vitamin D

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vitamin D
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{{short description|Group of molecules used as vitamin}}{{Other uses}}{{Use mdy dates|date=October 2014}}

calcitriol receptor>vitamin D receptor}}Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and multiple other biological effects. In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol).JOURNAL, Holick MF, High prevalence of vitamin D inadequacy and implications for health, Mayo Clinic Proceedings, 81, 3, 353–73, March 2006, 16529140, 10.4065/81.3.353, The major natural source of the vitamin is synthesis of cholecalciferol in the lower layers of epidermis skin through a chemical reaction that is dependent on sun exposure (specifically UVB radiation).WEB, James, MacDonald, How Does the Body Make Vitamin D from Sunlight?, JSTOR Daily, 18 July 2019,weblink 22 July 2019, JOURNAL, Holick MF, MacLaughlin JA, Clark MB, Holick SA, Potts JT, Anderson RR, Blank IH, Parrish JA, Elias P, Photosynthesis of previtamin D3 in human skin and the physiologic consequences, Science, 210, 4466, 10 October 1980, 203–5, 6251551, 10.1126/science.6251551, 1685024, 0036-8075, 6, 1980Sci...210..203H, Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements.JOURNAL, Calvo MS, Whiting SJ, Barton CN, Vitamin D intake: a global perspective of current status, The Journal of Nutrition, 135, 2, 310–6, February 2005, 15671233, 10.1093/jn/135.2.310, JOURNAL, Norman AW, From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health, The American Journal of Clinical Nutrition, 88, 2, 491S–499S, August 2008, 18689389, 10.1093/ajcn/88.2.491S, Only a few foods, such as the flesh of fatty fish, contain significant amounts of vitamin D, and fish does not contain enough vitamin D to achieve optimal Vitamin D status without sunlight or supplements.JOURNAL, Efficacy of fish intake on vitamin D status: a meta-analysis of randomized controlled trials, Jutta, Dierkes, Gabriele I., Stangl, Gerda K., Pot, Arja T., Erkkilä, Anita Lill, Hansen, Helen, Lindqvist, Lotte, Lauritzen, Gunnar, Mellgren, Per Magne, Ueland, Oddrun Anita, Gudbrandsen, Andreas, Mueller-Belecke, Frank, Hirche, Hanne Rosendahl, Gjessing, Ulrike, Lehmann, October 1, 2015, The American Journal of Clinical Nutrition, 102, 4, 837–847, 10.3945/ajcn.114.105395, 26354531, Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, as sun exposure in the population is variable and recommendations about the amount of sun exposure that is safe are uncertain in view of the skin cancer risk. Vitamin D from the diet, or from skin synthesis, is biologically inactive. A protein enzyme must hydroxylate it to convert it to the active form. This is done in the liver and in the kidneys. As vitamin D can be synthesized in adequate amounts by most mammals exposed to sufficient sunlight, it is not an essential dietary factor, and so not technically a vitamin. Instead it could be considered a hormone, with activation of the vitamin D pro-hormone resulting in the active form, calcitriol, which then produces effects via a nuclear receptor in multiple locations. Cholecalciferol is converted in the liver to calcifediol (25-hydroxycholecalciferol); ergocalciferol is converted to 25-hydroxyergocalciferol. These two vitamin D metabolites (called 25-hydroxyvitamin D or 25(OH)D) are measured in serum to determine a person's vitamin D status.WEB, Vitamin D Tests,weblink Lab Tests Online (USA), American Association for Clinical Chemistry, June 23, 2013, JOURNAL, Hollis BW, Assessment of vitamin D nutritional and hormonal status: what to measure and how to do it, Calcified Tissue International, 58, 1, 4–5, January 1996, 8825231, 10.1007/BF02509538, Calcifediol is further hydroxylated by the kidneys to form calcitriol (also known as 1,25-dihydroxycholecalciferol), the biologically active form of vitamin D.JOURNAL, Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ, Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine, Biochemistry, 10, 14, 2799–804, July 1971, 4326883, 10.1021/bi00790a023, Calcitriol circulates as a hormone in the blood, having a major role regulating the concentration of calcium and phosphate, and promoting the healthy growth and remodeling of bone. Calcitriol also has other effects, including some on cell growth, neuromuscular and immune functions, and reduction of inflammation.WEB, Vitamin D Fact Sheet for Health Professionals,weblink National Institutes of Health (NIH), June 6, 2017, February 11, 2016, {{PD-notice}}Vitamin D has a significant role in calcium homeostasis and metabolism. Its discovery was due to effort to find the dietary substance lacking in children with rickets (the childhood form of osteomalacia).JOURNAL, Wolf G, The discovery of vitamin D: the contribution of Adolf Windaus, The Journal of Nutrition, 134, 6, 1299–302, June 2004, 15173387, 10.1093/jn/134.6.1299, Vitamin D supplements are given to treat or to prevent osteomalacia and rickets, but the evidence for other health effects of vitamin D supplementation in the general population is inconsistent.JOURNAL, Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM, 6, Systematic review: Vitamin D and cardiometabolic outcomes, Annals of Internal Medicine, 152, 5, 307–14, March 2010, 20194237, 3211092, 10.7326/0003-4819-152-5-201003020-00009, The effect of vitamin D supplementation on mortality is not clear, with one meta-analysis finding a small decrease in mortality in elderly people, and another concluding no clear justification exists for recommending supplementation for preventing many diseases, and that further research of similar design is not needed in these areas.{{TOC limit|3}}

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! scope="col" style="width: 70px;" | Name! scope="col" width="70px" | Chemical composition! scope="col" width="80px" | Structure! Vitamin D1| Mixture of molecular compounds of ergocalciferol with lumisterol, 1:1! Vitamin D2| ergocalciferol (made from ergosterol)File:Ergocalciferol.svgNote double bonddouble bond! Vitamin D3| cholecalciferol (made from 7-dehydrocholesterol in the skin).(File:Cholecalciferol.svg|70px)! Vitamin D422-dihydroergocalciferol >(File:22-Dihydroergocalciferol.svg|70px)! Vitamin D5| sitocalciferol (made from 7-dehydrositosterol)(File:Vitamin D5 structure.svg|80px)Several forms (vitamers) of vitamin D exist. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol; vitamin D without a subscript refers to either D2 or D3 or both. These are known collectively as calciferol.Dorland's Illustrated Medical Dictionary, under Vitamin (Table of Vitamins) Vitamin D2 was chemically characterized in 1931. In 1935, the chemical structure of vitamin D3 was established and proven to result from the ultraviolet irradiation of 7-dehydrocholesterol.Chemically, the various forms of vitamin D are secosteroids, i.e., steroids in which one of the bonds in the steroid rings is broken.WEB,weblink About Vitamin D, University of California, Riverside, November 2011, January 24, 2015, The structural difference between vitamin D2 and vitamin D3 is the side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.


File:Calcium regulation.png|thumb|Calcium regulationCalcium regulationThe active vitamin D metabolite calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells. The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine.JOURNAL, Bouillon R, Van Cromphaut S, Carmeliet G, Intestinal calcium absorption: Molecular vitamin D mediated mechanisms, Journal of Cellular Biochemistry, 88, 2, 332–9, February 2003, 12520535, 10.1002/jcb.10360, The vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDRs are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast.VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content.JOURNAL, Holick MF, Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease, The American Journal of Clinical Nutrition, 80, 6 Suppl, 1678S–88S, December 2004, 15585788, 10.1093/ajcn/80.6.1678S, One of the most important roles of vitamin D is to maintain skeletal calcium balance by promoting calcium absorption in the intestines, promoting bone resorption by increasing osteoclast number, maintaining calcium and phosphate levels for bone formation, and allowing proper functioning of parathyroid hormone to maintain serum calcium levels. Vitamin D deficiency can result in lower bone mineral density and an increased risk of reduced bone density (osteoporosis) or bone fracture because a lack of vitamin D alters mineral metabolism in the body.JOURNAL, Bell TD, Demay MB, Burnett-Bowie SA, The biology and pathology of vitamin D control in bone, Journal of Cellular Biochemistry, 111, 1, 7–13, September 2010, 20506379, 4020510, 10.1002/jcb.22661, Thus, vitamin D is also critical for bone remodeling through its role as a potent stimulator of bone resorption.The VDR regulates cell proliferation and differentiation. Vitamin D also affects the immune system, and VDRs are expressed in several white blood cells, including monocytes and activated T and B cells.JOURNAL, Watkins RR, Lemonovich TL, Salata RA, An update on the association of vitamin D deficiency with common infectious diseases, Canadian Journal of Physiology and Pharmacology, 93, 5, 363–8, May 2015, 25741906, 10.1139/cjpp-2014-0352, In vitro, vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells, and affects the synthesis of neurotrophic factors, nitric oxide synthase, and glutathione.JOURNAL, Puchacz E, Stumpf WE, Stachowiak EK, Stachowiak MK, Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells, Brain Research. Molecular Brain Research, 36, 1, 193–6, February 1996, 9011759, 10.1016/0169-328X(95)00314-I,


