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Causes of vitamin D deficiency and resistance

Causes of vitamin D deficiency and resistance
Author:
Bess Dawson-Hughes, MD
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jun 2022. | This topic last updated: Jul 06, 2021.

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 "Hypophosphatemia: Causes of hypophosphatemia" and "Etiology of hypocalcemia in adults".)

DEFINITION — Measurement of 25-hydroxyvitamin D (25[OH]D) is the best index for determination of normal or subnormal vitamin D in the body. However, the optimal serum 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. The majority of groups define vitamin D sufficiency as a 25(OH)D concentration greater than 20 ng/mL (50 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 D3 (cholecalciferol) is normally synthesized in the skin under the influence of sunlight in a nonenzymatic manner and is also available in foods of animal origin (eg, fish and egg yolks). In addition, vitamin D2 (ergocalciferol) may be ingested in limited amounts from plant sources (eg, some mushrooms and yeast). Vitamin D is then hydroxylated in the liver to 25-hydroxyvitamin D (calcidiol or calcifediol, 25[OH]D), which is the major circulating form of vitamin D and the widely used index of vitamin D sufficiency (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 adults. 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], levels well below the recommended intake. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Optimal intake to prevent deficiency'.)

Many clinicians believe that there is an age-dependent resistance to calcitriol that limits calcium absorption [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. The prevalence varies considerably among different countries and subpopulations because of differences in risk factors, especially skin pigmentation, sun exposure, and dietary vitamin D intake. (See "Vitamin D insufficiency and deficiency in children and adolescents".)

Vitamin D deficiency is also a concern for breastfed infants, particularly those who are exclusively breastfed [13]. (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 [14]. 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 [15].

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]) [16]. 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 [17,18]. 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 [16].

In a study of 135 patients admitted directly to an intensive care unit in Barcelona, Spain, the mean 25(OH)D level was 11 ng/mL [27.5 nmol/L] and the mean of the 63 non-survivors was even lower, at 8.1 ng/mL (20 nmol/L) [19]. It is unclear to what extent the very low 25(OH)D levels in these ill patients may have been the result of systemic inflammation as opposed to insufficient vitamin D substrate [20].

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 adult 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 "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Metabolic bone disorders'.)

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, in patients treated with variable amounts of vitamin D, 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 supplementation with doses of <800 international units daily in patients with vitamin D deficiency was, in general, insufficient, suggesting malabsorption and suboptimal treatment. Use of higher doses of vitamin D or use of the less hydrophobic (more absorbable) calcidiol may be necessary to sustain a normal level of serum 25(OH)D. (See "Bariatric surgery: Postoperative nutritional management", section on 'Vitamin D'.)

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.

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 urban 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]) [31]. 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 [32], 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 [33].

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) [34]. 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 and increases the circulating concentration of 25(OH)D only negligibly, while administration of 25(OH)D (calcidiol) therapy results in dramatic improvements in clinical symptoms, biochemical abnormalities, and bone densitometry. Patients with a heterozygous mutation of CYP2R1 may have more moderate biochemical and clinical features of vitamin D deficiency than those with a homozygous defect and, in accord, respond favorably to large doses of vitamin D, which supports a semidominant inheritance of these mutations [35]. (See "Etiology and treatment of calcipenic rickets in children", section on '25-hydroxylase deficiency'.)

Increased catabolism — Certain drugs can increase vitamin D catabolism, which may result in vitamin D deficiency. Phenytoin, phenobarbital, carbamazepine, oxcarbazepine, isoniazid, theophylline, and rifampin increase P450 enzyme activity, which metabolizes calcidiol to inactive vitamin D metabolites, decreasing circulating levels of calcidiol [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 "Antiseizure medications and bone disease", section on 'Effect of ASM type' and "Antiseizure medications 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, hypophosphatemia, and hypocalcemia and inhibited by hyperphosphatemia, hypercalcemia, 1,25-dihydroxyvitamin D, and fibroblast growth factor 23 (FGF23) [45,46]. (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: (1) diminished glomerular filtration; (2) limited availability of the substrate for calcitriol production, secondary to decreased protein (megalin)-mediated reabsorption of glomerular-filtered 25(OH)D in renal proximal tubular epithelial cells; and (3) the loss of the 1-alpha-hydroxylase enzyme secondary to structural renal compromise and suppression of enzyme activity as a consequence of hyperphosphatemia and resultant increased circulating FGF23 levels. The net result is a tendency to hypocalcemia, hyperparathyroidism, and bone disease. (See "Overview of vitamin D", section on 'Renal' and "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: (1) the biochemical evidence of rickets becomes evident, despite a normal circulating level of 25(OH)D, but generally in the presence of low levels of 1,25(OH)2D; and (2) the associated rickets and biochemical abnormalities, which are unresponsive to vitamin D/25(OH)D therapy, can be corrected with 1,25-dihydroxyvitamin D (calcitriol) treatment, maintained for life [47].

