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Causes of vitamin D deficiency and resistance

Author: Marc K Drezner, MD

Section Editor: Clifford J Rosen, MD
Deputy Editor: Jean E Mulder, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2018. | This topic last updated: Oct 23, 2017.

INTRODUCTION — Vitamin D has a variety of actions on calcium, phosphate, and bone metabolism. Its most
important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium and
phosphorus, thereby promoting bone mineralization. At high vitamin D concentrations, under conditions of
calcium and phosphate deficiency, it also stimulates bone resorption, thereby helping to maintain the supply of
these ions to other tissues (figure 1). (See "Normal skeletal development and regulation of bone formation and
resorption", section on 'Calcitriol'.)

Vitamin D deficiency or resistance interferes with these processes, sometimes causing hypocalcemia and
hypophosphatemia. Since hypocalcemia stimulates the release of parathyroid hormone (PTH), however, the
development of hypocalcemia is often masked. The secondary hyperparathyroidism, via its actions on bone and
the kidney, partially corrects the hypocalcemia but enhances urinary phosphate excretion, thereby contributing to
the development of hypophosphatemia and osteomalacia. (See "Epidemiology and etiology of osteomalacia" and
"Clinical manifestations, diagnosis, and treatment of osteomalacia", section on 'Laboratory findings'.)

This topic will review the major causes of vitamin D deficiency and resistance. Optimal serum vitamin D
concentrations, the treatment of vitamin D deficiency, and the role of vitamin D therapy for osteoporosis are
discussed in detail separately (see "Vitamin D deficiency in adults: Definition, clinical manifestations, and
treatment" and "Calcium and vitamin D supplementation in osteoporosis"). The major causes of
hypophosphatemia and hypocalcemia are also reviewed elsewhere. (See "Causes of hypophosphatemia" and
"Etiology of hypocalcemia in adults".)

DEFINITION — The optimal serum 25-hydroxyvitamin D (25[OH]D) concentration for skeletal health and
extraskeletal health is controversial, and it has not been rigorously established for the population in general or for
specific ethnic groups. Clinicians variably consider the optimal serum 25(OH)D concentration to range between
20 and 40 ng/mL (50 to 100 nmol/L) or between 30 and 50 ng/mL (75 to 125 nmol/L). The range of common
agreement is 30 to 40 ng/mL (75 to 100 nmol/L). This topic is reviewed in detail elsewhere. (See "Vitamin D
deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Defining vitamin D
sufficiency'.)

VITAMIN D METABOLISM — Vitamin D (cholecalciferol) is normally synthesized in the skin under the influence of
sunlight in a nonenzymatic manner. In addition, vitamin D (ergocalciferol) may be ingested from fish or plant
sources. Vitamin D is then hydroxylated in the liver to 25-hydroxyvitamin D (calcidiol, 25[OH]D), which is the major
circulating form of vitamin D and the best index of vitamin D sufficiency. Calcidiol is hydroxylated primarily in the
kidney to 1,25-dihydroxyvitamin D (calcitriol), which is the most active form (figure 1). 1,25-dihydroxyvitamin D is
also formed in some other tissues but is used only within those tissues and not circulated. (See "Overview of
vitamin D", section on 'Metabolism'.)

Vitamin D deficiency can therefore occur as a result of decreased intake or absorption, reduced sun exposure,
increased hepatic catabolism, or decreased endogenous synthesis (via decreased 25-hydroxylation in the liver or
1-hydroxylation in the kidney). End-organ resistance to vitamin D causes the equivalent result as deficiency (table
1).

NUTRITIONAL DEFICIENCY AND REDUCED CUTANEOUS SYNTHESIS — In many developed countries, most
vitamin D is derived from foods that are rich in the vitamin (fatty fishes) or fortified with the vitamin (milk and
related products and cereals). The remainder is synthesized in the skin from 7-dehydrocholesterol under the
influence of ultraviolet light, at a similar wavelength that can cause sunburn (figure 1). Vitamin D deficiency can
occur in people who live without sun exposure (including those whose skin is constantly protected from the sun)
and/or have enhanced skin pigmentation, or whose dietary intake is low. In some individuals, however, abundant
sun exposure does not preclude vitamin D insufficiency for reasons that are poorly understood [1]. Nevertheless,
vitamin D deficiency occurs most commonly in people who live in countries distant from the equator and who
consume foods that are not fortified with vitamin D [2]. Vitamin D deficiency can also occur with adequate intake
if there is intestinal malabsorption of vitamin D, as occurs with celiac disease.

