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High Prevalence of Vitamin D Inadequacy and Implications for Health

  • Author Footnotes
    * Dr Holick is an Academic Associate for Nichols Institute Diagnostics.
    Michael F. Holick
    Correspondence
    Individual reprints of this article are not available. Address correspondence to Michael F. Holick, PhD, MD, Vitamin D, Skin and Bone Research Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University School of Medicine, 715 Albany St, Room M-1013, Boston, MA 02118
    Footnotes
    * Dr Holick is an Academic Associate for Nichols Institute Diagnostics.
    Affiliations
    Vitamin D, Skin and Bone Research Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Mass
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  • Author Footnotes
    * Dr Holick is an Academic Associate for Nichols Institute Diagnostics.
      During the past decade, major advances have been made in vitamin D research that transcend the simple concept that vitamin D is important for the prevention of rickets in children and has little physiologic relevance for adults. Inadequate vitamin D, in addition to causing rickets, prevents children from attaining their genetically programmed peak bone mass, contributes to and exacerbates osteoporosis in adults, and causes the often painful bone disease osteomalacia. Adequate vitamin D is also important for proper muscle functioning, and controversial evidence suggests it may help prevent type 1 diabetes mellitus, hypertension, and many common cancers. Vitamin D inadequacy has been reported in approximately 36% of otherwise healthy young adults and up to 57% of general medicine inpatients in the United States and in even higher percentages in Europe. Recent epidemiological data document the high prevalence of vitamin D inadequacy among elderly patients and especially among patients with osteoporosis. Factors such as low sunlight exposure, age-related decreases in cutaneous synthesis, and diets low in vitamin D contribute to the high prevalence of vitamin D inadequacy. Vitamin D production from cutaneous synthesis or intake from the few vitamin D-rich or enriched foods typically occurs only intermittently. Supplemental doses of vitamin D and sensible sun exposure could prevent deficiency in most of the general population. The purposes of this article are to examine the prevalence of vitamin D inadequacy and to review the potential implications for skeletal and extraskeletal health.
      1α(OH)D3 (1α-hydroxyvitamin D3), 1,25(OH)2D (1,25-dihydroxyvitamin D), 25(OH)D (25-hydroxyvitamin D), BMD (bone mineral density), PTH (parathyroid hormone), RCT (randomized controlled trial), RECORD (Record Evaluation of Calcium or Vitamin D), VDR (vitamin D receptor)
      During the past decade, important advances in the study of vitamin D have been made. In addition to its important role in skeletal development and maintenance, evidence is mounting that vitamin D produces beneficial effects on extraskeletal tissues and that the amounts needed for optimal health are probably higher than previously thought.
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      At the same time, numerous reports have shown that relatively high proportions of people have inadequate levels of vitamin D. The extraskeletal health benefits of vitamin D and high prevalence of inadequate levels of vitamin D have been largely unrecognized by both physicians and patients.
      • Grant WB
      • Holick MF
      Benefits and requirements of vitamin D for optimal health: a review.
      The purposes of this review article are to examine the prevalence of vitamin D inadequacy as defined by low serum 25-hydroxyvitamin D (25[OH]D), the major circulating form of vitamin D and standard indicator of vitamin D status, and to review the potential implications on both skeletal and extraskeletal health.

      SOURCES OF VITAMIN D

      Solar UV-B (wavelengths of 290-315 nm) irradiation is the primary source of vitamin D (other than diet supplements) for most people.
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Holick MF
      Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.
      • Holick MF
      Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
      Dietary sources of vitamin D are limited. They include oily fish such as salmon (approximately 400 IU per 3.5 oz), mackerel, and sardines; some fish oils such as cod liver oil (400 IU/tsp); and egg yolks (approximately 20 IU). Some foods are fortified in the United States, including milk (100 IU per 8 oz) and some cereals (100 IU per serving), orange juice (100 IU per 8 oz), some yogurts (100 IU per serving), and margarine.
      • Holick MF
      Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
      • Tangpricha V
      • Koutkia P
      • Rieke SM
      • Chen TC
      • Perez AA
      • Holick MF
      Fortification of orange juice with vitamin D: a novel approach to enhance vitamin D nutritional health.
      • Holick MF
      • Shao Q
      • Liu WW
      • Chen TC
      The vitamin D content of fortified milk and infant formula.
      Milk is not vitamin D enriched in most European countries; however, margarine and some cereals are. There are 2 forms of vitamin D. Vitamin D2 (ergocalciferol) comes from irradiation of the yeast and plant sterol ergosterol, and vitamin D3 (cholecalciferol) is found in oily fish and cod liver oil and is made in the skin. Vitamin D represents vitamin D2 and vitamin D3.
      Vitamin D from cutaneous synthesis or dietary sources typically occurs only intermittently. Irregular intake of vitamin D, irrespective of the source, can lead to chronic vitamin D inadequacy. This condition has been reported across all age groups, geographic regions, and seasons.
      • Gordon CM
      • DePeter KC
      • Feldman HA
      • Grace E
      • Emans SJ
      Prevalence of vitamin D deficiency among healthy adolescents.
      • Outila TA
      • Karkkainen MU
      • Lamberg-Allardt CJ
      Vitamin D status affects serum parathyroid hormone concentrations during winter in female adolescents: associations with forearm bone mineral density.
      • Chapuy MC
      • Preziosi P
      • Maamer M
      • et al.
      Prevalence of vitamin D insufficiency in an adult normal population.
      • Kinyamu HK
      • Gallagher JC
      • Rafferty KA
      • Balhorn KE
      Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites.
      • Malabanan A
      • Veronikis IE
      • Holick MF
      Redefining vitamin D insufficiency [letter].
      • Kauppinen-Mäkelin R
      • Tähtelä R
      • Löyttyniemi E
      • Kärkkäinen J
      • Välimäki MJ
      High prevalence of hypovitaminosis D in Finnish medical in- and outpatients.
      • Looker AC
      • Dawson-Hughes B
      • Calvo MS
      • Gunter EW
      • Sahyoun NR
      Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III.
      • Lips P
      • Duong T
      • Oleksik A
      • et al.
      A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].
      • Sullivan SS
      • Rosen CJ
      • Halteman WA
      • Chen TC
      • Holick MF
      Adolescent girls in Maine are at risk for vitamin D insufficiency.
      • Holick M
      • Jenkins M
      Enhancing vitamin D levels by taking supplements is usually necessary to achieve the minimum recommended daily intakes; however, compliance is often problematic. In particular, some groups who may be at high risk of vitamin D inadequacy often do not follow regular daily dosing guidelines. Adherence to vitamin D supplementation recommendations is low among elderly patients with osteoporosis. One study showed that, despite receiving counseling on the importance of vitamin D and calcium supplementation, 76% of elderly patients with hip fractures did not comply with recommendations.
      • Segal E
      • Zinnman H
      • Raz B
      • Tamir A
      • Ish-Shalom S
      Adherence to vitamin D supplementation in elderly patients after hip fracture [letter].
      This is not surprising given thatcompliance declines as the number of medications increases, and elderly patients often take many medications. Similarly, achieving adequate vitamin D intake through milk consumption is unreliable among elderly patients because of the high prevalence of lactose intolerance among this population and the often low levels of vitamin D in the milk supply.
      • Holick MF
      • Shao Q
      • Liu WW
      • Chen TC
      The vitamin D content of fortified milk and infant formula.

      VITAMIN D PHOTOBIOCHEMISTRY, METABOLISM, AND FUNCTIONS

      UV-B irradiation of skin triggers photolysis of 7-dehydrocholesterol (provitamin D3) to previtamin D3 in the plasma membrane of human skin keratinocytes.
      • Holick MF
      McCollum Award Lecture, 1994: vitamin D—new horizons for the 21st century.
      • MacLaughlin JA
      • Anderson RR
      • Holick MF
      Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin.
      • Holick MF
      • Tian XQ
      • Allen M
      Evolutionary importance for the membrane enhancement of the production of vitamin D3 in the skin of poikilothermic animals.
      Once formed in the skin, cell plasma membrane previtamin D3 is rapidly converted to vitamin D3 by the skin's temperature. Vitamin D3 from the skin and vitamin D from the diet undergo 2 sequential hydroxylations, first in the liver to 25(OH)D and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D (1,25[OH]2D) (Figure 1). Excessive solar UV-B irradiation will not cause vitamin D intoxication because excess vitamin D3 and previtamin D3 are photolyzed to biologically inactive photoproducts.
      • MacLaughlin JA
      • Anderson RR
      • Holick MF
      Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin.
      • Holick MF
      • Tian XQ
      • Allen M
      Evolutionary importance for the membrane enhancement of the production of vitamin D3 in the skin of poikilothermic animals.
      • Webb AR
      • deCosta BR
      • Holick MF
      Sunlight regulates the cutaneous production of vitamin D3 by causing its photodegradation.
      Melanin skin pigmentation is an effective natural sunscreen, and increased skin pigment can greatly reduce UV-B-mediated cutaneous synthesis of vitamin D3 by as much as 99%, similar to applying a sunscreen with a sun protection factor of 15.
      • Clemens TL
      • Adams JS
      • Henderson SL
      • Holick MF
      Increased skin pigment reduces the capacity of skin to synthesise vitamin D3.
      • Matsuoka LY
      • Ide L
      • Wortsman J
      • MacLaughlin JA
      • Holick MF
      Sunscreens supress cutaneous vitamin D3 synthesis.
      Keratinocytes are also capable of hydroxylating 25(OH)D to produce 1,25(OH)2D.
      • Bikle DD
      Vitamin D: role in skin and hair.
      The 1,25(OH)2D (from keratinocyte or renal sources) may regulate keratinocyte differentiation, melanocyte apoptosis, and melanin production,
      • Bikle DD
      Vitamin D: role in skin and hair.
      • Hosomi J
      • Hosoi J
      • Abe E
      • Suda T
      • Kuroki T
      Regulation of terminal differentiation of cultured mouse epidermal cells by 1 alpha, 25-dihydroxyvitamin D3.
      • Smith EL
      • Walworth NC
      • Holick MF
      Effect of 1α,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions.
      and this may be another mechanism for regulating the cutaneous synthesis of vitamin D3 by negative feedback.
      Figure thumbnail gr1
      FIGURE 1Cutaneous production of vitamin D and its metabolism and regulation for calcium homeostasis and cellular growth. 7-Dehydrocholesterol or provitamin D3 (proD3) in the skin absorbs solar UV-B radiation and is converted to previtamin D3 (preD3). D3 undergoes thermally induced (δH) transformation to vitamin D3. Vitamin D from the diet or from the skin is metabolized in the liver by the vitamin D-25-hydroxylase to 25-hydroxyvitamin D3 (25[OH]D3). 25(OH)D3 is converted in the kidney by the 25(OH)D3-1α-hydroxylase to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. A variety of factors, including serum phosphorus (PO2−4) and parathyroid hormone (PTH), regulate the renal production of 1,25(OH)2D3. 1,25(OH)2D regulates calcium metabolism through its interaction with its major target tissues, the bone and the intestine. From Osteoporos Int,
      • Holick MF
      Vitamin D requirements for humans of all ages: new increased requirements for women and men 50 years and older.
      with permission from Springer Science and Business Media.
      The 1,25(OH)2D ligand binds with high affinity to the vitamin D receptor (VDR) and triggers an increase in intestinal absorption of both calcium and phosphorus. In addition, vitamin D is involved in bone formation, resorption, and mineralization and in maintaining neuromuscular function
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Holick MF
      Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.
      (Figure 1). Circulating 1,25(OH)2D reduces serum parathyroid hormone (PTH) levels directly by decreasing parathyroid gland activity and indirectly by increasing serum calcium. The 1,25(OH)2D regulates bone metabolism in part by interacting with the VDR in osteoblasts to release biochemical signals, leading to formation of mature osteoclasts. The osteoclasts release collagenases and hydrochloric acid to dissolve the matrix and mineral, releasing calcium into the blood.
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Holick MF
      Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.
      • Holick MF
      Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
      When vitamin D levels are inadequate, calcium and phosphorus homeostasis becomes impaired. Vitamin D is primarily responsible for regulating the efficiency of intestinal calcium absorption. In a low vitamin D state, the small intestine can absorb approximately 10% to 15% of dietary calcium. When vitamin D levels are adequate, intestinal absorption of dietary calcium more than doubles, rising to approximately 30% to 40%.
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Holick MF
      Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.
      • Holick MF
      Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
      • Heaney RP
      • Dowell MS
      • Hale CA
      • Bendich A
      Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D.
      Thus, when vitamin D levels (25[OH]D) are low, calcium absorption is insufficient to satisfy the calcium requirements not only for bone health but also for most metabolic functions and neuromuscular activity. The body responds by increasing the production and release of PTH into the circulation (Figure 1). The increase in PTH restores calcium homeostasis by increasing tubular reabsorption of calcium in the kidney, increasing bone calcium mobilization from the bone, and enhancing the production of 1,25(OH)2 D.
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Holick MF
      Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.

