Vitamin D#Synthesis in the skin

Several forms (vitamers) of vitamin D exist, with the two major forms being vitamin D₂ or ergocalciferol, and vitamin D₃ or cholecalciferol. The common-use term "vitamin D" refers to both D₂ and D₃, which were chemically characterized, respectively, in 1931 and 1935. Vitamin D₃ was shown to result from the ultraviolet irradiation of 7-dehydrocholesterol. Although a chemical nomenclature for vitamin D forms was recommended in 1981,{{cite journal | vauthors = | title = IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN): Nomenclature of vitamin D. Recommendations 1981 | journal = European Journal of Biochemistry | volume = 124 | issue = 2 | pages = 223–227 | date = May 1982 | pmid = 7094913 | doi = 10.1111/j.1432-1033.1982.tb06581.x | title-link = doi | doi-access = free }} alternative names remain commonly used.

Chemically, the various forms of vitamin D are secosteroids, meaning that one of the bonds in the steroid rings is broken.{{cite book |vauthors=Fleet JC, Shapses SA |title = Present Knowledge in Nutrition | edition = Eleventh |chapter = Vitamin D | veditors = Marriott BP, Birt DF, Stallings VA, Yates AA |publisher = Academic Press (Elsevier) |year=2020 |location = London, United Kingdom |pages = 93–114 |isbn=978-0-323-66162-1}} The structural difference between vitamin D₂ and vitamin D₃ lies in the side chain: vitamin D₂ has a double bond between carbons 22 and 23, and a methyl group on carbon 24. Vitamin D analogues have also been synthesized.

The active vitamin D metabolite, calcitriol, exerts its biological effects by binding to the vitamin D receptor (VDR), which is primarily located in the nuclei of target cells. When calcitriol binds to the VDR, it enables the receptor to act as a transcription factor, modulating the gene expression of transport proteins involved in calcium absorption in the intestine, such as TRPV6 and calbindin.{{cite journal | vauthors = Bouillon R, Van Cromphaut S, Carmeliet G | title = Intestinal calcium absorption: Molecular vitamin D mediated mechanisms | journal = Journal of Cellular Biochemistry | volume = 88 | issue = 2 | pages = 332–339 | date = February 2003 | pmid = 12520535 | doi = 10.1002/jcb.10360 | s2cid = 9853381 }} The VDR is part of the nuclear receptor superfamily of steroid hormone receptors, which are hormone-dependent regulators of gene expression. These receptors are expressed in cells across most organs. VDR expression decreases as age increases.

Activation of VDR in the intestine, bone, kidney, and parathyroid gland cells plays a crucial role in maintaining calcium and phosphorus levels in the blood, a process that is assisted by parathyroid hormone and calcitonin, thereby supporting bone health.{{cite journal | vauthors = Holick MF | title = Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease | journal = The American Journal of Clinical Nutrition | volume = 80 | issue = 6 Suppl | pages = 1678S–1688S | date = December 2004 | pmid = 15585788 | doi = 10.1093/ajcn/80.6.1678S | title-link = doi | doi-access = free }} VDR also regulates cell proliferation and differentiation. Additionally, vitamin D influences the immune system, with VDRs being expressed in several types of white blood cells, including monocytes and activated T and B cells.{{cite journal | vauthors = Watkins RR, Lemonovich TL, Salata RA | title = An update on the association of vitamin D deficiency with common infectious diseases | journal = Canadian Journal of Physiology and Pharmacology | volume = 93 | issue = 5 | pages = 363–368 | date = May 2015 | pmid = 25741906 | doi = 10.1139/cjpp-2014-0352 }}