A diet with insufficient vitamin D in conjunction with inadequate sun exposure causes vitamin D deficiency. Severe vitamin D deficiency in children causes rickets, a softening and weakening of bones, which is a rare disease in the developed world.WEB, March 8, 2012, Rickets, National Health Service,weblink July 9, 2012, Vitamin D deficiency is found worldwide in the elderly and remains common in children and adults.JOURNAL, Munns, CF, Shaw, N, Kiely, M, Specker, BL, Thacher, TD, Ozono, K, Michigami, T, Tiosano, D, Mughal, MZ, Mäkitie, O, Ramos-Abad, L, Ward, L, DiMeglio, LA, Atapattu, N, Cassinelli, H, Braegger, C, Pettifor, JM, Seth, A, Idris, HW, Bhatia, V, Fu, J, Goldberg, G, Sävendahl, L, Khadgawat, R, Pludowski, P, Maddock, J, Hyppönen, E, Oduwole, A, Frew, E, Aguiar, M, Tulchinsky, T, Butler, G, Högler, W, 6, Global Consensus Recommendations on Prevention and Management of Nutritional Rickets., The Journal of Clinical Endocrinology and Metabolism, February 2016, 101, 2, 394–415, 10.1210/jc.2015-2175, 26745253, 4880117, JOURNAL, Eriksen EF, Glerup H, Vitamin D deficiency and aging: implications for general health and osteoporosis, Biogerontology, 3, 1–2, 73–7, 2002, 12014847, 10.1023/A:1015263514765, JOURNAL, Holick MF, Vitamin D deficiency, The New England Journal of Medicine, 357, 3, 266–81, July 2007, 17634462, 10.1056/NEJMra070553, Deficiency results in impaired bone mineralization and bone damage which leads to bone-softening diseases,BOOK, Judith E., Brown, Janet, Isaacs, Bea, Krinke, Ellen, Lechtenberg, Maureen, Murtaugh, vanc, Nutrition Through the Life Cycle, {{google books, y, TeQZBQAAQBAJ, |date=June 28, 2013|publisher=Cengage Learning|isbn=978-1-285-82025-5}} including rickets in children and osteomalacia in adults. Low blood calcifediol (25-hydroxy-vitamin D) can result from avoiding the sun.JOURNAL, Schoenmakers I, Goldberg GR, Prentice A, Abundant sunshine and vitamin D deficiency, The British Journal of Nutrition, 99, 6, 1171–3, June 2008, 18234141, 2758994, 10.1017/S0007114508898662, Being deficient in vitamin D can cause intestinal absorption of dietary calcium to fall to 15%. When not deficient, an individual usually absorbs between 60-80%.

Bone health


Rickets, a childhood disease, is characterized by impeded growth and soft, weak, deformed long bones that bend and bow under their weight as children start to walk. This condition is characterized by bow legs, which can be caused by calcium or phosphorus deficiency, as well as a lack of vitamin D; today, it is largely found in low-income countries in Africa, Asia, or the Middle EastJOURNAL, Lerch C, Meissner T, Interventions for the prevention of nutritional rickets in term born children, The Cochrane Database of Systematic Reviews, 4, CD006164, October 2007, 17943890, 10.1002/14651858.CD006164.pub2, Lerch, Christian, vanc, and in those with genetic disorders such as pseudovitamin D deficiency rickets.JOURNAL, Zargar AH, Mithal A, Wani AI, Laway BA, Masoodi SR, Bashir MI, Ganie MA, 6, Pseudovitamin D deficiency rickets--a report from the Indian subcontinent, Postgraduate Medical Journal, 76, 896, 369–72, June 2000, 10824056, 1741602, 10.1136/pmj.76.896.369, Maternal vitamin D deficiency may cause overt bone disease from before birth and impairment of bone quality after birth.JOURNAL, Elidrissy AT, The Return of Congenital Rickets, Are We Missing Occult Cases?, Calcified Tissue International, 99, 3, 227–36, September 2016, 27245342, 10.1007/s00223-016-0146-2, Review, JOURNAL, Paterson CR, Ayoub D, Congenital rickets due to vitamin D deficiency in the mothers, Clinical Nutrition, 34, 5, 793–8, October 2015, 25552383, 10.1016/j.clnu.2014.12.006, Review, Nutritional rickets exists in countries with intense year-round sunlight such as Nigeria and can occur without vitamin D deficiency.JOURNAL, Oramasionwu GE, Thacher TD, Pam SD, Pettifor JM, Abrams SA, Adaptation of calcium absorption during treatment of nutritional rickets in Nigerian children, The British Journal of Nutrition, 100, 2, 387–92, August 2008, 18197991, 10.1017/S0007114507901233,weblink JOURNAL, Fischer PR, Rahman A, Cimma JP, Kyaw-Myint TO, Kabir AR, Talukder K, Hassan N, Manaster BJ, Staab DB, Duxbury JM, Welch RM, Meisner CA, Haque S, Combs GF, 6, Nutritional rickets without vitamin D deficiency in Bangladesh, Journal of Tropical Pediatrics, 45, 5, 291–3, October 1999, 10584471, 10.1093/tropej/45.5.291, Although rickets and osteomalacia are now rare in the UK, outbreaks have happened in some immigrant communities in which osteomalacia sufferers included women with seemingly adequate daylight outdoor exposure wearing Western clothing.JOURNAL, Dunnigan MG, Henderson JB, An epidemiological model of privational rickets and osteomalacia, The Proceedings of the Nutrition Society, 56, 3, 939–56, November 1997, 9483661, 10.1079/PNS19970100, Having darker skin and reduced exposure to sunshine did not produce rickets unless the diet deviated from a Western omnivore pattern characterized by high intakes of meat, fish, and eggs, and low intakes of high-extraction cereals.JOURNAL, Robertson I, Ford JA, McIntosh WB, Dunnigan MG, 6, The role of cereals in the aetiology of nutritional rickets: the lesson of the Irish National Nutrition Survey 1943-8, The British Journal of Nutrition, 45, 1, 17–22, January 1981, 6970590, 10.1079/BJN19810073, JOURNAL, Clements MR, The problem of rickets in UK Asians, Journal of Human Nutrition and Dietetics, 2, 2, 1989, 10.1111/j.1365-277X.1989.tb00015.x, 105–116, JOURNAL, Pettifor JM, Nutritional rickets: deficiency of vitamin D, calcium, or both?, The American Journal of Clinical Nutrition, 80, 6 Suppl, 1725S–9S, December 2004, 15585795, 10.1093/ajcn/80.6.1725S, The dietary risk factors for rickets include abstaining from animal foods.JOURNAL, Dunnigan MG, Henderson JB, Hole DJ, Barbara Mawer E, Berry JL, Meat consumption reduces the risk of nutritional rickets and osteomalacia, The British Journal of Nutrition, 94, 6, 983–91, December 2005, 16351777, 10.1079/BJN20051558, Vitamin D deficiency remains the main cause of rickets among young infants in most countries, because breast milk is low in vitamin D and social customs and climatic conditions can prevent adequate sun exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh, where rickets occurs among older toddlers and children, it has been attributed to low dietary calcium intakes, which are characteristic of cereal-based diets with limited access to dairy products.Rickets was formerly a major public health problem among the US population; in Denver, where ultraviolet rays are about 20% stronger than at sea level on the same latitude,WEB,weblink Cell Biology and Cancer Curriculum Supplement, Office of Science Education, August 24, 2010, live,weblink June 8, 2010, mdy-all, {{PD-notice}} almost two-thirds of 500 children had mild rickets in the late 1920s.JOURNAL, Weick MT, A history of rickets in the United States, The American Journal of Clinical Nutrition, 20, 11, 1234–41, November 1967, 4862158, 10.1093/ajcn/20.11.1234, An increase in the proportion of animal proteinBOOK, Garrison RH, Somer E, The Nutrition Desk Reference, {{google books, y, Z4hFKXI7EhsC, |year=1997 |publisher=McGraw-Hill |isbn=978-0-87983-826-3}} in the 20th century American diet coupled with increased consumption of milkBOOK, E. Melanie, Dupuis, Nature's Perfect Food: How Milk Became America's Drink, {{google books, y, Nr1_u2DvDckC, |date=February 1, 2002|publisher=NYU Press|isbn=978-0-8147-1938-1 | name-list-format = vanc}}JOURNAL, Teegarden D, Lyle RM, Proulx WR, Johnston CC, Weaver CM, Previous milk consumption is associated with greater bone density in young women, The American Journal of Clinical Nutrition, 69, 5, 1014–7, May 1999, 10232644, 10.1093/ajcn/69.5.1014, fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases. Also, in the United States and Canada, vitamin D-fortified milk, infant vitamin supplements, and vitamin supplements have helped to eradicate the majority of cases of rickets for children with fat malabsorption conditions.

Osteoporosis and osteomalacia

Osteomalacia is a disease in adults that results from vitamin D deficiency. Characteristics of this disease are softening of the bones, leading to bending of the spine, bowing of the legs, proximal muscle weakness, bone fragility, and increased risk for fractures. Osteomalacia reduces calcium absorption and increases calcium loss from bone, which increases the risk for bone fractures. Osteomalacia is usually present when 25-hydroxyvitamin D levels are less than about 10{{nbsp}}ng/mL. Although the effects of osteomalacia are thought to contribute to chronic musculoskeletal pain,JOURNAL, Holick MF, Vitamin D: A millenium perspective, Journal of Cellular Biochemistry, 88, 2, 296–307, 2003, 12520530, 10.1002/jcb.10338, there is no persuasive evidence of lower vitamin D levels in chronic pain sufferersJOURNAL, Straube S, Andrew Moore R, Derry S, McQuay HJ, Vitamin D and chronic pain, Pain, 141, 1–2, 10–13, 2009, 19084336, 10.1016/j.pain.2008.11.010, or that supplementation alleviates chronic nonspecific musculoskeletal pain.JOURNAL, Gaikwad M, Vanlint S, Mittinity M, Moseley GL, Stocks N, 6, Does vitamin D supplementation alleviate chronic nonspecific musculoskeletal pain? A systematic review and meta-analysis, Clinical Rheumatology, 36, 5, 1201–1208, 2016, 26861032, 10.1007/s10067-016-3205-1,weblink