      ASSESSMENT OF VITAMIN D STATUS

      Serum 25(OH)D is the major circulating metabolite of vitamin D and reflects vitamin D inputs from cutaneous synthesis and dietary intake. The serum 25(OH)D level is the standard clinical measure of vitamin D status.
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Lips P
      • Duong T
      • Oleksik A
      • et al.
      A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].
      Although 1,25(OH)2D is the active form of vitamin D, it should not be measured to determine vitamin D status. It usually is normal or even elevated in patients with vitamin D deficiency.
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Holick MF
      Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.
      • Holick MF
      Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
      Testing of serum 25(OH)D is most useful in patients who are at risk of vitamin D deficiency, including elderly patients, infirm patients, children and adults with increased skin pigmentation, patients with fat malabsorption syndromes, and patients with osteoporosis. This measurement is also useful for purposes of planning or monitoring vitamin D therapy. Clinical assays of 25(OH)D include the Nichols Advantage Assay (chemiluminescence protein-binding assay, the DiaSorin radioimmunoassay, and the benchmark high-performance liquid chromatography assays
      • Binkley N
      • Krueger D
      • Cowgill CS
      • et al.
      Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization.
      and liquid chromatography mass spectroscopy assays.
      • Holick MF
      • Siris ES
      • Binkley N
      • et al.
      Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
      The chemiluminescence protein-binding assay and the radioimmunoassay are most commonly used to determine patient vitamin D status. Recent reports have raised concerns about the degree of variability between assays and between laboratories, even when using the same assay.
      • Binkley N
      • Krueger D
      • Cowgill CS
      • et al.
      Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization.
      • Holick MF
      • Siris ES
      • Binkley N
      • et al.
      Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
      • Lips P
      • Chapuy MC
      • Dawson-Hughes B
      • Pols HA
      • Holick MF
      An international comparision of serum 25-hydroxyvitamin D measurements.
      • Holick MF
      25-OH-vitamin D assays [letter].
      • Glendenning P
      • Fraser WD
      25-OH-vitamin D assays [letter].
      Although reliable and consistent evaluation of serum 25(OH)D levels remains an issue, reliable laboratories currently exist, and efforts are in progress to improve and standardize assays to enhance accuracy and reproducibility at other laboratories.
      • Holick MF
      • Siris ES
      • Binkley N
      • et al.
      Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
      • Holick MF
      25-OH-vitamin D assays [letter].
      • Glendenning P
      • Fraser WD
      25-OH-vitamin D assays [letter].
      As noted previously, vitamin D plays a central role in calcium and phosphorus homeostasis and skeletal health. Since impaired calcium metabolism due to low serum 25(OH)D levels triggers secondary hyperparathyroidism, increased bone turnover, and progressive bone loss,
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Lips P
      Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications.
      • Heaney RP
      Functional indices of vitamin D status and ramifications of vitamin D deficiency.
      • McKenna MJ
      • Freany R
      Secondary hyperparathyroidism in the elderly: means to defining hypovitaminosis D.
      • Krall EA
      • Sahyoun N
      • Tannenbaum S
      • Dallal GE
      • Dawson-Hughes B
      Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women.
      • Kinyamu HK
      • Gallagher JC
      • Balhorn KE
      • Petranick KM
      • Rafferty KA
      Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women living in nursing homes [published correction appears in Am J Clin Nutr. 1997;66:454].
      the optimal range of circulating 25(OH)D for skeletal health has been proposed as the range that reduces PTH levels to a minimum
      • Chapuy MC
      • Preziosi P
      • Maamer M
      • et al.
      Prevalence of vitamin D insufficiency in an adult normal population.
      • Malabanan A
      • Veronikis IE
      • Holick MF
      Redefining vitamin D insufficiency [letter].
      • Heaney RP
      Functional indices of vitamin D status and ramifications of vitamin D deficiency.
      and calcium absorption is maximal.
      • Heaney RP
      • Dowell MS
      • Hale CA
      • Bendich A
      Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D.
      Several studies have shown that PTH levels plateau to a minimum steady-state level as serum 25(OH)D levels approach and rise above approximately 30 ng/mL (75 nmol/L)
      • Chapuy MC
      • Preziosi P
      • Maamer M
      • et al.
      Prevalence of vitamin D insufficiency in an adult normal population.
      • Holick MF
      • Siris ES
      • Binkley N
      • et al.
      Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
      • Heaney RP
      Functional indices of vitamin D status and ramifications of vitamin D deficiency.
      • McKenna MJ
      • Freany R
      Secondary hyperparathyroidism in the elderly: means to defining hypovitaminosis D.
      • Krall EA
      • Sahyoun N
      • Tannenbaum S
      • Dallal GE
      • Dawson-Hughes B
      Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women.
      • Kinyamu HK
      • Gallagher JC
      • Balhorn KE
      • Petranick KM
      • Rafferty KA
      Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women living in nursing homes [published correction appears in Am J Clin Nutr. 1997;66:454].
      (Figure 2, left).
      Figure thumbnail gr2
      FIGURE 2Left, Relationship between serum 25-hydroxyvitamin D (25[OH]D) concentrations and mean ± SE (error bars) serum concentrations of parathyroid hormone in patients with osteoporosis receiving treatment. Right, Percentage of subjects with secondary hyperparathyroidism by 25(OH)D level. The percentage of subjects with secondary hyperparathyroidism (parathyroid hormone level >40 pg/mL) sorted by subgroups with serum 25(OH)D concentrations delineated by predefined cutoffs for analyses of 25(OH)D inadequacy. Left and right, From J Endocrinol Metab,
      • Holick MF
      • Siris ES
      • Binkley N
      • et al.
      Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
      with permission from The Endocrine Society, Copyright 2005.

