 mothers of children
who had been affected previously by nutritional rickets.
The calcium concentrations in the breast-milk was signifi-
cantly reduced compared with control mothers in the same
community, possibly indicating a maternally-influenced
predisposition in some children to nutritional rickets.38
Compared with the regions with a low prevalence of rick-
ets, concentrations of calcium in soil, corn and drinking
water were 47.6, 26.6, and 79.1% lower, respectively, in
7
Creo et al. Nutritional rickets around the world
areas of high prevalence (up to 40% of children) in cen-
tral Nigeria, indicating a potential effect of environmental
factors.135 An effect of variable gut microbiome on mineral
metabolism has also been suggested.132,135,136 Other factors
such as meat in the diet could alter calcium absorption by
these children.47,132,137
In a large population-based survey in West Kiang, The
Gambia, 1.5% of children aged<5years had clinical fea-
tures of rickets, but only 0.05% of the children screened
had radiological rickets.138 The most common clinical
finding was genu varum which was slightly more com-
mon than genu valgum. The cause of nutritional rickets
in children in The Gambia is thought to be related to a
low calcium diet rather than vitamin D deficiency. All the
children with clinical deformities suggestive of rickets had
25(OH)D levels above 20nmol/L (8ng/mL) and elevated
fibroblast growth factor 23 (FGF23) concentrations, which
were significantly inversely related to phosphorus concen-
trations.139 This latter finding aligns with new evidence
suggesting a role of iron deficiency in FGF23 expres-
sion.76,78 Investigating the role of maternal iron deficiency,
infant FGF23 expression and mineral metabolism, infants
whose mothers were iron deficient had significantly higher
C-terminal FGF23 levels and alkaline phosphatase levels,
but similar intact FGF23 and phosphorus concentrations
between infants with and without iron-deficient mothers.75
In Kenya,140 Congo141 and Malawi,142 children may have
both calcium and vitamin D deficiency. In a Kenyan refu-
gee settlement, 82 children with rickets were characterised
on the basis of clinical diagnosis.140 The majority of chil-
dren were still breastfeeding but were malnourished. Many
of the children (71%) had less than 3h of sun exposure a
week. In 194 rachitic Congolese children, a lack of expo-
sure to sunlight was deemed the most important factor in
the development of nutritional rickets (OR 18.4, 95% CI
6.761.6), followed by having a sibling with nutritional
rickets.141 Maternal breastfeeding was slightly protective
(OR 0.94, 95% CI 0.940.98). In Malawi, screening 77
children with lower leg deformities identified 20 children
with rickets.142 All had a biochemical profile similar to that
in other African countries in which PTH, 1,25(OH)2D and
urinary phosphate excretion are elevated.142
Earlier reviews in Ethiopia concluded that a lack of sun-
shine exposure along with overall malnutrition were the
greatest contributory factors to the development of nutritional
rickets, especially as daily calcium intake (646665mg) was
similar in rachitic and non-rachitic children.143,144 A study of
the predictors of vitamin D deficiency [<50nmol/L (20ng/
mL)] in adolescents aged 1118 years reported that 42%
had levels of<50nmol/L (20ng/mL); urban location, better
maternal education and socio-economic status, and owner-
ship of a computer/TV were predictive of poorer vitamin D
status.145 In a cross-sectional study of 746 younger children
aged 415years, those living in rural areas were more likely
than urban children to have 25(OH)D values<75nmol/L
(30ng/mL) [odds ratio 5.9 (3.79.5)]146
8 Paediatrics and International Child Health 2016
Many cases of nutritional rickets in Africa are linked
to both calcium and vitamin D deficiency. In countries
such as Ethiopia and Kenya, a lack of sun exposure may
be important. Further work is needed to confirm interac-
tions between iron deficiency in mothers and infants and
its role in bone mineral development. Misunderstanding
of the causes of nutritional rickets, with a large majority
of mothers still believing it to be hereditary or related to
cancer or a bone infection, is another challenge in treating
nutritional rickets in Africa.147
Although the prevalence of nutritional rickets in South
Africa has fallen steeply since the 1960s and dietary cal-
cium deficiency rickets seems to have almost disappeared,
nutritional rickets is not uncommon. Over a 7year period,
59 children with radiologically confirmed nutritional rick-
ets were seen at a metabolic bone clinic in Johannesburg
(latitude 26S).148 The mean age of the children was
20months, the vast majority had vitamin D deficiency,
and many of those affected lived in crowded inner-city
apartment blocks. In older black and white children living
in Johannesburg, vitamin D deficiency (<30 nmol/L) is
uncommon.149
Europe
Most cases of rickets in Europe have been linked to vitamin
D deficiency, particularly in immigrants from the Middle
East, Africa and the Indian subcontinent. Throughout the
European Union, it has been recommended that infants
be supplemented with 400IU/day.150 A recent report con-
cludes that most children in Europe can maintain sufficient
25(OH)D levels with 400IU daily.151
In Italy, it was estimated that, of all children aged
between 0 and 21years, slightly less than half had 25(OH)
D concentrations<50nmol/L (20ng/mL), and the levels
were lowest in adolescents.152,153 Non-white and obese
adolescents and those who had less than 3h a week of
outdoor exercise had a much higher risk of vitamin D
deficiency.152,153 Of those who were deficient, 10% had
sufficiently low levels of 25(OH)D to have secondary
hyperparathyroidism. The isolated cases of children with
nutritional rickets in Italy were all estimated to have min-
imal sunlight exposure and all had an African or Asian
background.154
In France, where most cases of nutritional rickets are
related to vitamin D deficiency, it has been recommended
that infants be supplemented with 400IU daily vitamin
D and possibly higher doses for children at risk.155,156 In a
cohort study of 326 children aged 610years, 3.1% had
severe vitamin D deficiency [<25nmol/L (10ng/mL)] with
an additional 34.4% having values of 2550nmol/L (10
20ng/mL); cases of rickets were not reported.157 In women
of child-bearing age, 14% had deficient vitamin D levels
[<30nmol/L (12ng/mL)] which might predispose infants
to vitamin D deficiency rickets.158 Children in northern
France had lower overall levels of 25(OH)D than children
in southern France, with an overall increase in deficiency

in the winter compared with the summer. Although more
than 95% of children received dairy products, only 38%
received vitamin D supplementation. Those who did not
receive a supplement had a significantly increased risk of
vitamin D deficiency by the end of the winter (OR 8.8,
95% CI 4.616.8). Adherence to national supplementation
of French infants was assessed: 9.8% had prescriptions
below the recommended dose and a sizeable 24% had
prescriptions above the recommended dose.156 Only 15%
of older children aged 56years received a prescription
for vitamin supplementation.
In Spain and Belgium there have been only isolated
reports of nutritional rickets in young, exclusively breast-
fed infants or older, recently immigrated children.159,160
A recent review suggests that, after 1year of age, solar
exposure continues to be a sufficient source of vitamin D
in this population.161 In the Netherlands, mothers clothing
was a risk factor for vitamin D deficiency in their infants
and 25(OH)D was<25nmol/L (10ng/mL) in 63% com- from 120 to 49/100 000.176 Programmes to prevent rickets
pared with 16% in control children.162
Nordic countries continue to explore the optimal
dose for vitamin D supplementation.163 In Denmark, the
reported overall incidence of nutritional rickets during
19952005 was 2.9/100 000 children aged 015 years, found to have recommended vitamin D for breastfeeding
which was higher than in the preceding 10years (1.7/100
000).164 Seventy-four per cent of cases were children of
ethnic minorities, and the highest incidence was in those
whose parents originated from the Middle East.5 The aver-
age age of presentation was 1.4years, and 88% did not
receive adequate vitamin D supplementation. Denmark
recommends routine vitamin D supplementation for
infants which should be continued in children of immi-
grant families for another year. In children>4years of
age with nutritional rickets, 78% wore a hijab or niqab.
Most were recent immigrants, and only 31% of them had
received guidelines on vitamin D supplementation.165,166 In
adolescent girls of immigrant Pakistani families, 25(OH)
D concentrations averaged 12.5nmol/L (5ng/mL) and
47% had elevated serum PTH levels; both improved after
vitamin D administration.167,168 In Iceland, average daily
vitamin D intake was estimated to be 320IU, and in 76
infants aged 12months, average 25(OH)D levels were
98nmol/L (39.2ng/mL).169 Breastfeeding and season did
not affect vitamin D status in this cohort.