Skin pigmentation

Dark-skinned people living in temperate climates have been shown to have low vitamin D levels but the significance of this is not certain.JOURNAL, Lowe NM, Bhojani I, Special considerations for vitamin D in the south Asian population in the UK, Therapeutic Advances in Musculoskeletal Disease, 9, 6, 137–144, 2017, 28620422, 5466148, 10.1177/1759720X17704430, JOURNAL, O'Connor MY, Thoreson CK, Ramsey NL, Ricks M, Sumner AE, The uncertain significance of low vitamin D levels in African descent populations: a review of the bone and cardiometabolic literature, Progress in Cardiovascular Diseases, 56, 3, 261–269, 2013, 24267433, 3894250, 10.1016/j.pcad.2013.10.015, JOURNAL, Freedman BI, Register TC, Effect of race and genetics on vitamin D metabolism, bone and vascular health, Nature Reviews Nephrology, 8, 8, 459–466, 2012, 22688752, 10.1038/nrneph.2012.112, Dark-skinned people are less efficient at making vitamin D because melanin in the skin hinders vitamin D synthesis.JOURNAL, Khalid AT, Moore CG, Hall C, Olabopo F, Rozario NL, Holick MF, Greenspan SL, Rajakumar K, 6, Utility of sun-reactive skin typing and melanin index for discerning vitamin D deficiency, Pediatric Research, 82, 3, 444–451, 2017, 28467404, 5570640, 10.1038/pr.2017.114,

Non-bone diseases

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Mortality, all cause

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Use of supplements

The effects of vitamin D supplementation on health are uncertain.JOURNAL, Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, Lichtenstein A, Patel K, Raman G, Tatsioni A, Terasawa T, Trikalinos TA, 6, Vitamin D and calcium: a systematic review of health outcomes, Evidence Report/Technology Assessment, 183, 1–420, August 2009, 20629479, 4781105, JOURNAL, Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP, Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials, BMJ, 348, g2035, April 2014, 24690624, 3972415, 10.1136/bmj.g2035, A 2013 review did not find any effect from supplementation on the rates of disease, other than a tentative decrease in mortality in the elderly.JOURNAL, Autier P, Boniol M, Pizot C, Mullie P, Vitamin D status and ill health: a systematic review, The Lancet Diabetes & Endocrinology, 2, 1, 76–89, January 2014, 24622671, 10.1016/S2213-8587(13)70165-7, Vitamin D supplements do not alter the outcomes for myocardial infarction, stroke or cerebrovascular disease, cancer, bone fractures or knee osteoarthritis.JOURNAL, Hussain S, Singh A, Akhtar M, Najmi AK, Vitamin D supplementation for the management of knee osteoarthritis: a systematic review of randomized controlled trials, Rheumatology International, 37, 9, 1489–1498, September 2017, 28421358, 10.1007/s00296-017-3719-0, Low vitamin D levels may result from disease rather than cause disease.A United States Institute of Medicine report states: "Outcomes related to cancer, cardiovascular disease and hypertension, and diabetes and metabolic syndrome, falls and physical performance, immune functioning and autoimmune disorders, infections, neuropsychological functioning, and preeclampsia could not be linked reliably with calcium or vitamin D intake and were often conflicting."{{rp|5}} Some researchers claim the IOM was too definitive in its recommendations and made a mathematical mistake when calculating the blood level of vitamin D associated with bone health. Members of the IOM panel maintain that they used a "standard procedure for dietary recommendations" and that the report is solidly based on the data. Research on vitamin D supplements, including large-scale clinical trials, is continuing.JOURNAL, Maxmen A, Nutrition advice: the vitamin D-lemma, Nature, 475, 7354, 23–5, July 2011, 21734684, 10.1038/475023a,

Mortality, all-cause

Vitamin D3 supplementation has been tentatively found to lead to a reduced risk of death in the elderly, but the effect has not been deemed pronounced, or certain enough, to make taking supplements recommendable. Other forms (vitamin D2, alfacalcidol, and calcitriol) do not appear to have any beneficial effects with regard to the risk of death.JOURNAL, Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C, 6, Vitamin D supplementation for prevention of mortality in adults, The Cochrane Database of Systematic Reviews, 1, 1, CD007470, January 2014, 24414552, 10.1002/14651858.CD007470.pub3, Systematic review, High blood levels appear to be associated with a lower risk of death, but it is unclear if supplementation can result in this benefit.JOURNAL, Schöttker B, Jorde R, Peasey A, Thorand B, Jansen EH, Groot LD, Streppel M, Gardiner J, Ordóñez-Mena JM, Perna L, Wilsgaard T, Rathmann W, Feskens E, Kampman E, Siganos G, Njølstad I, Mathiesen EB, Kubínová R, Pająk A, Topor-Madry R, Tamosiunas A, Hughes M, Kee F, Bobak M, Trichopoulou A, Boffetta P, Brenner H, 6, Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States, BMJ, 348, jun17 16, g3656, June 2014, 24938302, 4061380, 10.1136/bmj.g3656, Consortium on Health Ageing: Network of Cohorts in Europe the United States, Both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging.JOURNAL, Tuohimaa P, Vitamin D and aging, The Journal of Steroid Biochemistry and Molecular Biology, 114, 1–2, 78–84, March 2009, 19444937, 10.1016/j.jsbmb.2008.12.020, JOURNAL, Tuohimaa P, Keisala T, Minasyan A, Cachat J, Kalueff A, Vitamin D, nervous system and aging, Psychoneuroendocrinology, 34 Suppl 1, S278–86, December 2009, 19660871, 10.1016/j.psyneuen.2009.07.003, JOURNAL, Manya H, Akasaka-Manya K, Endo T, Klotho protein deficiency and aging, Geriatrics & Gerontology International, 10 Suppl 1, Suppl 1, S80–7, July 2010, 20590845, 10.1111/j.1447-0594.2010.00596.x, The relationship between serum calcifediol level and all-cause mortality is parabolic. Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population.{{rp|435}}

Bone health

In general, no good evidence supports the commonly held belief that vitamin D supplements can help prevent osteoporosis. Its general use for prevention of this disease in those without vitamin D deficiency is thus likely not needed.JOURNAL, Reid IR, Bolland MJ, Grey A, Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis, Lancet, 383, 9912, 146–55, January 2014, 24119980, 10.1016/s0140-6736(13)61647-5, For older people with osteoporosis, taking vitamin D with calcium may help prevent hip fractures, but it also slightly increases the risk of stomach and kidney problems.JOURNAL, Avenell A, Mak JC, O'Connell D, 6, Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men, The Cochrane Database of Systematic Reviews, 4, 4, CD000227, April 2014, 24729336, 10.1002/14651858.CD000227.pub4, Supplementation with higher doses of vitamin D, in those older than 65 years, may decrease fracture risk.JOURNAL, Bischoff-Ferrari HA, Willett WC, Orav EJ, Oray EJ, Lips P, Meunier PJ, Lyons RA, Flicker L, Wark J, Jackson RD, Cauley JA, Meyer HE, Pfeifer M, Sanders KM, Stähelin HB, Theiler R, Dawson-Hughes B, 6, A pooled analysis of vitamin D dose requirements for fracture prevention, The New England Journal of Medicine, 367, 1, 40–9, July 2012, 22762317, 10.1056/NEJMoa1109617, 1871/48765,weblink The effect is small or none for people living independently.JOURNAL, Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA, Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force, Annals of Internal Medicine, 155, 12, 827–38, December 2011, 22184690, 10.7326/0003-4819-155-12-201112200-00005, JOURNAL, Zhao JG, Zeng XT, Wang J, Liu L, 6, Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis, JAMA, 318, 24, 2466–2482, December 2017, 29279934, 5820727, 10.1001/jama.2017.19344, Low serum vitamin D levels have been associated with falls, and low bone mineral density.JOURNAL, Cranney A, Horsley T, O'Donnell S, Weiler H, Puil L, Ooi D, Atkinson S, Ward L, Moher D, Hanley D, Fang M, Yazdi F, Garritty C, Sampson M, Barrowman N, Tsertsvadze A, Mamaladze V, 6, Effectiveness and safety of vitamin D in relation to bone health, Evidence Report/Technology Assessment, 158, 1–235, August 2007, 18088161, 4781354, Taking extra vitamin D, however, does not appear to change the risk.JOURNAL, Bolland MJ, Grey A, Gamble GD, Reid IR, Vitamin D supplementation and falls: a trial sequential meta-analysis, The Lancet Diabetes & Endocrinology, 2, 7, 573–80, July 2014, 24768505, 10.1016/S2213-8587(14)70068-3, Athletes who are vitamin D deficient are at an increased risk of stress fractures and/or major breaks, particularly those engaging in contact sports. The greatest benefit with supplementation is seen in athletes who are deficient (25(OH)D serum levels 70 years || 800 || 4,000| 4,000 Australia and New Zealand! scope="col" | Age group ! scope="col" | Adequate Intake (μg)! scope="col" | Upper Level of Intake (μg)| 25| 80| 80| 80 70 years >| 80 European Food Safety Authority! scope="col" | Age group ! scope="col" | Adequate Intake (μg)! scope="col" | Tolerable upper limit (μg)| 25| 50| 100| 100| 100 * Adequate intake, no RDA/RDI yet establishedConversion: 1{{nbsp}}µg = 40{{nbsp}}IU.Various institutions have proposed different recommendations for the amount of daily intake of vitamin D. These vary according to precise definition, age, pregnancy or lactation, and the extent assumptions are made regarding skin synthesis of vitamin D.