{{Main|Vitamin D deficiency}}

Worldwide, more than one billion people{{cite journal | vauthors = Holick MF, Chen TC | title = Vitamin D deficiency: a worldwide problem with health consequences | journal = The American Journal of Clinical Nutrition | volume = 87 | issue = 4 | pages = 1080S–1086S | date = April 2008 | pmid = 18400738 | doi = 10.1093/ajcn/87.4.1080S }} - infants, children, adults and elderly - can be considered vitamin D deficient, with reported percentages dependent on what measurement is used to define "deficient".{{Cite web|url=https://www.health.harvard.edu/blog/vitamin-d-whats-right-level-2016121910893 | vauthors = Tello M |title=Vitamin D: What's the "right" level? |date=16 April 2020 |website=Harvard Health Publishing|access-date=15 December 2024}} Deficiency is common in the Middle-East,{{cite journal | vauthors = Palacios C, Gonzalez L | title = Is vitamin D deficiency a major global public health problem? | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 144 | issue = Pt A | pages = 138–145 | date = October 2014 | pmid = 24239505 | pmc = 4018438 | doi = 10.1016/j.jsbmb.2013.11.003 }} Asia,{{cite journal | vauthors = Jiang Z, Pu R, Li N, Chen C, Li J, Dai W, Wang Y, Hu J, Zhu D, Yu Q, Shi Y, Yang G | title = High prevalence of vitamin D deficiency in Asia: A systematic review and meta-analysis | journal = Critical Reviews in Food Science and Nutrition | volume = 63 | issue = 19 | pages = 3602–3611 | date = 2023 | pmid = 34783278 | doi = 10.1080/10408398.2021.1990850 }} Africa{{cite journal | vauthors = Mogire RM, Mutua A, Kimita W, Kamau A, Bejon P, Pettifor JM, Adeyemo A, Williams TN, Atkinson SH | title = Prevalence of vitamin D deficiency in Africa: a systematic review and meta-analysis | journal = The Lancet. Global Health | volume = 8 | issue = 1 | pages = e134–e142 | date = January 2020 | pmid = 31786117 | pmc = 7024961 | doi = 10.1016/S2214-109X(19)30457-7 }} and South America,{{cite journal | vauthors = Mendes MM, Gomes AP, Araújo MM, Coelho AS, Carvalho KM, Botelho PB | title = Prevalence of vitamin D deficiency in South America: a systematic review and meta-analysis | journal = Nutrition Reviews | volume = 81 | issue = 10 | pages = 1290–1309 | date = September 2023 | pmid = 36882047 | doi = 10.1093/nutrit/nuad010 }} but also exists in North America and Europe.{{cite journal | vauthors = Amrein K, Scherkl M, Hoffmann M, Neuwersch-Sommeregger S, Köstenberger M, Tmava Berisha A, Martucci G, Pilz S, Malle O | title = Vitamin D deficiency 2.0: an update on the current status worldwide | journal = European Journal of Clinical Nutrition | volume = 74 | issue = 11 | pages = 1498–1513 | date = November 2020 | pmid = 31959942 | pmc = 7091696 | doi = 10.1038/s41430-020-0558-y }}{{cite journal | vauthors = Harvey NC, Ward KA, Agnusdei D, Binkley N, Biver E, Campusano C, Cavalier E, Clark P, Diaz-Curiel M, Fuleihan GE, Khashayar P, Lane NE, Messina OD, Mithal A, Rizzoli R, Sempos C, Dawson-Hughes B | title = Optimisation of vitamin D status in global populations | journal = Osteoporosis International | volume = 35 | issue = 8 | pages = 1313–1322 | date = August 2024 | pmid = 38836946 | doi = 10.1007/s00198-024-07127-z | hdl = 2268/319515 | hdl-access = free }} Dark-skinned populations in North America, Europe and Australia have a higher percentage of deficiency compared to light-skinned populations that had their origins in Europe.{{cite journal | vauthors = 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 | title = Vitamin D deficiency in Europe: pandemic? | journal = The American Journal of Clinical Nutrition | volume = 103 | issue = 4 | pages = 1033–1044 | date = April 2016 | pmid = 26864360 | pmc = 5527850 | doi = 10.3945/ajcn.115.120873 }}{{cite journal | vauthors = Martin CA, Gowda U, Renzaho AM | title = The prevalence of vitamin D deficiency among dark-skinned populations according to their stage of migration and region of birth: A meta-analysis | journal = Nutrition | volume = 32 | issue = 1 | pages = 21–32 | date = January 2016 | pmid = 26643747 | doi = 10.1016/j.nut.2015.07.007 }}{{cite journal | vauthors = Lowe NM, Bhojani I | title = Special considerations for vitamin D in the south Asian population in the UK | journal = Therapeutic Advances in Musculoskeletal Disease | volume = 9 | issue = 6 | pages = 137–144 | date = June 2017 | pmid = 28620422 | pmc = 5466148 | doi = 10.1177/1759720X17704430 }}