To the far north-west of Europe, in addition to the many
other medical problems, the prevalence of nutritional rick-
ets in orphanages in Murmansk, Russia has been reported
to be 21% on the basis of clinical examination.170
There has been concern about the increasing inci-
dence of nutritional rickets in the UK.171 Children with
darker skin born to mothers who are veiled and/or are
recent immigrants account for most of the increase,171173
although a few cases have been related to frequent use of
sunscreen. In England, rates of admission to hospital for
nutritional rickets have increased over the past 2 decades.6
Rates were lowest from 1991 to 1996 and highest from
 Paediatrics and International Child Health2016
Creo et al. Nutritional rickets around the world
2007 to 2011. The person-based rate was 3.2/100 000 chil-
dren<15years. A case series found a bimodal distribution,
with cases either being children aged<3years or adoles-
cent girls>10years of age, and all but one case had darker
skin.174 These groups also have the highest level of vitamin
D deficiency. In a Glasgow childrens hospital, the number
of cases of symptomatic vitamin D deficiency doubled
between 2004 and 2008 and 2008 and 2012, and 93% of
cases were of South Asian, Middle Eastern or sub-Saha-
ran African backgrounds.175 Almost half (40%) of these
children initially presented with bowed legs before the
severe vitamin D deficiency was identified. Despite these
findings, in the inner city of Birmingham where a pro-
gramme of free vitamin D supplements for infants, at-risk
children and pregnant women was introduced, the number
of cases of symptomatic vitamin D deficiency [defined as
25(OH)D levels<25ng/mL (10ng/mL)] with radiological
rickets, hypocalcaemia or muscular weakness) have fallen
in the UK target specific groups such as pregnant women
and infants, although some advocate for supplementing
only pregnant women who are at high risk.177 In a study to
assess primary care health visitors knowledge, 81% were
infants<6months of age.178 The participants also recog-
nised that children of Asian background were the most
at risk of developing nutritional rickets, but only 29 and
16% identified that Black Africans and Black Caribbean
children, respectively, were also at risk.
In summary, nutritional rickets has been increasing
in European children. Most cases are children who have
recently emigrated from another region, have darker skin
pigmentation or are born to mothers who wear the cus-
tomary veil. Nutritional rickets in Europe may be mostly
attributed to vitamin D deficiency, although the presence of
concurrent calcium deficiency cannot be excluded in some
cases. Most countries continue to recommend vitamin D
supplementation in pregnancy, for breastfeeding infants
and in childhood.
The Americas
The incidence of nutritional rickets has been increasing in
North America also. In Canada, a survey of paediatricians
nationwide reported an annual incidence of 2.9 cases of
vitamin D deficiency rickets per 100 000 children.179 The
highest rates were in Aboriginal children in the northern
Yukon, Nunavut and Northwest Territories.180 Average age
at diagnosis was 1.4years, and 89% of the children had
skin of a darker pigment. Also being a recent immigrant or
refugee was associated with an increased risk of nutritional
rickets.181,182 All but three cases were breastfed and none
had received vitamin D supplementation. A study which
assessed vitamin D supplementation of infants in Montreal
found that 90% of mothers breastfed their infants in the
first 6months and 53% did so exclusively. Of those who
exclusively breastfed, 74% reported daily supplementation
9
Creo et al. Nutritional rickets around the world
with 400IU of vitamin D.183 In a group of 811-year-old
children at high risk of obesity, 7% had 25(OH)D con-
centrations of 3nmol/L (<15ng/mL)) during winter and
spring.184
In the United States, a similar pattern of increasing
nutritional rickets has been reported. In Minnesota, the
incidences of nutritional rickets in children<3years were
0.0, 2.2, 3.7 and 24.1/100 000 children for the decades
beginning 1970, 1980, 1990 and 2000, respectively.185
Nutritional rickets was associated with dark skin pigmen-
tation, LBW and stunted growth. The increasing incidence
was temporally associated with an immigrant influx of
Somali refugees. In Nevada, nutritional rickets was found
in 58 children over a 10-year period, and the incidence
has increased recently.186 In this cohort, 81% were African
Americans and 14% were Arabic children.186 As in other
North American reports, 98% of infants were breastfed
without vitamin D supplementation.186 Farther north, the
prevalence of nutritional rickets in Alaskan Native chil-
dren was 2.23/100 000.187 Children with nutritional rickets
were much more likely than controls to have malnutrition,
a history of prolonged breastfeeding and a lack of vitamin
D supplementation.187,188 In a recent survey of American
paediatricians in the north-west, only 36% routinely
recommended vitamin D supplementation for breastfed
infants.189 Of the predominately breastfed infants whose
doctor recommended vitamin D, only 44.5% actually
received it.189
Most cases of nutritional rickets in the United States are
likely to be vitamin D-related. Breastfed infants who did
not receive vitamin D supplementation and children with
darker skin pigmentation had the greatest risk of being
vitamin D-deficient.190 Compared with 9.7% of white
infants, 46% of African American neonates had 25(OH)
D levels of 38nmol/L (<15ng/mL). Limited evidence sug-
gests that universal vitamin D supplementation of infants
may not be warranted in south-eastern states.191
Few reports of nutritional rickets in Central and South
America have been published, probably reflecting its rar-
ity, but vitamin D deficiency has been studied. In Mexico,
a survey of children aged 212years reported that 24%
of pre-school children had 25(OH)D levels of<50nmol/L
(20ng/mL).192 A survey of obese children aged 612years
in north-eastern Mexico found that 20% of children had
25(OH)D concentrations <50 nmol/L (20 ng/mL).193
Similarly high levels of 25(OH)D [<50 nmol/L (20 ng/
mL) have been reported in 26% of Hispanic children in
the United States.194 Recently, 23% of infants in Tijuana,
Mexico were found to be vitamin D-deficient at birth, and
10% of pregnant women were deficient [<37.5 nmol/L
(<15 ng/mL)].195 Infants given a single oral dose of 50
000IU had improved 25(OH)D levels at 2 and 6months;
calcium and parathyroid levels were not measured.195
In Argentina, a survey of children aged 672months
found that only 2.8% were vitamin D-deficient.196 Children
in the southernmost region of Argentina had a mean 25(OH)
10 Paediatrics and International Child Health 2016
D level of 74nmol/L (29.5ng/mL) in the autumn.197 In
Brazil, pregnant adolescents had a mean 25(OH)D level
of 59 nmol/L (23.6 ng/mL).198 Approximately 11% of
the 974 Amazonian children were vitamin D-deficient
[<50nmol/L (20ng/mL)].199 The presence of the Bsm1
polymorphism of the VDR gene, lower socio-economic
level and lower serum folate was significantly correlated
with lower 25(OH)D levels.
As in Europe, the number of children with nutritional
rickets in the Americas is increasing. Information on the
current prevalence of rickets in Central America is scarce,
but the rates of vitamin D deficiency are similar to those
in North America. Reports on the vitamin D status of
children in South America may indicate a slightly lower
prevalence of vitamin D deficiency than in Central and
North America.
Oceania
In Sydney, Australia, the most recent survey of nutritional
rickets, published in 2006, reported 126 cases over the
previous decade.200 These cases were mostly children of
families who had recently immigrated to Australia, pre-
dominately from India and Africa. The majority (70%)
were breastfed. Shortly after the study, a consensus was
reached to prevent rickets in children at risk (defined as
those with darker skin pigmentation or born to a mother
who is veiled) by providing 400IU vitamin D per day or an
annual dose of 150 000IU.201203 Similarly in New Zealand,
ten cases of nutritional rickets were reported in Wellington,
prompting a survey of 90 pregnant women in the same
practice.204 A total of 61.2% of the women had 25(OH)D
levels<25nmol/L (10ng/mL) and ten had elevated PTH
levels. In this particular practice, 22% of women were
veiled, and the majority of patients were of African, Maori,
Middle-Eastern, and Polynesian backgrounds.
