Pediatr Radiol (2013) 43:140–151
DOI 10.1007/s00247-012-2532-x
MINISYMPOSIUM
Rickets: Part I
Richard M. Shore & Russell W. Chesney
Received: 13 June 2012 / Revised: 3 August 2012 / Accepted: 15 August 2012 / Published online: 1 December 2012
# Springer-Verlag Berlin Heidelberg 2012
Abstract Rickets is characterized by impaired mineralization and ossification of the growth plates of growing children caused by a variety of disorders, the most frequent of
which is nutritional deficiency of vitamin D. Despite ample
knowledge of its etiology and the availability of costeffective methods of preventing it, vitamin D deficiency
rickets remains a significant problem in developing and
developed countries. This two-part review covers the history, etiology, pathophysiology and clinical and radiographical findings of vitamin D deficiency rickets. Other less
frequent causes of rickets and some of the disorders entering
into the differential diagnoses of rickets are also considered.
Controversial issues surrounding vitamin D deficiency include determination of what constitutes vitamin D sufficiency and the potential relationship between low levels of
vitamin D metabolites in many individuals and unexplained
fractures in infants.
Keywords Rickets . Vitamin D . Children . Bone .
Metabolic bone disease . Non-accidental trauma
R. M. Shore (*)
Department of Medical Imaging, Box 9, Ann & Robert H. Lurie
Children’s Hospital of Chicago,
225 E. Chicago Ave.,
Chicago, IL 60611, USA
e-mail: [email protected]
R. M. Shore
Department of Radiology,
Northwestern University Feinberg School of Medicine,
Chicago, IL, USA
R. W. Chesney
Department of Pediatrics, Le Bonheur Children’s Hospital,
University of Tennessee Health Science Center,
Memphis, TN, USA
Introduction
Rickets is a disorder of growth plate mineralization and
ossification, and hence is unique to children and adolescents
prior to skeletal maturity. Although many disorders can
cause rickets, the majority of cases, both historically and
presently, are caused by vitamin D deficiency, which is the
major topic of this two-part review. Other causes of rickets
and differential diagnoses are also considered, as are some
of the controversies surrounding vitamin D deficiency.
Table 1 provides the organization of this review. Part I
covers the history of rickets, as well as the basic principles
of bone and mineral physiology and growth plate anatomy
needed to understand its pathophysiology. Vitamin D deficiency is discussed, including controversies concerning the
amount of vitamin D needed by humans. Part II covers
more specific features of vitamin D deficiency rickets,
including its pathophysiology, clinical features, pathoanatomy and radiographical findings. Other forms of rickets
and differential diagnoses are also discussed. The potential relationship between low levels of vitamin D metabolites in many individuals and unexplained fractures in
infants is then considered.
History
Several reviews have covered the history of rickets [1–13].
Rickets is usually considered to have emerged primarily
during the industrial revolution in northern Europe, with a
demographic shift to urban environments and exposure to
ultraviolet light limited by indoor lifestyle, narrow streets
and dense smog from coal burning. Although rickets peaked
during the latter part of the 19th century, it has been well
documented in England since the 17th century [10]. The
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Table 1 Table of contents
Part I
Part II
History of rickets
Rickets and osteomalacia: definitions and basic
pathophysiology
Review of bone formation and mineralization
Mineral homeostasis
Bone mineral metabolism
Vitamin D metabolism and function
Vitamin D deficiency
Definitions
Controversial issues regarding vitamin D
requirements
Etiology/epidemiology
Prevention
Vitamin D deficiency rickets
Pathophysiology
Pathoanatomy and radiographic features
Other forms of rickets
Nutritional rickets variants
Non-nutritional calcipenic rickets
Phosphopenic rickets
Rickets in special circumstances
Renal osteodystrophy
Rickets with osteopetrosis
Differential diagnoses
Hypophosphatasia
Metaphyseal chondrodysplasias
Vitamin D deficiency/non-accidental trauma controversy
initial medical description of rickets is attributed to Daniel
Whistler, who as a medical student published “Inaugural
medical disputation on the disease of English children
which is popularly termed rickets” in 1645, likely a synthesis of the observations of others. However, as the title
indicates, it was a disease already recognized by the general
public, although not described in the medical literature. In
fact, documentation of rickets can be traced back at least
11 years earlier to 1634, when it was listed as the cause of
14 of the 10,900 deaths summarized in the Annual Bill of
Mortality for the City of London [10]. Subsequently Francis
Glisson, leading a team of investigators, published “De
Rachitide” in 1650, providing a more definitive delineation
of rickets, expanding on its clinical description and adding
its pathological basis with autopsy correlation. Interestingly,
the children investigated by Glisson were not from smogfilled cities but rather from more rural regions, children who
had to spend most of their time working indoors when wool
spinning became a home-based industry [9]. The origin of
the word “rickets” has remained elusive; it is possibly from
the Old English “wrickken” meaning “to twist” and possibly
a reference to spinal deformity with “rachitis” indicating
spinal inflammation. Both Whistler and Glisson addressed
this issue but were unable to account for it, even considering
that rickets had been named after an apothecary who had
treated the disease.
With progression of the industrial revolution, the incidence of rickets increased. By the turn of the 20th century it
was widespread in the industrialized cities of Europe and the
northern United States, with clinically obvious rickets in
60–80% of children and higher incidences in autopsy series,
including Georg Schmorl’s 1909 study showing evidence of
rickets in 96% of children younger than 18 months. During
this time, many observations and studies eventually came
together to define vitamin D deficiency, which seemed to
have dietary and environmental causation. Although not
always mentioned, several earlier observations in the
mid-1800s by Armand Trousseau (best known for his sign
of hypocalcemia) included that rickets was caused by combined nutritional deficiency and a sunless environment,
that it became manifest during periods of rapid growth
and could be successfully treated with cod liver oil, and
that there were similarities between rickets in children and
osteomalacia in the mature skeleton [7]. In addition to
widespread recognition that cod liver oil was effective in
preventing rickets, other fats were also found to have an
anti-rachitic effect. In 1919, Edward Mellanby demonstrated that cod liver oil, milk and butter were effective in
preventing rickets and concluded that the anti-rachitic factor was either vitamin A or had a similar distribution.