Serum 25(OH)D concentration is used as a biomarker for vitamin D deficiency. Units of measurement are either ng/mL or nmol/L, with one{{nbsp}}ng/mL equal to 2.5{{nbsp}}nmol/L. There is no consensus on defining vitamin D deficiency, insufficiency, sufficiency, or optimal for all aspects of health. According to the US Institute of Medicine Dietary Reference Intake Committee, below 30{{nbsp}}nmol/L significantly increases the risk of vitamin D deficiency caused rickets in infants and young children and reduces absorption of dietary calcium from the normal range of 60–80% to as low as 15%, whereas above 40{{nbsp}}nmol/L is needed to prevent osteomalacia bone loss in the elderly, and above 50{{nbsp}}nmol/L to be sufficient for all health needs.{{rp|75–111}} Other sources have defined deficiency as less than 25{{nbsp}}nmol/L, insufficiency as 30–50{{nbsp}}nmol/L{{cite journal | vauthors = Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM | title = Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 96 | issue = 7 | pages = 1911–1930 | date = July 2011 | pmid = 21646368 | doi = 10.1210/jc.2011-0385 | title-link = doi | doi-access = free }} and optimal as greater than 75{{nbsp}}nmol/L.{{Cite book |vauthors=Bischoff-Ferrari HA |chapter=Optimal Serum 25-Hydroxyvitamin D Levels for Multiple Health Outcomes |series=Advances in Experimental Medicine and Biology |date=2008 |title=Sunlight, Vitamin D and Skin Cancer |volume=810 |pages=500–25 |publisher=Springer |pmid=25207384 |doi=10.1007/978-0-387-77574-6_5 |type=Review |isbn=978-0-387-77573-9}}{{cite journal | vauthors = Dahlquist DT, Dieter BP, Koehle MS | title = Plausible ergogenic effects of vitamin D on athletic performance and recovery | journal = Journal of the International Society of Sports Nutrition | volume = 12 | pages = 33 | year = 2015 | pmid = 26288575 | pmc = 4539891 | doi = 10.1186/s12970-015-0093-8 | doi-access = free | type = Review }} Part of the controversy is because studies have reported differences in serum levels of 25(OH)D between ethnic groups, with studies pointing to genetic as well as environmental reasons behind these variations. African-American populations have lower serum 25(OH)D than their age-matched white population, but at all ages have superior calcium absorption efficiency, a higher bone mineral density, and as elderly, a lower risk of osteoporosis and fractures.{{rp|pages=439–440}} Supplementation in this population to achieve proposed 'standard' concentrations could, in theory, cause harmful vascular calcification.

Using the 25(OH)D assay as a screening tool of the generally healthy population to identify and treat individuals is considered not as cost-effective as a government-mandated fortification program. Instead, there is a recommendation that testing should be limited to those showing symptoms of vitamin D deficiency or who have health conditions known to cause vitamin deficiency.

Causes of insufficient vitamin D synthesis in the skin include insufficient exposure to UVB light from sunlight due to living in high latitudes (farther distance from the equator with resultant shorter daylight hours in winter). Serum concentration by the end of winter can be lower by one-third to half that at the end of summer.{{rp|100–101,371–379}} The prevalence of vitamin D deficiency increases with age due to a decrease in 7-dehydrocholesterol synthesis in the skin and a decline in kidney capacity to convert calcidiol to calcitriol,{{cite journal |vauthors=Giustina A, Bouillon R, Dawson-Hughes B, Ebeling PR, Lazaretti-Castro M, Lips P, Marcocci C, Bilezikian JP |title=Vitamin D in the older population: a consensus statement |journal=Endocrine |volume=79 |issue=1 |pages=31–44 |date=January 2023 |pmid=36287374 |pmc=9607753 |doi=10.1007/s12020-022-03208-3 |url=}} the latter seen to a greater degree in people with chronic kidney disease.{{cite journal |vauthors=Jean G, Souberbielle JC, Chazot C |title=Vitamin D in Chronic Kidney Disease and Dialysis Patients |journal=Nutrients |volume=9 |issue=4 |date=March 2017 |page=328 |pmid=28346348 |pmc=5409667 |doi=10.3390/nu9040328 |doi-access=free |url=}} Despite these age effects, elderly people can still synthesize sufficient calcitriol if enough skin is exposed to UVB light. Absent that, a dietary supplement is recommended. Other causes of insufficient synthesis are sunlight being blocked by air pollution,{{cite journal | vauthors = Hoseinzadeh E, Taha P, Wei C, Godini H, Ashraf GM, Taghavi M, Miri M | title = The impact of air pollutants, UV exposure and geographic location on vitamin D deficiency | journal = Food and Chemical Toxicology | volume = 113 | issue = | pages = 241–254 | date = March 2018 | pmid = 29409825 | doi = 10.1016/j.fct.2018.01.052 }} urban/indoor living, long-term hospitalizations and stays in extended care facilities, cultural or religious lifestyle choices that favor sun-blocking clothing, recommendations to use sun-blocking clothing or sunscreen to reduce risk of skin cancer, and lastly, the UV-B blocking nature of dark skin.

Consumption of foods that naturally contain vitamin D is rarely sufficient to maintain a recommended serum concentration of 25(OH)D in the absence of the contribution of skin synthesis. Fractional contributions are roughly 20% diet and 80% sunlight. Vegans had a lower dietary intake of vitamin D and lower serum 25(OH)D when compared to omnivores, with lacto-ovo-vegetarians falling in between due to the vitamin content of egg yolks and fortified dairy products.{{cite journal | vauthors = Neufingerl N, Eilander A | title = Nutrient Intake and Status in Adults Consuming Plant-Based Diets Compared to Meat-Eaters: A Systematic Review | journal = Nutrients | volume = 14 | issue = 1 | page = 29 | date = December 2021 | pmid = 35010904 | pmc = 8746448 | doi = 10.3390/nu14010029 | doi-access = free }} Governments have mandated or voluntary food fortification programs to bridge the difference in, respectively, 15 and 10 countries. The United States is one of the few mandated countries. The original fortification practices, circa the early 1930s, were limited to cow's milk, which had a large effect on reducing infant and child rickets. In July 2016 the US Food and Drug Administration approved the addition of vitamin D to plant milk beverages intended as milk alternatives, such as beverages made from soy, almond, coconut, and oats. At an individual level, people may choose to consume a multivitamin/mineral product or else a vitamin-D-only product.