There have been reports of vitamin D deficiency in
Polynesia. In a sample of 86 infants of military officers,
46% of cord blood samples had 25(OH)D levels<50nmo-
l/L (20ng/mL).205 In a multi-ethnic group of infants, 28%
of 100 cord blood samples had 25(OH)D levels<50nmo-
l/L (20ng/mL).206 Overall, Caucasians had the highest con-
centrations of cord blood 25(OH)D, followed by Asians,
Hispanics, Pacific Islanders and African Americans.
Discussion
Nutritional rickets continues to be an important global
health problem. The prevalence is greatest in children in
the Middle East, Asia and Africa. Immigration from these
regions probably accounts for the increased prevalence
in Europe, North America and Australasia. In the Middle
East, where nutritional rickets is primarily caused by vita-
min D deficiency, standardised supplementation of infants
and pregnant women in some areas has reduced the preva-
lence of nutritional rickets. Despite this, some countries in
the Middle East still have a high rate of nutritional rickets
because many adolescent girls and women of child-bearing

age have very poor vitamin D status and sometimes very
low calcium intakes. In the Americas, nutritional rickets is
most frequently reported in far northern regions.
Infants and toddlers are those most at risk of nutri-
tional rickets. This is related to the prevalence of women
of child-bearing age with poor vitamin D status, which
continues to be significant and influences the propensity
of their offspring to develop nutritional rickets. Not only
do these mothers have poorer status to begin with, but
those who practice extended breastfeeding may put infants
at further risk of nutritional rickets owing to the infants
poor vitamin D and calcium intakes. There is another peak
in nutritional rickets and osteomalacia in adolescent girls
in the Middle East and the Indian subcontinent as well as
among those from these regions who have immigrated to
other parts of the world. While studies from Africa dis-
tinguish between vitamin D-related nutritional rickets,
which occurs earlier in infancy, and calcium-deficiency
nutritional rickets, which manifests in older children, the
pattern may be different in other regions.
The fact that a variety of clinical and diagnostic features
have been used to diagnose the condition poses a challenge
in identifying the true prevalence and possible change in
nutritional rickets. Radiological diagnosis continues to be
the gold standard and grading the clinical severity of rick-
ets in toddlers and older children might be improved with
wider use of a radiographic scoring system that has been
independently validated.61 In settings where biochemical
studies are available, serum ALP continues to be a reason-
ably good predictor of nutritional rickets that correlates
with radiographic severity. More studies are needed to
clarify the role of urinary phosphate and sebacic acid in
making the diagnosis.
The primary causes of nutritional rickets continue to
warrant further investigation, and in the majority of cases
there are probably several contributory factors. In many
parts of the world, it is likely that calcium and vitamin D
deficiency interact to cause nutritional rickets, and it is
important to target both in therapy and prevention. Other
modifying factors such as iron status regulating FGF23
levels may make matters more complex. With increasing
population density, pollution and more indoor electronic
activities for children and, at the same time, the risk of later
skin cancers, adequate sunlight exposure may be either
difficult to obtain or undesirable in many regions.
Ideally, the provision of adequate calcium and vitamin
D or sunshine would prevent many if not most cases of
nutritional rickets. However, in a resource-limited envi-
ronment it continues to be difficult to prioritise vitamin
versus mineral supplementation. A universal approach of
recommending supplementation with only one or the other
will probably not be as effective as advising geographi-
cally tailored advice and resources. Some countries have
seen a dramatic reduction in cases of nutritional rickets by
providing vitamin D to all infants or infants of higher-risk
mothers. It is likely that other countries will have to focus
 Paediatrics and International Child Health2016
Creo et al. Nutritional rickets around the world
on increasing sources of dietary and supplemental calcium
to reduce cases of nutritional rickets.
Nutritional rickets continues to be an evolving and
multi-factorial problem worldwide, which results not
only in short-term morbidity and mortality but also may
have long-term deleterious consequences. Specific areas
to emphasise include employing a consistent community
approach to screening and diagnosis, vitamin D supple-
mentation to infants and children at risk, prevention of
maternal vitamin D deficiency, and providing sources of
calcium in areas with low calcium diets. Further work will
be needed to effectively address the operational challenges
to eradicate nutritional rickets, which is a preventable
global health problem.
ORCID
Ana L. Creo http://orcid.org/0000-0002-4513-1800
Tom D. Thacher http://orcid.org/0000-0002-7644-8173
References
1 zkan B. Nutritional rickets-review. J Clin Res Pediatr Endocrinol.
2010;2:13743.
2 Pettifor JM. Nutritional rickets. Deficiency of vitamin D, calcium,
or both? Am J Clin Nutr. 2004;80:17259S.
3 Thacher TD, Fischer PR, Strand MA, Pettifor JM. Nutritional rickets
around the world: causes and future directions. Ann Trop Paediatr.
2006;26:116.
4 Tezer H, Siklar Z, Dallar Y, Dogankoc S. Early and severe presentation
of vitamin D deficiency and nutritional rickets among hospitalized
infants and the effective factors. Turk J Pediatr. 2009;51:1101.
5 Beck-Nielsen SS, Jensen TK, Gram J, Brixen K, Brock-Jacobsen B.
Nutritional rickets in Denmark: a retrospective review of children's
medical records from 1985 to 2005. Eur J Pediatr. 2009;168:9419.
6 Goldacre M, Hall N, Yeates DG. Hospitalisation for children with
rickets in England: a historical perspective. Lancet. 2014;383:5978.
7 Matsuo K, Mukai T, Suzuki S, Fujieda K. Prevalence and risk factors
of vitamin D deficiency rickets in Hokkaido, Japan. Pediatr Int.
2009;51:55962.
8 Unuvar T, Buyukgebiz A. Nutritional rickets and vitamin D
deficiency in infants, children and adolescents. Pediatr Endocrinol
Rev. 2010;7:28391.
9 Palacios C, Gonzalez L. Is vitamin D deficiency a major global public
health problem? J Steroid Biochem Mol Biol. 2014;144:13845.
10 Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem
with health consequences. Am J Clin Nutr. 2008;87:10806S.
11 Calvo MS, Whiting SJ, Barton CN. Vitamin D intake: a global
perspective of current status. J Nutr. 2005;135:3106.
12 Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono
K, et al. Global consensus recommendations on prevention and
management of nutritional rickets. Horm Res Paediatr. 2016;85:83
106.
13 Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono
K, et al. Global consensus recommendations on prevention and
management of nutritional rickets. J Clin Endocrinol Metab.
2016;101:394415.
14 Bodnar LM, Catov JM, Roberts JM, Simhan HN. Prepregnancy
obesity predicts poor vitamin D status in mothers and their neonates.
J Nutr. 2007;137:243742.
15 Bodnar LM, Simhan HN, Powers RW, Frank MP, Cooperstein E,
Roberts JM. High prevalence of vitamin D insufficiency in black
and white pregnant women residing in the northern United States
and their neonates. J Nutr. 2007;137:44752.
16 Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin
D supplementation during pregnancy: double-blind, randomized
clinical trial of safety and effectiveness. J Bone Miner Res.
2011;26:234157.
17 Molla AM, Al Badawi M, Hammoud MS, Shukkur M, Thalib L,
Eliwa MS. Vitamin D status of mothers and their neonates in Kuwait.
Pediatr Int. 2005;47:64952.
11
Creo et al. Nutritional rickets around the world
18 Prentice A, Goldberg GR, Schoenmakers I. Vitamin D across the
lifecycle: physiology and biomarkers. Am J Clin Nutr. 2008;88:500
6S.
19 Prentice A. Vitamin D deficiency: a global perspective. Nutr Rev.
2008;66:S15364.
20 Thandrayen K, Pettifor JM. Maternal vitamin D status: implications
for the development of infantile nutritional rickets. Endocrinol
Metab Clin North Am. 2010;39:30320.
21 Specker BL, Tsang RC, Hollis BW. Effect of race and diet on
human-milk vitamin D and 25-hydroxyvitamin D. Am J Dis Child.
1985;139:11347.
22 Hollis BW, Roos BA, Draper HH, Lambert PW. Vitamin D and its
metabolites in human and bovine milk. J Nutr. 1981;111:12401248.
23 Taylor SN, Wagner CL, Hollis BW. Vitamin D supplementation
during lactation to support infant and mother. J Am Coll Nutr.