      EPIDEMIOLOGY OF VITAMIN D INADEQUACY

      Vitamin D inadequacy constitutes a largely unrecognized epidemic in many populations worldwide.
      • Gaugris S
      • Heaney RP
      • Boonen S
      • Kurth H
      • Bentkover JD
      • Sen SS
      Vitamin D inadequacy among post-menopausal women: a systematic review.
      • Isaia G
      • Giorgino R
      • Rini GB
      • Bevilacqua M
      • Maugeri D
      • Adami S
      Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors.
      • Plotnikoff GA
      • Quigley JM
      Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain.
      • Carnevale V
      • Manfredi G
      • Romagonoli E
      • et al.
      Vitamin D status in female patients with primary hyperparathyroidism: does it play a role in skeletal damage?.
      • Harwood RH
      • Sahota O
      • Gaynor K
      • Masud T
      • Hosking DJ
      A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study.
      • Glowacki J
      • Hurwitz S
      • Thornhill TS
      • Kelly M
      • LeBoff MS
      Osteoporosis and vitamin-D deficiency among postmenopausal women with osteoarthritis undergoing total hip arthroplasty.
      • Gomez-Alonso C
      • Naves-Diaz ML
      • Fernandez-Martin JL
      • Diaz-Lopez JB
      • Fernandez-Coto MT
      • Cannata-Andia JB
      Vitamin D status and secondary hyperparathyroidism: the importance of 25-hydroxyvitamin D cut-off levels.
      • Blau EM
      • Brenneman SK
      • Bruning AL
      • Chen Y
      Prevalence of vitamin D insufficiency in an osteoporosis population in Southern California [abstract].
      • Simonelli C
      • Weiss TW
      • Morancey J
      • Swanson L
      • Chen YT
      Prevalence of vitamin D inadequacy in a minimal trauma fracture population.
      It has been reported in healthy children,
      • Gordon CM
      • DePeter KC
      • Feldman HA
      • Grace E
      • Emans SJ
      Prevalence of vitamin D deficiency among healthy adolescents.
      • Outila TA
      • Karkkainen MU
      • Lamberg-Allardt CJ
      Vitamin D status affects serum parathyroid hormone concentrations during winter in female adolescents: associations with forearm bone mineral density.
      • Looker AC
      • Dawson-Hughes B
      • Calvo MS
      • Gunter EW
      • Sahyoun NR
      Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III.
      • Sullivan SS
      • Rosen CJ
      • Halteman WA
      • Chen TC
      • Holick MF
      Adolescent girls in Maine are at risk for vitamin D insufficiency.
      • El-HajjFuleihan G
      • Nabulsi M
      • Choucair M
      • et al.
      Hypovitaminosis D in healthy schoolchildrren.
      young adults,
      • Kinyamu HK
      • Gallagher JC
      • Balhorn KE
      • Petranick KM
      • Rafferty KA
      Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women living in nursing homes [published correction appears in Am J Clin Nutr. 1997;66:454].
      • Gaugris S
      • Heaney RP
      • Boonen S
      • Kurth H
      • Bentkover JD
      • Sen SS
      Vitamin D inadequacy among post-menopausal women: a systematic review.
      • Tangpricha V
      • Pearce EN
      • Chen TC
      • Holick MF
      Vitamin D insufficiency among free-living healthy young adults.
      especially African Americans,
      • Gordon CM
      • DePeter KC
      • Feldman HA
      • Grace E
      • Emans SJ
      Prevalence of vitamin D deficiency among healthy adolescents.
      • Plotnikoff GA
      • Quigley JM
      Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain.
      • Carnevale V
      • Manfredi G
      • Romagonoli E
      • et al.
      Vitamin D status in female patients with primary hyperparathyroidism: does it play a role in skeletal damage?.
      • Tangpricha V
      • Pearce EN
      • Chen TC
      • Holick MF
      Vitamin D insufficiency among free-living healthy young adults.
      • Nesby-O'Dell S
      • Scanlon KS
      • Cogswell ME
      • et al.
      Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994.
      and middle-aged and elderly adults.
      • Chapuy MC
      • Preziosi P
      • Maamer M
      • et al.
      Prevalence of vitamin D insufficiency in an adult normal population.
      • Kinyamu HK
      • Gallagher JC
      • Rafferty KA
      • Balhorn KE
      Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites.
      • Malabanan A
      • Veronikis IE
      • Holick MF
      Redefining vitamin D insufficiency [letter].
      • Kauppinen-Mäkelin R
      • Tähtelä R
      • Löyttyniemi E
      • Kärkkäinen J
      • Välimäki MJ
      High prevalence of hypovitaminosis D in Finnish medical in- and outpatients.
      • Lips P
      • Duong T
      • Oleksik A
      • et al.
      A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].
      • McKenna MJ
      • Freany R
      Secondary hyperparathyroidism in the elderly: means to defining hypovitaminosis D.
      • Krall EA
      • Sahyoun N
      • Tannenbaum S
      • Dallal GE
      • Dawson-Hughes B
      Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women.
      • Isaia G
      • Giorgino R
      • Rini GB
      • Bevilacqua M
      • Maugeri D
      • Adami S
      Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors.
      • Harwood RH
      • Sahota O
      • Gaynor K
      • Masud T
      • Hosking DJ
      A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study.
      • Glowacki J
      • Hurwitz S
      • Thornhill TS
      • Kelly M
      • LeBoff MS
      Osteoporosis and vitamin-D deficiency among postmenopausal women with osteoarthritis undergoing total hip arthroplasty.
      • Gomez-Alonso C
      • Naves-Diaz ML
      • Fernandez-Martin JL
      • Diaz-Lopez JB
      • Fernandez-Coto MT
      • Cannata-Andia JB
      Vitamin D status and secondary hyperparathyroidism: the importance of 25-hydroxyvitamin D cut-off levels.
      • Blau EM
      • Brenneman SK
      • Bruning AL
      • Chen Y
      Prevalence of vitamin D insufficiency in an osteoporosis population in Southern California [abstract].
      • Simonelli C
      • Weiss TW
      • Morancey J
      • Swanson L
      • Chen YT
      Prevalence of vitamin D inadequacy in a minimal trauma fracture population.
      • El-HajjFuleihan G
      • Nabulsi M
      • Choucair M
      • et al.
      Hypovitaminosis D in healthy schoolchildrren.
      • Tangpricha V
      • Pearce EN
      • Chen TC
      • Holick MF
      Vitamin D insufficiency among free-living healthy young adults.
      • Hanley DA
      • Davison KS
      Vitamin D insufficiency in North America.
      • Romagnoli E
      • Caravella P
      • Scarnecchia L
      • Martinez P
      • Minisola S
      Hypovitaminosis D in an Italian population of healthy subjects and hospitalized patients.
      • van der Wielen RP
      • Lowik MR
      • van den Berg H
      • et al.
      Serum vitamin D concentrations among elderly people in Europe.
      • Gloth III, FM
      • Gundberg CM
      • Hollis BW
      • Haddad Jr, JG
      • Tobin JD
      Vitamin D deficiency in homebound elderly persons.
      • Passeri G
      • Pini G
      • Troiano L
      • et al.
      Low vitamin D status, high bone turnover, and bone fractures in centenarians.
      • Harris SS
      • Soteriades E
      • Coolidge JA
      • Mudgal S
      • Dawson-Hughes B
      Vitamin D insufficiency and hyperparathyroidism in a low income, multiracial, elderly population.
      Typically, the prevalence of low 25(OH)D levels (<20 ng/mL [50 nmol/L]) is approximately 36% in otherwise healthy young adults aged 18 to 29 years,
      • Tangpricha V
      • Pearce EN
      • Chen TC
      • Holick MF
      Vitamin D insufficiency among free-living healthy young adults.
      42% in black women aged 15 to 49 years,
      • Nesby-O'Dell S
      • Scanlon KS
      • Cogswell ME
      • et al.
      Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994.
      41% in outpatients aged 49 to 83 years,
      • Malabanan A
      • Veronikis IE
      • Holick MF
      Redefining vitamin D insufficiency [letter].
      up to 57% in general medicine inpatients in the United States,
      • Thomas MK
      • Lloyd-Jones DM
      • Thadhani RI
      • et al.
      Hypovitaminosis D in medical inpatients.
      and even higher in Europe (28%-100% of healthy and 70%-100% of hospitalized adults).
      • Isaia G
      • Giorgino R
      • Rini GB
      • Bevilacqua M
      • Maugeri D
      • Adami S
      Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors.
      • Passeri G
      • Pini G
      • Troiano L
      • et al.
      Low vitamin D status, high bone turnover, and bone fractures in centenarians.
      • McKenna MJ
      Differences in vitamin D status between countries in young adults and the elderly.
      Vitamin D inadequacy is particularly common among patients with osteoporosis (Table 1). A recent systematic review by Gaugris et al
      • Gaugris S
      • Heaney RP
      • Boonen S
      • Kurth H
      • Bentkover JD
      • Sen SS
      Vitamin D inadequacy among post-menopausal women: a systematic review.
      concluded that the prevalence of inadequate 25(OH)D levels appears to be high in postmenopausal women and especially those with osteoporosis and a history of fracture. This review, which included 30 studies published between January 1994 and April 2004, examined the prevalence of vitamin D inadequacy reported as serum 25(OH)D levels below various values. The results of a recent cross-sectional, observational study conducted at 61 sites across North America showed that 52% of postmenopausal women receiving therapy for osteoporosis had 25(OH)D levels of less than 30 ng/mL (75 nmol/L).
      • Holick MF
      • Siris ES
      • Binkley N
      • et al.
      Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
      The high prevalence of vitamin D inadequacy in that study was consistent across all age groups and North American geographic regions studied.
      • Holick MF
      • Siris ES
      • Binkley N
      • et al.
      Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
      The prevalence of very low serum 25(OH)D levels (<12 ng/mL [30 nmol/L]) was 76% among patients with osteoporosis in another study.
      • Passeri G
      • Pini G
      • Troiano L
      • et al.
      Low vitamin D status, high bone turnover, and bone fractures in centenarians.
      A global study of vitamin D status in postmenopausal women with osteoporosis showed that 24% had 25(OH)D levels less than 10 ng/mL (25 nmol/L), with the highest prevalence reported in central and southern Europe.
      • Lips P
      • Duong T
      • Oleksik A
      • et al.
      A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].
      Vitamin D inadequacy is common even among patients with osteoporosis living at lower latitudes in highly sunny climates. For instance, 53% of community-dwelling women with osteoporosis living in Southern California had 25(OH)D levels less than 30 ng/mL (75 nmol/L).
      • Blau EM
      • Brenneman SK
      • Bruning AL
      • Chen Y
      Prevalence of vitamin D insufficiency in an osteoporosis population in Southern California [abstract].
      In a study of patients 50 years and older hospitalized for nontraumatic fractures, 97% had 25(OH)D levels less than 30 ng/mL (75 nmol/L).
      • Simonelli C
      • Morancey JA
      • Swanson L
      • et al.
      A high prevalence of vitamin D insufficiency/deficiency in a minimal trauma fracture population [abstract].
      Studies in the United Kingdom and South Africa reported that 13% to 33% of patients with hip fractures had histological evidence of osteomalacia that may have been caused by chronic vitamin D deficiency.
      • LeBoff MS
      • Kohlmeier L
      • Hurwitz S
      • Franklin J
      • Wright J
      • Glowacki J
      Occult vitamin D deficiency in postmenopausal US women with acute hip fracture.
      • Aaron JE
      • Gallagher JC
      • Anderson J
      • et al.
      Frequency of osteomalacia and osteoporosis in fractures of the proximal femur.
      • Solomon L
      Fracture of the femoral neck in the elderly: bone ageing or disease?.
      • Hordon LD
      • Peacock M
      Osteomalacia and osteoporosis in femoral neck fracture.
      TABLE 1Vitamin D Inadequacy in Osteoporosis: Summary of Reports Published in 2003 and 2004
      25(OH)D = 25-hydroxyvitamin D; B = both low sun/winter-spring and high sun/summer-fall; L = low sun/winter-spring; NA = not available.
      ReferencePopulation characteristicsLocationSeasonSample sizeMean age (y)Prevalence of low serum 25(OH)D (%)Definition of low serum vitamin D (ng/mL)
      Isaia et al,
      • Isaia G
      • Giorgino R
      • Rini GB
      • Bevilacqua M
      • Maugeri D
      • Adami S
      Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors.
      2003
      Elderly women referred to an osteoporosis centerItalyB7006827<5
      76<12
      Plotnikoff et al,
      • Plotnikoff GA
      • Quigley JM
      Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain.
      2003
      Various ethnic groups referred for chronic musculoskeletal painMinnesotaB15010-65 (range)33<8
      93<20
      Carnevale et al,
      • Carnevale V
      • Manfredi G
      • Romagonoli E
      • et al.
      Vitamin D status in female patients with primary hyperparathyroidism: does it play a role in skeletal damage?.
      2004
      Patients with primary hyperparathyroidismItalyB625027<12
      Harwood et al,
      • Harwood RH
      • Sahota O
      • Gaynor K
      • Masud T
      • Hosking DJ
      A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study.
      2004
      Female patients with hip fracturesUnited KingdomNA1508170<12
      Glowacki et al,
      • Glowacki J
      • Hurwitz S
      • Thornhill TS
      • Kelly M
      • LeBoff MS
      Osteoporosis and vitamin-D deficiency among postmenopausal women with osteoarthritis undergoing total hip arthroplasty.
      2003
      Postmenopausal osteoarthritic white womenBoston, MassB686622<15
      Segal et al,
      • Segal E
      • Zinnman H
      • Raz B
      • Tamir A
      • Ish-Shalom S
      Adherence to vitamin D supplementation in elderly patients after hip fracture [letter].
      2004
      Patients with hip fracture at time of hospitalizationIsraelB967260<15
      Gomez-Alonso et al,
      • Gomez-Alonso C
      • Naves-Diaz ML
      • Fernandez-Martin JL
      • Diaz-Lopez JB
      • Fernandez-Coto MT
      • Cannata-Andia JB
      Vitamin D status and secondary hyperparathyroidism: the importance of 25-hydroxyvitamin D cut-off levels.
      2003
      Healthy population in osteoporosis studySpainB2686967<18
      Holick et al,
      • Holick MF
      • Siris ES
      • Binkley N
      • et al.
      Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
      2005
      Postmenopausal women receiving antiresorptive or anabolic therapy for osteoporosisNorth AmericaL15367152<30
      Blau et al,
      • Blau EM
      • Brenneman SK
      • Bruning AL
      • Chen Y
      Prevalence of vitamin D insufficiency in an osteoporosis population in Southern California [abstract].
      2004
      Community-dwelling women referred to osteoporosis clinicSouthern CaliforniaL252NA53<30
      Simonelli et al,
      • Simonelli C
      • Weiss TW
      • Morancey J
      • Swanson L
      • Chen YT
      Prevalence of vitamin D inadequacy in a minimal trauma fracture population.
      2005
      Patients hospitalized for nontraumatic fractureMinnesotaL82≥5097<30
      * 25(OH)D = 25-hydroxyvitamin D; B = both low sun/winter-spring and high sun/summer-fall; L = low sun/winter-spring; NA = not available.
      Vitamin D inadequacy is also common among nonwhite populations and populations with low dietary or supplementary vitamin D intake or minimal exposure to sunlight. A study of Asian adults in the United Kingdom showed that 82% had 25(OH)D levels less than 12 ng/mL (30 nmol/L) during the summer season, with the proportion increasing to 94% during the winter months.
      • Pal BR
      • Marshall T
      • James C
      • Shaw NJ
      Distribution analysis of vitamin D highlights differences in population subgroups: preliminary observations from a pilot study in UK adults.
      A study of 1546 African American women in the United States, ranging in age from 15 to 49 years, showed that more than 40% had serum 25(OH)D levels less than 15 ng/mL (37 nmol/L).
      • Nesby-O'Dell S
      • Scanlon KS
      • Cogswell ME
      • et al.
      Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994.
      A much higher proportion (84%) of elderly black adults in Boston, Mass, had serum 25(OH)D levels less than 20 ng/mL (50 nmol/L).
      • Holick MF
      Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.
      Even children are at risk. A cross-sectional clinic-based study of 307 children (11-18 years old) in Boston reported that 52% of African American and Hispanic children had 25(OH)D levels of 20 ng/mL (50 nmol/L) or less.
      • Gordon CM
      • DePeter KC
      • Feldman HA
      • Grace E
      • Emans SJ
      Prevalence of vitamin D deficiency among healthy adolescents.
      Sullivan et al
      • Sullivan SS
      • Rosen CJ
      • Halteman WA
      • Chen TC
      • Holick MF
      Adolescent girls in Maine are at risk for vitamin D insufficiency.
      observed that at the end of winter and summer 48% and 17%, respectively, of white girls (9-11 years of age) in Maine also had 25(OH)D levels less than 20 ng/mL (50 nmol/L). Even in sunny countries such as Lebanon, vitamin D inadequacy is common in schoolchildren.
      • El-HajjFuleihan G
      • Nabulsi M
      • Choucair M
      • et al.
      Hypovitaminosis D in healthy schoolchildrren.