There are many disease states, medical treatments, and medications that put people at risk for vitamin D deficiency. Chronic diseases that increase risk include kidney and liver failure, Crohn's disease, inflammatory bowel disease, and malabsorption syndromes such as cystic fibrosis, and hyper- or hypo-parathyroidism. Obesity sequesters vitamin D in fat tissues, thereby lowering serum levels, but bariatric surgery to treat obesity interferes with dietary vitamin D absorption, also causing deficiency. Medications interacting with vitamin D metabolism include antiretrovirals, anti-seizure drugs, glucocorticoids, systemic antifungals such as ketoconazole, cholestyramine, and rifampicin.{{cite journal | vauthors = Giustina A, Bilezikian JP, Adler RA, Banfi G, Bikle DD, Binkley NC, Bollerslev J, Bouillon R, Brandi ML, Casanueva FF, di Filippo L, Donini LM, Ebeling PR, Fuleihan GE, Fassio A, Frara S, Jones G, Marcocci C, Martineau AR, Minisola S, Napoli N, Procopio M, Rizzoli R, Schafer AL, Sempos CT, Ulivieri FM, Virtanen JK | title = Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows | journal = Endocrine Reviews | volume = 45 | issue = 5 | pages = 625–654 | date = September 2024 | pmid = 38676447 | pmc = 11405507 | doi = 10.1210/endrev/bnae009 }} Organ transplant recipients receive immunosuppressive therapy that is associated with an increased risk to develop skin cancer, so they are advised to avoid sunlight exposure, and to take a vitamin D supplement.{{cite book |vauthors=Saternus R, Vogt T, Reichrath J |title=Sunlight, Vitamin D and Skin Cancer |chapter=Update: Solar UV Radiation, Vitamin D, and Skin Cancer Surveillance in Organ Transplant Recipients (OTRs) |series=Adv Exp Med Biol |volume=1268 |pages=335–53 |date=2020 |pmid=32918227 |doi=10.1007/978-3-030-46227-7_17 |isbn=978-3-030-46226-0 |chapter-url=}}

Daily dose regimens are preferred to admission of large doses at weekly or monthly schedules, and D₃ may be preferred over D₂, but there is a lack of consensus as to optimal type, dose, duration or what to measure to deem success. Daily regimens on the order of 4,000 IU/day (for other than infants) have a greater effect on 25(OH)D recovery from deficiency and a lower risk of side effects compared to weekly or monthly bolus doses, with the latter as high as 100,000 IU. The only advantage of bolus dosing could be better compliance, as bolus dosing is usually administered by a healthcare professional rather than self-administered. While some studies have found that vitamin D₃ raises 25(OH)D blood levels faster and remains active in the body longer,{{cite journal | vauthors = Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, Hyppönen E, Berry J, Vieth R, Lanham-New S | title = Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis | journal = The American Journal of Clinical Nutrition | volume = 95 | issue = 6 | pages = 1357–1364 | date = June 2012 | pmid = 22552031 | pmc = 3349454 | doi = 10.3945/ajcn.111.031070 }}{{cite journal | vauthors = Alshahrani F, Aljohani N | title = Vitamin D: deficiency, sufficiency and toxicity | journal = Nutrients | volume = 5 | issue = 9 | pages = 3605–3616 | date = September 2013 | pmid = 24067388 | pmc = 3798924 | doi = 10.3390/nu5093605 | title-link = doi | doi-access = free }} others contend that vitamin D₂ sources are equally bioavailable and effective for raising and sustaining 25(OH)D.{{cite journal | vauthors = Keegan RJ, Lu Z, Bogusz JM, Williams JE, Holick MF | title = Photobiology of vitamin D in mushrooms and its bioavailability in humans | journal = Dermato-Endocrinology | volume = 5 | issue = 1 | pages = 165–176 | date = January 2013 | pmid = 24494050 | pmc = 3897585 | doi = 10.4161/derm.23321 }}{{cite journal | vauthors = Borel P, Caillaud D, Cano NJ | title = Vitamin D bioavailability: state of the art | journal = Critical Reviews in Food Science and Nutrition | volume = 55 | issue = 9 | pages = 1193–1205 | year = 2015 | pmid = 24915331 | doi = 10.1080/10408398.2012.688897 | url = https://www.hal.inserm.fr/inserm-01478467/file/Vitamin%20D%20bioavailability%20HAL.pdf | access-date = 27 April 2021 | url-status = live | s2cid = 9818323 | archive-url = https://web.archive.org/web/20210713200358/https://www.hal.inserm.fr/inserm-01478467/file/Vitamin%20D%20bioavailability%20HAL.pdf | archive-date = 13 July 2021 }} If digestive disorders compromise absorption, then intramuscular injection of up to 100,000 IU of vitamin D₃ is therapeutic.