2008;27:690701.
24 Basile LA, Taylor SN, Wagner CL, Horst RL, Hollis BW. The effect
of high-dose vitamin D supplementation on serum vitamin D levels
and milk calcium concentration in lactating women and their infants.
Breastfeed Med. 2006;1:2735.
25 Oberhelman SS, Meekins ME, Fischer PR, Lee BR, Singh RJ,
Cha SS, et al. Maternal vitamin D supplementation to improve the
vitamin D status of breast-fed infants: a randomized controlled trial.
Mayo Clin Proc. 2013;88:137887.
26 Hollis BW, Wagner CL, Howard CR, Ebeling M, Shary JR, Smith
PG, et al. Maternal versus infant vitamin D supplementation during
lactation: a randomized controlled trial. Pediatrics. 2015;136:625
34.
27 Ketha H, Wadams H, Lteif A, Singh RJ. Iatrogenic vitamin D
toxicity in an infant a case report and review of literature. J
Steroid Biochem Mol Biol. 2015;148:148.
28 Barrueto F Jr, Wang-Flores HH, Howland MA, Hoffman RS,
Nelson LS. Acute vitamin D intoxication in a child. Pediatrics.
2005;116:e4536.
29 Fischer PR, Thacher TD, Pettifor JM. Pediatric vitamin D and
calcium nutrition in developing countries. Rev Endocr Metab Disord.
2008;9:18192.
30 DeLucia MC, Mitnick ME, Carpenter TO. Nutritional rickets with
normal circulating 25-hydroxyvitamin D: a call for reexamining
the role of dietary calcium intake in north american infants. J Clin
Endocrinol Metab. 2003;88:353945.
31 Graff M, Thacher TD, Fischer PR, Stadler D, Pam SD, Pettifor JM,
et al. Calcium absorption in Nigerian children with rickets. Am J
Clin Nutr. 2004;80:141521.
32 Pettifor JM. Calcium and vitamin D metabolism in children in
developing countries. Ann Nutr Metab. 2014;64(s2):1522.
33 Thacher TD, Abrams SA. Relationship of calcium absorption with
25(OH)D and calcium intake in children with rickets. Nutr Rev.
2010;68:6828.
34 Pascussi JM, Robert A, Nguyen M, Walrant-Debray O, Garabedian
M, Martin P, et al. Possible involvement of pregnane X receptor-
enhanced CYP24 expression in drug-induced osteomalacia. J Clin
Invest. 2005;115:17786.
35 Clements MR, Johnson L, Fraser DR. A new mechanism for induced
vitamin D deficiency in calcium deprivation. Nature. 1987;325:625.
36 Thacher TD, Fischer PR, Isichei CO, Pettifor JM. Early response to
vitamin D2 in children with calcium deficiency rickets. J Pediatr.
2006;149:8404.
37 Redmond J, Jarjou LM, Zhou B, Prentice A, Schoenmakers I. Ethnic
differences in calcium, phosphate and bone metabolism. Proc Nutr
Soc. 2014;73:34051.
38 Thacher TD, Pettifor JM, Fischer PR, Okolo SN, Prentice A. Case-
control study of breast milk calcium in mothers of children with and
without nutritional rickets. Acta Paediatr. 2006;95:82632.
39 Thacher TD. Wet-nursing and rickets. J R Soc Med. 2006;99:5456.
40 Prentice A. Milk intake, calcium and vitamin D in pregnancy and
lactation: effects on maternal, fetal and infant bone in low- and
high-income countries. Nestle Nutr Workshop Ser Pediatr Program.
2011;67:115.
41 Burckhardt P. Calcium revisited, part III: effect of dietary calcium on
BMD and fracture risk. Bonekey Rep. 2015;4:708. Available from:
http://dx.doi.org/10.1038/bonekey.2015.77.
42 Zhao Y, Martin BR, Weaver CM. Calcium bioavailability of calcium
carbonate fortified soymilk is equivalent to cow's milk in young
women. J Nutr. 2005;135:237982.
43 Wills MR, Phillips JB, Day RC, Bateman EC. Phytic acid and
nutritional rickets in immigrants. Lancet. 1972;299:7713.
44 Sanders TA, Reddy S. Nutritional implications of a meatless diet.
Proc Nutr Soc. 1994;53:297307.
12 Paediatrics and International Child Health 2016
45 Sanders TA, Reddy S. Vegetarian diets and children. Am J Clin Nutr.
1994;59:117681S.
46 Thacher TD, Aliu O, Griffin IJ, Pam SD, O'Brien KO, Imade GE,
et al. Meals and dephytinization affect calcium and zinc absorption
in Nigerian children with rickets. J Nutr. 2009;139:92632.
47 Dunnigan MG, Henderson JB, Hole DJ, Mawer E, Berry JL. Meat
consumption reduces the risk of nutritional rickets and osteomalacia.
Br J Nutr. 2005;94:983991.
48 Dawodu A, Davidson B, Woo JG, Peng YM, Ruiz-Palacios GM,
Guerrero M, et al. Sun exposure and vitamin D supplementation in
relation to vitamin D status of breastfeeding mothers and infants in
the global exploration of human milk study. Nutrients. 2015;7:1081
93.
49  Saraff V, Shaw N. Sunshine and vitamin D. Arch Dis Child.
2016;101:19092.
50 Agarwal KS, Mughal MZ, Upadhyay P, Berry JL, Mawer EB, Puliyel
JM. The impact of atmospheric pollution on vitamin D status of
infants and toddlers in Delhi, India. Arch Dis Child. 2002;87:1113.
51 Engelsen O. The relationship between ultraviolet radiation exposure
and vitamin D status. Nutrients. 2010;2:48295.
52 Bora G, Ozkan B, Dayangac-Erden D, Erdem-Yurter H, Coskun T.
Vitamin D receptor gene polymorphisms in Turkish children with
vitamin D deficient rickets. Turk J Pediatr. 2008;50:303.
53 Baroncelli GI, Bereket A, El Kholy M, Aud L, Cesur Y, Ozkan B,
et al. Rickets in the Middle East: role of environment and genetic
predisposition. J Clin Endocrinol Metab. 2008;93:174350.
54 Fischer PR, Thacher TD, Pettifor JM, Jorde LB, Eccleshall TR,
Feldman D. Vitamin D receptor polymorphisms and nutritional
rickets in Nigerian children. J Bone Miner Res. 2000;15:220610.
55 Zhang Y, Yang S, Liu Y, Ren L. Relationship between polymorphisms
in vitamin D metabolismrelated genes and the risk of rickets in Han
Chinese children. BMC Med Genet. 2013;14:260. Available from:
https://dx.doi.org/10.1186/1471-2350-14-101.
56 Thacher TD, Fischer PR, Singh RJ, Roizen J, Levine MA. CYP2R1
mutations impair generation of 25-hydroxyvitamin D and cause an
atypical form of vitamin D deficiency. J Clin Endocrinol Metab.
2015;100:E100513.
57 Thacher TD, Fischer PR, Pettifor JM. The usefulness of clinical
features to identify active rickets. Ann Trop Paediatr. 2002;22:229
37.
58 Strand MA, Perry J, Jin M, Tracer DP, Fischer PR, Zhang P, et al.
Diagnosis of rickets and reassessment of prevalence among rural
children in northern China. Pediatr Int. 2007;49:20209.
59 Kumar A, Agrawal A, Shaharyar A, Bhat MS. Revisiting the
double malleoli sign in nutritional rickets. J Clin Orthop Trauma.
2015;6:2056.
60 Chapman T, Sugar N, Done S, Marasigan J, Wambold N, Feldman
K. Fractures in infants and toddlers with rickets. Pediatr Radiol.
2010;40:11849.
61 Thacher TD, Fischer PR, Pettifor JM, Lawson JO, Manaster BJ,
Reading JC. Radiographic scoring method for the assessment of
the severity of nutritional rickets. J Trop Pediatr. 2000;46:1329.
62 Chatterjee D, Gupta V, Sharma V, Sinha B, Samanta S. A reliable and
cost effective approach for radiographic monitoring in nutritional
rickets. Br J Radiol. 2014;87:20130648. Available from: https://
dx.doi.org/10.1259/bjr.20130648.