United States

The dietary reference intake for vitamin D issued in 2010 by the Institute of Medicine (IoM) (renamed National Academy of Medicine in 2015), superseded previous recommendations which were expressed in terms of Adequate Intake. The recommendations were formed assuming the individual has no skin synthesis of vitamin D because of inadequate sun exposure. The reference intake for vitamin D refers to total intake from food, beverages and supplements, and assumes that calcium requirements are being met.{{rp|5}} The tolerable upper intake level (UL) is defined as "the highest average daily intake of a nutrient that is likely to pose no risk of adverse health effects for nearly all persons in the general population."{{rp|403}} Although ULs are believed to be safe, information on the long-term effects is incomplete and these levels of intake are not recommended for long-term consumption.{{rp|403}}{{rp|433}}For U.S food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin D labeling purposes, 100% of the Daily Value was 400{{nbsp}}IU (10{{nbsp}}μg), but on May 27, 2016, it was revised to 800{{nbsp}}IU (20{{nbsp}}μg) to bring it into agreement with the RDA.WEB,weblink Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels. FR page 33982., August 20, 2019, {{PD-notice}} The deadline to be in compliance was extended to January 1, 2020 for large companies and January 1, 2021 for small companies.WEB,weblink Changes to the Nutrition Facts Label, June 18, 2019, Food and Drug Administration (FDA), July 16, 2019, {{PD-notice}}


Health Canada published recommended dietary allowances (RDA) and tolerable upper intake levels for vitamin D in 2012WEB,weblink Vitamin D and Calcium: Updated Dietary Reference Intakes, Nutrition and Healthy Eating, Health Canada, April 28, 2018, 2008-12-05, based on the Institute of Medicine report.

Australia and New Zealand

Australia and New Zealand published nutrient reference values including guidelines for dietary vitamin D intake in 2005.WEB,weblink Nutrient reference values for Australia and New Zealand, April 28, 2018, September 9, 2005, National Health and Medical Research Council,weblink January 21, 2017, dead, About a third of Australians have vitamin D deficiency.WEB, Salleh A, Vitamin D food fortification on the table, June 12, 2012, Australian Broadcasting Corporation,weblink

European Union

The European Food Safety Authority (EFSA) in 2016JOURNAL, EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Dietary reference values for vitamin D, EFSA Journal, 14, 10, e04547, 10.2903/j.efsa.2016.4547, June 29, 2016, reviewed the current evidence, finding the relationship between serum 25(OH)D concentration and musculoskeletal health outcomes is widely variable. They considered that average requirements and population reference intakes values for vitamin D cannot be derived, and that a serum 25(OH)D concentration of 50{{nbsp}}nmol/L was a suitable target value. For all people over the age of 1, including women who are pregnant or lactating, they set an adequate intake of 15{{nbsp}}μg/day (600{{nbsp}}IU).The EFSA reviewed safe levels of intake in 2012,JOURNAL, EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Scientific Opinion on the Tolerable Upper Intake Level of vitamin D, EFSA Journal, 10, 7, 10.2903/j.efsa.2012.2813, 2012, Submitted manuscript, setting the tolerable upper limit for adults at 100{{nbsp}}μg/day (4000{{nbsp}}IU), a similar conclusion as the IOM.The UK National Health Service recommends babies and young children aged six months to five years, pregnant or breastfeeding women, and sun-deprived elderly people should take daily vitamin supplements to ensure sufficient vitamin D intake.WEB,weblink Vitamins and minerals – Vitamin D, National Health Service (England), National Health Service, February 18, 2015, July 21, 2016, In July 2016, Public Health England recommended that everyone consider taking a daily supplement containing 10{{nbsp}}µg of vitamin D during autumn and winter because of inadequate sunlight for vitamin D synthesis.WEB,weblink PHE publishes new advice on vitamin D, Public Health England, July 21, 2016, July 21, 2016, The Swedish National Food Agency recommends a daily intake of 10{{nbsp}}μg (400{{nbsp}}IU) of vitamin D3 for children and adults up to 75 years, and 20{{nbsp}}μg (800{{nbsp}}IU) for adults 75 and older.WEB,weblink Vitamin D (translated), Swedish National Food Agency, sv, 2018-10-19, Non-government organisations in Europe have made their own recommendations. The German Society for Nutrition recommends 20{{nbsp}}µg.[// Vitamin-D-Bedarf bei fehlender endogener Synthese] Deutsche Gesellschaft für Ernährung, January 2012 The European Menopause and Andropause Society recommends postmenopausal women consume15{{nbsp}}µg (600{{nbsp}}IU) until age 70, and 20{{nbsp}}µg (800{{nbsp}}IU) from age 71. This dose should be increased to 100{{nbsp}}µg (4,000{{nbsp}}IU) in some patients with very low vitamin D status or in case of co-morbid conditions.JOURNAL, Pérez-López FR, Brincat M, Erel CT, Tremollieres F, Gambacciani M, Lambrinoudaki I, Moen MH, Schenck-Gustafsson K, Vujovic S, Rozenberg S, Rees M, 6, EMAS position statement: Vitamin D and postmenopausal health, Maturitas, 71, 1, 83–8, January 2012, 22100145, 10.1016/j.maturitas.2011.11.002,


Although vitamin D is not present naturally in most foods, it is commonly added as a fortification in manufactured foods. In some countries, staple foods are artificially fortified with vitamin D.BOOK, DRI, Dietary reference intakes: for calcium, phosphorus, magnesium, vitamin D, and fluoride, National Academy Press, Washington, D.C, 1997, 250, 978-0-309-06350-0,weblink 10.17226/5776, 23115811, Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes,

Natural sources

In general, vitamin D2 is found in fungi and vitamin D3 is found in animals. Vitamin D2 is produced by ultraviolet irradiation of ergosterol found in many fungi. The vitamin D2 content in mushrooms and Cladina arbuscula, a lichen, increase with exposure to ultraviolet light.WEB, Haytowitz DB, Vitamin D in mushrooms,weblink Nutrient Data Laboratory, US Department of Agriculture, April 16, 2018, 2009, {{PD-notice}} This process is emulated by industrial ultraviolet lamps, concentrating vitamin D2 levels to higher levels.JOURNAL, Keegan RJ, Lu Z, Bogusz JM, Williams JE, Holick MF, Photobiology of vitamin D in mushrooms and its bioavailability in humans, Dermato-Endocrinology, 5, 1, 165–76, January 2013, 24494050, 3897585, 10.4161/derm.23321, The United States Department of Agriculture reports D2 and D3 content combined in one value.{| class="wikitable"|+ Fungal sources! scope="col" colspan="2" | Source! scope="col" |{{nbsp}}μg/g! scope="col" | IU/g C. arbuscula (lichen), thallus, dryWANG T, BENGTSSON G, KäRNEFELT I, BJöRN LO JOURNAL=JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY ISSUE=1–2 DATE=SEPTEMBER 2001 DOI=10.1016/S1011-1344(01)00160-9 TYPE=SUBMITTED MANUSCRIPT, ! scope="row" | vitamin D3| 0.67{{en dash}}2.04| 27{{en dash}}82! scope="row" | vitamin D2| 0.22{{en dash}}0.55| 8.8{{en dash}}22! scope="col" colspan="4" | Agaricus bisporus (common mushroom): D2 + D3! scope="row" rowspan="2" | Portobello| Raw| 0.003| 0.1| Exposed to ultraviolet light| 0.112| 4.46! scope="row" rowspan="2" | Crimini| Raw| 0.001| 0.03| Exposed to ultraviolet light| 0.319| 12.76{| class="wikitable"egg (food)>egg yolk| 0.7| 44{{nbsp}}IU for a 61g egg| Beef liver, cooked, braised| 0.5| | Fish liver oils, such as cod liver oil| 100| 450{{nbsp}}IU per teaspoon (4.5{{nbsp}}g)! scope="col" colspan="3" | Fatty fish species| Salmon, pink, cooked, dry heat| 5.2| | Mackerel, Pacific and jack, mixed species, cooked, dry heat| 4.6| | Tuna, canned in oil| 2.7| Canned sardines>Sardines, canned in oil, drained| 1.9|

Food fortification

Manufactured foods fortified with vitamin D include some fruit juices and fruit juice drinks, meal replacement energy bars, soy protein-based beverages, certain cheese and cheese products, flour products, infant formulas, many breakfast cereals, and milk.JOURNAL, de Lourdes Samaniego-Vaesken M, Alonso-Aperte E, Varela-Moreiras G, Vitamin food fortification today, Food & Nutrition Research, 56, 5459, 2012, 22481896, 3319130, 10.3402/fnr.v56i0.5459, JOURNAL, Spiro A, Buttriss JL, Vitamin D: An overview of vitamin D status and intake in Europe, Nutrition Bulletin, 39, 4, 322–350, December 2014, 25635171, 4288313, 10.1111/nbu.12108, In 2016 in the United States, the Food and Drug Administration (FDA) amended food additive regulations for milk fortification,WEB,weblink Vitamin D for Milk and Milk Alternatives, July 15, 2016, Food and Drug Administration (FDA), February 22, 2017, {{PD-notice}} stating that vitamin D3 levels not exceed 42{{nbsp}}IU vitamin D per 100{{nbsp}}g (400{{nbsp}}IU per US quart) of dairy milk, 84{{nbsp}}IU of vitamin D2 per 100{{nbsp}}g (800{{nbsp}}IU per quart) of plant milks, and 89{{nbsp}}IU per 100{{nbsp}}g (800{{nbsp}}IU per quart) in plant-based yogurts or in soy beverage products.WEB,weblink Federal Register: Food Additives Permitted for Direct Addition to Food for Human Consumption; Vitamin D2, Food and Drug Administration, US Department of Health and Human Services, July 18, 2016, February 22, 2017, {{PD-notice}}WEB,weblink §172.379 Vitamin D2, July 16, 2019, Electronic Code of Federal Regulations, {{PD-notice}}WEB,weblink §172.380 Vitamin D3, July 16, 2019, Electronic Code of Federal Regulations, {{PD-notice}} Plant milks are defined as beverages made from soy, almond, rice, among other plant sources intended as alternatives to dairy milk.{{cn|date=July 2019}}While some studies have found that vitamin D3 raises 25(OH)D blood levels faster and remains active in the body longer,JOURNAL, Vitamin D2 vs. vitamin D3: Are they one and the same?, 2013, Nutrition Bulletin, 38, 2, 243–248, Tripkovic L, 10.1111/nbu.12029, JOURNAL, Alshahrani F, Aljohani N, Vitamin D: deficiency, sufficiency and toxicity, Nutrients, 5, 9, 3605–16, September 2013, 24067388, 3798924, 10.3390/nu5093605, others contend that vitamin D2 sources are equally bioavailable and effective as D3 for raising and sustaining 25(OH)D.JOURNAL, Biancuzzo RM, Clarke N, Reitz RE, Travison TG, Holick MF, Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation, The Journal of Clinical Endocrinology and Metabolism, 98, 3, 973–9, March 2013, 23386645, 3590486, 10.1210/jc.2012-2114, JOURNAL, Borel P, Caillaud D, Cano NJ, Vitamin D bioavailability: state of the art, Critical Reviews in Food Science and Nutrition, 55, 9, 1193–205, 2015, 24915331, 10.1080/10408398.2012.688897,