This form of rickets is an autosomal recessive disease due to an inactivating mutation in the CYP27B1 gene that encodes 25(OH)D-1-alpha-hydroxylase [48-50]. As a result, calcidiol is not hydroxylated to calcitriol, and calcium is not absorbed normally, resulting in hypocalcemia and an increase in parathyroid hormone levels, which increase 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 120 cases reported, in which inactivating homozygous or compound heterogeneous mutations in the vitamin D receptor gene have been identified, which change amino acids in either the N-terminal, DNA-binding domain (HVDRR type 2A) or the C-terminal ligand-binding domain of the vitamin D receptor protein, causing end-organ resistance to calcitriol (HVDRR type 2B) [47,51-57]. In both forms of this rachitic disease, the serum calcitriol level is markedly elevated, which could be used as a clue for diagnosis in an untreated patients with rickets.

The clinical spectrum of this disorder varies widely, probably reflecting the type of mutation within the vitamin D receptor and the amount of residual vitamin D receptor activity (see "Etiology and treatment of calcipenic rickets in children", section on 'Hereditary resistance to vitamin D'):

HVDRR type 2A – In patients where identified defects occur in the N-terminal, DNA-binding domain of the vitamin D receptor, preventing binding to DNA and causing total 1,25-dihydroxyvitamin D resistance, affected children usually appear normal at birth but develop rickets within the first two years of life (image 1). They also develop alopecia, resulting from the lack of vitamin D receptor action within keratinocytes [58-61]. Additional ectodermal anomalies may also be seen, including multiple milia, epidermal cysts, and oligodontia.

HVDRR type 2B – In patients with mutations in the C-terminal ligand-binding domain of the vitamin D receptor, partial resistance or total resistance occurs due to disruption of 1,25-dihyroxyvitamin D binding, heterodimerization with the retinoid X receptor, or coactivator binding to the vitamin D receptor. Affected patients with this abnormality have the classical phenotype of the HVDRR 2A disease, but without alopecia or other ectodermal anomalies.

The genetic abnormalities affecting the binding domain of the vitamin D receptor protein can cause:

A failure of 1,25-dihydroxyvitamin D binding to available receptors [51].

A reduction in 1,25-dihydroxyvitamin D receptor binding sites [52].

Abnormal binding affinity of 1,25-dihydroxyvitamin D to receptor [57].

Inadequate translocation of 1,25-dihydroxyvitamin D-receptor complex to the nucleus [62].

Alternatively, genetic abnormalities affecting the ligand-binding domain of the vitamin D receptor can cause:

Variably severe 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 [55].

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 articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond 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

Mechanisms – 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.

Prevalence – 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.)

Clinical manifestations and treatment – 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'.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Zalman Agus, MD, and Marc K Drezner, MD, who contributed to earlier versions of this topic review.

  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. 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.
  14. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med 2002; 112:659.
  15. 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.
  16. Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998; 338:777.
  17. Perin A, Zanatta E, Pigatto E, et al. Hypovitaminosis D in an hospitalized old population of Western Friuli. Reumatismo 2012; 64:166.
  18. 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.
  19. Zapatero A, Dot I, Diaz Y, et al. Severe vitamin D deficiency upon admission in critically ill patients is related to acute kidney injury and a poor prognosis. Med Intensiva (Engl Ed) 2018; 42:216.
  20. Duncan A, Talwar D, McMillan DC, et al. Quantitative data on the magnitude of the systemic inflammatory response and its effect on micronutrient status based on plasma measurements. Am J Clin Nutr 2012; 95:64.
  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. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 2003; 78:1463.
  32. 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.
  33. Klein GL, Chen TC, Holick MF, et al. Synthesis of vitamin D in skin after burns. Lancet 2004; 363:291.
  34. 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.
  35. Thacher TD, Levine MA. CYP2R1 mutations causing vitamin D-deficiency rickets. J Steroid Biochem Mol Biol 2016.
  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. Quarles LD. Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res 2012; 318:1040.
  47. Malloy PJ, Feldman D. Genetic disorders and defects in vitamin d action. Endocrinol Metab Clin North Am 2010; 39:333.
  48. 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.
  49. Kitanaka S, Takeyama K, Murayama A, Kato S. The molecular basis of vitamin D-dependent rickets type I. Endocr J 2001; 48:427.
  50. 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.
  51. 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.
  52. 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.
  53. 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.
  54. 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.
  55. 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.
  56. 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.
  57. 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.
  58. Sakai Y, Kishimoto J, Demay MB. Metabolic and cellular analysis of alopecia in vitamin D receptor knockout mice. J Clin Invest 2001; 107:961.
  59. 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.
  60. 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.
  61. 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.
  62. 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.
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