63 Thacher TD, Fischer PR, Pettifor JM. The effect of nutritional rickets
on bone mineral density. J Clin Endocrinol Metab. 2014;99:417480.
64 Thacher TD, Fischer PR, Obadofin MO, Levine MA, Singh RJ,
Pettifor JM. Comparison of metabolism of vitamins D2 and D3 in
children with nutritional rickets. J Bone Miner Res. 2010;25:1988
95.
65 Prentice A. Nutritional rickets around the world. J Steroid Biochem
Mol Biol. 2013;136:2016.
66 Taylor JA, Richter M, Done S, Feldman KW. The utility of alkaline
phosphatase measurement as a screening test for rickets in breast-fed
infants and toddlers: a study from the puget sound pediatric research
network. Clin Pediatr (Phila). 2010;49:110310.
67 Wang M, Yang X, Ren L, Li S, He X, Wu X, et al. Biomarkers
identified by urinary metabonomics for noninvasive diagnosis of
nutritional rickets. J Proteome Res. 2014;13:413142.
68 Mirams M, Robinson BG, Mason RS, Nelson AE. Bone as a source
of FGF23: regulation by phosphate? Bone. 2004;35:11929.
69 Takei Y, Minamizaki T, Yoshiko Y. Functional diversity of fibroblast
growth factors in bone formation. Int J Endocrinol. 2015;2015:729352.
Available from: https://dx.doi.org/10.1155/2015/729352.
70 Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, et al. Fibroblast
growth factor 23 is a counter-regulatory phosphaturic hormone for
vitamin D. J Am Soc Nephrol. 2006;17:130515.

71 Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi
Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and
phosphate homeostasis. J Bone Miner Res. 2004;19:42935.
72 Bland R, Zehnder D, Hewison M. Expression of 25-hydroxyvitamin
D3-1-hydroxylase along the nephron: new insights into renal
vitamin D metabolism. Curr Opin Nephrol Hypertens. 2000;9:1722.
73 Hewison M, Zehnder D, Bland R, Stewart PM. 1alpha-hydroxylase
and the action of vitamin D. J Mol Endocrinol. 2000;25:1418.
74 Kiela PR, Ghishan FK. Recent advances in the renal-skeletal-gut
axis that controls phosphate homeostasis. Lab Invest. 2009;89:714.
75 Braithwaite VS, Prentice A, Darboe MK, Prentice AM, Moore SE.
The effects of maternal iron deficiency on infant fibroblast growth
factor-23 and mineral metabolism. Bone. 2016;83:18.
76 Braithwaite V, Jarjou LM, Goldberg GR, Prentice A. Iron status
and fibroblast growth factor-23 in Gambian children. Bone.
2012;50:13516.
77 Braithwaite V, Prentice AM, Doherty C, Prentice A. FGF23 is
correlated with iron status but not with inflammation and decreases
after iron supplementation: a supplementation study. Int J Pediatr
Endocrinol. 2012;2012:27. Available from: https://dx.doi.
org/10.1186/1687-9856-2012-27.
78 Braithwaite V, Jones KS, Assar S, Schoenmakers I, Prentice A.
Predictors of intact and C-terminal fibroblast growth factor 23 in
gambian children. Endocr Connect. 2014;3:110.
79 Cipriani C, Romagnoli E, Pepe J, Russo S, Carlucci L, Piemonte S,
et al. Long-term bioavailability after a single oral or intramuscular
administration of 600,000 IU of ergocalciferol or cholecalciferol:
implications for treatment and prophylaxis. J Clin Endocrinol
Metab. 2013;98:270915.
80 Zabihiyeganeh M, Jahed A, Nojomi M. Treatment of hypovitaminosis
D with pharmacologic doses of cholecalciferol, oral vs intramuscular;
an open labeled RCT. Clin Endocrinol (Oxf). 2013;78:2106.
81 Mondal K, Seth A, Marwaha RK, Dhanwal D, Aneja S, Singh R,
et al. A randomized controlled trial on safety and efficacy of single
intramuscular versus staggered oral dose of 600 000IU vitamin D
in treatment of nutritional rickets. J Trop Pediatr. 2014;60:20310.
82 Thacher TD, Smith L, Fischer PR, Isichei CO, Cha SS, Pettifor
JM. Optimal dose of calcium for treatment of nutritional rickets:
a randomized controlled trial. J Bone Miner Res. 2016. doi:
http://dx.doi.org/10.1002/jbmr.2886.
83 Thacher TD, Bommersbach TJ, Pettifor JM, Isichei CO, Fischer PR.
Comparison of limestone and ground fish for treatment of nutritional
rickets in children in Nigeria. J Pediatr. 2015;167:14854e1.
84 Thacher TD, Obadofin MO, O'Brien KO, Abrams SA. The effect
of vitamin D2 and vitamin D3 on intestinal calcium absorption
in Nigerian children with rickets. J Clin Endocrinol Metab.
2009;94:331421.
85 Aggarwal V, Seth A, Marwaha RK, Sharma B, Sonkar P, Singh
S, et al. Management of nutritional rickets in indian children: a
randomized controlled trial. J Trop Pediatr. 2013;59:12733.
86 Thacher TD, Fischer PR, Pettifor JM. Vitamin D treatment in
calcium-deficiency rickets: a randomised controlled trial. Arch Dis
Child. 2014;99:80711.
87 Gallo S, Comeau K, Vanstone C, Agellon S, Sharma A, Jones G,
et al. Effect of different dosages of oral vitamin D supplementation on
vitamin D status in healthy, breastfed Infants. JAMA. 2013;309:178592.
88 Kalra P, Das V, Agarwal A, Kumar M, Ramesh V, Bhatia E, et al.
Effect of vitamin D supplementation during pregnancy on neonatal
mineral homeostasis and anthropometry of the newborn and infant.
Br J Nutr. 2012;108:10528.
89 Stagi S, Pelosi P, Strano M, Poggi G, Manoni C, de Martino M, et al.
Determinants of vitamin D levels in Italian children and adolescents:
a longitudinal evaluation of cholecalciferol supplementation versus
the improvement of factors influencing 25(OH)D Status. Int J
Endocrinol. 2014;2014:583039. Available from: https://dx.doi.
org/10.1155/2014/583039.
90 Hgler W, Munns CF. Rickets and osteomalacia: a call for action
to protect immigrants and ethnic risk groups. Lancet Glob Health.
2016;4:e22930.
91 Huh K, Woo MK, Yoon JR, Shim GH, Chey MJ, Park MJ. Clinical
characteristics of vitamin D deficiency rickets in infants and
preschool children. Korean J Pediatr. 2010;53:1527.
92 Chung IH, Kim HJ, Chung S, Yoo EG. Vitamin D deficiency in
Korean children: prevalence, risk factors, and the relationship
with parathyroid hormone levels. Ann Pediatr Endocrinol Metab.
2014;19:8690.
93 Kim MJ, Na B, No SJ, Han HS, Jeong EH, Lee W, et al. Nutritional
status of vitamin D and the effect of vitamin D supplementation in
Korean breast-fed infants. J Korean Med Sci. 2010;25:839.
 Paediatrics and International Child Health2016
Creo et al. Nutritional rickets around the world
94 Miyako K, Kinjo S, Kohno H. Vitamin D deficiency rickets caused by
improper lifestyle in Japanese children. Pediatr Int. 2005;47:1426.
95 Rooze S, Dramaix-Wilmet M, Mathieu F, Bally P, Yangzom D, Li JZ,
et al. Growth, nutritional status, and signs of rickets in 05-year-old
children in a KashinBeck disease endemic area of Central Tibet.
Eur J Pediatr. 2012;171:118591.
96 Uush T. Prevalence of classic signs and symptoms of rickets and
vitamin D deficiency in Mongolian children and women. J Steroid
Biochem Mol Bio. 2013;136:20710.
97 Craviari T, Pettifor JM, Thacher TD, Meisner C, Arnaud J, Fischer
PR, et al. Rickets: an overview and future directions, with special
reference to Bangladesh. A summary of the Rickets Convergence
Group meeting, Dhaka, 2627 January 2006. J Health Popul Nutr.
2008;26:11221.