Vitamin D deficiency due to reduced vitamin D intake, absorption, or cutaneous production should be considered
especially in the following populations:

Older adults — Cutaneous vitamin D production and vitamin D stores decline with age [3]. This change is most
prominent in the winter. In temperate areas such as Boston and Edmonton, as an example, cutaneous production
of vitamin D virtually ceases in winter, especially in older adults [4,5].

In addition to reduced endogenous production, vitamin D intake is often low in older subjects. As an example, in a
study of postmenopausal women living in France, mean daily vitamin D intake from food was 144.8 international
units/day, and more than one-third of women consumed <100 international units/day from food [6], despite a
recommended intake of 400 international units/day for people 51 to 70 years old and 600 international units/day
for people 71 years old and older [5]. Moreover, many clinicians believe that even in those with adequate vitamin
D intake, achlorhydria, which is common in older adults, limits calcium absorption, as does an age-dependent
resistance to calcitriol [7]. The net effect of the many factors influencing vitamin D metabolism and the effects of
vitamin D in older adults is the presence of relative hypocalcemia and high serum parathyroid hormone (PTH)
concentrations [8,9]; this secondary hyperparathyroidism can be attenuated by the administration of
physiological doses of vitamin D [10]. However, older persons confined indoors may have low serum 25-
hydroxyvitamin D (calcidiol, 25[OH]D) concentrations even with the current recommendations for vitamin D
intake [11,12].

Children — Dietary vitamin D deficiency can also occur in children, with notable differences among ethnic groups
[13]. Among 618 Asian children in the United Kingdom, 27 percent had serum 25(OH)D <10 ng/mL (25 nmol/L)
[14]. Serum 25(OH)D concentrations were correlated with ingestion of vitamin D supplements in these children,
notwithstanding that increasing skin pigmentation is associated with less cutaneous vitamin D production. (See
'Immigrants to cold climates from warm climates' below and "Vitamin D insufficiency and deficiency in children
and adolescents".)

Vitamin D deficiency is also a concern for breastfed infants, particularly those with an allergy to cow's milk
protein [15]. (See "Vitamin D insufficiency and deficiency in children and adolescents".)

Healthy adults in the winter — Vitamin D deficiency is also common in healthy, young adults at the end of the
winter. In a study of healthy adults in the Boston area who underwent 25(OH)D testing at the end of winter and
summer, 36 percent of 69 subjects ages 18 to 29 had vitamin D concentrations below 20 ng/mL (50 nmol/L), but
the prevalence decreased to 4 percent by the end of the summer [16]. Similar seasonal differences were seen in
older groups. The impact of winter on the serum 25(OH)D is affected by several ancillary factors, most notably
ancestry and skin pigmentation [17].

Hospitalized patients — In a study of 290 patients hospitalized on a general medical service, vitamin D deficiency
(<15 ng/mL [37 nmol/L]) was detected in 164 patients (57 percent), of whom 65 (22 percent) were considered
severely deficient (serum concentration of 25[OH]D <8 ng/mL [20 nmol/L]) [18]. Inadequate vitamin D intake,
winter season, and housebound status were independent predictors of vitamin D deficiency. The prevalence of
vitamin D deficiency in hospitalized patients may also be dependent, in part, upon the age of the patients on the
hospital wards [19,20]. However, in a subgroup of 77 patients less than age 65 years without known risk factors,
the prevalence of vitamin D deficiency was still 42 percent [18].

Women treated for osteoporosis — Unrecognized vitamin D insufficiency or deficiency is also common in

postmenopausal women seeking advice or receiving therapy for osteoporosis [12,21]. In a study of 1536
community-dwelling postmenopausal women (evenly distributed by latitude) who were receiving osteoporosis
drug therapy (bisphosphonates, raloxifene, calcitonin, or PTH), serum 25(OH)D concentrations were less than 20
and 30 ng/mL in 18 and 52 percent, respectively [12]. Not surprisingly, the prevalence of vitamin D insufficiency
was higher in women taking less than 400 compared with ≥400 international units of vitamin D per day. (See
"Calcium and vitamin D supplementation in osteoporosis".)

Chronic renal disease — Patients with chronic kidney disease (CKD) have 1,25-dihydroxyvitamin D (calcitriol)
deficiency, related in part to an increased production of fibroblast growth factor 23 (FGF23) with progressive
renal failure [22]. In some patients, 25(OH)D deficiency may also occur [23-25]. This has been demonstrated in
patients on dialysis and in patients with stages 3 and 4 CKD predialysis [23,25].