Food preparation

Vitamin D content in typical foods is reduced variably by cooking. Boiled, fried and baked foods retained 69{{en dash}}89% of original vitamin D.JOURNAL, Jakobsen J, Knuthsen P, Stability of vitamin D in foodstuffs during cooking, Food Chemistry, 148, 170–5, April 2014, 24262542, 10.1016/j.foodchem.2013.10.043,

Recommended serum levels

{{See also|Reference ranges for blood tests#Vitamins|Hypervitaminosis D#Ethnic differences}}(File:Vitamin D serum levels in adults world map.svg|thumb|upright=1.4|Global vitamin D serum levels among adults (nmol/L).JOURNAL, Wahl DA, Cooper C, Ebeling PR, Eggersdorfer M, Hilger J, Hoffmann K, Josse R, Kanis JA, Mithal A, Pierroz DD, Stenmark J, Stöcklin E, Dawson-Hughes B, 6, A global representation of vitamin D status in healthy populations, Archives of Osteoporosis, 7, 1–2, 155–72, 2012-08-29, 23225293, 10.1007/s11657-012-0093-0, 11343/220606,weblink JOURNAL, Wahl DA, Cooper C, Ebeling PR, Eggersdorfer M, Hilger J, Hoffmann K, Josse R, Kanis JA, Mithal A, Pierroz DD, Stenmark J, Stöcklin E, Dawson-Hughes B, 6, A global representation of vitamin D status in healthy populations: reply to comment by Saadi, Archives of Osteoporosis, 8, 1–2, 122, 2013-02-01, 23371520, 10.1007/s11657-013-0122-7, {{legend|green|> 75}}{{legend|yellow|50-74}}{{legend|orange|25-49}})Recommendations on recommended 25(OH)D serum levels vary across authorities, and vary based on factors like age. US labs generally report 25(OH)D levels in ng/mL.{{cn|date=July 2019}} Other countries often use nmol/L.{{cn|date=July 2019}} One{{nbsp}}ng/mL is approximately equal to 2.5{{nbsp}}nmol/L.{{cn|date=July 2019}}A 2014 review concluded that the most advantageous serum levels for 25(OH)D for all outcomes appeared to be close to 30{{nbsp}}ng/mL (75{{nbsp}}nmol/L).BOOK, Bischoff-Ferrari HA, Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes, Advances in Experimental Medicine and Biology, 810, 500–25, 2014, 25207384, 10.1007/978-0-387-77574-6_5, Review, 978-0-387-77573-9, The optimal vitamin D levels are still controversial and another review concluded that ranges from 30 to 40{{nbsp}}ng/mL (75 to 100{{nbsp}}nmol/L) were to be recommended for athletes. Part of the controversy is because numerous studies have found differences in serum levels of 25(OH)D between ethnic groups; studies point to genetic as well as environmental reasons behind these variations.JOURNAL, Engelman CD, Fingerlin TE, Langefeld CD, Hicks PJ, Rich SS, Wagenknecht LE, Bowden DW, Norris JM, 6, Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans, The Journal of Clinical Endocrinology and Metabolism, 93, 9, 3381–8, September 2008, 18593774, 2567851, 10.1210/jc.2007-2702, Supplementation to achieve these standard levels could cause harmful vascular calcification.A 2012 meta-analysis showed that the risk of cardiovascular diseases increases when blood levels of vitamin D are lowest in a range of 8 to 24{{nbsp}}ng/mL (20 to 60{{nbsp}}nmol/L), although results among the studies analyzed were inconsistent.JOURNAL, Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD, 6, Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies, Circulation: Cardiovascular Quality and Outcomes, 5, 6, 819–29, 2012, 23149428, 3510675, 10.1161/CIRCOUTCOMES.112.967604, In 2011 an IOM committee concluded a serum 25(OH)D level of 20{{nbsp}}ng/mL (50{{nbsp}}nmol/L) is needed for bone and overall health. The dietary reference intakes for vitamin D are chosen with a margin of safety and 'overshoot' the targeted serum value to ensure the specified levels of intake achieve the desired serum 25(OH)D levels in almost all persons. No contributions to serum 25(OH)D level are assumed from sun exposure and the recommendations are fully applicable to people with dark skin or negligible exposure to sunlight. The Institute found serum 25(OH)D concentrations above 30{{nbsp}}ng/mL (75{{nbsp}}nmol/L) are "not consistently associated with increased benefit". Serum 25(OH)D levels above 50{{nbsp}}ng/mL (125{{nbsp}}nmol/L) may be cause for concern. However, some people with serum 25(OH)D between 30 and 50{{nbsp}}ng/mL (75{{nbsp}}nmol/L-125{{nbsp}}nmol/L) will also have inadequate vitamin D.


{{details|hypervitaminosis D}}Vitamin D toxicity is rare. It is caused by supplementing with high doses of vitamin D rather than sunlight. The threshold for vitamin D toxicity has not been established; however, according to some research, the tolerable upper intake level (UL) is 4,000 IU/day for ages 9–71JOURNAL, Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA, 6, The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know, The Journal of Clinical Endocrinology and Metabolism, 96, 1, 53–8, January 2011, 21118827, 3046611, 10.1210/jc.2010-2704, (100{{nbsp}}µg/day), while other research concludes that, in healthy adults, sustained intake of more than 1250{{nbsp}}μg/day (50,000{{nbsp}}IU) can produce overt toxicity after several months and can increase serum 25-hydroxyvitamin D levels to 150{{nbsp}}ng/mL and greater. Those with certain medical conditions, such as primary hyperparathyroidism, are far more sensitive to vitamin D and develop hypercalcemia in response to any increase in vitamin D nutrition, while maternal hypercalcemia during pregnancy may increase fetal sensitivity to effects of vitamin D and lead to a syndrome of mental retardation and facial deformities.BOOK, Tolerable Upper Intake Limits for Vitamins And Minerals, European Food Safety Authority, December 2006, 978-92-9199-014-6,weblink Idiopathic infantile hypercalcemia is caused by a mutation of the CYP24A1 gene, leading to a reduction in the degradation of vitamin D. Infants suffering from such a mutation have an increased sensitivity to vitamin D and in case of additional intake a risk of hypercalcaemia.JOURNAL, Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U, Misselwitz J, Klaus G, Kuwertz-Bröking E, Fehrenbach H, Wingen AM, Güran T, Hoenderop JG, Bindels RJ, Prosser DE, Jones G, Konrad M, 6, Mutations in CYP24A1 and idiopathic infantile hypercalcemia, The New England Journal of Medicine, 365, 5, 410–21, August 2011, 21675912, 10.1056/NEJMoa1103864, JOURNAL, De Paolis E, Scaglione GL, De Bonis M, Minucci A, Capoluongo E, CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia: from genotype to phenotype, Clinical Chemistry and Laboratory Medicine, June 2019, 31188746, 10.1515/cclm-2018-1208, The disorder can continue into adulthood.JOURNAL, Tebben PJ, Singh RJ, Kumar R, Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment, Endocrine Reviews, 37, 5, 521–547, October 2016, 27588937, 5045493, 10.1210/er.2016-1070, A review published in 2015 noted that adverse effects have been reported only at 25(OH)D serum concentrations above 200{{nbsp}}nmol/L.JOURNAL, Dahlquist DT, Dieter BP, Koehle MS, Plausible ergogenic effects of vitamin D on athletic performance and recovery, Journal of the International Society of Sports Nutrition, 12, 33, 2015, 26288575, 4539891, 10.1186/s12970-015-0093-8, Review, Published cases of toxicity involving hypercalcemia in which the vitamin D dose and the 25-hydroxy-vitamin D levels are known all involve an intake of ≥40,000{{nbsp}}IU (1,000{{nbsp}}μg) per day.Pregnant or breastfeeding women should consult a doctor before taking a vitamin D supplement. The FDA advised manufacturers of liquid vitamin D supplements that droppers accompanying these products should be clearly and accurately marked for 400 international units (1{{nbsp}}IU is the biological equivalent of 25{{nbsp}}ng cholecalciferol/ergocalciferol). In addition, for products intended for infants, the FDA recommends the dropper hold no more than 400{{nbsp}}IU.PRESS RELEASE,weblink FDA Cautions on Accurate Vitamin D Supplementation for Infants, June 15, 2010, Food and Drug Administration (FDA),weblink" title="">weblink January 12, 2017, dead, {{PD-notice}} For infants (birth to 12 months), the tolerable upper limit (maximum amount that can be tolerated without harm) is set at 25{{nbsp}}μg/day (1,000{{nbsp}}IU). One thousand micrograms per day in infants has produced toxicity within one month.{{MerckManual|01|004|k||Vitamin D}} After being commissioned by the Canadian and American governments, the Institute of Medicine (IOM) {{as of|2010|11|30|lc=y}}, has increased the tolerable upper limit (UL) to 2,500{{nbsp}}IU per day for ages 1–3 years, 3,000{{nbsp}}IU per day for ages 4–8 years and 4,000{{nbsp}}IU per day for ages 9–71+ years (including pregnant or lactating women).Calcitriol itself is auto-regulated in a negative feedback cycle, and is also affected by parathyroid hormone, fibroblast growth factor 23, cytokines, calcium, and phosphate.JOURNAL, Olmos-Ortiz A, Avila E, Durand-Carbajal M, Díaz L, Regulation of calcitriol biosynthesis and activity: focus on gestational vitamin D deficiency and adverse pregnancy outcomes, Nutrients, 7, 1, 443–80, January 2015, 25584965, 4303849, 10.3390/nu7010443,