Elmer McCollum then showed in 1922 that oxidation of
cod liver oil destroyed its effectiveness in preventing xerophthalmia but not rickets, distinguishing the anti-rachitic
factor from vitamin A and identifying it as a new vitamin,
designated as vitamin D.
The role of sun exposure in the prevention and cure of
rickets was first suggested by Jedrzej Sniadecki in 1822.
In 1890, Theobald Palm also proposed the importance of
sunlight based on the geographical distribution of rickets,
being rare in tropical countries despite poverty and unclean living conditions. However, it was not until nearly
30 years later that the anti-rachitic effect of ultraviolet
light was shown, with such evaluation stimulated by rampant rickets in central Europe, which had been starved of
dietary sources of vitamin D in the wake of World War I.
Using a mercury vapour lamp in 1919, Kurt Huldschinsky
showed that even the non-exposed arm was cured, indicating a systemic effect. Subsequently Alfred Hess and
Lester Unger demonstrated sunlight to be effective. Further controlled studies of sunlight and cod liver oil by
Harriette Chick verified the effectiveness of each in the
prevention of rickets, paving the way for the eventual
demonstration that dietary vitamin D and the cutaneously
photosynthesized substance were the same.
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In 1924, Harry Steenbock and Archie Black, followed by
Hess and Mildred Weinstock, showed that UV irradiation of
various foods produced an anti-rachitic substance. This led to
the ability to produce plentiful vitamin D, initially from yeast,
enabling prevention of rickets. In the United States this was
accomplished mostly by vitamin D supplementation of milk,
with long-acting intramuscular injections used in Europe.
These methods were remarkably effective in eliminating the
first wave of rickets that engulfed the northern hemisphere in
the 19th and early 20th centuries. However, smaller epidemics
of rickets have subsequently re-emerged, as discussed under
the section on etiology and epidemiology.
This brief historical review is limited to rickets, the
discovery of vitamin D and initial success in its treatment
and prevention. The history of vitamin D biochemistry is
provided elsewhere [6].
Rickets and osteomalacia—definitions and basic
pathophysiology
Although rickets and osteomalacia are both disorders of
deficient mineralization of organic matrix, there are fundamental differences. Rickets is a disease of the physes
(growth plates) characterized not only by deficient mineralization of cartilage and osteoid but also by retarded endochondral ossification, which causes excessive accumulation
of physeal cartilage, growth failure and skeletal deformities
[11, 14]. Failure of normal apoptosis of hypertrophic chondrocytes is now recognized as the key abnormality causing
this ossification defect. The abnormalities of mineralization
and ossification are caused by insufficient circulating levels
of calcium and phosphate ions. Although mineralization
depends on the calcium × phosphate (Ca × P) product, the
defect in endochondral ossification more specifically results
from hypophosphatemia, which impairs chondrocyte apoptosis by inhibition of the caspase-9-mediated mitochondrial pathway [15, 16].
As rickets is a disorder of open growth plates, it is seen
only in children. In osteomalacia, an insufficient Ca × P
product causes failure of normal mineralization of osteoid,
laid down either at sites of bone turnover or by the periosteum in the process of membranous bone formation. These
processes occur in both adults and children. Hence osteomalacia can be present at any age. It is an oversimplification
to define rickets as a mineralization disorder of children and
osteomalacia as the equivalent condition in adults. Rickets
involves the physes, and osteomalacia involves other sites of
bone formation, but the more important concept for understanding rickets is recognition that the abnormalities of
mineral ion homeostasis lead to skeletal deformity by disrupting endochondral ossification rather than just causing
deficient mineralization of cartilage and osteoid. Rickets and
Pediatr Radiol (2013) 43:140–151
osteomalacia are bone disorders that can be present simultaneously in children with disorders of mineral metabolism.
Distinguishing between these is not just a matter of definition. Parfitt [17] indicated that these processes might differ
in their pathophysiology, temporal course and response to
therapy, referring to the different processes of crystal deposition at the physes versus appositional bone formation.
When chondrocyte apoptosis and its effect on endochondral
bone formation are considered, the differences between
rickets and osteomalacia are even more pronounced.
Rickets and osteomalacia result from insufficient mineral
ion concentrations, which are caused by many disorders.
These are usually divided into “calcipenic” and “phosphopenic” categories, with these designations referring to whether
the initial defect results in insufficient calcium absorption or
excessive phosphate excretion, respectively. It does not divide
rickets into hypocalcemic and hypophosphatemic groups. Because of compensatory changes, even calcipenic disorders
lead to hypophosphatemia, and hence this categorization is
not inconsistent with the current concept that hypophosphatemia is the common pathway to all rickets [16].
Calcipenic causes include vitamin D abnormalities and
calcium deficiency. The most common vitamin D abnormality
is vitamin D deficiency, requiring insufficiency of both dietary
vitamin D and sunlight. It can also be caused by malabsorption, and obesity is an increasingly common cause of vitamin
D deficiency from sequestration of vitamin D in adipose tissue
[18, 19]. Much less common vitamin D abnormalities include
defects in vitamin D metabolism and end-organ responsiveness. Although uncommon in most parts of the world, dietary
calcium deficiency can cause rickets. In vitamin D disorders
and calcium deficiency, rickets results from insufficient intestinal absorption of calcium.