● In a study of patients with glomerular filtration rates (GFR) <30 and 30 to 59 mL/min, serum 25(OH)D
concentrations were <10 ng/mL (25 nmol/L) in 14 and 26 percent, respectively, and between 10 and 30
ng/mL (25 and 75 nmol/L) in 57 and 58 percent, respectively [23].

● In a study of 242 patients with CKD on dialysis, vitamin D deficiency (<15 ng/mL [37 nmol/L]), was evident in
up to 28 percent of patients [25]. Women, patients with diabetes, and patients on peritoneal dialysis were at
greater risk for vitamin D deficiency. In addition, 25(OH)D concentrations were positively associated with
bone mineral density (BMD) at the lumbar spine and wrist.

Despite these associations, it is unclear if improving 25(OH)D concentrations has any benefit on metabolic bone
disease in these patients (see "Management of secondary hyperparathyroidism in adult nondialysis patients with
chronic kidney disease" and "Management of secondary hyperparathyroidism in dialysis patients"). The Kidney
Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for bone metabolism and disease in CKD,
as well as other KDOQI guidelines, can be accessed through the National Kidney Foundation website.

Gastrointestinal disease — Gastrointestinal malabsorption, associated with diseases of the small intestine,

hepatobiliary tree, and pancreas, may result in decreased absorption of vitamin D and/or depletion of
endogenous 25(OH)D stores due to disruption of enterohepatic circulation [26-28]. In general, malabsorption of
vitamin D occurs as a consequence of steatorrhea, which disturbs fat emulsification and chylomicron-facilitated
absorption. While this may be associated with rickets and/or osteomalacia, many affected patients are
asymptomatic or exhibit only a reduction in bone volume rather than evidence of defective bone mineralization.

Adult celiac disease is a common example of a disorder in which vitamin D malabsorption occurs and in which
the suspicion for vitamin D deficiency should be high [29]. These patients often present with low BMD, most
commonly without evidence of abnormal bone mineralization. (See "Pathogenesis, epidemiology, and clinical
manifestations of celiac disease in adults", section on 'Metabolic bone disease'.)

Metabolic bone disease associated with gastrointestinal disorders is discussed in more detail separately. (See
"Metabolic bone disease in inflammatory bowel disease".)

Gastric bypass — Gastrointestinal malabsorption of vitamin D can occur after gastric surgery.

● Bariatric surgery – In a systematic review of studies evaluating vitamin D status before and after bariatric
surgery, the median preoperative vitamin D level was 19 ng/mL (47 nmol/L) [30]. Median postoperative
vitamin D levels were higher at multiple time points tested, ranging from 24 ng/mL (60 nmol/L) at one month
to 29 ng/mL (72 nmol/L) at one year and 25 ng/mL (62 nmol/L) at two years. However, vitamin D repletion
with doses of <800 international units daily in patients with vitamin D deficiency was, in general, insufficient,
suggesting malabsorption and suboptimal treatment. (See "Bariatric surgery: Postoperative nutritional
management", section on 'Micronutrient management'.)

● Gastrectomy – Vitamin D deficiency may also develop in patients who have had partial or total gastrectomy
for peptic ulcer disease, gastric cancer, or other indications. Loss of gastrointestinal acidity or malfunction
of the proximal small bowel underlies the vitamin D malabsorption in such circumstances. Absence of
sufficient absorbing surface or failure of intestinal mucosal cells to respond to vitamin D or its metabolites
may also cause vitamin D malabsorption. Such patients may also have selective calcium malabsorption.

Immigrants to cold climates from warm climates — Vitamin D deficiency has been reported in dark-skinned
immigrants from warm climates to cold climates in North America and Europe. Asian Indian immigrants to the
United States may have vitamin D deficiency even with what is considered adequate sun exposure [31].

Patients who have musculoskeletal pain — Nonspecific musculoskeletal pain is a common symptom of vitamin
D deficiency, and the prevalence of unrecognized vitamin D deficiency among patients with these symptoms is
extremely high. As an example, in a study of 150 subjects with persistent, nonspecific musculoskeletal pain
presenting to an inner city health clinic in Minneapolis, 93 percent were vitamin D deficient (serum 25[OH]D
concentration ≤20 ng/mL [50 nmol/L]), and 28 percent of all patients had severe deficiency (concentration ≤8
ng/mL [20 nmol/L]) [32]. Thus, patients who present with nonspecific musculoskeletal pain should be screened
for vitamin D deficiency.