98 Combs GF Jr, Hassan N, Dellagana N, Staab D, Fischer P, Hunt
C, et al. Apparent efficacy of food-based calcium supplementation
in preventing rickets in Bangladesh. Biol Trace Elem Res.
2008;121:193204.
99 Roth DE, Shah MR, Black RE, Baqui AH. Vitamin D status of
infants in northeastern rural Bangladesh: preliminary observations
and a review of potential determinants. J Health Popul Nutr.
2010;28:45869.
100 Arnaud J, Pettifor JM, Cimma JP, Fischer PR, Craviari T, Meisner
C, et al. Clinical and radiographic improvement of rickets in
Bangladeshi children as a result of nutritional advice. Ann Trop
Paediatr. 2007;27:18591.
101 G R, Gupta A. Vitamin D deficiency in India: prevalence, causalities
and interventions. Nutrients. 2014;6:72975. (Brian: believe it or
not, these authors are correctly cited!).
102 Joshi K, Bhatia V. Vitamin D deficiency in a tropical country
treatment and prevention in children. Indian J Pediatr. 2014;81:84
9.
103 Babu US, Calvo MS. Modern India and the vitamin D dilemma:
evidence for the need of a national food fortification program. Mol
Nutr Food Res. 2010;54:113447.
104 Ekbote VH, Khadilkar AV, Mughal MZ, Hanumante N, Sanwalka N,
Khadilkar VV, et al. Sunlight exposure and development of rickets
in Indian toddlers. Indian J Pediatr. 2010;77:615.
105 Girish M, Subramaniam G. Rickets in exclusively breast fed babies.
Indian J Pediatr. 2008;75:6413.
106 Agarwal R, Virmani D, Jaipal ML, Gupta S, Gupta N, Sankar
MJ, et al. Vitamin D status of low birth weight infants in Delhi: a
comparative study. J Trop Pediatr. 2012;58:44650.
107 Agarwal A, Gulati D. Early adolescent nutritional rickets. J Orthop
Surg (Hong Kong). 2009;17:3405.
108 Balasubramanian K, Rajeswari J, Gulab Govil YC, Agarwal AK,
Kumar A, et al. Varying role of vitamin D deficiency in the etiology
of rickets in young children vs. adolescents in northern India. J Trop
Pediatr. 2003;49:2016.
109 Aggarwal V, Seth A, Aneja S, Sharma B, Sonkar P, Singh S, et al.
Role of calcium deficiency in development of nutritional rickets
in Indian children: a case control study. J Clin Endocrinol Metab.
2012;97:34616.
110 Cesur Y, Dogan M, Ariyuca S, Basaranoglu M, Bektas MS, Peker
E, et al. Evaluation of children with nutritional rickets. J Pediatr
Endocrinol Metab. 2011;24:3543.
111 Hatun S, Bereket A, Ozkan B, Coskun T, Kose R, Calykoglu AS.
Free vitamin D supplementation for every infant in Turkey. Arch
Dis Child. 2007;92:3734.
112 Hatun S, Ozkan B, Bereket A. Vitamin D deficiency and prevention:
Turkish experience. Acta Paediatrica. 2011;100:11959.
113 Mutlu GY, Kusdal Y, Ozsu E, Cizmecioglu FM, Hatun S. Prevention
of vitamin D deficiency in infancy: daily 400 IU vitamin D is
sufficient. Int J Pediatr Endocrinol. 2011;2011:4. Available from:
https://dx.doi.org/10.1186/1687-9856-2011-4.
114 Ozkan B, Doneray H, Karacan M, Vanelik S, Yldrm ZK, Ozkan
A, et al. Prevalence of vitamin D deficiency rickets in the eastern
part of Turkey. Euro J Pediatr. 2009;168:95100.
115 Korchia G, Amitai Y, Moshe G, Korchia L, Tenenbaum A, Rosenblum
J, et al. Vitamin D deficiency in children in Jerusalem: the need for
updating the recommendation for supplementation. Isr Med Assoc
J. 2013;15:3338.
116 Soliman AT, El-Dabbagh M, Adel A, Ali M, Aziz Bedair EM,
ElAlaily RK. Clinical responses to a mega-dose of vitamin D3
in infants and toddlers with vitamin D deficiency rickets. J Trop
Pediatr. 2010;56:1926.
117 Bener A, Al-Ali M, Hoffmann GF. Vitamin D deficiency in healthy
children in a sunny country: associated factors. Int J Food Sci Nutr.
2009;60(sup5):6070.
13
Creo et al. Nutritional rickets around the world
118 Bener A, Al-Ali M, Hoffmann GF. High prevalence of vitamin D
deficiency in young children in a highly sunny humid country: a
global health problem. Minerva Pediatr. 2009;61:1522.
119 Bener A, Hoffmann GF. Nutritional rickets among children in a sun
rich country. Int J Pediatr Endocrinol. 2010;2010:410502. Available
from: https://dx.doi.org/10.1155/2010/410502.
120 Hazzazi MA, Alzeer I, Tamimi W, Al Atawi M, Al Alwan I. Clinical
presentation and etiology of osteomalacia/rickets in adolescents.
Saudi J Kidney Dis Transpl. 2013;24:93841.
121 
Abu Shady MM, Youssef MM, Salah El-Din EM, Abdel
Samie OM, Megahed HS, Salem SM, et al. Predictors of serum
25-hydroxyvitamin D concentrations among a sample of Egyptian
schoolchildren. Sci World J. 2016;2016:8175768. Available from:
https://dx.doi.org/10.1155/2016/8175768.
122 Botros RM, Sabry IM, Abdelbaky RS, Eid YM, Nasr MS, Hendawy
LM. Vitamin D deficiency among healthy Egyptian females.
Endocrinol Nutr. 2015;62:31421.
123 El Koumi MA, Ali YF, Abd El Rahman RN. Impact of maternal
vitamin D status during pregnancy on neonatal vitamin D status.
Turk J Pediatr. 2013;55:3717.
124 El Rifai NM, Abdel Moety GA, Gaafar HM, Hamed DA. Vitamin
D deficiency in Egyptian mothers and their neonates and possible
related factors. J Matern Fetal Neonatal Med. 2014;27:10648.
125 Habibesadat S, Ali K, Shabnam JM, Arash A. Prevalence of vitamin
D deficiency and its related factors in children and adolescents living
in north Khorasan. Iran. J Pediatr Endocrinol Metab. 2014;27:431
6.
126 Dahifar H, Faraji A, Yassobi S, Ghorbani A. Asymptomatic rickets
in adolescent girls. Indian J Pediatr. 2007;74:5715.
127 Dahifar H, Faraji A, Ghorbani A, Mousavi F, Yassobi S. Hypocalcemia
in healthy young girls in Tehran. Arch Iran Med. 2006;9:3647.
128 Dahifar H, Faraji A, Ghorbani A, Yassobi S. Impact of dietary and
lifestyle on vitamin D in healthy student girls aged 1115years. J
Med Invest. 2006;53:2048.
129 Nichols EK, Khatib IM, Aburto NJ, Sullivan KM, Scanlon KS,
Wirth JP, et al. Vitamin D status and determinants of deficiency
among non-pregnant Jordanian women of reproductive age. Eur J
Clin Nutr. 2012;66:7516.
130 Bassil D, Rahme M, Hoteit M, Fuleihan Gel H. Hypovitaminosis
D in the Middle East and North Africa. Dermato-Endocrinology.
2013;5:274298.
131 Sharp CA, Magnusson P, Davie MW, Oginni LM. We are what we
eat is it time to reconsider calcium-deficiency rickets in Nigeria?
(FA) Trop Med Int Health. 2015;20:40810.
132 Thacher TD, Fischer PR, Isichei CO, Zoakah AI, Pettifor JM.
Prevention of nutritional rickets in Nigerian children with dietary
calcium supplementation. Bone. 2012;50:107480.
133 Umaretiya PJ, Thacher TD, Fischer PR, Cha SS, Pettifor JM. Bone
mineral density in Nigerian children after discontinuation of calcium
supplementation. Bone. 2013;55:648.
134 Mann E, Schmitz-Esser S, Zebeli Q, Wagner M, Ritzmann M,
Metzler-Zebeli BU. Mucosa-associated bacterial microbiome of the
gastrointestinal tract of weaned pigs and dynamics linked to dietary
calcium-phosphorus. PLoS ONE. 2014;9:e86950. Available from:
https://dx.doi.org/10.1371/journal.pone.0086950.