Phosphopenic rickets is mostly caused by hereditary or
acquired disorders of renal tubular phosphate wasting, the
most frequent of which is X-linked hypophosphatemia
(XLH, also known as familial vitamin D resistant rickets).
Review of bone formation and mineralization
Understanding the pathophysiology of rickets requires a
review of normal endochondral bone formation (EBF) and
mineralization [20]. In EBF, the skeleton is pre-formed in
cartilage and then replaced by bone. This begins with mesenchymal condensation followed by differentiation to chondrocytes that secrete extracellular matrix proteins to form
cartilage. Conversion of cartilage to bone begins in the
centrally located primary ossification center, which grows
peripherally, progressively forming bone. Its leading edge is
called the ossification front, although it is the chondrocytes
ahead of the ossification front that pave the way for its
advancement. Subsequently, secondary ossification centers,
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the epiphyses, develop at the ends of long bones. The
primary and secondary ossification centers continue to enlarge and grow toward each other, leaving only a thin strip
of growth cartilage between them and the growth plate, or
physis. The process of endochondral ossification is reflected
in the histology of the physis (Fig. 1). Farthest from the
ossification front is the resting zone with relatively few and
randomly distributed small round chondrocytes. Moving
centrally, the chondrocytes proliferate more rapidly and
become flattened and arranged in orderly columns, forming
the proliferating zone. Next, they stop proliferating and
enlarge, forming the hypertrophic zone. Hypertrophic differentiation is a key step in endochondral ossification, which
is highly regulated by many physiological factors, the most
important being Indian hedgehog (Ihh) and parathyroid
hormone-related peptide (PTHrP), to maintain normal
growth plate organization and function [21]. Hypertrophic
chondrocytes then undergo terminal differentiation and mineralize the surrounding cartilage matrix, forming the zone of
provisional calcification (ZPC). Mineralization of cartilage
is believed to be required for subsequent resorption by
osteoclasts/chondroclasts [22]. Mineralization is followed
by apoptosis of terminally differentiated chondrocytes. This
removes the chondrocytes from cartilage columns and promotes the ingrowth of marrow elements, osteoblasts, osteoclasts and vessels from the metaphysis into tunnels between
bars of calcified cartilage [16]. Osteoclasts/chondroclasts
then resorb much of the cartilage matrix, and osteoblasts
deposit osteoid (bone matrix) on the scaffold of residual
calcified cartilage, forming the primary spongiosa.
Many of the processes involved in EBF are regulated by
Ihh, a locally acting factor produced by hypertrophic chondrocytes [23]. It promotes chondrocyte proliferation, osteoblastic differentiation of mesenchymal cells and the
perichondrial cells surrounding the growth plate. The membranous bone produced by these osteoblasts forms the leading edge of the cortex. Formation of this peripheral
membranous bone might precede mineralization of the adjacent ZPC, producing a small bone spur, the “bone bark”,
which is a normal finding [12]. Along with vascular endothelial growth factor (VEGF), Ihh also promotes vascular
ingrowth for establishing the primary spongiosa.
In the simpler process of membranous bone formation,
osteoblasts differentiate directly from mesenchymal cells and
secrete osteoid. This accounts for formation of the calvarium,
some other flat bones, the cortex of long bones and the bone
formation that accompanies bone turnover and remodelling.
Biological mineralization is a complex process, not
explained simply by precipitation of crystals from a supersaturated solution [17, 24]. In addition to an adequate Ca × P
product, other conditions are required. Initiation of crystal
formation, a particularly difficult process, begins either in
specialized matrix vesicles or along collagen fibrils that have
undergone specific modification to permit mineralization.
Fig. 1 Diagram of the functional anatomy of the growth plate. Growth
plate function is reflected in its anatomy, which temporally progresses
from the reserve or resting (R) chondrocytes closest to the epiphysis to
metaphyseal (M) trabecular bone. As reserve chondrocytes proliferate
they form columns in the proliferative zone (P) and also secrete
chondroid matrix. These chondrocytes eventually stop proliferating
and enter hypertrophic differentiation, a step that is highly regulated
to enable normal growth plate function. In the hypertrophic zone (H),
chondrocytes enlarge and release matrix vesicles (not shown), leading
to cartilage calcification (C). Terminally differentiated hypertrophic
chondrocytes then undergo apoptosis. There is vascular ingrowth with
arrival of chondroclasts/osteoclasts, which resorb much of the calcified
cartilage, and osteoblasts, which lay down osteoid on the remaining
scaffold of calcified cartilage, forming trabecular bone of the metaphysis (M) (Drawing by Kittie Yohe and modified from Anderson and
Shapiro [20] and Wallis [74])
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Pediatr Radiol (2013) 43:140–151
Overview of mineral homeostasis, bone mineral
metabolism and vitamin D
Mineral homeostasis refers to the maintenance of normal
circulating levels of calcium and phosphate ions, which are
required for a wide array of physiological functions [25, 26].
Bone mineral metabolism refers to the processes that deposit
or resorb mineral from bone, with a proper balance of these
processes needed to maintain a normally mineralized skeleton. Mineral homeostasis and bone mineral metabolism are
conceptually different and in some conditions at odds with
each other. The major organs involved in these processes
include the parathyroid, kidney, intestine and bone.
Basic mineral homeostasis [25–27]
The major organ charged with maintaining a normal circulating calcium concentration is the parathyroid, with calcium levels monitored by its calcium sensing receptor
(CaSR). If the ionized calcium concentration falls below a
certain level, the CaSR instructs the parathyroid to increase
the synthesis and release of parathyroid hormone (PTH).