Cystic fibrosis — Patients with advanced cystic fibrosis are usually deficient in vitamin D [33], and they require
more than the usual recommended dose for young adults (eg, more than 400 international units/day). (See
"Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Musculoskeletal disorders'.)

Extensive burns — In patients with a history of extensive burn injuries, vitamin D synthesis in skin is below
normal, even with sun exposure [34].

DEFICIENCY RELATED TO ABNORMAL SYNTHESIS AND CATABOLISM

Calcidiol (25-hydroxyvitamin D) — Calcidiol deficiency can result from decreased synthesis in the liver, increased
catabolism, or renal loss of calcidiol bound to vitamin D-binding protein.

Decreased synthesis — Since vitamin D is hydroxylated in the liver by hepatic 25-hydroxylase (CYP2R1,

11p15.2) to produce calcidiol (25-hydroxyvitamin D [25(OH)D]), patients with severe parenchymal or obstructive
hepatic disease may have reduced production of this metabolite [26,28]. The majority of the liver must be
dysfunctional before calcidiol synthesis is reduced. Thus, these patients rarely manifest biochemical or
histologic evidence of osteomalacia unless concomitant nutritional deficiency or interruption of the
enterohepatic circulation occurs (figure 1).
Homozygous loss-of-function mutations of CYP2R1, the gene that encodes the enzyme principally responsible
for 25-hydroxylation of vitamin D, causes vitamin D-dependent rickets type 1B (VDDR-1B) [35]. This very rare
disorder significantly reduces production of 25(OH)D and could easily be mistaken for classical vitamin D
deficiency. However, unlike the classical disorder, traditional treatment with vitamin D is ineffective, while
administration of 25(OH)D (calcidiol) therapy results in dramatic improvements in clinical symptoms,
biochemical abnormalities, and bone densitometry. (See "Etiology and treatment of calcipenic rickets in children",
section on '25-hydroxylase deficiency'.)

Drugs — Decreased circulating levels of calcidiol may also occur in patients treated with drugs such as
phenytoin, phenobarbital, carbamazepine, oxcarbazepine, isoniazid, theophylline, and rifampin, due to induction
of P450 enzyme activity, which metabolizes calcidiol to inactive vitamin D metabolites [36-41]. Supplementation
with vitamin D (400 to 4000 international units/day; 1 mcg = 40 international units) may be necessary to prevent
vitamin D deficiency in these patients [41,42]. (See "Antiepileptic drugs and bone disease", section on 'Effect of
AED type' and "Antiepileptic drugs and bone disease", section on 'Calcium and vitamin D'.)

Renal loss — Most of the calcidiol in serum is bound to vitamin D-binding protein. Patients with the nephrotic
syndrome can excrete enough vitamin D-binding protein (with calcidiol bound to it) to become vitamin D
deficient, as evidenced by decreased circulating levels of 25(OH)D and bioavailable 25(OH)D, and may develop
hypocalcemia and hypophosphatemia [43,44].

Calcitriol (1,25-dihydroxyvitamin D) — The final step in the metabolic activation of vitamin D is 1-hydroxylation of
calcidiol in the proximal convoluted tubule cells of the kidney to produce calcitriol (1,25-dihydroxyvitamin D)
(figure 1). This reaction is stimulated by parathyroid hormone (PTH), calcitonin, and hypophosphatemia, and
inhibited by calcium, 1,25-dihydroxyvitamin D, and hyperphosphatemia [45]. (See "Overview of vitamin D", section
on 'Metabolism'.)

The substrate for 1-hydroxylation is incorporated into the kidney following glomerular filtration of the 25(OH)D
linked to its binding protein and megalin-directed transfer of the substrate into the renal proximal convoluted
tubule cell.

Renal failure — In patients with renal failure, calcitriol (1,25 dihydroxyvitamin D) production is low due to
diminished glomerular filtration, loss of the 1-alpha-hydroxylase enzyme secondary to structural renal
compromise, and suppression of enzyme activity due to hyperphosphatemia and resultant increased circulating
fibroblast growth factor 23 (FGF23) levels. The net result is a tendency to hypocalcemia, hyperparathyroidism,
and bone disease. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Vitamin D-dependent rickets type IA (VDDR-1A) — Vitamin D-dependent rickets type IA (VDDR-1A) is also
known as pseudovitamin D-deficient rickets because the clinical and biochemical evidence of rickets can be
corrected with 1,25-dihydroxyvitamin D (calcitriol) treatment, maintained for life [46].