Melanin, specifically the sub-type eumelanin, is a biomolecule consisting of linked molecules of oxidized amino acid tyrosine. It is produced by cells called melanocytes in a process called melanogenesis. In the skin, melanin is located in the bottom layer (the stratum basale) of the skin's epidermis. Melanin can be permanently incorporated into the skin, resulting in dark skin, or else have its synthesis initiated by exposure to UV radiation, causing the skin to darken as a temporary sun tan. Eumelanin is an effective absorbent of light; the pigment can dissipate over 99.9% of absorbed UV radiation.{{cite journal | vauthors = Meredith P, Riesz J | title = Radiative relaxation quantum yields for synthetic eumelanin | journal = Photochemistry and Photobiology | volume = 79 | issue = 2 | pages = 211–216 | date = February 2004 | pmid = 15068035 | doi = 10.1111/j.1751-1097.2004.tb00012.x | arxiv = cond-mat/0312277 | s2cid = 222101966 }} Because of this property, eumelanin is thought to protect skin cells from sunlight's ultraviolet A (UVA) and ultraviolet B (UVB) radiation damage, reducing the risk of skin tissue folate depletion, preventing premature skin aging and reducing the risks of sunburn and skin cancer.{{citation|url=http://www.skincancer.org/prevention/uva-and-uvb/understanding-uva-and-uvb|title=Understanding UVA and UVB|access-date=2012-04-30|url-status=live|archive-url=https://web.archive.org/web/20120501231522/http://www.skincancer.org/prevention/uva-and-uvb/understanding-uva-and-uvb|archive-date=1 May 2012}} Melanin inhibits UVB-powered vitamin D synthesis in the skin. In areas of the world not distant from the equator, abundant, year-round exposure to sunlight means that even dark-skinned populations have adequate skin synthesis. However, when dark-skinned people cover much of their bodies with clothing for cultural or climate reasons, or are living a primarily indoor life in urban conditions, or live at higher latitudes which provide less sunlight in winter, they are at risk for vitamin D deficiency.{{cite journal | vauthors = Khalid AT, Moore CG, Hall C, Olabopo F, Rozario NL, Holick MF, Greenspan SL, Rajakumar K | title = Utility of sun-reactive skin typing and melanin index for discerning vitamin D deficiency | journal = Pediatric Research | volume = 82 | issue = 3 | pages = 444–451 | date = September 2017 | pmid = 28467404 | pmc = 5570640 | doi = 10.1038/pr.2017.114 }} The last cause has been described as a "latitude-skin color mismatch".

In the United States, vitamin D deficiency is particularly common among non-white Hispanic and African-American populations.{{cite journal | vauthors = Ames BN, Grant WB, Willett WC | title = Does the High Prevalence of Vitamin D Deficiency in African Americans Contribute to Health Disparities? | journal = Nutrients | volume = 13 | issue = 2 | page = 499 | date = February 2021 | pmid = 33546262 | pmc = 7913332 | doi = 10.3390/nu13020499 | doi-access = free }}{{cite journal | vauthors = O'Connor MY, Thoreson CK, Ramsey NL, Ricks M, Sumner AE | title = The uncertain significance of low vitamin D levels in African descent populations: a review of the bone and cardiometabolic literature | journal = Progress in Cardiovascular Diseases | volume = 56 | issue = 3 | pages = 261–269 | year = 2013 | pmid = 24267433 | pmc = 3894250 | doi = 10.1016/j.pcad.2013.10.015 }} However, despite having on-average 25(OH)D serum concentrations below the 50 nmol/L amount considered sufficient, African Americans have higher bone mineral density and lower fracture risk when compared to European-origin people. Possible mechanisms may include higher calcium retention, lower calcium excretion, and greater bone resistance to parathyroid hormone,{{cite journal | vauthors = Shieh A, Aloia JF | title = Assessing Vitamin D Status in African Americans and the Influence of Vitamin D on Skeletal Health Parameters | journal = Endocrinology and Metabolism Clinics of North America | volume = 46 | issue = 1 | pages = 135–152 | date = March 2017 | pmid = 28131129 | doi = 10.1016/j.ecl.2016.09.006 }} also genetically lower serum vitamin D-binding protein which would result in adequate bioavailable 25(OH)D despite total serum 25(OH)D being lower.{{cite journal | vauthors = Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, Tamez H, Zhang D, Bhan I, Karumanchi SA, Powe NR, Thadhani R | title = Vitamin D-binding protein and vitamin D status of black Americans and white Americans | journal = The New England Journal of Medicine | volume = 369 | issue = 21 | pages = 1991–2000 | date = November 2013 | pmid = 24256378 | pmc = 4030388 | doi = 10.1056/NEJMoa1306357 }} The bone density and fracture risk paradox does not necessarily carry over to non-skeletal health conditions such as arterial calcification, cancer, diabetes or all-cause mortality. There is conflicting evidence that in the African American population, 'deficiency' as currently defined increases the risk of non-skeletal health conditions, and some evidence that supplementation increases risk, including for harmful vascular calcification.{{cite journal | vauthors = Freedman BI, Register TC | title = Effect of race and genetics on vitamin D metabolism, bone and vascular health | journal = Nature Reviews. Nephrology | volume = 8 | issue = 8 | pages = 459–466 | date = June 2012 | pmid = 22688752 | pmc = 10032380 | doi = 10.1038/nrneph.2012.112 | s2cid = 29026212 }} African Americans, and by extension other dark-skinned populations, may need different definitions for vitamin D deficiency, insufficiency, and adequate.