PTH then directs metabolic effects in bone, kidney and,
indirectly, the intestine to raise the calcium concentration
back to normal. For bone, PTH mobilizes calcium and
phosphate by increasing osteoclastic bone resorption. In
the kidney, PTH increases renal tubular reabsorption of
calcium, decreases reabsorption of phosphate and upregulates the enzyme that produces the active form of vitamin D. Activated vitamin D in turn has many functions, the
most important of which is to increase intestinal absorption
of calcium. This system accounts for calcium homeostasis,
but not phosphate. Although our understanding of phosphate homeostasis has lagged behind that of calcium, considerable advances during the last decade have involved
recognition of “phosphatonins”, which cause renal tubular
phosphate wasting [28–30]. The main phosphatonin is fibroblast growth factor-23 (FGF-23), discussed in the section
on phosphopenic rickets. The major factors involved in
mineral homeostasis are summarized in Fig. 2 and Table 2.
Vitamin D metabolism and function
Vitamin D metabolism and function has been the subject of
many excellent reviews [6, 8, 14, 27, 31, 32]. There are two
forms of vitamin D. Ergocalciferol (vitamin D2) is produced
by UV irradiation of ergosterol from plants, including yeast.
Cholecalciferol (vitamin D3) is photosynthesized in skin
from 7-dehydrocholesterol upon exposure to ultraviolet B
(UV-B, 290–315 nm). Both forms follow the same metabolic pathways, are equivalent in their physiological effects,
and henceforth are discussed together as vitamin D [18].
Vitamin D has essentially no metabolic activity of its own.
Fig. 2 Diagram of basic calcium homeostasis. Solid arrows positive
effect, dashed arrows negative effect. Circulating ionized calcium, via
the parathyroid calcium sensing receptor, inhibits PTH synthesis and
secretion. Hence, low Ca++ increases PTH. PTH then promotes osteoclastic bone resorption to mobilize calcium and phosphate. In the
kidney, PTH increases tubular calcium reabsorption and synthesis of
calcitriol by 1-OHase. Calcitriol then acts on the intestine to increase
calcium absorption. Calcium mobilized from bone and absorbed from
the intestine then corrects the hypocalcemia that initially induced PTH.
The conjoined arrows for the effects of calcitriol and PTH on bone
resorption reflect the permissive effect of calcitriol. Although bone
resorption is predominantly an effect of PTH, it also requires the
presence of calcitriol
Rather it is considered a pro-hormone, requiring further
modification to become biologically active. It initially
undergoes 25-hydroxylation in the liver by one of many
cytochrome P450 enzymes to form 25-hydroxy-vitamin D
(25D, also known as calcidiol). Because hepatic 25hydroxylation is not physiologically regulated, serum 25D
levels reflect vitamin D availability. 25D is also the major
circulating metabolite and is stable, with a half-life of 2–
3 weeks. Hence, the circulating 25D level is considered to be
the best indicator of vitamin D status. 25D is then 1αhydroxylated in renal proximal tubular cells by 25-hydroxyvitamin D-1α-hydroxylase (1-OHase) to the active substance
1,25-dihydroxy-vitamin D, henceforth called calcitriol, its
joint pharmaceutical and trivial chemical designation. Renal
production of calcitriol by 1-OHase is highly regulated to
maintain mineral and bone homeostasis, with 1-OHase activity up-regulated by PTH and down-regulated by FGF-23.
Calcitriol in turn suppresses PTH not only by increasing
calcium but by sensitizing the CaSR to suppression by calcium. Calcitriol also stimulates FGF-23 synthesis and inhibits
its own synthesis. The effects of calcium and phosphate on
calcitriol are largely mediated by PTH and FGF-23. After
calcitriol is produced in the kidney, it enters the circulation
to act remotely on the intestine, bone and parathyroid to
correct the physiological conditions that stimulated its production, thus fulfilling the requirements for an endocrine
hormone. Calcitriol is also structurally and functionally similar to steroid hormones, with its effects brought about by
regulating gene expression. Like other steroids, calcitriol
Pediatr Radiol (2013) 43:140–151
Table 2 Major regulators of
mineral homeostasis
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Factor
Major effects
Major regulating factors
PTH
(1) Bone resorption to mobilise calcium
and phosphate
(1) Increased by low Ca++ concentration
via CaSR
(2) Up-regulates 1-OHase to promote
calcitriol synthesis
(3) Increases calcium reabsorption in
distal tubule
(4) Decreases phosphate reabsorption in
proximal tubule
(1) Increases gut absorption of Ca and
phosphate
(2) Permissive for PTH effect on bone
resorption
(1) Increases phosphate excretion by
decreasing tubular reabsorption
(2) Down-regulates 1-OHase to
decrease calcitriol synthesis
(2) Decreased by calcitriol
Calcitriol
PTH parathyroid hormone, calcitriol 1,25-dihydroxy-vitamin
D, FGF-23 fibroblast growth
factor-23, 1-OHase 25-hydroxyvitamin D-1α-hydroxylase,
CaSR parathyroid calcium sensing receptor
FGF-23
binds to an intracellular receptor (the vitamin D receptor,
VDR) which then forms a heterodimer with the retinoid X
receptor (RXR) and binds to DNA, specifically the vitamin D
response element in the promoter region of 200–2,000 genes,
triggering gene expression [8, 14, 27].
There are three categories of vitamin D effects to consider. Foremost is the maintenance of normal mineral ion concentrations, needed not only for prevention of rickets and
osteomalacia but for many cellular functions and neuromuscular transmission [8]. Next there are skeletal effects, which
are independent of the effects on mineral ions. Finally there
are extraskeletal effects of vitamin D.