This form of rickets is an autosomal recessive disease due to an inactivating mutation in the 1-hydroxylase gene
[47-49]. As a result, calcidiol is not hydroxylated to calcitriol, and calcium is not absorbed normally. As a result of
the hypocalcemia, parathyroid hormone levels rise, resulting in an increase in urinary excretion of amino acids
and phosphate. In addition to these biochemical abnormalities, within the first year of life, patients present with
rickets and signs of hypocalcemia, tetany, or convulsions and exhibit muscle weakness and hypotonia, motor
retardation, and stunted growth. Laboratory investigations show low serum concentrations of calcium and
phosphorus and elevated alkaline phosphatase. With progression, patients develop the classic radiographic
signs of vitamin D deficiency rickets and bone biopsy evidence of osteomalacia. This disorder, as well as other
types of rickets, is discussed in more detail separately. (See "Etiology and treatment of calcipenic rickets in
children", section on '1-alpha-hydroxylase deficiency' and "Overview of rickets in children".)
VITAMIN D RESISTANCE — What had been called type 2 vitamin D-dependent rickets is actually a form of vitamin
D resistance and is now known as hereditary vitamin D-resistant rickets (HVDRR). HVDRR, an autosomal
recessive disorder, is a very rare form of rickets with approximately 100 cases reported, in which 50 unique
heterogeneous mutations in the vitamin D receptor gene have been identified, which change amino acids in
either the N-terminal, DNA-binding domain or the C-terminal ligand binding domain of the vitamin D receptor
protein, causing end-organ resistance to calcitriol [46,50-56].

The clinical spectrum varies widely, probably reflecting the type of mutation within the vitamin D receptor and the
amount of residual vitamin D receptor activity. Affected children usually appear normal at birth but develop
rickets within the first two years of life (image 1). A peculiar feature of the syndrome is alopecia, which appears
in approximately two-thirds of cases and is a marker of disease severity. Alopecia results from the lack of vitamin
D receptor action within keratinocytes [57-60]. Additional ectodermal anomalies may also be seen including
multiple milia, epidermal cysts, and oligodontia. (See "Etiology and treatment of calcipenic rickets in children",
section on 'Hereditary resistance to vitamin D'.)

The identified defects in the vitamin D binding domain of the vitamin D receptor prevent binding to DNA and
cause total 1,25-dihydroxyvitamin D resistance, while the mutations in the ligand-binding domain of the vitamin D
receptor disrupt 1,25-dihydroxyvitamin D binding, heterodimerization with the retinoid X receptor, or coactivator
binding to the vitamin D receptor, which cause partial or total hormone resistance. These genetic abnormalities
can cause:

● Failure of 1,25-dihydroxyvitamin D binding to available receptors [50]

● A reduction in 1,25-dihydroxyvitamin D receptor binding sites [51]

● Abnormal binding affinity of 1,25-dihydroxyvitamin D to receptor [56]

● Inadequate translocation of 1,25-dihydroxyvitamin D-receptor complex to the nucleus [61]

● Diminished affinity of the 1,25-dihydroxyvitamin D-receptor complex for the DNA binding domain secondary
to changes in the structure of receptor zinc binding fingers [54]

The treatment of HVDRR is discussed in detail separately. (See "Etiology and treatment of calcipenic rickets in
children", section on 'Hereditary resistance to vitamin D'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries
and regions around the world are provided separately. (See "Society guideline links: Vitamin D deficiency".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
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the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Vitamin D deficiency (The Basics)")

● Beyond the Basics topics (see "Patient education: Vitamin D deficiency (Beyond the Basics)")
SUMMARY

● Vitamin D deficiency can be caused by several mechanisms (see 'Nutritional deficiency and reduced
cutaneous synthesis' above and 'Deficiency related to abnormal synthesis and catabolism' above and
'Vitamin D resistance' above):

• Impaired availability of vitamin D, secondary to inadequate dietary vitamin D, malabsorptive disorders,

and/or diminished cutaneous synthesis.

• Impaired hydroxylation by the liver to produce 25-hydroxyvitamin D (25[OH]D).

• Increased hepatic catabolism of 25(OH)D.

• Impaired kidney production of 1,25-dihydroxyvitamin D.

• Renal loss of vitamin D and vitamin D-binding proteins.

• End-organ insensitivity (resistance) to vitamin D metabolites is rare. Hereditary vitamin D-resistant

rickets (HVDRR) is associated with end-organ resistance to calcitriol due to variable mutations in the
gene encoding the vitamin D receptor.

● The prevalence of vitamin D deficiency is particularly high in older adults, due to an age-associated decline
in cutaneous vitamin D production, decreased dietary vitamin D intake, and age-dependent intestinal
resistance to calcitriol. Individuals with limited sun exposure and malabsorptive gastrointestinal disease are
also at risk. (See 'Older adults' above.)