Comparative studies carried out in lactating mothers indicate a mean value of vitamin D content in the breast milk of 45 IU/liter.{{cite journal | vauthors = Durá-Travé T, Gallinas-Victoriano F | title = Pregnancy, Breastfeeding, and Vitamin D | journal = International Journal of Molecular Sciences | volume = 24 | issue = 15 | page = 11881 | date = July 2023 | pmid = 37569256 | pmc = 10418507 | doi = 10.3390/ijms241511881 | doi-access = free }} This vitamin D content is too low to meet the vitamin D requirement of 400 IU/day recommended by several government organizations ("...as breast milk is not a meaningful source of vitamin D."{{rp|385}}). The same government organizations recommend that lactating women consume 600 IU/day, but this is insufficient to raise breast milk content to deliver recommended intake. There is evidence that breast milk content can be increased, but because the transfer of the vitamin from the lactating mother's serum to milk is inefficient, this requires that she consume a dietary supplement above the government-set safe upper limit of 4,000 IU/day. Given the shortfall, there are recommendations that breast-fed infants be fed a vitamin D dietary supplement of 400 IU/day during the first year of life. If not breastfeeding, infant formulas are designed to deliver 400 IU/day for an infant consuming a liter of formula per day{{cite journal | vauthors = Kim YJ | title = Comparison of the serum vitamin D level between breastfed and formula-fed infants: several factors which can affect serum vitamin D concentration | journal = Korean Journal of Pediatrics | volume = 56 | issue = 5 | pages = 202–204 | date = May 2013 | pmid = 23741233 | pmc = 3668200 | doi = 10.3345/kjp.2013.56.5.202 }} - a normal volume for a full-term infant after the first month.{{cite web |url=https://my.clevelandclinic.org/health/articles/9693-feeding-your-baby-the-first-year |title=Feeding Your Baby: The First Year |date=13 September 2023 |website=Cleveland Clinic |access-date=28 December 2024}}

{{further|Vitamin D toxicity}}

Vitamin D toxicity, or hypervitaminosis D, is the toxic state of an excess of vitamin D. It is rare, having occurred historically during a time of unregulated fortification of foods, especially those provided to infants,{{rp|431–432}} or in more recently, with consumption of high-dose vitamin D dietary supplements following inappropriate prescribing, non-prescribed consumption of high-dose, over-the-counter preparations, or manufacturing errors resulting in content far in excess of what is on the label.{{cite journal | vauthors = Dudenkov DV, Yawn BP, Oberhelman SS, Fischer PR, Singh RJ, Cha SS, Maxson JA, Quigg SM, Thacher TD | title = Changing Incidence of Serum 25-Hydroxyvitamin D Values Above 50 ng/mL: A 10-Year Population-Based Study | journal = Mayo Clinic Proceedings | volume = 90 | issue = 5 | pages = 577–586 | date = May 2015 | pmid = 25939935 | pmc = 4437692 | doi = 10.1016/j.mayocp.2015.02.012 }}{{cite journal | vauthors = Taylor PN, Davies JS | title = A review of the growing risk of vitamin D toxicity from inappropriate practice | journal = British Journal of Clinical Pharmacology | volume = 84 | issue = 6 | pages = 1121–1127 | date = June 2018 | pmid = 29498758 | pmc = 5980613 | doi = 10.1111/bcp.13573 }} Ultraviolet light alone - sunlight or tanning beds - can raise serum 25(OH)D concentration to a bit higher than 100 nmol/L, but not to a level that causes hypervitaminosis D, the reasons being that there is a limiting amount of the precursor 7-dehydrocholesterol synthesized in the skin and a negative feedback in the kidney wherein the presence of calcitriol induces diversion to metabolically inactive 24,25-hydroxyvitamin D rather than metabolically active calcitriol (1,25-hydroxyvitamin D).{{cite journal | vauthors = Macdonald HM | title = Contributions of sunlight and diet to vitamin D status | journal = Calcified Tissue International | volume = 92 | issue = 2 | pages = 163–176 | date = February 2013 | pmid = 23001438 | doi = 10.1007/s00223-012-9634-1 }} Further metabolism yields calcitroic acid, an inactive water-soluble compound that is excreted in bile.{{cite journal | vauthors = Yu OB, Arnold LA | title = Calcitroic Acid-A Review | journal = ACS Chemical Biology | volume = 11 | issue = 10 | pages = 2665–72 | date = October 2016 | pmid = 27574921 | pmc = 5074857 | doi = 10.1021/acschembio.6b00569 }}