      FACTORS THAT CONTRIBUTE TO VITAMIN D INADEQUACY

      Physical factors that attenuate UV-B exposure, including clothing, sunscreens, and glass shielding, markedly reduce or completely eliminate the production of vitamin D3 in the skin.
      • Holick MF
      McCollum Award Lecture, 1994: vitamin D—new horizons for the 21st century.
      At latitudes above 37°N and below 37°S, sunlight is insufficient to induce cutaneous vitamin D3 synthesis during the winter months.
      • Holick M
      • Jenkins M
      • 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.
      • Chen TC
      Photobiology of vitamin D.
      Nevertheless, latitude is not the only determinant of 25(OH)D levels.
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Holick MF
      Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.
      • Outila TA
      • Karkkainen MU
      • Lamberg-Allardt CJ
      Vitamin D status affects serum parathyroid hormone concentrations during winter in female adolescents: associations with forearm bone mineral density.
      • Park S
      • Johnson MA
      Living in low-latitude regions in the United States does not prevent poor vitamin D status.
      • Kimlin MG
      • Schallhorn KA
      Estimations of the human ‘vitamin D’ UV exposure in the USA.
      • Engelsen O
      • Brustad M
      • Aksnes L
      • Lund E
      Daily duration of vitamin D synthesis in human skin with relation to latitude, total ozone, altitude, ground cover, aerosols and cloud thickness.
      The high prevalence of osteomalacia in Saudi Arabian women, rickets in Saudi children, and vitamin D deficiencies in both may be attributable to their cultural practice of wearing clothing that covers the entire body and avoiding direct sunlight.
      • Taha SA
      • Dost SM
      • Sedrani SH
      25-Hydroxyvitamin D and total calcium: extraordinarily low plasma concentrations in Saudi mothers and their neonates.
      • Sedrani SH
      Low 25-hydroxyvitamin D and normal serum calcium concentrations in Saudi Arabia: Riyadh region.
      Biological factors that inhibit cutaneous vitamin D synthesis and bioavailability include skin pigmentation,
      • Clemens TL
      • Adams JS
      • Henderson SL
      • Holick MF
      Increased skin pigment reduces the capacity of skin to synthesise vitamin D3.
      • Matsuoka LY
      • Wortsman J
      • Chen TC
      • Holick MF
      Compensation for the interracial variance in the cutaneous synthesis of vitamin D.
      • Matsuoka LY
      • Wortsman J
      • Haddad JG
      • Kolm P
      • Hollis BW
      Racial pigmentation and the cutaneous synthesis of vitamin D.
      medication use,
      • Pascussi JM
      • Robert A
      • Nguyen M
      • et al.
      Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia.
      body fat content,
      • Wortsman J
      • Matsuoka LY
      • Chen TC
      • Lu Z
      • Holick MF
      Decreased bioavailability of vitamin D in obesity [published correction appears in Am J Clin Nutr. 2003;77:1342].
      fat malabsorption,
      • Koutkia P
      • Lu Z
      • Chen TC
      • Holick MF
      Treatment of vitamin D deficiency due to Crohn's disease with tanning bed ultraviolet B radiation.
      and age.
      • MacLaughlin J
      • Holick MF
      Aging decreases the capacity of human skin to produce vitamin D3.
      • Holick MF
      • Matsuoka LY
      • Wortsman J
      Age, vitamin D, and solar ultraviolet.
      Increased skin pigmentation can reduce cutaneous vitamin D3 production as much as 99.9%.
      • Clemens TL
      • Adams JS
      • Henderson SL
      • Holick MF
      Increased skin pigment reduces the capacity of skin to synthesise vitamin D3.
      • Matsuoka LY
      • Wortsman J
      • Chen TC
      • Holick MF
      Compensation for the interracial variance in the cutaneous synthesis of vitamin D.
      • Matsuoka LY
      • Wortsman J
      • Haddad JG
      • Kolm P
      • Hollis BW
      Racial pigmentation and the cutaneous synthesis of vitamin D.
      Certain drugs (eg, anticonvulsants, corticosteroids, rifampin, and cholestyramine) may adversely affect metabolism or bioavailability of vitamin D.
      • Pascussi JM
      • Robert A
      • Nguyen M
      • et al.
      Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia.
      • Walker-Bone K
      • Wood A
      • Hull R
      • et al.
      The prevention and treatment of glucocorticoid-induced osteoporosis in clinical practice.
      • Di Munno O
      • Mazzantini M
      • Delle Sedie A
      • Mosca M
      • Bombardieri S
      Risk factors for osteoporosis in female patients with systemic lupus erythematosus.
      Recent studies have shown that body mass index and body fat content are inversely related to serum 25(OH)D levels and directly related to PTH levels,
      • Wortsman J
      • Matsuoka LY
      • Chen TC
      • Lu Z
      • Holick MF
      Decreased bioavailability of vitamin D in obesity [published correction appears in Am J Clin Nutr. 2003;77:1342].
      • Snijder MB
      • van Dam RM
      • Visser M
      • et al.
      Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women.
      • Arunabh S
      • Pollack S
      • Yeh J
      • Aloia JF
      Body fat content and 25-hydroxyvitamin D levels in healthy women.
      • Bell NH
      • Epstein S
      • Greene A
      • Shary J
      • Oexmann MJ
      • Shaw S
      Evidence for alteration of the vitamin D-endocrine system in obese subjects.
      which is likely due to vitamin D sequestration in body fat compartments.
      • Wortsman J
      • Matsuoka LY
      • Chen TC
      • Lu Z
      • Holick MF
      Decreased bioavailability of vitamin D in obesity [published correction appears in Am J Clin Nutr. 2003;77:1342].
      Dietary sources of vitamin D are limited, and obtaining a sufficient amount from regular diet is often problematic for many people whose diet does not normally include the few foods that are naturally rich in vitamin D. Patients with fat malabsorption syndromes, including sprue, cystic fibrosis, and Crohn disease, are at especially high risk of vitamin D deficiency.
      • Koutkia P
      • Lu Z
      • Chen TC
      • Holick MF
      Treatment of vitamin D deficiency due to Crohn's disease with tanning bed ultraviolet B radiation.
      • Lo CW
      • Paris PW
      • Clemens TL
      • Nolan J
      • Holick MF
      Vitamin D absorption in healthy subjects and in patients with intestinal malabsorption syndromes.
      Among elderly patients, multiple factors contribute to vitamin D inadequacy, including dietary deficiencies and decreased cutaneous synthesis due to reduced ability of the skin to synthesize vitamin D3. A 70-year-old produces approximately 4 times less vitamin D via cutaneous synthesis compared with a 20-year-old.
      • MacLaughlin J
      • Holick MF
      Aging decreases the capacity of human skin to produce vitamin D3.
      • Holick MF
      • Matsuoka LY
      • Wortsman J
      Age, vitamin D, and solar ultraviolet.
      Increasing age has been associated with lower 25(OH)D levels regardless of season.
      • Rucker D
      • Allan JA
      • Fick GH
      • Hanley DA
      Vitamin D insufficiency in a population of healthy western Canadians [published correction appears in CMAJ. 2002;167:850].
      Age does not alter dietary vitamin D absorption, but if an individual is taking cholestyramine, vitamin D will not be absorbed efficiently.
      • Lo CW
      • Paris PW
      • Clemens TL
      • Nolan J
      • Holick MF
      Vitamin D absorption in healthy subjects and in patients with intestinal malabsorption syndromes.