Effect of excess

Vitamin D overdose causes hypercalcemia, which is a strong indication of vitamin D toxicity – this can be noted with an increase in urination and thirst. If hypercalcemia is not treated, it results in excess deposits of calcium in soft tissues and organs such as the kidneys, liver, and heart, resulting in pain and organ damage.BOOK, Paul, Insel, Don, Ross, Melissa, Bernstein, Kimberley, McMahon, vanc, Discovering Nutrition, {{google books, y, 6IWHCgAAQBAJ, |date=March 18, 2015|publisher=Jones & Bartlett Publishers|isbn=978-1-284-06465-0}}The main symptoms of vitamin D overdose which are those of hypercalcemia including anorexia, nausea, and vomiting. These may be followed by polyuria, polydipsia, weakness, insomnia, nervousness, pruritus and ultimately renal failure. Furthermore, proteinuria, urinary casts, azotemia, and metastatic calcification (especially in the kidneys) may develop. Other symptoms of vitamin D toxicity include mental retardation in young children, abnormal bone growth and formation, diarrhea, irritability, weight loss, and severe depression.Vitamin D toxicity is treated by discontinuing vitamin D supplementation and restricting calcium intake. Kidney damage may be irreversible. Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity. The concentrations of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D produced is degraded.JOURNAL, Vieth R, Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety, The American Journal of Clinical Nutrition, 69, 5, 842–56, May 1999, 10232622,weblink 10.1093/ajcn/69.5.842,


Synthesis of vitamin D in nature is dependent on the presence of UV radiation and subsequent activation in liver and in kidney. Many animals synthesize vitamin D3 from 7-dehydrocholesterol, and many fungi synthesize vitamin D2 from ergosterol.JOURNAL, Holick MF, Evolutionary biology and pathology of vitamin D, J. Nutr. Sci. Vitaminol., Spec No, 79–83, 1992, 1297827, 10.3177/jnsv.38.Special_79,weblink

Interactive pathway

Click on icon in lower right corner to open.{{VitaminDSynthesis_WP1531|highlight=Calcifediol}}


(File:Vitamin D biosynthesis in fungi and animals.svg|thumb|300px|The photochemistry of vitamin D biosynthesis in animal and fungi)File:Calcitriol-Biosynthese 2.svg|thumb|300px|Thermal isomerization of previtamin{{nbsp}}D3 to vitamin D3]]The transformation that converts 7-dehydrocholesterol to vitamin D3 occurs in two steps.JOURNAL, Holick MF, Photosynthesis of vitamin D in the skin: effect of environmental and life-style variables, Federation Proceedings, 46, 5, 1876–82, April 1987, 3030826, JOURNAL, Deluca HF, History of the discovery of vitamin D and its active metabolites, BoneKEy Reports, 3, 479, January 2014, 24466410, 3899558, 10.1038/bonekey.2013.213, First, 7-dehydrocholesterol is photolyzed by ultraviolet light in a 6-electron conrotatory ring-opening electrocyclic reaction; the product is previtamin{{nbsp}}D3. Second, previtamin{{nbsp}}D3 spontaneously isomerizes to vitamin{{nbsp}}D3 (cholecalciferol) in an antarafacial sigmatropic [1,7] hydride shift. At room temperature, the transformation of previtamin{{nbsp}}D3 to vitamin D3 in an organic solvent takes about 12 days to complete. The conversion of previtamin{{nbsp}}D3 to vitamin D3 in the skin is about 10 times faster than in an organic solvent.The conversion from ergosterol to vitamin D2 follows a similar procedure, forming previtamin{{nbsp}}D2 by photolysis, which isomerizes to vitamin D2.JOURNAL, Eyley, Stephen C., Williams, Dudley H., vanc, Photolytic production of vitamin D. The preparative value of a photo-sensitiser, Journal of the Chemical Society, Chemical Communications, 1975, 20, 858a, 10.1039/C3975000858A, The transformation of previtamin{{nbsp}}D2 to vitamin D2 in methanol has a rate comparable to that of previtamin{{nbsp}}D3. The process is faster in white button mushrooms.{{rp|at=fig. 3}}

Synthesis in the skin

(File:Skinlayers.png|thumb|250px|In the epidermal strata of the skin, vitamin D production is greatest in the stratum basale (colored red in the illustration) and stratum spinosum (colored light brown).)Vitamin D3 is produced photochemically from 7-dehydrocholesterol in the skin of most vertebrate animals, including humans.JOURNAL, Crissey SD, Ange KD, Jacobsen KL, Slifka KA, Bowen PE, Stacewicz-Sapuntzakis M, Langman CB, Sadler W, Kahn S, Ward A, 6, Serum concentrations of lipids, vitamin d metabolites, retinol, retinyl esters, tocopherols and selected carotenoids in twelve captive wild felid species at four zoos, The Journal of Nutrition, 133, 1, 160–6, January 2003, 12514284, 10.1093/jn/133.1.160, The precursor of vitamin D3, 7-dehydrocholesterol is produced in relatively large quantities. 7-Dehydrocholesterol reacts with UVB light at wavelengths of 290–315 nm.BOOK, 978-0-12-809965-0, Michael F., Holick, Chapter 4: Photobiology of Vitamin D, Vitamin D: Volume 1: Biochemistry, Physiology and Diagnostics, 4th, Academic Press, London, UK, Feldman, David, Wesley Pike, J., Bouillon, Roger, Giovannucci, Edward, Goltzman, David, Hewison, Martin, 2018, vanc, These wavelengths are present in sunlight, as well as in the light emitted by the UV lamps in tanning beds (which produce ultraviolet primarily in the UVA spectrum, but typically produce 4% to 10% of the total UV emissions as UVB). Exposure to light through windows is insufficient because glass almost completely blocks UVB light.NEWS,weblink Q&A Sunshine Vitamin D, C. Claiborne, Ray, vanc, The New York Times, May 17, 2005, March 8, 2013, live,weblink" title="">weblink February 21, 2013, WEB,weblink UV FAQs, Bolton J, International Ultraviolet Association, dead,weblink" title="">weblink May 30, 2013, Adequate amounts of vitamin D can be produced with moderate sun exposure to the face, arms and legs, averaging 5–30 minutes twice per week, or approximately 25% of the time for minimal sunburn. The darker the skin, and the weaker the sunlight, the more minutes of exposure are needed. Vitamin D overdose is impossible from UV exposure; the skin reaches an equilibrium where the vitamin degrades as fast as it is created.JOURNAL, Holick MF, February 2002, Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health, Current Opinion in Endocrinology, Diabetes and Obesity, 9, 1, 87–98, 10.1097/00060793-200202000-00011, JOURNAL, Holick MF, Sunlight and vitamin D: both good for cardiovascular health, Journal of General Internal Medicine, 17, 9, 733–5, September 2002, 12220371, 1495109, 10.1046/j.1525-1497.2002.20731.x, Sunscreen absorbs or reflects ultraviolet light and prevents much of it from reaching the skin. Sunscreen with a sun protection factor (SPF) of 8 based on the UVB spectrum decreases vitamin D synthetic capacity by 95%, and SPF 15 decreases it by 98%.BOOK, Institute of Medicine (IoM), 8, Implications and Special Concerns,weblink Ross AC, Taylor CL, Yaktine AL, Del Valle HB, Dietary Reference Intakes for Calcium and Vitamin D, National Academies Press, 2011, 978-0-309-16394-1, 21796828, 10.17226/13050,weblink The National Academies Collection: Reports funded by National Institutes of Health, The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer, thinner epidermis.WEB,weblink Anatomy of the skin, National Cancer Institute, US National Institutes of Health, Bethesda, 2016, December 19, 2016, Thick epidermis in the soles and palms consists of five strata; from outer to inner, they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. Vitamin D is produced in the keratinocytesWEB, Vitamin D and Skin Health,weblink LINUS PAULING INSTITUTE Micronutrient Information Center, Oregon State University, March 30, 2017, 2016-11-07, of two innermost strata, the stratum basale and stratum spinosum.JOURNAL, Holick MF, Smith E, Pincus S, Skin as the site of vitamin D synthesis and target tissue for 1,25-dihydroxyvitamin D3. Use of calcitriol (1,25-dihydroxyvitamin D3) for treatment of psoriasis, Archives of Dermatology, 123, 12, 1677–1683a, December 1987, 2825606, 10.1001/archderm.1987.01660360108022,