There is no general agreement about the intake levels at which vitamin D may cause harm. According to the IOM review, "Doses below 10,000 IU/day are not usually associated with toxicity, whereas doses equal to or above 50,000 IU/day for several weeks or months are frequently associated with toxic side effects including documented hypercalcemia."{{rp|427}} The normal range for blood concentration of 25-hydroxyvitamin D in adults is 20 to 50 nanograms per milliliter (ng/mL; equivalent to 50 to 125 nmol/L). Blood levels necessary to cause adverse effects in adults are thought to be greater than about 150 ng/mL.{{rp|pages=424–446}}

An excess of vitamin D causes abnormally hypercalcaemia (high blood concentrations of calcium), which can cause overcalcification of the bones and soft tissues including arteries, heart, and kidneys. Untreated, this can lead to irreversible kidney failure. Symptoms of vitamin D toxicity may include the following: increased thirst, increased urination, nausea, vomiting, diarrhea, decreased appetite, irritability, constipation, fatigue, muscle weakness, and insomnia.

In 2011, the U.S. National Academy of Medicine revised tolerable upper intake levels (UL) to protect against vitamin D toxicity. Before the revision the UL for ages 9+ years was 50 μg/d (2000 IU/d).{{rp|424–445}} Per the revision: "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".{{cite journal | vauthors = 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 | title = The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 96 | issue = 1 | pages = 53–58 | date = January 2011 | pmid = 21118827 | pmc = 3046611 | doi = 10.1210/jc.2010-2704 }} The U.S. ULs in microgram (mcg or μg) and International Units (IU) for both males and females, by age, are:

• 0–6 months: 25 μg/d (1000 IU/d)
• 7–12 months: 38 μg/d (1500 IU/d)
• 1–3 years: 63 μg/d (2500 IU/d)
• 4–8 years: 75 μg/d (3000 IU/d)
• 9+ years: 100 μg/d (4000 IU/d)
• Pregnant and lactating: 100 μg/d (4000 IU/d)

Although in the U.S. the adult UL is set at 4,000 IU/day, over-the-counter products are available at 5,000, 10,000 and even 50,000 IU (the last with directions to take once a week). The percentage of the U.S. population taking over 4,000 IU/day has increased since 1999.{{cite journal | vauthors = Rooney MR, Harnack L, Michos ED, Ogilvie RP, Sempos CT, Lutsey PL | title = Trends in Use of High-Dose Vitamin D Supplements Exceeding 1000 or 4000 International Units Daily, 1999-2014 | journal = JAMA | volume = 317 | issue = 23 | pages = 2448–2450 | date = June 2017 | pmid = 28632857 | pmc = 5587346 | doi = 10.1001/jama.2017.4392 }}

In almost every case, stopping the vitamin D supplementation combined with a low-calcium diet and corticosteroid drugs will allow for a full recovery within a month.{{MerckManual|01|004|k||Vitamin D}}{{cite book|vauthors=Brown JE, Isaacs J, Krinke B, Lechtenberg E, Murtaugh M|title=Nutrition Through the Life Cycle|url=https://books.google.com/books?id=TeQZBQAAQBAJ|date=28 June 2013|publisher=Cengage Learning|isbn=978-1-285-82025-5|access-date=9 April 2017|archive-date=19 March 2023|archive-url=https://web.archive.org/web/20230319220616/https://books.google.com/books?id=TeQZBQAAQBAJ|url-status=live}}{{cite book|vauthors=Insel P, Ross D, Bernstein M, McMahon K|title=Discovering Nutrition|url=https://books.google.com/books?id=6IWHCgAAQBAJ|date=18 March 2015|publisher=Jones & Bartlett Publishers|isbn=978-1-284-06465-0|access-date=9 April 2017|archive-date=19 March 2023|archive-url=https://web.archive.org/web/20230319220620/https://books.google.com/books?id=6IWHCgAAQBAJ|url-status=live}}