For maintaining mineral ion levels, the single most
important effect of calcitriol is promotion of calcium
absorption by the intestine. With vitamin D deficiency,
only 10–15% of dietary calcium is absorbed, compared
with 30–40% with vitamin D sufficiency. The first
mechanism demonstrated for increasing calcium absorption is promotion of the gene for the calcium binding
protein calbindin, which transports calcium across the
enterocyte. Additionally, calcitriol promotes the formation of calcium channels, permitting entry of calcium
into the enterocyte and extrusion of calcium from the
enterocyte into the circulation [27]. Although intestinal
phosphate absorption is also enhanced, this effect is
relatively unimportant. While calcium balance is regulated by gut absorption as controlled by calcitriol, phosphate is absorbed more efficiently even without
calcitriol and phosphate balance is regulated by renal
tubular reabsorption, controlled by PTH and FGF-23.
Calcitriol is also permissive for the effect of PTH on
promoting osteoclastic bone resorption to mobilize calcium and phosphate; although primarily an effect of
PTH, some calcitriol must also be present. The shared
(3) Decreased by FGF-23
(1) Increased by PTH
(2) Decreased by FGF-23
(1) Increased by calcitriol
(2) Increased by high dietary or circulating
phosphate, although no phosphate sensing
receptor found
responsibilities of PTH and vitamin D in mineral metabolism can be viewed in two ways. Temporally, PTH
is the rapid responder to aberrations in the calcium
concentration, whereas vitamin D is more concerned
with long-term mineral balance [26]. Functionally, PTH
controls the circulating calcium concentration, whereas
vitamin D is responsible for maintaining a normally
mineralized skeleton [14].
There are conflicting data regarding whether vitamin D
metabolites have direct effects in preventing rickets and
osteomalacia, or if this is entirely explained by their effects
on mineral ion concentrations. Reports of healing of rickets
with vitamin D prior to correction of the mineral ion abnormalities argue for some direct effect, and many effects of
vitamin D should directly promote bone mineralization [33].
For example, formation of organic matrix with the capability
of being mineralized depends on calcitriol produced locally
by 1-OHase in osteoblasts [26]. Extrarenal production of
calcitriol in embryonic growth plate chondrocytes might
have a role in normal endochondral ossification, including
promotion of vascular invasion and prevention of rachiticlike widening of the hypertrophic zone [34]. Calcitriol also
stimulates production of the calcium binding proteins osteopontin and osteocalcin by osteoblasts [27]. Despite these
indicators of direct skeletal effects of vitamin D, there are
compelling data that its anti-rachitic effects are caused solely by normalization of mineral ion concentrations [14, 35].
In calcitriol-resistant rickets (Part II), absence of a functioning calcitriol receptor prevents vitamin D signalling and
severe rickets develops soon after birth. However, the rickets can be completely healed by calcium administration,
suggesting that maintenance of mineral ion concentrations
alone is sufficient to account for the anti-rachitic effects of
vitamin D.
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Vitamin D deficiency and nutritional rickets
Definition of vitamin D deficiency and associated
controversies
Vitamin D sufficiency refers to how well the physiological
requirements for vitamin D are being met, whereas vitamin
D status refers to how well-supplied an individual is with
vitamin D. While it is agreed that serum 25D levels are the
best indicator of vitamin D status, the relation between
vitamin D status and vitamin D sufficiency, although a
matter of considerable importance, is not resolved. The
bases for determining what constitutes vitamin D sufficiency are intertwined with many of the major controversies
surrounding vitamin D. These include what constitutes full
suppression of rickets and osteomalacia, the contribution of
vitamin D toward preventing other skeletal disorders such as
osteoporosis and fractures, and the potential role of vitamin
D in prevention of non-skeletal disorders.
In vitamin D deficiency rickets, serum 25D levels are less
than 15 ng/ml, and often less than 5 ng/ml1 [11]. The 1997
Institute of Medicine (IOM) report defined vitamin D deficiency by 25D levels less than 11 ng/ml [36]. Subsequently,
higher values have been used for defining vitamin D deficiency and sufficiency. Many leaders in vitamin D research,
and the World Health Organization, designate 25D levels
less than 20 ng/ml as deficiency, 20–29 ng/ml as insufficiency, and 30 ng/ml or higher as sufficiency [31, 32, 37].
Because “deficiency” and “insufficiency” both mean that
sufficiency has not been met, the term “insufficiency” when
used in the context of vitamin D appears to refer to levels
that are high enough to prevent clinically evident rickets and
osteomalacia but not high enough, some knowledgeable
people believe, to satisfy other health benefits of vitamin D.
Determination of vitamin D sufficiency involves assessment of whether its physiological functions are being fulfilled. Its most well-established role is the prevention of
rickets and osteomalacia, for which its single most important effect is promotion of intestinal absorption of calcium.
If this fails, calcium levels fall and PTH increases, leading to
phosphaturia, hypophosphatemia and rickets. Hence, more
sensitive means to determine whether vitamin D sufficiency
has been achieved would be to determine whether the effects
of vitamin D on calcium absorption and PTH suppression
are satisfied. Studies suggest that maximal calcium absorption is reached at 25D levels of 32 ng/ml and that maximal
PTH suppression is not reached until 25D levels of 30–
40 ng/ml [32, 38]. Autopsy data showing elevated osteoid
volumes (the hallmark of osteomalacia) in half of those with
1
As is customary in the United States and Canada, 25D levels are
expressed in ng/ml. However, there is a trend toward using nmol/l;
1 ng/ml02.5 nmol/l
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25D levels between 20 ng/ml and 30 ng/ml support the
contention that 20 ng/ml is not sufficient for suppression
of osteomalacia [39]. Largely based on these considerations,
many have indicated the need for levels of at least 30 ng/ml,
hence the designation of 20–29 ng/ml as insufficiency.