Vitamin D can be synthesized only by a photochemical process. Phytoplankton in the ocean (such as coccolithophore and Emiliania huxleyi) have been photosynthesizing vitamin D for more than 500{{nbsp}}million years. Primitive vertebrates in the ocean could absorb calcium from the ocean into their skeletons and eat plankton rich in vitamin D.Land vertebrates required another source of vitamin D other than plants for their calcified skeletons. They had to either ingest it or be exposed to sunlight to photosynthesize it in their skin.JOURNAL, Holick MF, Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis, The American Journal of Clinical Nutrition, 79, 3, 362–71, March 2004, 14985208, 10.1093/ajcn/79.3.362, Land vertebrates have been photosynthesizing vitamin D for more than 350{{nbsp}}million years.BOOK, {{google books, y, P4xbcP19H0AC, 27, |title=The Vitamin D Solution: A 3-Step Strategy to Cure Our Most Common Health Problems|last=Holick|first=Michael F.|date=April 1, 2010|publisher=Penguin Publishing Group|isbn=978-1-101-22293-5| name-list-format = vanc}}In birds and fur-bearing mammals, fur or feathers block UV rays from reaching the skin. Instead, vitamin D is created from oily secretions of the skin deposited onto the feathers or fur, and is obtained orally during grooming.BOOK, Sabrina C., Agarwal, Samuel D., Stout, vanc, Bone Loss and Osteoporosis: An Anthropological Perspective, {{google books, y, _JV3BQAAQBAJ, |date=June 28, 2011|publisher=Springer Science & Business Media|isbn=978-1-4419-8891-1 |quote=The high 25(OH)D concentrations, and relatively high vitamin D requirements of apes and monkeys are understandable in light of their biology—their body surface area relative to mass is generally greater than for humans, and they are inveterate groomers, consuming by mouth the vitamin D generated from the oils secreted by skin into fur. Although much of the vitamin D produced within human skin is absorbed directly, birds and furbearing animals acquire most of their vitamin D orally, as they groom themselves (Bicknell and Prescott, 1946; Carpenter and Zhao, 1999). Vitamin D is generated from the oily secretions of skin into fur. The oral consumption of UV-exposed dermal excretion is the way many animals acquire the "nutrient," vitamin D. Although Fraser (1983) has argued that dermal absorption of vitamin D may be more natural, what we know from animals indicates that oral consumption is equally physiological. Since vitamin D can be extracted from UV-exposed human sweat and skin secretions (Bicknell and Prescott, 1946), it is also reasonable to think that early humans obtained some of their vitamin D by mouth as well, by licking the skin. |archive-url= |archive-date=29 January 2006 |url-status=live}} However, some animals, such as the naked mole-rat, are naturally cholecalciferol-deficient, as serum 25-OH vitamin D levels are undetectable.JOURNAL, Yahav S, Buffenstein R, January 1993, Cholecalciferol supplementation alters gut function and improves digestibility in an underground inhabitant, the naked mole rat (Heterocephalus glaber), when fed on a carrot diet, The British Journal of Nutrition, 69, 1, 233–41, 10.1079/BJN19930025, 8384476,

Industrial synthesis

Vitamin D3 (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB light, followed by purification.JOURNAL, Holick MF, The vitamin D epidemic and its health consequences, The Journal of Nutrition, 135, 11, 2739S–48S, November 2005, 16251641,weblink [Vitamin D3] is produced commercially by extracting 7-dehydrocholesterol from wool fat, followed by UVB irradiation and purification [...] [Vitamin D2] is commercially made by irradiating and then purifying the ergosterol extracted from yeast, 10.1093/jn/135.11.2739S, The 7-dehydrocholesterol is a natural substance in fish organs, especially the liver,JOURNAL, Takeuchi A, Okano T, Sayamoto M, Sawamura S, Kobayashi T, Motosugi M, Yamakawa T, 6, Tissue distribution of 7-dehydrocholesterol, vitamin D3 and 25-hydroxyvitamin D3 in several species of fishes, Journal of Nutritional Science and Vitaminology, 32, 1, 13–22, February 1986, 3012050, 10.3177/jnsv.32.13,weblink or in wool grease (lanolin) from sheep. Vitamin D2 (ergocalciferol) is produced in a similar way using ergosterol from yeast or mushrooms as a starting material.

Mechanism of action

Metabolic activation

File:Cholecalciferol_to_calcidiol_CH3.svg|thumb|300px|Liver hydroxylation of cholecalciferol to calcifediolcalcifediolFile:Calcidiol_to_calcitriol_CH3.svg|thumb|300px|Kidney hydroxylation of calcifediol to calcitriolcalcitriolVitamin D is carried in the bloodstream to the liver, where it is converted into the prohormone calcifediol. Circulating calcifediol may then be converted into calcitriol, the biologically active form of vitamin D, in the kidneys.JOURNAL, Adams JS, Hewison M, Update in vitamin D, The Journal of Clinical Endocrinology and Metabolism, 95, 2, 471–8, February 2010, 20133466, 2840860, 10.1210/jc.2009-1773, Whether it is made in the skin or ingested, vitamin D is hydroxylated in the liver at position 25 (upper right of the molecule) to form 25-hydroxycholecalciferol (calcifediol or 25(OH)D).JOURNAL, Bikle, DD, Vitamin D metabolism, mechanism of action, and clinical applications., Chemistry & Biology, March 20, 2014, 21, 3, 319–29, 10.1016/j.chembiol.2013.12.016, 24529992, 3968073, vanc, This reaction is catalyzed by the microsomal enzyme vitamin D 25-hydroxylase, the product of the CYP2R1 human gene, and expressed by hepatocytes.JOURNAL, Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW, Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase, Proceedings of the National Academy of Sciences of the United States of America, 101, 20, 7711–5, May 2004, 15128933, 419671, 10.1073/pnas.0402490101, 2004PNAS..101.7711C, Once made, the product is released into the plasma, where it is bound to an α-globulin carrier protein named the vitamin D-binding protein.BOOK, Laing CJ, Cooke NE, Section I: Ch. 8: Vitamin D Binding Protein, Feldman D, Glorieux FH, Pike JW, Vitamin D, 1, Academic Press, 2, 2004, 978-0122526879, 117–134, {{google books, y, 5c66r0KrPUMC, }}Calcifediol is transported to the proximal tubules of the kidneys, where it is hydroxylated at the 1-α position (lower right of the molecule) to form calcitriol (1,25-dihydroxycholecalciferol, 1,25(OH)2D). The conversion of calcifediol to calcitriol is catalyzed by the enzyme 25-hydroxyvitamin D3 1-alpha-hydroxylase, which is the product of the CYP27B1 human gene. The activity of CYP27B1 is increased by parathyroid hormone, and also by low calcium or phosphate.Following the final converting step in the kidney, calcitriol is released into the circulation. By binding to vitamin D-binding protein, calcitriol is transported throughout the body, including to the classical target organs of intestine, kidney and bone. Calcitriol is the most potent natural ligand of the vitamin D receptor, which mediates most of the physiological actions of vitamin D.In addition to the kidneys, calcitriol is also synthesized by certain other cells including monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, modulating body defenses against microbial invaders by stimulating the innate immune system.


The activity of calcifediol and calcitriol can be reduced by hydroxylation at position 24 by vitamin D3 24-hydroxylase, forming secalciferol and calcitetrol, respectively.

Difference between substrates

Vitamin{{nbsp}}D2 (ergocalciferol) and vitamin{{nbsp}}D3 (cholecaliferol) share a similar mechanism of action as outlined above. Metabolites produced by vitamin D2 are sometimes named with an er- or ergo prefix to differentiate them from the D3-based counterparts.JOURNAL, IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN): Nomenclature of vitamin D. Recommendations 1981., European Journal of Biochemistry, May 17, 1982, 124, 2, 223–7, 10.1111/j.1432-1033.1982.tb06581.x, 7094913,
  • Metabolites produced from vitamin{{nbsp}}D2 tend to bind less well to the vitamin D-binding protein.
  • Vitamin{{nbsp}}D3 can alternatively be hydroxylated to calcifediol by sterol 27-hydroxylase (CYP27A1), but vitamin{{nbsp}}D2 cannot.
  • Ergocalciferol can be directly hydroxylated at position 24. This hydroxylation also leads to a greater degree of inactivation: while calcitriol's activity decreases to 60% of original after 24-hydroxylation, JOURNAL, Holick MF, Kleiner-Bossaller A, Schnoes HK, Kasten PM, Boyle IT, DeLuca HF, 1,24,25-Trihydroxyvitamin D3. A metabolite of vitamin D3 effective on intestine, The Journal of Biological Chemistry, 248, 19, 6691–6, October 1973, 4355503, ercalcitriol suffers a 10-fold decrease in activity on conversion to ercalcitetrol.JOURNAL, Horst RL, Reinhardt TA, Ramberg CF, Koszewski NJ, Napoli JL, 24-Hydroxylation of 1,25-dihydroxyergocalciferol. An unambiguous deactivation process, The Journal of Biological Chemistry, 261, 20, 9250–6, July 1986, 3013880,