135 Hartmann L, Sponholz B. Spatial distribution of calcium in food,
water and soil and its possible influence on rickets disease in
Northern Nigeria. Environ Geochem Health. 2012;34:50312.
136 Cnit MC, Matzaraki V, Tigchelaar EF, Zhernakova A. Rapidly
expanding knowledge on the role of the gut microbiome in health
and disease. Biochim Biophys Acta. 2014;1842:198192.
137 Henderson JB, Dunnigan MG, McIntosh WB, Abdul Motaal A,
Hole D. Asian osteomalacia is determined by dietary factors when
exposure to ultraviolet radiation is restricted: a risk factor model. Q
J Med. 1990;76:92333.
138 Jones HL, Jammeh L, Owens S, Fulford AJ, Moore SE, Pettifor JM,
et al. Prevalence of rickets-like bone deformities in rural Gambian
children. Bone. 2015;77:15.
139 Prentice A, Ceesay M, Nigdikar S, Allen SJ, Pettifor JM. FGF23 is
elevated in gambian children with rickets. Bone. 2008;42:78897.
140 Edwards JK, Thiong A, Van den Bergh R, Kizito W, Kosgei RJ,
Sobry A, et al. Preventable but neglected: rickets in an informal
settlement, Nairobi, Kenya. Public Health Action. 2014;4:1227.
141 Echarri JJ, Bazeboso JA, Guillen-Grima F. Rachitic deformities
of lower members in congolese children. An Sist Sanit Navar.
2008;31:23540.
142 Braithwaite VS, Freeman R, Greenwood CL, Summers DM,
Nigdikar S, Lavy CB, et al. The aetiology of rickets-like lower limb
deformities in Malawian children. Osteoporos Int. 2016:236772. doi:
http://dx.doi.org/10.1007/s00198-016-3541-7.
14 Paediatrics and International Child Health 2016
143 Wondale Y, Shiferaw F, Lulseged S. A systematic review of
nutritional rickets in Ethiopia: status and prospects. Ethiop Med J.
2005;43:20310.
144 Belachew T, Nida H, Getaneh T, Woldemariam D, Getinet W.
Calcium deficiency and causation of rickets in Ethiopian children.
East Afr Med J. 2005;82:1539.
145 Wakayo T, Belachew T, Vatanparast H, Whiting SJ. Vitamin D
deficiency and its predictors in a country with thirteen months of
sunshine: the case of school children in central Ethiopia. PLOS ONE.
2015;10:e0120963. Available from: https://dx.doi.org/10.1371/
journal.pone.0120963.
146 Herrador Z, Sordo L, Gadisa E, Buno A, Gomez-Rioja R, Iturzaeta
JM, et al. Micronutrient deficiencies and related factors in school-
aged children in Ethiopia: a cross-sectional study in libo kemkem and
fogera districts, amhara regional state. PLoS ONE. 2014;9:e112858.
Available from: https://dx.doi.org/10.1371/journal.pone.0112858.
147 Adegbehingbe OO, Adegbenro CA, Awowole IO, Tomori PO,
Oyelami OA. Perception and knowledge of mothers on causes and
treatment of rickets associated knee deformity in Ile-Ife, Osun State.
Nigeria. Tanzan J Health Res. 2009;11:405.
148 Agaba FPJ, Thandrayen K. Comparative study of children
with calciopenic and phosphopenic rickets seen at Chris Hani
Baragwanath Hospital. SA Orthopaed J. 2016. [in press].
149 Poopedi MA, Norris SA, Pettifor JM. Factors influencing the vitamin
D status of 10-year-old urban South African children. Public Health
Nutr. 2011;14:3349.
150 Spiro A, Buttriss JL. Vitamin D: an overview of vitamin D status
and intake in Europe. Nutr Bull. 2014;39:32250.
151 Braegger C, Campoy C, Colomb V, Decsi T, Domellof M, Fewtrell
M, et al. Vitamin D in the healthy European paediatric population.
J Pediatr Gastroenterol Nutr. 2013;56:692701.
152 Vierucci F, Del Pistoia M, Fanos M, Erba P, Saggese G. Prevalence
of hypovitaminosis D and predictors of vitamin D status in Italian
healthy adolescents. Ital J Pediatr. 2014;40:54. Available from:
https://dx.doi.org/10.1186/1824-7288-40-54.
153 Vierucci F, Del Pistoia M, Fanos M, Gori M, Carlone G, Erba P,
et al. Vitamin D status and predictors of hypovitaminosis D in Italian
children and adolescents: a cross-sectional study. Eur J Pediatr.
2013;172:160717.
154 D'Eufemia P, Parisi P, Celli M, Finocchiaro R, Roggini M, Raccio I,
et al. Vitamin D deficiency rickets in five at-risk children. Pediatr
Int. 2012;54:1525.
155 Vidailhet M, Garabdian M. Les besoins en vitamine D des enfants
franais. Archives de Pdiatrie. 2010;17:8089.
156 Mallet E, Gaudelus J, Reinert P, Stagnara J, Bnichou J, Castanet
M, et al. Prophylactic prescription of vitamin D in France: national
multicenter epidemiological study of 3240 children under 6years
of age. Arch Pediatr. 2012;19:1293302.
157 Mallet E, Gaudelus J, Reinert P, Stagnara J, Bnichou J, Basuyau
JP, et al. Vitamin D status in 6- to 10-year-old children: a French
multicenter study in 326 children. Arch Pediatr. 2014;21:110614.
158 Schott AM, Belaid S, Legoaziou MF. A possible re-emergence of
osteomalacia in women and severe hypovitaminosis D in newborn
infants in France. Arch Dis Child. 2008;93:354.
159 Ojeda L, Ros MA, Tomas C, Alcon JJ, Ardit J. Nutritional rickets
in a 5month-old child. A rare disease in Spain. An Pediatr (Barc).
2010;72:2257.
160 Brouwers HF, Verburg AD, Looij BJ, Jansen EJ. Rickets in the
Benelux. A case report of two Indian immigrants. Acta Orthop Belg.
2010;76:8503.
161 Villamil Cajoto I, Villacian Vicedo MJ, Araujo Vilar D. Vitamin
D treatment in childhood: an evidence based discussion. An Med
Interna. 2006;23:4468.
162 Dijkstra SH, van Beek A, Janssen JW, de Vleeschouwer LH,
Huysman WA, van den Akker EL. High prevalence of vitamin D
deficiency in newborn infants of high-risk mothers. Arch Dis Child.
2007;92:7503.
163 Akeson PK, Casswall T, Kull I. Risk of vitamin D deficiency
among certain groups in Sweden. New recommendations can be
considered optimal vitamin D status still unknown. Lakartidningen.
2012;109:12859.
164 Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK.
Incidence and prevalence of nutritional and hereditary rickets in
southern Denmark. Eur J Endocrinol. 2009;160:4917.
165 Beck-Nielsen SS. Rickets in Denmark. Dan Med J. 2012;59:B4384.
166 Brok J, Huusom L, Cortes D. Severe vitamin D deficiency in
children born in Denmark of dark-skinned women. Ugeskr Laeger.
2011;173:18623.
167 Andersen R, Mlgaard C, Skovgaard LT, Brot C, Cashman KD,
Jakobsen J, et al. Pakistani immigrant children and adults in

Denmark have severely low vitamin D status. Eur J Clin Nutr.
2008;62:62534.
168 Andersen R, Molgaard C, Skovgaard LT, Brot C, Cashman KD,
Jakobsen J, et al. Effect of vitamin D supplementation on bone
and vitamin D status among Pakistani immigrants in Denmark: a
randomised double-blinded placebo-controlled intervention study.
Br J Nutr. 2008;100:197207.
169 Thorisdottir B, Gunnarsdottir I, Steingrimsdottir L, Palsson GI,
Thorsdottir I. Vitamin D Intake and Status in 12-Month-Old Infants
at 6366 N. Nutrients. 2014;6:118293.
170 Miller LC, Chan W, Litvinova A, Rubin A, Tirella L, Cermak S.
Medical diagnoses and growth of children residing in Russian
orphanages. Acta Paediatr. 2007;96:17659.