      SKELETAL CONSEQUENCES OF VITAMIN D INADEQUACY

      Chronic severe vitamin D deficiency in infants and children causes bone deformation due to poor mineralization, commonly known as rickets.
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Holick MF
      Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
      In adults, proximal muscle weakness, bone pain, and osteomalacia may develop.
      • Passeri G
      • Pini G
      • Troiano L
      • et al.
      Low vitamin D status, high bone turnover, and bone fractures in centenarians.
      • Malabanan AO
      • Turner AK
      • Holick MF
      Severe generalized bone pain and osteoporosis in a premenopausal black female: effect of vitamin D replacement.
      • Eriksen EF
      • Glerup H
      Vitamin D deficiency and aging: implications for general health and osteoporosis.
      • Exton-Smith AN
      • Hodkinson HM
      • Stanton BR
      Nutrition and metabolic bone disease in old age.
      • Glerup H
      • Mikkelsen K
      • Poulsen L
      • et al.
      Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited.
      Less severe vitamin D inadequacy prevents children and adolescents from attaining their optimal genetically programmed peak bone mass and in adults leads to secondary hyperparathyroidism, increased bone turnover, and progressive loss of bone, increasing the risk of osteoporosis.
      Vitamin D deficiency during skeletal maturation disrupts chondrocyte maturation and inhibits the normal mineralization of the growth plates. This causes a widening of the epiphyseal plates at the end of the long bones in rachitic children and bulging of costochondral junctions (rachitic rosary).
      • Holick MF
      Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.
      • Holick MF
      Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
      Secondary hyperparathyroidism causes phosphaturia and hypophosphatemia. The resulting inadequate calcium-phosphorus product results in poor mineralization, making the skeleton less rigid. When the rachitic child begins to stand, gravity causes bowing of the long bones in the lower extremities, resulting in bowed legs or knocked knees.
      • Holick MF
      Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
      • Holick MF
      McCollum Award Lecture, 1994: vitamin D—new horizons for the 21st century.
      In adults, the epiphyseal plates are fused, and secondary hyperparathyroidism and resulting phosphaturia have moresubtle, but equally devastating, skeletal consequences. Chronic vitamin D inadequacy in adults can result in secondary hyperparathyroidism, increased bone turnover, enhanced bone loss, increased risk of fragility fracture, and (rarely) hypocalcemic tetany.
      • Lips P
      Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications.
      • Heaney RP
      Functional indices of vitamin D status and ramifications of vitamin D deficiency.
      • McKenna MJ
      • Freany R
      Secondary hyperparathyroidism in the elderly: means to defining hypovitaminosis D.
      • Krall EA
      • Sahyoun N
      • Tannenbaum S
      • Dallal GE
      • Dawson-Hughes B
      Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women.
      • Eriksen EF
      • Glerup H
      Vitamin D deficiency and aging: implications for general health and osteoporosis.
      • Exton-Smith AN
      • Hodkinson HM
      • Stanton BR
      Nutrition and metabolic bone disease in old age.
      • Glerup H
      • Mikkelsen K
      • Poulsen L
      • et al.
      Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited.
      The increase in PTH-mediated osteoclastogenesis results in increased numbers and activity of osteoclasts. The osteoclasts resorb bone via enzymatic degradation of the collagen matrix and secretion of hydrochloric acid, releasing calcium and phosphorus into the extracellular space. The result is increased skeletal porosity, defective bone mineralization, decreased bone mineral density (BMD), osteoporosis, and increased fragility-fracture risk.
      • Holick MF
      Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
      • Holick MF
      • Siris ES
      • Binkley N
      • et al.
      Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
      • Nesby-O'Dell S
      • Scanlon KS
      • Cogswell ME
      • et al.
      Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994.
      • Eriksen EF
      • Glerup H
      Vitamin D deficiency and aging: implications for general health and osteoporosis.
      • Exton-Smith AN
      • Hodkinson HM
      • Stanton BR
      Nutrition and metabolic bone disease in old age.
      When 25(OH)D levels are less than approximately 10 ng/mL (25 nmol/L), osteomalacia is usually present.
      • Gordon CM
      • DePeter KC
      • Feldman HA
      • Grace E
      • Emans SJ
      Prevalence of vitamin D deficiency among healthy adolescents.
      • Chapuy MC
      • Preziosi P
      • Maamer M
      • et al.
      Prevalence of vitamin D insufficiency in an adult normal population.
      • Aaron JE
      • Gallagher JC
      • Anderson J
      • et al.
      Frequency of osteomalacia and osteoporosis in fractures of the proximal femur.
      • Exton-Smith AN
      • Hodkinson HM
      • Stanton BR
      Nutrition and metabolic bone disease in old age.
      • Glerup H
      • Mikkelsen K
      • Poulsen L
      • et al.
      Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited.
      • Feskanich D
      • Willett WC
      • Colditz GA
      Calcium, vitamin D, milk consumption, and hip fractures: a prospective study among postmenopausal women.
      Some studies suggest that serum 25(OH)D levels greater than 30 ng/mL (75 nmol/L) may be required to maximize intestinal calcium absorption
      • Heaney RP
      • Dowell MS
      • Hale CA
      • Bendich A
      Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D.
      and prevent secondary hyperparathyroidism-induced skeletal conditions
      • Lips P
      • Duong T
      • Oleksik A
      • et al.
      A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].
      • Holick MF
      • Siris ES
      • Binkley N
      • et al.
      Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.
      • van der Wielen RP
      • Lowik MR
      • van den Berg H
      • et al.
      Serum vitamin D concentrations among elderly people in Europe.
      • Snijder MB
      • van Dam RM
      • Visser M
      • et al.
      Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women.
      • Glerup H
      • Mikkelsen K
      • Poulsen L
      • et al.
      Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited.
      • Feskanich D
      • Willett WC
      • Colditz GA
      Calcium, vitamin D, milk consumption, and hip fractures: a prospective study among postmenopausal women.
      (Figure 2).
      Unlike patients with osteoporosis, patients with osteomalacia often complain of skeletal pain.
      • Plotnikoff GA
      • Quigley JM
      Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain.
      • Malabanan AO
      • Turner AK
      • Holick MF
      Severe generalized bone pain and osteoporosis in a premenopausal black female: effect of vitamin D replacement.
      • Glerup H
      • Mikkelsen K
      • Poulsen L
      • et al.
      Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited.
      This pain can be elicited on physical examination by applying minimal pressure with the thumb or forefinger on the sternum or anterior tibia. Although the exact cause of the aching sensation that patients often complain of is unknown, it is possible that the collagen-rich osteoid that is laid down on the periosteal surface of the skeleton may become swollen similar to the hydration of gelatin-based food products (eg, Jell-O). This swelling could put outward pressure on the periosteal covering that is innervated with nocioceptors.
      • Holick MF
      Vitamin D deficiency: what a pain it is [editorial].
      Patients with osteomalacia are often misdiagnosed as having fibromyalgia, chronic fatigue syndrome, or myocytis and treated inappropriately with nonsteroidal anti-inflammatory agents.
      • Plotnikoff GA
      • Quigley JM
      Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain.
      • Holick MF
      Vitamin D deficiency: what a pain it is [editorial].
      Some, but not all, observational studies have linked vitamin D inadequacy (or lower vitamin D intake) to an increased risk of hip and other nonvertebral fractures.
      • LeBoff MS
      • Kohlmeier L
      • Hurwitz S
      • Franklin J
      • Wright J
      • Glowacki J
      Occult vitamin D deficiency in postmenopausal US women with acute hip fracture.
      • Feskanich D
      • Willett WC
      • Colditz GA
      Calcium, vitamin D, milk consumption, and hip fractures: a prospective study among postmenopausal women.
      Moreover some, but not all, clinical trials and observational studies have reported that dietary vitamin D supplementation (often given together with calcium) lowers fracture risk
      • Lips P
      Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications.
      • Dawson-Hughes B
      • Harris SS
      • Krall EA
      • Dallal GE
      Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.
      • Chapuy MC
      • Arlot ME
      • Duboeuf F
      • et al.
      Vitamin D3 and calcium to prevent hip fractures in elderly women.
      • Trivedi DP
      • Doll R
      • Khaw KT
      Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.
      • Larsen ER
      • Mosekilde L
      • Foldspang A
      Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study.
      • Vieth R
      The pharmacology of vitamin D, including fortification strategies.
      (Figure 3). Bischoff-Ferrari et al
      • Bischoff-Ferrari HA
      • Willet WC
      • Wong JB
      • Giovannucci E
      • Dietrich T
      • Dawson-Hughes B
      Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.
      recently conducted a systematic review and meta-analysis of double-blind randomized controlled trials (RCTs), the highest level of evidence, to assess the efficacy of vitamin D (vitamin D3 [cholecalciferol] or vitamin D2 [ergocalciferol]) supplementation with or without calcium supplementation vs calcium supplementation alone or placebo for preventing hip and nonvertebral fractures in elderly patients (≥60 years of age). Statistical justification was provided for pooling trials with higher vitamin D doses separately from those with lower doses. On the basis of the analysis of 3 RCTs for hip fracture risk involving 5572 subjects and 5 RCTs for nonvertebreal fracture risk involving 6098 subjects, the authors concluded that daily vitamin D supplementation between 700 and 800 IU with or without calcium appears to reduce hip fracture risk by 26% and nonvertebral fracture risk by 23% vs calcium alone or placebo in ambulatory or institutionalized elderly persons. No effect on fracture risk was observed in 2 trials that used a lower dose of 400 IU/d. A population-based, 3-year cluster randomized intervention study involving 9605 community-dwelling elderly adults (≥66 years of age) found that 400 IU/d of vitamin D with 1000 mg of calcium produced a 16% fracture risk reduction,
      • Larsen ER
      • Mosekilde L
      • Foldspang A
      Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study.
      although this lower-quality trial did not meet the inclusion criteria for the meta-analysis described herein. A separate systematic review and meta-analysis conducted several years earlier that included RCTs involving either vitamin D or its analogues reported a 37% reduction in the relative risk of vertebral fracture.
      • Cranney A
      • Guyatt G
      • Griffith L
      • Wells G
      • Tugwell P
      • Rosen C
      • Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
      Meta-analyses of therapies for postmenopausal osteoporosis, IX: summary of meta-analyses of therapies for postmenopausal osteoporosis.
      • Papadimitropoulos E
      • Wells G
      • Shea B
      • Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
      • et al.
      Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
      Figure thumbnail gr3
      FIGURE 3Mean ± SD (error bars) serum 25-hydroxyvitamin D (25[OH]D) concentrations (shown as nmol/L and ng/mL) in women older than 70 years, stratified by supplement use and residential status. Adapted from J Clin Endocrinol Metab,
      • Lips P
      • Wiersinga A
      • van Ginkel FC
      • et al.
      The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects.
      with permission from The Endocrine Society, Copyright 1988.
      Two trials that failed to detect an effect on fracture risk were published soon after the meta-analysis was conducted. Porthouse et al
      • Porthouse J
      • Cockayne S
      • King C
      • et al.
      Randomized controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.
      conducted an open-label RCT to assess whether 1000 mg of calcium daily with 800 IU of vitamin D3 supplementation reduced fracture risk among 3314 women 70 years and older with one or more risk factors for hip fracture. The incidence of hip and other clinical fractures did not differ significantly between groups after a median follow-up of 25 months. Another randomized, double-blinded, controlled trial with a factorial design examined the effect on fracture risk.
      • Grant AM
      • Avenell A
      • Campbell MK
      • RECORD Trial Group
      • et al.
      Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial.
      A total of 5292 patients were randomized to receive vitamin D with or without calcium, calcium alone, or placebo. After a 24-month follow-up, the authors found no significant differences in fracture rates among the 4 groups. However, compliance with the medication had declined to 63% after 24 months and may have been as low as 45% if nonresponders to the evaluation questionnaire were included. Data from a randomized, double-blind, placebo-controlled trial of 9440 community-dwelling adults (75-100 years old) randomized to receive either an annual injection of 300,000 IU of cholecalciferol (comparable to a 822-IU daily dose) or matching placebo disclosed no effect on fracture occurrence between groups.
      • Anderson FH
      • Smith HE
      • Raphael HM
      • Crozier SR
      • Cooper C
      Effect of annual intramuscular vitamin D supplementation on fracture risk in 9440 community-living older people: the Wessex Fracture Prevention Trial [abstract].
      However, since 25(OH)D levels were not evaluated, it is unknown whether the intramuscular vitamin D3 was completely bioavailable. Most intramuscular preparations are not very bioavailable, which is why they are no longer available in the United States.
      Decreased BMD is a major risk factor for fractures,
      • Cauley JA
      • Lui LY
      • Ensrud KE
      • et al.
      Bone mineral density and the risk of incident nonspinal fractures in black and white women.
      and some studies have linked vitamin D inadequacy or low intake of vitamin D to low BMD.