When using 30 ng/ml as the cut-off for vitamin D sufficiency, the prevalence of vitamin D deficiency/insufficiency is
quite high. Based on data from the 2004 National Health
and Nutrition Examination Survey (NHANES III), Adams
and Hewison [31] indicate an overall prevalence of vitamin
D deficiency/insufficiency in the United States of 90% for
pigmented races and approximately 75% for whites. They
also note that this represents a near doubling of the prevalence of deficiency/insufficiency over 10 years, considered
largely due to increasing obesity with sequestration of vitamin D in adipose tissue.
In addition to the prevention of recognizable rickets and
osteomalacia, vitamin D might have other beneficial effects
on overall bone health. Many adult studies have shown
positive effects of vitamin D supplementation on bone mineral density (BMD) and high correlations between 25D
levels and BMD [40]. The effects of vitamin D (with or
without calcium) supplementation on fracture rates have
been summarized in meta-analyses. The 2006 metaanalysis by Bischoff-Ferrari et al. [41] suggested that optimal prevention of fractures is associated with 25D levels of
at least 40 ng/ml, with a beneficial effect seen only in trials
using at least 700 IU of vitamin D per day.
There are also arguments for benefits of higher levels of
25D than those needed to prevent clinically evident rickets
and osteomalacia based on extraskeletal effects of vitamin
D. Calcitriol directly or indirectly affects the function of at
least 200, and perhaps as many as 2,000, genes, including
those involved in regulation of cellular proliferation, differentiation, apoptosis and angiogenesis [27, 32, 42]. The
presence of vitamin D receptors in many tissues suggests
that they are influenced by vitamin D. 1-OHase is also
present in many extrarenal tissues. Calcitriol produced at
these extrarenal sites acts locally and its synthesis is not
subject to the physiological regulation that controls renal
production of systemic calcitriol, suggesting that these
effects are particularly dependent on circulating 25D levels
[27, 43]. All of these considerations suggest widespread
physiological roles of vitamin D. Correspondingly, there
has been considerable work linking vitamin D deficiency
to a large variety of non-skeletal disorders, including lower
extremity function and risk of falling, many cancers, autoimmune diseases including multiple sclerosis and rheumatoid arthritis, diabetes mellitus types 1 and 2, susceptibility
to infectious diseases including TB, influenza and upper
respiratory tract infections, neurological disorders, hypertension, peripheral vascular disease, asthma and many other
disorders [32, 42, 44]. Multiple lines of evidence support
Pediatr Radiol (2013) 43:140–151
roles of vitamin D in the prevention of these disorders,
including laboratory evidence of underlying mechanisms,
epidemiological evidence, case-control studies of vitamin
D levels and clinical trials of vitamin D supplementation.
Of these, the effects of vitamin D on the immune system—
particularly with respect to tuberculosis—and on colorectal
cancer are briefly reviewed, as illustrative examples of the
vast amount of work that has been done on extraskeletal
effects of vitamin D, and to indicate the difficulty and lack
of consensus in determining whether this work supports the
need for vitamin D supplementation.
Historically, TB and rickets/vitamin D deficiency have
been linked [45, 46]. During the industrial revolution when
rickets was ubiquitous, TB was also rampant, leading to
initial supposition that rickets was an infectious disorder
that spread through crowded urban slums, although Robert
Koch was unable to isolate an infectious agent. A specific
association of rickets and TB was also recognized by Sir
William Jenner in 1895. Prior to effective antimicrobial
therapy, the benefits of “fresh air and sunlight” were also
appreciated, including recognition that high-altitude sunlight, which enhanced UV-B exposure, was particularly
beneficial, with the first high-altitude TB sanatorium established by Hermann Brehmer in 1854. Niels Finsen’s successful treatment of lupus vulgaris (cutaneous TB) with
sunlight led to a Nobel Prize in 1903. More recently, casecontrol studies have shown a relationship between low 25D
levels and TB as summarized in a meta-analysis [47].
Extensive evaluation of the effects of vitamin D on the
immune system has shown an overall suppressive effect on
the adaptive immune response, considered to account for its
preventive effect against certain autoimmune disorders.
However, it has a positive effect on innate immunity, which
is believed to be important in protection against tuberculosis
[27, 46] and might represent the primitive function of vitamin D, predating its endocrine role in mineral metabolism
[31]. In 1986, Rook et al. [48] showed that calcitriol promotes intracellular killing of TB-infected macrophages in
vitro. Subsequent work has shown that intracellular killing
involves antimicrobial peptides, the most important being
cathelicidin, and that their synthesis depends on calcitriol
produced locally by macrophages. Along with these observational and laboratory indicators of a role of vitamin D in
protection against TB, controlled clinical trials of vitamin D
added to standard antibiotic therapy have shown beneficial
effects in both children and adults, although the data are
limited [49, 50].
Multiple lines of evidence also support a protective effect
of vitamin D against colorectal cancer. The initial link was
based on disease incidences at varying distances from the
equator, and hence incident sunlight [51]. Numerous studies
have demonstrated an association between colorectal cancer
and low serum 25D levels [52]. Extensive laboratory work
147
supporting a protective role of vitamin D includes the ability
of calcitriol to decrease proliferation and increase differentiation of colorectal cancer cells, and effects on protooncogenes, growth factor-activated pathways and detoxification of carcinogens [53]. There is also an inverse correlation between 25D levels and the proliferative component of
the colonic mucosa. Despite these observational and experimental suggestions that vitamin D should be helpful in
preventing colorectal cancer, whether there is a beneficial
effect of vitamin D supplementation, as supported by randomized clinical trials (RCTs), is not clear. Davis and Milner [54] have concluded that the available RCTs have failed
to show a beneficial effect, and they further warn that
excessive vitamin D exposure might be a risk factor for
cancer of the oesophagus, pancreas and prostate. However,
Bischoff-Ferrari et al. [41] claim that if analysis of the
available studies is limited to subjects receiving sufficient
vitamin D, then a beneficial effect is demonstrated. It is also
argued that the long latencies of many cancers make them
not amenable to evaluation by RCTs, and that the observational and mechanistic data should be sufficient [55].