American researchers Elmer McCollum and Marguerite Davis in 1914 discovered a substance in cod liver oil which later was called "vitamin A". British doctor Edward Mellanby noticed dogs that were fed cod liver oil did not develop rickets and concluded vitamin A, or a closely associated factor, could prevent the disease. In 1922, Elmer McCollum tested modified cod liver oil in which the vitamin A had been destroyed. The modified oil cured the sick dogs, so McCollum concluded the factor in cod liver oil which cured rickets was distinct from vitamin A. He called it vitamin D because it was the fourth vitamin to be named.NEWS,weblink Age-old children's disease back in force, Suzanne, Carere, vanc, Toronto Star, July 25, 2007, August 24, 2010, dead,weblink" title="">weblink May 17, 2008, mdy-all, NEWS,weblink Elena, Conis, vanc, Fortified foods took out rickets, Los Angeles Times, July 24, 2006, August 24, 2010, BOOK, McClean FC, Budy AM, Vitamin A, Vitamin D, Cartilage, Bones, and Teeth, Vitamins and Hormones, {{google books, y, gGb7vm2SapcC, 51, |date = January 28, 1964 | publisher = Academic Press | isbn = 978-0-12-709821-0 | volume = 21 | pages = 51–52}} It was not initially realized that, unlike other vitamins, vitamin D can be synthesised by humans through exposure to UV light.In 1925, it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble vitamin is produced (now known as D3). Alfred Fabian Hess stated: "Light equals vitamin D."WEB,weblink History of Vitamin D, University of California at Riverside, 2011, May 9, 2014, Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928 for his work on the constitution of sterols and their connection with vitamins.WEB,weblink Adolf Windaus â€“ Biography,, March 25, 2010, March 25, 2010, In 1929, a group at NIMR in Hampstead, London, were working on the structure of vitamin D, which was still unknown, as well as the structure of steroids. A meeting took place with J.B.S. Haldane, J.D. Bernal, and Dorothy Crowfoot to discuss possible structures, which contributed to bringing a team together. X-ray crystallography demonstrated the sterol molecules were flat, not as proposed by the German team led by Windaus. In 1932, Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids which found immediate acceptance.JOURNAL, Rosenheim O, King H, The Ring-system of sterols and bile acids. Part II, J. Chem. Technol. Biotechnol., 51, 954–7, 1932, 10.1002/jctb.5000514702, 47, The informal academic collaboration between the team members Robert Benedict Bourdillon, Otto Rosenheim, Harold King, and Kenneth Callow was very productive and led to the isolation and characterization of vitamin D. At this time, the policy of the Medical Research Council was not to patent discoveries, believing the results of medical research should be open to everybody. In the 1930s, Windaus clarified further the chemical structure of vitamin D.BOOK, Hirsch AL, Industrial aspects of vitamin D, Vitamin D, 2011, Feldman DJ, Pike JW, Adams JS, Academic Press, London; Waltham, MA, 73, {{google books, y, w7hMAFmsM84C, 73, | isbn = 978-0-12-387035-3 }}In 1923, American biochemist Harry Steenbock at the University of Wisconsin demonstrated that irradiation by ultraviolet light increased the vitamin D content of foods and other organic materials.BOOK, Ziedonis AA, Mowery DC, Nelson RR, Bhaven NS, Ivory tower and industrial innovation: university-industry technology transfer before and after the Bayh-Dole Act in the United States, Stanford Business Books, Stanford, Calif, 2004, 39–40, 978-0-8047-4920-6, {{google books, y, sCscGlm2Q8YC, 39, }} After irradiating rodent food, Steenbock discovered the rodents were cured of rickets. A vitamin D deficiency is a known cause of rickets. Using $300 of his own money, Steenbock patented his invention. His irradiation technique was used for foodstuffs, most memorably for milk. By the expiration of his patent in 1945, rickets had been all but eliminated in the US.BOOK, James, Marshall, vanc, Elbridge a Stuart: Founder of Carnation Company, {{google books, y, 6fICTwEACAAJ, |date=September 2010|publisher=Kessinger Publishing|isbn=978-1-164-49678-6}}In 1969, after studying nuclear fragments of intestinal cells, a specific binding protein for vitamin D called the vitamin D receptor was identified by Mark Haussler and Tony Norman.JOURNAL, Haussler MR, Norman AW, Chromosomal receptor for a vitamin D metabolite, Proceedings of the National Academy of Sciences of the United States of America, 62, 1, 155–62, January 1969, 5253652, 285968, 10.1073/pnas.62.1.155, 1969PNAS...62..155H, In 1971–72, the further metabolism of vitamin D to active forms was discovered. In the liver, vitamin D was found to be converted to calcifediol. Calcifediol is then converted by the kidneys to calcitriol, the biologically active form of vitamin D. Calcitriol circulates as a hormone in the blood, regulating the concentration of calcium and phosphate in the bloodstream and promoting the healthy growth and remodeling of bone. The vitamin D metabolites, calcifediol and calcitriol, were identified by competing teams led by Michael F. Holick in the laboratory of Hector DeLuca and by Tony Norman and colleagues.JOURNAL, Holick MF, Schnoes HK, DeLuca HF, Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine, Proceedings of the National Academy of Sciences of the United States of America, 68, 4, 803–4, April 1971, 4323790, 389047, 10.1073/pnas.68.4.803, 1971PNAS...68..803H, JOURNAL, Norman AW, Myrtle JF, Midgett RJ, Nowicki HG, Williams V, Popják G, 1,25-dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine, Science, 173, 3991, 51–4, July 1971, 4325863, 10.1126/science.173.3991.51, 1971Sci...173...51N, JOURNAL, Holick MF, DeLuca HF, Avioli LV, Isolation and identification of 25-hydroxycholecalciferol from human plasma, Archives of Internal Medicine, 129, 1, 56–61, January 1972, 4332591, 10.1001/archinte.1972.00320010060005,


There is considerable research activity looking at effects of vitamin D and its metabolites in animal models, cell systems, gene expression studies, epidemiology and clinical therapeutics. These different types of studies can produce conflicting evidence as to the benefits of interventions with vitamin D.JOURNAL, Dankers W, Colin EM, van Hamburg JP, Lubberts E, Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential, Front Immunol, 7, 697, 2016, 28163705, 5247472, 10.3389/fimmu.2016.00697, One school of thought contends the human physiology is fine-tuned to an intake of 4,000–12,000{{nbsp}}IU/day from sun exposure with concomitant serum 25-hydroxyvitamin D levels of 40 to 80{{nbsp}}ng/mL and this is required for optimal health. Proponents of this view, who include some members of the panel that drafted a now-superseded 1997 report on vitamin D from the IOM, contend the IOM's warning about serum concentrations above 50{{nbsp}}ng/mL lacks biological plausibility. They suggest, for some people, reducing the risk of preventable disease requires a higher level of vitamin D than that recommended by the IOM.JOURNAL, Heaney RP, Holick MF, Why the IOM recommendations for vitamin D are deficient, Journal of Bone and Mineral Research, 26, 3, 455–7, March 2011, 21337617, 10.1002/jbmr.328, JOURNAL, Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, 6, Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline, The Journal of Clinical Endocrinology and Metabolism, 96, 7, 1911–30, July 2011, 21646368, 10.1210/jc.2011-0385, The United States National Institutes of Health Office of Dietary Supplements established a Vitamin D Initiative in 2014 to track current research and provide education to consumers.WEB,weblink ODS Vitamin D Initiative, Office of Dietary Supplements, US National Institutes of Health, Bethesda, MD, 2014, In their 2016 review, they recognize that a growing body of research suggests that vitamin D might play some role in the prevention and treatment of types 1 and 2 diabetes, glucose intolerance, hypertension, multiple sclerosis, and other medical conditions. They state further: "however, most evidence for these roles comes from in vitro, animal, and epidemiological studies, not the randomized clinical trials considered to be more definitive. Until such trials are conducted, the implications of the available evidence for public health and patient care will be debated".Some preliminary studies link low vitamin D levels with disease later in life.BOOK, Pyrżak B, Witkowska-Sędek E, Krajewska M, Demkow U, Kucharska AM, Metabolic and immunological consequences of vitamin D deficiency in obese children, 840, 13–9, 2015, 25315624, 10.1007/5584_2014_81, 978-3-319-10249-8, Advances in Experimental Medicine and Biology, Body Metabolism and Exercise, Evidence as of 2013 is insufficient to determine whether vitamin D affects the risk of cancer.WEB,weblink How is vitamin D being studied now in clinical cancer research?, National Cancer Institute, US National Institutes of Health, Bethesda, MD, October 21, 2013, One meta-analysis found a decrease in mortality in elderly people. Another meta-analysis covering over 350,000 people concluded that vitamin D supplementation in unselected community-dwelling individuals does not reduce skeletal (total fracture) or non-skeletal outcomes (myocardial infarction, ischemic heart disease, stroke, cerebrovascular disease, cancer) by more than 15%, and that further research trials with similar design are unlikely to change these conclusions. A 2019 meta-analysis found that there may be an increased risk of stroke when taking both calcium and vitamin D.JOURNAL, Khan SU, Khan MU, Riaz H, Valavoor S, Zhao D, Vaughan L, Okunrintemi V, Riaz IB, Khan MS, Kaluski E, Murad MH, Blaha MJ, Guallar E, Michos ED, 6, Effects of Nutritional Supplements and Dietary Interventions on Cardiovascular Outcomes, Annals of Internal Medicine, 171, 3, 190–198, July 9, 2019, 0003-4819, 10.7326/m19-0341, 31284304, Vitamin D deficiency is widespread in the European population.JOURNAL, Cashman KD, Dowling KG, Škrabáková Z, Gonzalez-Gross M, Valtueña J, De Henauw S, Moreno L, Damsgaard CT, Michaelsen KF, Mølgaard C, Jorde R, Grimnes G, Moschonis G, Mavrogianni C, Manios Y, Thamm M, Mensink GB, Rabenberg M, Busch MA, Cox L, Meadows S, Goldberg G, Prentice A, Dekker JM, Nijpels G, Pilz S, Swart KM, van Schoor NM, Lips P, Eiriksdottir G, Gudnason V, Cotch MF, Koskinen S, Lamberg-Allardt C, Durazo-Arvizu RA, Sempos CT, Kiely M, 6, Vitamin D deficiency in Europe: pandemic?, The American Journal of Clinical Nutrition, 103, 4, 1033–44, April 2016, 26864360, 5527850, 10.3945/ajcn.115.120873, European research is assessing vitamin D intake levels in association with disease rates and policies of dietary recommendations, food fortification, vitamin D supplementation, and small amounts of sun exposure.Apart from VDR activation, various alternative mechanisms of action are under study, such as inhibition of signal transduction by hedgehog, a hormone involved in morphogenesis.JOURNAL, Sarkar FH, Li Y, Wang Z, Kong D, The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer, Cancer Metastasis Reviews, 29, 3, 383–94, September 2010, 20711635, 2974632, 10.1007/s10555-010-9233-4,



Further reading

External links

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