● Other aspects of vitamin D deficiency, including its treatment, are discussed separately. (See "Vitamin D
deficiency in adults: Definition, clinical manifestations, and treatment" and "Calcium and vitamin D
supplementation in osteoporosis" and "Vitamin supplementation in disease prevention", section on 'Vitamin
D'.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Zalman Agus, MD, who
contributed to an earlier version of this topic review.

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REFERENCES

1. Binkley N, Novotny R, Krueger D, et al. Low vitamin D status despite abundant sun exposure. J Clin
Endocrinol Metab 2007; 92:2130.
2. Lamberg-Allardt CJ, Outila TA, Kärkkainen MU, et al. Vitamin D deficiency and bone health in healthy adults
in Finland: could this be a concern in other parts of Europe? J Bone Miner Res 2001; 16:2066.
3. Tsai KS, Wahner HW, Offord KP, et al. Effect of aging on vitamin D stores and bone density in women. Calcif
Tissue Int 1987; 40:241.
4. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3:
exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J
Clin Endocrinol Metab 1988; 67:373.
5. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest
1985; 76:1536.
 6. Czernichow S, Fan T, Nocea G, Sen SS. Calcium and vitamin D intake by postmenopausal women with
osteoporosis in France. Curr Med Res Opin 2010; 26:1667.
7. de Jongh RT, van Schoor NM, Lips P. Changes in vitamin D endocrinology during aging in adults. Mol Cell
Endocrinol 2017; 453:144.
8. Harris SS, Soteriades E, Coolidge JA, et al. Vitamin D insufficiency and hyperparathyroidism in a low
income, multiracial, elderly population. J Clin Endocrinol Metab 2000; 85:4125.
9. Passeri G, Pini G, Troiano L, et al. Low vitamin D status, high bone turnover, and bone fractures in
centenarians. J Clin Endocrinol Metab 2003; 88:5109.
10. Krall EA, Sahyoun N, Tannenbaum S, et al. Effect of vitamin D intake on seasonal variations in parathyroid
hormone secretion in postmenopausal women. N Engl J Med 1989; 321:1777.
11. Gloth FM 3rd, Gundberg CM, Hollis BW, et al. Vitamin D deficiency in homebound elderly persons. JAMA
1995; 274:1683.
12. Holick MF, Siris ES, Binkley N, et al. Prevalence of Vitamin D inadequacy among postmenopausal North
American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005; 90:3215.
13. Callaghan AL, Moy RJ, Booth IW, et al. Incidence of symptomatic vitamin D deficiency. Arch Dis Child 2006;
91:606.
14. Lawson M, Thomas M. Vitamin D concentrations in Asian children aged 2 years living in England:
population survey. BMJ 1999; 318:28.
15. Silva CM, Silva SAD, Antunes MMC, et al. Do infants with cow's milk protein allergy have inadequate levels
of vitamin D? J Pediatr (Rio J) 2017; 93:632.
16. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young
adults. Am J Med 2002; 112:659.
17. Sham L, Yeh EA, Magalhaes S, et al. Evaluation of fall Sun Exposure Score in predicting vitamin D status in
young Canadian adults, and the influence of ancestry. J Photochem Photobiol B 2015; 145:25.
18. Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med
1998; 338:777.
19. Perin A, Zanatta E, Pigatto E, et al. Hypovitaminosis D in an hospitalized old population of Western Friuli.
Reumatismo 2012; 64:166.
20. Ramel A, Jonsson PV, Bjornsson S, Thorsdottir I. Vitamin D deficiency and nutritional status in elderly
hospitalized subjects in Iceland. Public Health Nutr 2009; 12:1001.
21. Guardia G, Parikh N, Eskridge T, et al. Prevalence of vitamin D depletion among subjects seeking advice on
osteoporosis: a five-year cross-sectional study with public health implications. Osteoporos Int 2008; 19:13.
22. Nitta K, Nagano N, Tsuchiya K. Fibroblast growth factor 23/klotho axis in chronic kidney disease. Nephron
Clin Pract 2014; 128:1.
23. LaClair RE, Hellman RN, Karp SL, et al. Prevalence of calcidiol deficiency in CKD: a cross-sectional study
across latitudes in the United States. Am J Kidney Dis 2005; 45:1026.
24. Taskapan H, Ersoy FF, Passadakis PS, et al. Severe vitamin D deficiency in chronic renal failure patients on
peritoneal dialysis. Clin Nephrol 2006; 66:247.
25. Elder GJ, Mackun K. 25-Hydroxyvitamin D deficiency and diabetes predict reduced BMD in patients with
chronic kidney disease. J Bone Miner Res 2006; 21:1778.
26. Compston JE. Hepatic osteodystrophy: vitamin D metabolism in patients with liver disease. Gut 1986;
27:1073.
27. Dibble JB, Sheridan P, Losowsky MS. A survey of vitamin D deficiency in gastrointestinal and liver disorders.
Q J Med 1984; 53:119.
28. Kumar R. Hepatic and intestinal osteodystrophy and the hepatobiliary metabolism of vitamin D. Ann Intern
Med 1983; 98:662.
29. Shaker JL, Brickner RC, Findling JW, et al. Hypocalcemia and skeletal disease as presenting features of
celiac disease. Arch Intern Med 1997; 157:1013.
30. Peterson LA, Zeng X, Caufield-Noll CP, et al. Vitamin D status and supplementation before and after bariatric
surgery: a comprehensive literature review. Surg Obes Relat Dis 2016; 12:693.
31. Awumey EM, Mitra DA, Hollis BW, et al. Vitamin D metabolism is altered in Asian Indians in the southern
United States: a clinical research center study. J Clin Endocrinol Metab 1998; 83:169.
32. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific
musculoskeletal pain. Mayo Clin Proc 2003; 78:1463.
33. Donovan DS Jr, Papadopoulos A, Staron RB, et al. Bone mass and vitamin D deficiency in adults with
advanced cystic fibrosis lung disease. Am J Respir Crit Care Med 1998; 157:1892.
34. Klein GL, Chen TC, Holick MF, et al. Synthesis of vitamin D in skin after burns. Lancet 2004; 363:291.
35. Molin A, Wiedemann A, Demers N, et al. Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency):
A Rare Condition or a Misdiagnosed Condition? J Bone Miner Res 2017; 32:1893.
36. Hahn TJ. Drug-induced disorders of vitamin D and mineral metabolism. Clin Endocrinol Metab 1980; 9:107.
37. Sotaniemi EA, Hakkarainen HK, Puranen JA, Lahti RO. Radiologic bone changes and hypocalcemia with
anticonvulsant therapy in epilepsy. Ann Intern Med 1972; 77:389.
38. Välimäki MJ, Tiihonen M, Laitinen K, et al. Bone mineral density measured by dual-energy x-ray
absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J
Bone Miner Res 1994; 9:631.
39. Kovacs CS, Jones G, Yendt ER. Primary hyperparathyroidism masked by antituberculous therapy-induced
vitamin D deficiency. Clin Endocrinol (Oxf) 1994; 41:831.
40. Fortenbery EJ, McDermott MT, Duncan WE. Effect of theophylline on calcium metabolism and circulating
vitamin D metabolites. J Bone Miner Res 1990; 5:321.
41. Meier C, Kraenzlin ME. Antiepileptics and bone health. Ther Adv Musculoskelet Dis 2011; 3:235.
42. Collins N, Maher J, Cole M, et al. A prospective study to evaluate the dose of vitamin D required to correct
low 25-hydroxyvitamin D levels, calcium, and alkaline phosphatase in patients at risk of developing
antiepileptic drug-induced osteomalacia. Q J Med 1991; 78:113.
43. Aggarwal A, Yadav AK, Ramachandran R, et al. Bioavailable vitamin D levels are reduced and correlate with
bone mineral density and markers of mineral metabolism in adults with nephrotic syndrome. Nephrology
(Carlton) 2016; 21:483.
44. Selewski DT, Chen A, Shatat IF, et al. Vitamin D in incident nephrotic syndrome: a Midwest Pediatric
Nephrology Consortium study. Pediatr Nephrol 2016; 31:465.
45. Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in health and disease. N
Engl J Med 1989; 320:980.
46. Malloy PJ, Feldman D. Genetic disorders and defects in vitamin d action. Endocrinol Metab Clin North Am
2010; 39:333.
47. Wang X, Zhang MY, Miller WL, Portale AA. Novel gene mutations in patients with 1alpha-hydroxylase
deficiency that confer partial enzyme activity in vitro. J Clin Endocrinol Metab 2002; 87:2424.
 48. Kitanaka S, Takeyama K, Murayama A, Kato S. The molecular basis of vitamin D-dependent rickets type I.
Endocr J 2001; 48:427.
49. Kato S. Genetic mutation in the human 25-hydroxyvitamin D3 1alpha-hydroxylase gene causes vitamin D-
dependent rickets type I. Mol Cell Endocrinol 1999; 156:7.
50. Li YC, Pirro AE, Amling M, et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-
dependent rickets type II with alopecia. Proc Natl Acad Sci U S A 1997; 94:9831.
51. Whitfield GK, Selznick SH, Haussler CA, et al. Vitamin D receptors from patients with resistance to 1,25-
dihydroxyvitamin D3: point mutations confer reduced transactivation in response to ligand and impaired
interaction with the retinoid X receptor heterodimeric partner. Mol Endocrinol 1996; 10:1617.
52. Brooks MH, Bell NH, Love L, et al. Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-
dihydroxyvitamin D. N Engl J Med 1978; 298:996.
53. Yagi H, Ozono K, Miyake H, et al. A new point mutation in the deoxyribonucleic acid-binding domain of the
vitamin D receptor in a kindred with hereditary 1,25-dihydroxyvitamin D-resistant rickets. J Clin Endocrinol
Metab 1993; 76:509.
54. Malloy PJ, Weisman Y, Feldman D. Hereditary 1 alpha,25-dihydroxyvitamin D-resistant rickets resulting from
a mutation in the vitamin D receptor deoxyribonucleic acid-binding domain. J Clin Endocrinol Metab 1994;
78:313.
55. Rut AR, Hewison M, Kristjansson K, et al. Two mutations causing vitamin D resistant rickets: modelling on
the basis of steroid hormone receptor DNA-binding domain crystal structures. Clin Endocrinol (Oxf) 1994;
41:581.
56. Malloy PJ, Eccleshall TR, Gross C, et al. Hereditary vitamin D resistant rickets caused by a novel mutation in
the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness. J
Clin Invest 1997; 99:297.
57. Sakai Y, Kishimoto J, Demay MB. Metabolic and cellular analysis of alopecia in vitamin D receptor knockout
mice. J Clin Invest 2001; 107:961.
58. Chen CH, Sakai Y, Demay MB. Targeting expression of the human vitamin D receptor to the keratinocytes of
vitamin D receptor null mice prevents alopecia. Endocrinology 2001; 142:5386.
59. Malloy PJ, Wang J, Srivastava T, Feldman D. Hereditary 1,25-dihydroxyvitamin D-resistant rickets with
alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor.
Mol Genet Metab 2010; 99:72.
60. Forghani N, Lum C, Krishnan S, et al. Two new unrelated cases of hereditary 1,25-dihydroxyvitamin D-
resistant rickets with alopecia resulting from the same novel nonsense mutation in the vitamin D receptor
gene. J Pediatr Endocrinol Metab 2010; 23:843.
61. Hewison M, Rut AR, Kristjansson K, et al. Tissue resistance to 1,25-dihydroxyvitamin D without a mutation
of the vitamin D receptor gene. Clin Endocrinol (Oxf) 1993; 39:663.