Despite the vast amount of work on the skeletal and
extraskeletal beneficial effects of vitamin D, much of which
appears quite compelling, the 2011 IOM report did not
endorse the need for 25D levels greater than 20 ng/ml
[56]. Furthermore, recognizing individual variability in the
amount of vitamin D needed to support physiological function, the IOM indicated that its use of 20 ng/ml as a laboratory cut-off for vitamin D deficiency meant that it meets the
needs of 97% of individuals, with 16 ng/ml meeting the
needs of 50% and 12 ng/ml meeting the needs of 3%. IOM
also specifically indicated that presently there was insufficient RCT data for recommending higher vitamin D levels
based on potential extraskeletal effects of vitamin D. So
different were these conclusions from those of many
researchers in vitamin D that just prior to the release of the
2011 3rd edition of Vitamin D (editor D. Feldman), all of the
authors were asked to consider revising their chapters upon
consideration of that report, although many were not dissuaded from their belief in the importance of vitamin D for
prevention of many diseases [57]. The difference between
the IOM definition of vitamin D adequacy and 30 ng/ml, as
recommended by many, is huge. It changes whether the
majority of the United States population is considered to
have sufficient vitamin D status versus vitamin D insufficiency that requires supplementation, with obvious implications for public health policy. If benefits of higher vitamin D
levels exist, we would be remiss in not recommending
appropriate supplementation. However, to recommend this
for the entire population in the absence of supporting data is
not desirable, either from the standpoint of allocation of
healthcare resources or a scientific approach to the practice
of medicine.
148
Why is the amount of vitamin D needed by humans
unresolved and what is the basis for disagreement? There
was no shortage of scientific expertise or diligence on the
part of the IOM panel, nor on the part of many who disagree
with its conclusions. It is likely that the major factors contributing to this lack of consensus are the coexistence of
such a large volume of data to be reviewed, only a small
portion of it coming from RCTs, and the premise by the
IOM that its recommendations should be based largely on
RCTs. The non-applicability of RCTs for some of the potential long-term health benefits of vitamin D is an issue
[55]. An argument has also been made concerning where the
burden of proof ought to lie when the data are not conclusive. For drugs with pharmacological effects, no beneficial
effect should be assumed until proved. However, for a
physiological substance such as vitamin D, different rules
may be more appropriate. Based on estimates of sunlight
exposure and latitude, it has been suggested that during
much of human evolution enough vitamin D was photosynthesized to maintain 25D levels of 40–80 ng/ml, which
should be considered to be the natural state. While this does
not prove that these levels are needed, it is argued that it
might be more appropriate for the burden of proof to lie with
those who propose that lower levels are sufficient [58].
Expert consensus on the 25D levels needed for vitamin D
sufficiency remains a work in progress. All agree that levels
of at least 20 ng/ml should be maintained, and hence the
designation of deficiency for lower levels, recognizing that
not everyone below 20 ng/ml is actually physiologically
deficient. Although the IOM specifically indicates that levels of at least 20 ng/ml are considered normal, the subsequent 2011 clinical practice guidelines of The Endocrine
Society maintain a designation of insufficiency for 21–
29 ng/ml [59]. Of note, consideration of 25D levels between
21 ng/ml and 29 ng/ml as insufficient has not gained official
acceptance for children in the United States as reflected by
guidelines of the Committee on Nutrition of the American
Academy of Pediatrics [60] and the Pediatric Endocrine Society [61], likely related to a greater emphasis on the antirachitic effects of vitamin D by these paediatric organizations.
Etiology and epidemiology of vitamin D deficiency rickets
Most foods, other than oily fish, contain very little vitamin
D unless artificially supplemented. Cutaneous synthesis of
vitamin D is influenced by multiple factors, with effective
UV-B exposure decreased by latitude from the equator,
winter months, sunscreens and skin pigmentation. UV-B is
absorbed by melanin and darker-skinned persons require 5–
10 times the amount of sun exposure for equivalent vitamin
D production [62]. Races evolving distant from the equator
are usually fair-skinned, maximizing vitamin D synthesis
from limited UV-B, other than the darker-skinned arctic
Pediatr Radiol (2013) 43:140–151
Inuit population whose diet is rich in oily fish containing
vitamin D [63]. This suggests that over the course of human
evolution the major source of vitamin D has been cutaneous
photosynthesis, with little contribution from natural food.
Presently vitamin D fortification in the United States
includes milk and milk products, as well as some cereals
and breads. However, the vitamin D supplied by these
sources is limited; sunlight exposure remains important in
maintaining vitamin D sufficiency and factors limiting cutaneous photosynthesis play a substantial role in the etiology
of vitamin D deficiency rickets.