      • Feskanich D
      • Willett WC
      • Colditz GA
      Calcium, vitamin D, milk consumption, and hip fractures: a prospective study among postmenopausal women.
      • Khaw KT
      • Sneyd MJ
      • Compston J
      Bone density parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women.
      • Marshall D
      • Johnell O
      • Wedel H
      Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures.
      Some randomized trials have also shown a benefit.
      • Cranney A
      • Guyatt G
      • Griffith L
      • Wells G
      • Tugwell P
      • Rosen C
      • Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
      Meta-analyses of therapies for postmenopausal osteoporosis, IX: summary of meta-analyses of therapies for postmenopausal osteoporosis.
      • Papadimitropoulos E
      • Wells G
      • Shea B
      • Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
      • et al.
      Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
      • Khaw KT
      • Sneyd MJ
      • Compston J
      Bone density parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women.
      • Chapuy MC
      • Chapuy P
      • Thomas JL
      • Hazard MC
      • Meunier PJ
      Biochemical effects of calcium and vitamin D supplementation in elderly, institutionalized, vitamin D-deficient patients.
      • Lips P
      • Graafmans WC
      • Ooms ME
      • Bezemer PD
      • Bouter LM
      Vitamin D supplementation and fracture incidence in elderly persons: a randomized, placebo-controlled clinical trial.
      For example, a double-blinded RCT randomized 249 healthy ambulatory postmenopausal women with usual daily intakes of 100 IU of vitamin D to receive 400 IU of vitamin D supplements or placebo daily. All participants also received 377 mg/d of calcium. At the end of 1 year, the vitamin D group had significantly reduced wintertime bone loss and improved net BMD of the spine.
      • Dawson-Hughes B
      • Dallal GE
      • Krall EA
      • Harris S
      • Sokoll LJ
      • Falconer G
      Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women.
      By contrast, however, another RCT reported no effect of vitamin D supplementation on bone loss or bone turnover markers in calcium-replete postmenopausal African American women.
      • Aloia JF
      • Talwar SA
      • Pollack S
      • Yeh J
      A Randomized controlled trial of vitamin D3 supplementation in African American women.
      The earlier meta-analysis that pooled data from RCTs that included vitamin D analogues found a small nonsignificant BMD increase of 0.4% relative to the control groups.
      • Cranney A
      • Guyatt G
      • Griffith L
      • Wells G
      • Tugwell P
      • Rosen C
      • Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
      Meta-analyses of therapies for postmenopausal osteoporosis, IX: summary of meta-analyses of therapies for postmenopausal osteoporosis.
      • Papadimitropoulos E
      • Wells G
      • Shea B
      • Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
      • et al.
      Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
      Many of the vitamin D supplementation studies reported herein included concurrent calcium supplementation; therefore, the observed benefits of vitamin D supplementation may be confounded or obscured by the effects of concurrent calcium supplements and cannot be ascribed to vitamin D alone. Although the meta-analysis by Bischoff-Ferrari et al
      • Bischoff-Ferrari HA
      • Willet WC
      • Wong JB
      • Giovannucci E
      • Dietrich T
      • Dawson-Hughes B
      Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.
      reported that vitamin D supplementation with or without calcium supplementation reduced fracture risks, the factorial design of the Record Evaluation of Calcium or Vitamin D (RECORD) trial concluded that vitamin D supplementation with or without calcium supplementation had no significant effect on fracture risk reduction.
      • Grant AM
      • Avenell A
      • Campbell MK
      • RECORD Trial Group
      • et al.
      Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial.
      It is also possible that the benefits of vitamin D on fracture risk reduction (and BMD) may be greater in those with vitamin D deficiency or low calcium intake at baseline. In the RECORD trial, only 60 participants (1.1%) had their serum baseline 25(OH)D levels measured. Thus, we cannot know if the lack of effect on fracture risk in the RECORD trial might be related to pretreatment levels of vitamin D and/or calcium. The hierarchy of evidence for the role of vitamin D in BMD
      • Grant AM
      • Avenell A
      • Campbell MK
      • RECORD Trial Group
      • et al.
      Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial.
      • Anderson FH
      • Smith HE
      • Raphael HM
      • Crozier SR
      • Cooper C
      Effect of annual intramuscular vitamin D supplementation on fracture risk in 9440 community-living older people: the Wessex Fracture Prevention Trial [abstract].
      • Cauley JA
      • Lui LY
      • Ensrud KE
      • et al.
      Bone mineral density and the risk of incident nonspinal fractures in black and white women.
      • Khaw KT
      • Sneyd MJ
      • Compston J
      Bone density parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women.
      • Marshall D
      • Johnell O
      • Wedel H
      Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures.
      • Chapuy MC
      • Chapuy P
      • Thomas JL
      • Hazard MC
      • Meunier PJ
      Biochemical effects of calcium and vitamin D supplementation in elderly, institutionalized, vitamin D-deficient patients.
      • Lips P
      • Graafmans WC
      • Ooms ME
      • Bezemer PD
      • Bouter LM
      Vitamin D supplementation and fracture incidence in elderly persons: a randomized, placebo-controlled clinical trial.
      • Dawson-Hughes B
      • Dallal GE
      • Krall EA
      • Harris S
      • Sokoll LJ
      • Falconer G
      Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women.
      • Aloia JF
      • Talwar SA
      • Pollack S
      • Yeh J
      A Randomized controlled trial of vitamin D3 supplementation in African American women.
      • Inanir A
      • Ozoran K
      • Tutkak H
      • Mermerci B
      The effects of calcitriol therapy on serum interleukin-1, interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis.
      • Di Daniele N
      • Carbonelli MG
      • Candeloro N
      • Iacopino L
      • De Lorenzo A
      • Andreoli A
      Effect of supplementation of calcium and vitamin D on bone mineral density and bone mineral content in peri- and post-menopause women; a double-blind, randomized, controlled trial.
      • Sato Y
      • Asoh T
      • Kondo I
      • Satoh K
      Vitamin D deficiency and risk of hip fractures among disabled elderly stroke patients.
      • Gerdhem P
      • Ringsberg KA
      • Obrant KJ
      • Akesson K
      Association between 25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of Elderly Women.
      • Cummings SR
      • Browner WS
      • Bauer D
      • Study of Osteoporotic Fractures Research Group
      • et al.
      Endogenous hormones and the risk of hip and vertebral fractures among older women.
      • Cumming RG
      • Cummings SR
      • Nevitt MC
      • et al.
      Calcium intake and fracture risk: results from the study of osteoporotic fractures.
      • Gallagher SJ
      • McQuillian C
      • Harkness M
      • Finlay F
      • Gallagher AP
      • Dixon T
      Prevalence of vitamin D inadequacy in Scottish adults with nonverterbral fragility fractures.
      changes and fracture reduction is given in Table 2.
      TABLE 2Hierarchy of Evidence for Studies Relating Vitamin D to Pathologic Conditions
      References are provided for examples of each type of study. The most convincing evidence comes from randomized controlled trials. There is some evidence from clinical trials that vitamin D (often given with calcium) may reduce the risk of falls and fractures. Associations with most other diseases and conditions come from lower levels of evidence. 1α,25(OH)2D = 1α-25-hydroxyvitamin D; 1,25(OH)2D = 1,25 hydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; 1-H-vitamin D3 = 1 hydroxylated vitamin D3; BMD = bone mineral density; BP = blood pressure; CRP = C-reactive protein; DM = diabetes mellitus; EAE = experimental autoimmune encephalitis; IBD = inflammatory bowel disease; ICU = intensive care unit; IFN-γ = interferon-γ; IHD = ischemic heart disease; IL = interleukin; KO = knockout; MI = myocardial infarction; MS = multiple sclerosis; NA = not applicable; NHANES = National Health and Nutrition Examination Survey; NHS = Nurses' Health Study; NOD = nonobese diabetic; PTH = parathyroid hormone; RCT = randomized controlled trial; SLE = systemic lupus erythematosus; TNF-α = tumor necrosis factor α.
      LevelStudy typeData sourceTreatment or predictorOutcomeResultNotes
      1aMeta-analysesRCTsVitamin D and calciumBMD
      • Papadimitropoulos E
      • Wells G
      • Shea B
      • Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
      • et al.
      Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
      Small ↑Effect seen with low baseline vitamin D
      Fracture risk
      • Cranney A
      • Guyatt G
      • Griffith L
      • Wells G
      • Tugwell P
      • Rosen C
      • Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
      Meta-analyses of therapies for postmenopausal osteoporosis, IX: summary of meta-analyses of therapies for postmenopausal osteoporosis.
      • Papadimitropoulos E
      • Wells G
      • Shea B
      • Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
      • et al.
      Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
      Small ↓ or no effectEffect seen with low baseline 25(OH)D
      Falls
      • Bischoff-Ferrari HA
      • Dawson-Hughes B
      • Willett WC
      • et al.
      Effect of vitamin D on falls: a meta-analysis.
      Approximately 20% ↓Low baseline 25(OH)D
      1bRCTsVitamin D (or analogue) aloneBMD changes
      • Papadimitropoulos E
      • Wells G
      • Shea B
      • Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
      • et al.
      Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
      Small ↑Effect seen with vitamin D or 1-H-vitamin D3
      Fracture risk
      • Trivedi DP
      • Doll R
      • Khaw KT
      Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.
      Small ↓
      Neuromuscular function
      • Dhesi JK
      • Jackson SH
      • Bearne LM
      • et al.
      Vitamin D supplementation improves neuromuscular function in older people who fall.
      • Dukas L
      • Schacht E
      • Mazor Z
      • Stahelin HB
      Treatment with alfacalcidol in elderly people significantly decreases the high risk of falls associated with low creatinine clearance of <65 ml/min.
      Small ↓ in sway and reaction timeSingle small study in fallers
      Falls
      • Dukas L
      • Schacht E
      • Mazor Z
      • Stahelin HB
      Treatment with alfacalcidol in elderly people significantly decreases the high risk of falls associated with low creatinine clearance of <65 ml/min.
      • Dukas L
      • Bischoff HA
      • Lindpainter LS
      • et al.
      Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily.
      • Gallagher JC
      The effects of calcitriol on falls and fractures and physical performance tests.
      ↓ number of fallersBenefit only with good calcium intake
      • Cumming RG
      • Cummings SR
      • Nevitt MC
      • et al.
      Calcium intake and fracture risk: results from the study of osteoporotic fractures.
      CRP
      • van den Berghe G
      • Van Roosbroeck D
      • Vanhove P
      • Wouters PJ
      • De Pourcq L
      • Bouillon R
      Bone turnover in prolonged critical illness: effect of vitamin D.
      25% ↓ with approximately 500 IU; ICU patientsUnblinded study
      Vitamin D (or analogue) and calciumBMD changes
      • Inanir A
      • Ozoran K
      • Tutkak H
      • Mermerci B
      The effects of calcitriol therapy on serum interleukin-1, interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis.
      • Di Daniele N
      • Carbonelli MG
      • Candeloro N
      • Iacopino L
      • De Lorenzo A
      • Andreoli A
      Effect of supplementation of calcium and vitamin D on bone mineral density and bone mineral content in peri- and post-menopause women; a double-blind, randomized, controlled trial.
      Small ↑Benefits mostly seen with vitamin D deficiency at baseline
      Fracture risk
      • Porthouse J
      • Cockayne S
      • King C
      • et al.
      Randomized controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.
      • Grant AM
      • Avenell A
      • Campbell MK
      • RECORD Trial Group
      • et al.
      Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial.
      No effect
      Falls
      • Harwood RH
      • Sahota O
      • Gaynor K
      • Masud T
      • Hosking DJ
      A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study.
      Approximately 50% ↓ in falls in post–hip fracture post–hip fracture womenNonblinded
      BP
      • Krause R
      • Buhring M
      • Hopfenmuller W
      • Holick MF
      • Sharma AM
      Ultraviolet B and blood pressure [letter].
      9% ↓Low baseline 25(OH)D; small trial
      Cytokines in patients with MS
      • Mahon BD
      • Gordon SA
      • Cruz J
      • Cosman F
      • Cantorna MT
      Cytokine profile in patients with multiple sclerosis following vitamin D supplementation.
      ↑ TGF-β1No effect on TNF-α, IFN-γ, or IL-13
      Exposure to UV-BBP
      • Ahonen MH
      • Tenkanen L
      • Teppo L
      • Hakama M
      • Tuohimaa P
      Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland).
      BP ↓ to normalVery small double-blinded single study
      Exposure to UV-ABP
      • Krause R
      • Buhring M
      • Hopfenmuller W
      • Holick MF
      • Sharma AM
      Ultraviolet B and blood pressure [letter].
      No effect on BP
      2Cohort studiesProspective epidemiological studiesSerum 25(OH)DFracture risk
      • Sato Y
      • Asoh T
      • Kondo I
      • Satoh K
      Vitamin D deficiency and risk of hip fractures among disabled elderly stroke patients.
      ↑ risk of hip fracture when lowHemiplegic stroke patients
      Serum 25(OH)DFracture risk, gait speed, balance
      • Gerdhem P
      • Ringsberg KA
      • Obrant KJ
      • Akesson K
      Association between 25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of Elderly Women.
      No effect on fracture; poorer balance and gait speed when low
      Serum 1,25(OH)2DFracture risk
      • Cummings SR
      • Browner WS
      • Bauer D
      • Study of Osteoporotic Fractures Research Group
      • et al.
      Endogenous hormones and the risk of hip and vertebral fractures among older women.
      ↑ risk of hip fracture when low
      Vitamin D supplementsFracture risk
      • Cumming RG
      • Cummings SR
      • Nevitt MC
      • et al.
      Calcium intake and fracture risk: results from the study of osteoporotic fractures.