Topic 2048 Version 15.0

GRAPHICS

Pathways of vitamin D synthesis

Metabolic activation of vitamin D to calcitriol and its effects on calcium and phosphate
homeostasis. The result is an increase in the serum calcium and phosphate concentrations.

UV: ultraviolet.

Graphic 65360 Version 5.0

Causes of vitamin D deficiency or resistance

Deficient intake or absorption

Dietary

Malabsorption

Gastric bypass (bariatric surgery, gastrectomy)

Small bowel disease

Pancreatic insufficiency

Decreased skin synthesis

Inadequate sunlight exposure

Full sunscreen use 

Darkly pigmented skin

Defective 25-hydroxylation
Cirrhosis

Increased catabolism of vitamin D to inactive metabolites

Anticonvulsants

Loss of vitamin D binding protein

Nephrotic syndrome

Defective 1-alpha 25-hydroxylation

Hypoparathyroidism

Renal failure

1-alpha hydroxylase deficiency (vitamin D-dependent rickets, type 1)

Defective target organ response to calcitriol

Hereditary vitamin D-resistant rickets (vitamin D-dependent rickets, type 2)

Graphic 58837 Version 6.0

Vitamin D deficiency rickets in a child

Characteristic findings of rickets in children often include radiographic evidence of

decreased mineralization around the epiphyses and bowing of the lower extremities.

http://www.asbmr.org.

Graphic 53635 Version 2.0

Contributor Disclosures
Marc K Drezner, MD Nothing to disclose Clifford J Rosen, MD Nothing to disclose Jean E Mulder, MD Nothing
to disclose

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