171 Lowdon J. Rickets: concerns over the worldwide increase. J Fam
Health Care. 2011;21:259.
172 Odeka E, Tan J. Nutritional rickets is increasingly diagnosed in
children of ethnic origin. Arch Dis Child. 2005;90:12034.
173 Senniappan S, Elazabi A, Doughty I, Mughal MZ. Case 2:
fractures in under-6-month-old exclusively breast-fed infants born
to immigrant parents: nonaccidental injury? (case presentation).
Diagnosis: pathological fractures secondary to vitamin D deficiency
rickets in under-6-months-old, exclusively breast-fed infants, born
to immigrant parents. Acta Paediatr. 2008;97(7):9923.
174 Naseem H, Wall AP, Sangster M, Paton RW. The presentation of
rickets to orthopaedic clinics: return of the English disease. Acta
Orthop Belg. 2011;77:23945.
175 Ahmed SF, Franey C, McDevitt H, Somerville L, Butler S, Galloway
P, et al. Recent trends and clinical features of childhood vitamin D
deficiency presenting to a children's hospital in Glasgow. Arch Dis
Child. 2011;96:6946.
176 Moy RJ, McGee E, Debelle GD, Mather I, Shaw NJ. Successful
public health action to reduce the incidence of symptomatic vitamin
D deficiency. Arch Dis Child. 2012;97:9524.
177 Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH.
Association of maternal vitamin D status during pregnancy with
bone-mineral content in offspring: a prospective cohort study.
Lancet. 2013;381:217683.
178 Cleghorn S. Do health visitors advise mothers about vitamin
supplementation for their infants in line with government
recommendations to help prevent rickets? J Hum Nutr Diet.
2006;19:2038.
179 Ward LM, Gaboury I, Ladhani M, Zlotkin S. Vitamin D-deficiency
rickets among children in Canada. CMAJ. 2007;177:1616.
180 Eggertson L. Rickets re-emerges in northern Aboriginal children.
CMAJ. 2015;187:E21314.
181 Guigne F, Duke P, Rourke L. Is vitamin D deficiency an underreported
issue in refugee health?: two cases of infants presenting with vitamin
D-deficiency rickets. Can Fam Physician. 2013;59:6413.
182 Guigne F, Duke P, Rourke L. Looking beyond literacy: understanding
and approaching barriers to refugee health in 2 cases of vitamin
D-deficiency rickets. Can Fam Physician. 2013;59:6078.
183 Gallo S, Jean-Philippe S, Rodd C, Weiler HA. Vitamin D
supplementation of Canadian infants: practices of montreal mothers.
Appl Physiol Nutr Metab. 2010;35:3039.
184 Mark S, Lambert M, Delvin EE, O'Loughlin J, Tremblay A, Gray-
Donald K. Higher vitamin D intake is needed to achieve serum
25(OH)D levels greater than 50nmol/l in Quebec youth at high risk
of obesity. Eur J Clin Nutr. 2011;65:48692.
185 Thacher TD, Fischer PR, Tebben PJ, Singh RJ, Cha SS, Maxson
JA, et al. Increasing incidence of nutritional rickets: A population-
based study in Olmsted county, Minnesota. Mayo Clin Proc.
2013;88:17683.
186 Lazol JP, Cakan N, Kamat D. 10-year case review of nutritional
rickets in children's hospital of Michigan. Clin Pediatr (Phila).
2008;47:37984.
187 Singleton R, Lescher R, Gessner BD, Benson M, Bulkow L,
Rosenfeld J, et al. Rickets and vitamin D deficiency in Alaska native
children. J Pediatr Endocrinol Metab. 2015;28:81523.
 Paediatrics and International Child Health2016
Creo et al. Nutritional rickets around the world
188 Alouf B, Grigalonis M. Incidental finding of vitamin-D deficient
rickets in an otherwise healthy infant a reappraisal of current
vitamin-D supplementation guidelines. J Natl Med Assoc.
2005;97:11703.
189 Taylor JA, Geyer LJ, Feldman KW. Use of supplemental vitamin
D among infants breastfed for prolonged periods. Pediatrics.
2010;125:10511.
190 R ovner AJ, O'Brien KO. Hypovitaminosis D among healthy
children in the United States. Arch Pediatr Adolesc Med.
2008;162:5139.
191 Ponnapakkam T, Bradford E, Gensure R. A treatment trial of vitamin
D supplementation in breast-fed infants: universal supplementation
is not necessary for rickets prevention in Southern Louisiana. Clin
Pediatr (Phila). 2010;49:105360.
192 Flores M, Macias N, Lozada A, Snchez LM, Daz E, Barquera S.
Serum 25-hydroxyvitamin D levels among Mexican children ages
2 y to 12 y: a national survey. Nutrition. 2013;29:8024.
193 Elizondo-Montemayor L, Ugalde-Casas PA, Serrano-Gonzlez M,
Cuello-Garca CA, Borbolla-Escoboza JR. Serum 25-hydroxyvitamin
D concentration, life factors and obesity in Mexican children.
Obesity (Silver Spring). 2010;18:180511.
194 Mansbach JM, Ginde AA, Camargo CA Jr. Serum 25-hydroxyvitamin
D levels among US children aged 1 to 11 years: do children need
more vitamin D? Pediatrics. 2009;124:140410.
195 Moodley A, Spector SA. Single high-dose vitamin D at birth corrects
vitamin D deficiency in infants in Mexico. Int J Food Sci Nutr.
2015;66:33641.
196 Duran P, Mangialavori G, Biglieri A, Kogan L, Abeya Gilardon E.
Nutrition status in Argentinian children 6 to 72months old: results
from the National Nutrition and Health Survey (ENNyS)]. Arch
Argent Pediatr. 2009;107:397404.
197 Tau C, Ciriani V, Scaiola E, Acua M. Twice single doses of
100 000IU of vitamin D in winter is adequate and safe for
prevention of vitamin D deficiency in healthy children from
Ushuaia, Tierra Del Fuego. Argentina. J Steroid Biochem Mol
Biol. 2007;103:6514.
198 D iogenes ME, Bezerra FF, Rezende EP, Taveira MF,
Pinhal I, Donangelo CM. Effect of calcium plus vitamin D
supplementation during pregnancy in Brazilian adolescent
mothers: a randomized, placebo-controlled trial. Am J Clin
Nutr. 2013;98:8291.
199 Cobayashi F, Loureno BH, Cardoso MA. 25-hydroxyvitamin D3
levels, BsmI polymorphism and insulin resistance in Brazilian
Amazonian children. Int J Mol Sci. 2015;16:1253146.
200 Robinson PD, Hogler W, Craig ME, Verge CF, Walker JL, Piper AC,
et al. The re-emerging burden of rickets: a decade of experience from
Sydney. Arch Dis Child. 2006;91:5648.
201 Munns C, Zacharin MR, Rodda CP, Batch JA, Morley R, Cranswick
NE, et al. Prevention and treatment of infant and childhood vitamin
D deficiency in Australia and New Zealand: a consensus statement.
Med J Aust. 2006;185:26872.
202 Munns CF, Simm PJ, Rodda CP, Garnett SP, Zacharin MR, Ward LM,
et al. Incidence of vitamin D deficiency rickets among Australian
children: an Australian Paediatric Surveillance Unit study. Med J
Aust. 2012;196:4668.
203 Paxton GA, Teale GR, Nowson CA, Mason RS, McGrath JJ,
Thompson MJ, et al. Vitamin D and health in pregnancy, infants,
children and adolescents in Australia and New Zealand: a position
statement. Med J Aust. 2013;198:1423.
204 Judkins A, Eagleton C. Vitamin D deficiency in pregnant New
Zealand women. N Z Med J. 2006;119:U2144.
205 Palmer EG, Ramirez-Enriquez E, Frioux SM, Tyree MM. Vitamin
D deficiency at birth among military dependants in Hawai'i. Hawaii
Med J. 2013;72:8891.
206 Halm BM, Lai JF, Pagano I, Cooney W, Soon RA, Franke AA.
Vitamin D deficiency in cord plasma from multiethnic subjects living
in the tropics. J Am Coll Nutr. 2013;32:21523.
15