      No effect
      Serum 25(OH)DFalls
      • Sambrook PN
      • Chen JS
      • March LM
      • et al.
      Serum parathyroid hormone predicts time to fall independent of vitamin D status in a frail elderly population.
      ↑ risk when low
      Serum PTHFalls
      • Sambrook PN
      • Chen JS
      • March LM
      • et al.
      Serum parathyroid hormone predicts time to fall independent of vitamin D status in a frail elderly population.
      ↑ risk when high
      Serum 25(OH)DSarcopenia
      • Visser M
      • Deeg DJ
      • Lips P
      Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam.
      • Braun MM
      • Helzlsouer KJ
      • Hollis BW
      • Comstock GW
      Prostate cancer and prediagnostic levels of serum vitamin D metabolites (Maryland, United States).
      ↑ risk when low
      Dietary vitamin D and calciumColon cancer
      • Garland C
      • Shekelle RB
      • Barrett-Connor E
      • Criqui MH
      • Rossof AH
      • Paul O
      Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men.
      ↑ risk when low
      Serum 25(OH)DColon cancer
      • Garland CF
      • Comstock GW
      • Garland FC
      • Helsing KJ
      • Shaw EK
      • Gorham ED
      Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study.
      ↑ risk when low
      Dietary vitamin D and calciumColorectal cancer
      • Garland C
      • Shekelle RB
      • Barrett-Connor E
      • Criqui MH
      • Rossof AH
      • Paul O
      Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men.
      ↑ risk when lowSmall effect
      Dietary vitamin D and sunlight exposureBreast cancer risk
      • Garland FC
      • Garland CF
      • Gorham ED
      • Young JF
      Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation.
      • Freedman DM
      • Dosemeci M
      • McGlynn K
      Sunlight and mortality from breast, ovarian, colon, prostate, and non-melanoma skin cancer: a composite death certificate based case-control study.
      • Grant WB
      An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation.
      ↑ risk when lowNHANES I
      LatitudeMS
      • Hernan MA
      • Olek MJ
      • Ascherio A
      Geographic variation of MS incidence in two prospective studies of US women.
      ↑ risk at higher latitudesNHS I and II—effect seen in earlier cohort
      Dietary vitamin DIHD mortality
      • Lindén V
      Vitamin D and myocardial infarction.
      No effect on MI or IHD
      Dietary vitamin D in first year of lifeType 1 DM incidence
      • Hypponen E
      • Laara E
      • Reunanen A
      • Jarvelin MR
      • Virtanen SM
      Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study.
      ↓ risk with higher intakeBirth cohort, Finland, 11-year follow-up
      Dietary vitamin DRheumatoid arthritis
      • Merlino LA
      • Curtis J
      • Mikuls TR
      • et al.
      Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Womens's Health Study.
      33% ↓ risk in highest tertile of intake
      3Case-control studiesFracture cases and nonfracture controlsFracture vs no fractureSerum 25(OH)D
      • LeBoff MS
      • Kohlmeier L
      • Hurwitz S
      • Franklin J
      • Wright J
      • Glowacki J
      Occult vitamin D deficiency in postmenopausal US women with acute hip fracture.
      ↓ levels in women with hip fracture
      D-deficient cases, “normal” controlsCase vs controlMuscle function
      • Glerup H
      • Mikkelsen K
      • Poulsen L
      • et al.
      Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement.
      Reduced vitamin D deficiency
      Colorectal cancer cases (nested in cohort)Cancer vs controlSerum 25(OH)D and serum 1,25(OH)2D
      • Tangrea J
      • Helzlsouer K
      • Pietinen P
      • et al.
      Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men.
      ↑ risk with low 25(OH)D levelBlood drawn at baseline, before diagnosis
      Breast cancer cases at diagnosis, clinic controlsCancer vs controlSerum 25(OH)D and serum 1,25(OH)2D
      • Janowsky EC
      • Lester GE
      • Weinberg CR
      • et al.
      Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk.
      ↑ race-1,25(OH)2D interaction in black cases, ↓ in white, compared with controlsNo difference in 25(OH)D
      Prostate cancer cases (nested in cohort)Cancer vs controlSerum 25(OH)D
      • Ahonen MH
      • Tenkanen L
      • Teppo L
      • Hakama M
      • Tuohimaa P
      Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland).
      ↑ risk with low levels149 cases
      Prostate cancer cases (nested in cohort)Cancer vs controlSerum 25(OH)D and serum 1,25(OH)2D
      • Braun MM
      • Helzlsouer KJ
      • Hollis BW
      • Comstock GW
      Prostate cancer and prediagnostic levels of serum vitamin D metabolites (Maryland, United States).
      No difference61 cases
      MS cases, community controlsMS case vs controlLevel of sunlight exposure during childhood and adolescence
      • van der Mei IA
      • Ponsonby AL
      • Dwyer T
      • et al.
      Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study.
      • Hernan MA
      • Olek MJ
      • Ascherio A
      Geographic variation of MS incidence in two prospective studies of US women.
      • Ponsonby AL
      • McMichael A
      • van der Mei I
      Ultraviolet radiation and autoimmune disease: insights from epidemiological research.
      ↑ risk with less exposure
      Childhood-onset type 1 DM, community controls, nationwideDiabetic vs controlCod liver oil during pregnancy or first year of life
      • Stene LC
      • Joner G
      • Norwegian Childhood Diabetes Study Group
      Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study.
      26% ↓ risk with use in first year of life; no effect with prenatal useNorway
      Childhood-onset type 1 DM, community controls, 1 countyDiabetic vs controlCod liver oil during pregnancy or first year of life
      • Stene LC
      • Ulriksen J
      • Magnus P
      • Joner G
      Use of cod liver oil during pregnancy associated with lower risk of type I diabetes on the offspring [published correction appears in Diabetologia. 2000;43;1451].
      70% ↓ risk with prenatal use; no effect during first yearNorway
      4aCross-sectional surveys, ecological studiesOlder adultsSerum 25(OH)DLower-extremity function
      • Bischoff-Ferrari HA
      • Dietrich T
      • Orav EJ
      • et al.
      Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged ≥60 y.
      Better walking speed and sit-to-stand time with higher levels
      Breast cancer casesSunlightCancer mortality
      • Garland FC
      • Garland CF
      • Gorham ED
      • Young JF
      Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation.
      • Freedman DM
      • Dosemeci M
      • McGlynn K
      Sunlight and mortality from breast, ovarian, colon, prostate, and non-melanoma skin cancer: a composite death certificate based case-control study.
      • Grant WB
      An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation.
      • John EM
      • Schwartz GG
      • Dreon DM
      • Koo J
      Vitamin D and breast cancer risk: the NHANES I epidemiologic follow-up study, 1971-1975 to 1992: National Health and Nutrition Examination Survey.
      Higher in areas with less sunlight
      Ovarian cancer casesSunlightCancer mortality
      • Lefkowitz ES
      • Garland CF
      Sunlight, vitamin D, and ovarian cancer mortality rates in US women.
      • Spina C
      • Tangpricha V
      • Yao M
      • et al.
      Colon cancer and solar ultraviolet B radiation and prevention and treatment of colon cancer in mice with vitamin D and its Gemini analogs.
      Higher in areas with less sunlight
      Population-based, geographic areaSerum 1,25(OH)2DBP
      • Sowers MF
      • Wallace RB
      • Hollis BW
      • Lemke JH
      Relationship between 1,25-dihydroxyvitamin D3 and blood pressure in a geographically defined population.
      Higher systolic and diastolic BP with higher levels
      Population-based, TromsøVitamin D intakeBP
      • Jorde R
      • Bonaa K
      Calcium from dairy products, vitamin D intake, and blood pressure: the Tromso study.
      No effect
      Population-based, NHANES IIISerum 25(OH)DPeriodontal disease
      • Dietrich T
      • Joshipura KJ
      • Dawson-Hughes B
      • Bischoff-Ferrari HA
      Association between serum concentrations of 25-hydroxyvitamin D3 and periodontal disease in the US population.
      ↑ risk with low level, independently of BMD
      4bCase series (and poor-quality cohort and case-control studies)Patients with nonvertebral fractureNASerum 25(OH)D inadequacy
      • Gallagher SJ
      • McQuillian C
      • Harkness M
      • Finlay F
      • Gallagher AP
      • Dixon T
      Prevalence of vitamin D inadequacy in Scottish adults with nonverterbral fragility fractures.
      98% <28 ng/mL
      Patients with minimal trauma fractureNASerum 25(OH)D inadequacy
      • Simonelli C
      • Weiss TW
      • Morancey J
      • Swanson L
      • Chen YT
      Prevalence of vitamin D inadequacy in a minimal trauma fracture population.
      97% <30 ng/mL
      5Expert opinion without explicit critical appraisal or based on physiology, bench research, or “first principles”Laboratory or animal studies1,25(OH)2D3Leukemia (mouse)
      • Suda T
      • Abe E
      • Miyaura C
      • et al.
      Induction of differentiation of human myeloid leukemia cells by 1α,25-dihydroxyvitamin D3.
      Longer survival with treatment
      1,25(OH)2D3Lung cancer cell growth
      • Mawer EB
      • Hayes ME
      • Heys SE
      • et al.
      Constitutive synthesis of 1,25-dihydroxyvitamin D3 by a human small cell lung cancer cell line.
      Regulates cell growth
      1,25(OH)2D3 and analoguesCancer cells proliferation (breast, osteosarcoma, melanoma)
      • Holick MF
      Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.
      Antiproliferative effect
      Vitamin D analoguesProstate cancer
      • Swamy N
      • Persons KS
      • Chen TC
      • Ray R
      1α,25-Dihydroxyvitamin D3-3β-(2)-bromoacetate, an affinity labeling derivative of 1α,25-dihydroxyvitamin D3 displays strong antiproliferative and cytotoxic behavior in prostate cancer cells.
      Varying effects on serum calcium, depending on analogue used
      Vitamin D and nicotineAortic calcification
      • Niederhoffer N
      • Bobryshev YV
      • Lartaud-Idjouadiene I
      • Giummelly P
      • Atkinson J
      Aortic calcification produced by vitamin D3 plus nicotine.
      ↑ with treatment
      1α,25(OH)2DKeratinocytes
      • Smith EL
      • Walworth NC
      • Holick MF
      Effect of 1α,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions.
      ↓ proliferation
      1α,25(OH)2DKeratinocytes and fibroblasts of patients with psoriasis
      • Smith EL
      • Pincus SH
      • Donovan L
      • Holick MF
      A novel approach for the evaluation and treatment of psoriasis: oral or topical use of 1,25-dihydroxyvitamin D3 can be a safe and effective therapy for psoriasis.
      ↓ proliferation, ↑ differentiation
      1α,25(OH)2DDM (NOD mice)
      • Casteels K
      • Waer M
      • Bouillon R
      • et al.
      1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes.
      • Mathieu C
      • Waer M
      • Laureys J
      • Rutgeerts O
      • Bouillon R
      Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3.
      • Cantorna MT
      • Humpal-Winter J
      • DeLuca HF
      In vivo upregulation of interleukin-4 is one mechanism underlying the immunoregulatory effects of 1,25-dihydroxyvitamin D3.
      Protection against developing DMUp-regulates IL-4
      1α,25(OH)2DEAE, mice
      • DeLuca H
      Overview of general physiologic features and functions of vitamin D.
      Prevents EAE
      1α,25(OH)2DLyme arthritis, mice
      • Cantorna MT
      • Hayes CE
      • DeLuca HF
      1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthriti.
      Inhibits progressionIL-10 KO mice
      1α,25(OH)2DIBD, mice
      • Bemiss CJ
      • Mahon BD
      • Henry A
      • Weaver V
      • Cantorna MT
      Interleukin-2 is one of the targets of 1,25-dihydroxyvitamin D3 in the immune system.
      ↓ risk and severityIL-2 KO mice
      1α,25(OH)2D and calciumIBD, mice
      • Cantorna MT
      • Munsick C
      • Bemiss C
      • Mahon BD
      1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease.
      ↑ effect with bothIL-10 KO mice
      Vitamin D analoguesSLE
      • Abe J
      • Nakamura K
      • Takita Y
      • Nakano T
      • Irie H
      • Nishii Y
      Prevention of immunological disorders in MRL/1 mice by a new synthetic analogue of vitamin D3: 22-oxa-1α,25-dihydroxyvitamin D3.
      Inhibits lupus nephritisMRL/1 mice
      Vitamin D analogueAortic allograft intimal and advential damage
      • Raisanen-Sokolowski AK
      • Pakkala IS
      • Samila SP
      • Binderup L
      • Hayry PJ
      • Pakkala ST
      A vitamin D analog, MC1288, inhibits adventitial inflammation and suppresses intimal lesions in rat aortic allografts.
      ↓ damage
      1α,25(OH)2DHeart allograft survival, mice; heterotopic graft, rats
      • Hullett DA
      • Cantorna MT
      • Redaelli C
      • et al.
      Prolongation of allograft survival by 1,25-dihydroxyvitamin D3.
      Prolongs survival without bone loss or ↑ risk of infection
      Vitamin D analogueXenogenic pancreatic islets, mice
      • Gysemans C
      • Waer M
      • Laureys J
      • Bouillon R
      • Mathieu C
      A combination of KH1060, a vitamin D3 analog, and cyclosporin prevents early graft failure and prolongs graft survival of xenogenic islets in nonobese diabetic mice.
      Prolongs graft survival when used with cyclosporineNOD mice
      Vitamin D analogueLiver cancer
      • Dalhoff K
      • Dancey J
      • Astrup L
      • et al.
      A phase II study of the vitamin D analogue seocalcitol in patients with inoperable hepatocellular carcinoma.
      Patients with inoperable liver cancerHuman
      * References are provided for examples of each type of study. The most convincing evidence comes from randomized controlled trials. There is some evidence from clinical trials that vitamin D (often given with calcium) may reduce the risk of falls and fractures. Associations with most other diseases and conditions come from lower levels of evidence. 1α,25(OH)2D = 1α-25-hydroxyvitamin D; 1,25(OH)2D = 1,25 hydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; 1-H-vitamin D3 = 1 hydroxylated vitamin D3; BMD = bone mineral density; BP = blood pressure; CRP = C-reactive protein; DM = diabetes mellitus; EAE = experimental autoimmune encephalitis; IBD = inflammatory bowel disease; ICU = intensive care unit; IFN-γ = interferon-γ; IHD = ischemic heart disease; IL = interleukin; KO = knockout; MI = myocardial infarction; MS = multiple sclerosis; NA = not applicable; NHANES = National Health and Nutrition Examination Survey; NHS = Nurses' Health Study; NOD = nonobese diabetic; PTH = parathyroid hormone; RCT = randomized controlled trial; SLE = systemic lupus erythematosus; TNF-α = tumor necrosis factor α.