Because vitamin D deficiency rickets is particularly problematic in breast-fed infants, attention has been given to
those aspects of vitamin D related to the mother-infant pair
[19, 64, 65]. During pregnancy, there is free placental transfer of 25D, but neither vitamin D nor calcitriol. The fetal
requirement for vitamin D is limited as patients with essentially no vitamin D signalling appear normal at birth, although this does not exclude subtle effects of maternal
vitamin D deficiency. Relatively recently, low maternal
25D levels were shown to correlate with increased fetal
distal femoral splaying, determined by US measurements
of femoral length and metaphyseal width [66]. It has been
suggested that these findings are equivalent to rickets, possibly resulting from deficient production of calcitriol by
fetal chondrocytes [67]. With maternal vitamin D sufficiency, the fetus receives enough 25D for short-term postnatal
adequacy, limited by its half-life of 2–3 weeks. If additional
vitamin D is not supplied or synthesized, the infant becomes
vitamin D deficient—more quickly for those beginning with
low levels. Following birth, the pattern of transfer of vitamin
D from mother to infant changes, with breast milk containing 20–30% of the maternal vitamin D and essentially no
25D or calcitriol. Hence, the supply of vitamin D in breast
milk is limited, particularly if maternal vitamin D levels are
low. A high association between low maternal 25D levels
and vitamin D deficiency in breast-fed infants has been
demonstrated in multiple populations worldwide, as summarized by Thandrayen and Pettifor [19]. This reflects a
combination of insufficient vitamin D in breast milk from
these mothers as well as exposure of the infant to the same
environment as the mother, with limited sunlight exposure.
The epidemic of rickets linked to the industrial revolution
that was most prominent in the late 19th and early 20th
centuries constituted the first wave of rickets. This was
largely eliminated following the discovery of vitamin D
and food fortification. However, rickets re-emerged. The
second wave developed during the 1960s to 1980s in
breast-fed infants from distinct cultural groups, relatively
limited in overall numbers. These included infants born to
dark-skinned Asian women who had immigrated to England, Muslim women in the Middle East and Asia, and
members of certain religious sects in inner cities in the
Pediatr Radiol (2013) 43:140–151
149
United States, all of whom had cultural practices, including
extensive clothing, that limited sunlight exposure. With the
promotion of breast-feeding, the third wave of rickets then
emerged in the 1990s among breast-fed infants of darkskinned American women, mostly African Americans, and
this continues as an ongoing public health problem [3].
Unlike the second wave, these third-wave mothers are mostly normally dressed and part of mainstream society. However, vitamin D photosynthesis is limited for these mothers
and their infants by skin pigmentation and relatively limited
sun exposure in urban environments, a result of multiple
factors that prevent them from going outdoors, including fear
of community violence, work schedules and warnings against
the dangers of sun exposure [68]. The overall effects of race
on vitamin D deficiency in infants in the northern United
States are highlighted in data from Pittsburgh showing low
25D levels in 45.6% of African-American versus 9.7% of
white neonates, with skin pigmentation, socio-economic factors and cultural practices all considered to contribute to
vitamin D deficiency in African Americans [69].
Although breast-fed infants are at greatest risk, significant
vitamin D deficiency remains problematic throughout childhood and adolescence [70]. Adolescents with vitamin D deficiency might present with hypocalcemia rather than classic
rickets, thought to be related to increased demands for calcium
during periods of rapid growth, similar to early infancy [71].
The proper role of sun exposure in meeting our vitamin D
requirement is also controversial. Although sunlight has
been the major source of vitamin D, recognition of its role
in causing skin cancer has led to a strong public health
awareness campaign on the dangers of sunlight, initially
sponsored by the American Academy of Dermatology.
Some now regard any unprotected sun exposure as too risky
and suggest that vitamin D requirements be entirely met
orally. However, reliance on oral vitamin D is problematic.
As there are relatively few natural sources of vitamin D, this
usually requires the use of supplements. Because of adherence issues, recommendations for prevention of vitamin D
deficiency that are based on the use of supplements in lieu of
sun exposure have a risk of inadequate intake [60]. Although the 2011 IOM report did not consider a role for
sun exposure, without it the amounts of vitamin D recommended by the IOM would not achieve vitamin D sufficiency [58]. Recognizing clear risks of excessive sun exposure,
the current trend towards strict sun avoidance and use of
sunscreens might be over-zealous. Using sunlight in moderation would help provide for more reliable prevention of
vitamin D deficiency, and this might be considered by the
IOM in the future.
Prevention of vitamin D deficiency rickets
Part I of this review emphasizes the pathophysiological
processes that underlie rickets. Rickets is a disorder of the
growth plates of children in which impaired mineralization
and endochondral ossification result from deficient mineral
ion concentrations. The ossification defect is caused by an
arrest of apoptosis of hypertrophic chondrocytes.
The most common etiology of rickets, historically and presently, is vitamin D deficiency. Accordingly, vitamin D metabolism and function and the epidemiology of vitamin D
deficiency have been reviewed. Controversial issues related to
the definition of vitamin D deficiency and its prevention have
also been discussed.
Despite adequate knowledge of its etiology, vitamin D deficiency rickets remains a significant problem. The 1997 IOM
report [36], endorsed by the American Academy of Pediatrics
(AAP) in 2003 [72], suggested that infants, children and
adolescents receive 200 IU of vitamin D beginning in the first
2 months of life. That recommendation was based on data
showing that 200 IU prevented overt clinical manifestations of
rickets and maintained 25D levels of at least 11 ng/ml. With
the recognition that higher levels of 25D are needed, these
recommendations have been revised. Based on maintaining
25D levels of at least 20 ng/ml, the 2008 AAP report recommends that all infants, children and adolescents receive 400 IU
orally, either through diet or supplementation, beginning soon
after birth [60]. Alternatively, with high-dose maternal supplementation, breast milk can supply sufficient vitamin D for
the prevention of rickets [73], although the AAP stresses that
the safety of this approach is not well established. Similar to
the 2008 AAP recommendations, the 2011 IOM report also
recommends 400 IU/day during the first year of life [56].
Beyond the first year of life the IOM “recommended dietary
allowance” is 600 IU/day to age 70 and 800 IU beyond age 70.
However, if the goal of vitamin D supplementation is achievement of 25D levels of 30 ng/ml, daily doses of 1,500–
2,000 IU/day would be required [42, 59].
Summary
Conflicts of interest None.
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