      NEUROMUSCULAR FUNCTION

      The VDR has been identified in skeletal muscle tissue,
      • Simpson RU
      • Thomas GA
      • Arnold AJ
      Identification of 1,25-dihydroxyvitamin D3 receptors and activities in muscle.
      • Costa EM
      • Blau HM
      • Feldman D
      1,25-dihydroxyvitamin D3 receptors and hormonal responses in cloned human skeletal muscle cells.
      • Haddad JG
      • Walgate J
      • Min C
      • Hahn TJ
      Vitamin D metabolite-binding proteins in human tissue.
      and low serum 25(OH)D levels have been associated with reversible myopathy in patients with osteomalacia.
      • Glerup H
      • Mikkelsen K
      • Poulsen L
      • et al.
      Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited.
      • Schott GD
      • Wills MR
      Muscle weakness in osteomalacia.
      Patients with nonspecific muscle weakness, muscle aches and pains, and bone pain are sometimes discounted or diagnosed as having fibromyalgia or chronic fatigue syndrome despite strong scientific evidence that they have vitamin D inadequacy.
      • Plotnikoff GA
      • Quigley JM
      Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain.
      • Malabanan AO
      • Turner AK
      • Holick MF
      Severe generalized bone pain and osteoporosis in a premenopausal black female: effect of vitamin D replacement.
      • Glerup H
      • Mikkelsen K
      • Poulsen L
      • et al.
      Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited.
      • Holick MF
      Vitamin D deficiency: what a pain it is [editorial].
      Several studies support the hypothesis that vitamin D inadequacy contributes to age-related muscle weakness
      • Bischoff-Ferrari HA
      • Dietrich T
      • Orav EJ
      • et al.
      Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged ≥60 y.
      • Boland R
      Role of vitamin D in skeletal muscle function.
      and falls.
      • Dukas L
      • Bischoff HA
      • Lindpainter LS
      • et al.
      Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily.
      • Sambrook PN
      • Chen JS
      • March LM
      • et al.
      Serum parathyroid hormone predicts time to fall independent of vitamin D status in a frail elderly population.
      • Pfeifer M
      • Begerow B
      • Minne HW
      • et al.
      Vitamin D status, trunk muscle strength, body sway, falls, and fractures among 237 postmenopausal women with osteoporosis.