Idiopathic infantile hypercalcemia is caused by a mutation of the CYP24A1 gene, leading to a reduction in the degradation of vitamin D. Infants who have such a mutation have an increased sensitivity to vitamin D and in case of additional intake a risk of hypercalcaemia.{{cite journal | vauthors = De Paolis E, Scaglione GL, De Bonis M, Minucci A, Capoluongo E | title = CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia: from genotype to phenotype | journal = Clinical Chemistry and Laboratory Medicine | volume = 57 | issue = 11 | pages = 1650–1667 | date = October 2019 | pmid = 31188746 | doi = 10.1515/cclm-2018-1208 | title-link = doi | doi-access = free }} The disorder can continue into adulthood.{{cite journal | vauthors = Tebben PJ, Singh RJ, Kumar R | title = Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment | journal = Endocrine Reviews | volume = 37 | issue = 5 | pages = 521–547 | date = October 2016 | pmid = 27588937 | pmc = 5045493 | doi = 10.1210/er.2016-1070 }}

Supplementation with vitamin D is a reliable method for preventing or treating rickets. On the other hand, the effects of vitamin D supplementation on non-skeletal health are uncertain.{{cite journal | vauthors = Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, Lichtenstein A, Patel K, Raman G, Tatsioni A, Terasawa T, Trikalinos TA | title = Vitamin D and calcium: a systematic review of health outcomes | journal = Evidence Report/Technology Assessment | issue = 183 | pages = 1–420 | date = August 2009 | pmid = 20629479 | pmc = 4781105 }}{{cite journal | vauthors = Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP | title = Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials | journal = BMJ | volume = 348 | pages = g2035 | date = April 2014 | pmid = 24690624 | pmc = 3972415 | doi = 10.1136/bmj.g2035 }} A review did not find any effect from supplementation on the rates of non-skeletal disease, other than a tentative decrease in mortality in the elderly.{{cite journal | vauthors = Autier P, Boniol M, Pizot C, Mullie P | title = Vitamin D status and ill health: a systematic review | journal = The Lancet. Diabetes & Endocrinology | volume = 2 | issue = 1 | pages = 76–89 | date = January 2014 | pmid = 24622671 | doi = 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.{{cite journal | vauthors = Hussain S, Singh A, Akhtar M, Najmi AK | title = Vitamin D supplementation for the management of knee osteoarthritis: a systematic review of randomized controlled trials | journal = Rheumatology International | volume = 37 | issue = 9 | pages = 1489–1498 | date = September 2017 | pmid = 28421358 | doi = 10.1007/s00296-017-3719-0 | s2cid = 23994681 }}

A US Institute of Medicine (IOM) 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 intake of either calcium or vitamin D, and were often conflicting."{{cite book |author=Institute of Medicine | veditors=Ross AC, Taylor CL, Yaktine AL, Del Valle HB |title=Dietary Reference Intakes for Calcium and Vitamin D |publisher=National Academies Press |year=2011 |isbn=978-0-309-16394-1 |pmid=21796828 |doi=10.17226/13050 |url=https://www.ncbi.nlm.nih.gov/books/NBK56070/ |series=The National Academies Collection: Reports funded by National Institutes of Health |s2cid=58721779 |access-date=17 September 2017 |archive-date=26 January 2021 |archive-url=https://web.archive.org/web/20210126052042/https://www.ncbi.nlm.nih.gov/books/NBK56070/ |url-status=live }}{{rp|5}} Evidence for and against each disease state is provided in detail.{{rp|124–299}} 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.{{cite journal | vauthors = Maxmen A | title = Nutrition advice: the vitamin D-lemma | journal = Nature | volume = 475 | issue = 7354 | pages = 23–25 | date = July 2011 | pmid = 21734684 | doi = 10.1038/475023a | url = http://www.nature.com/news/2011/110706/pdf/475023a.pdf | access-date = 17 November 2011 | url-status = live | title-link = doi | doi-access = free | archive-url = https://web.archive.org/web/20200803081923/https://www.nature.com/news/2011/110706/pdf/475023a.pdf | archive-date = 3 August 2020 }}

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 concerning the risk of death.{{cite journal | vauthors = Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C | title = Vitamin D supplementation for prevention of mortality in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 1 | pages = CD007470 | date = January 2014 | pmid = 24414552 | pmc = 11285307 | doi = 10.1002/14651858.CD007470.pub3 | type = 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.{{cite journal | vauthors = Schöttker B, Jorde R, Peasey A, Thorand B, Jansen EH, Groot L, 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 | title = Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States | journal = BMJ | volume = 348 | issue = jun17 16 | pages = g3656 | date = June 2014 | pmid = 24938302 | pmc = 4061380 | doi = 10.1136/bmj.g3656 | collaboration = 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.{{cite journal | vauthors = Tuohimaa P | title = Vitamin D and aging | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 114 | issue = 1–2 | pages = 78–84 | date = March 2009 | pmid = 19444937 | doi = 10.1016/j.jsbmb.2008.12.020 | s2cid = 40625040 }}{{cite journal | vauthors = Tuohimaa P, Keisala T, Minasyan A, Cachat J, Kalueff A | title = Vitamin D, nervous system and aging | journal = Psychoneuroendocrinology | volume = 34 | issue = Suppl 1 | pages = S278–S286 | date = December 2009 | pmid = 19660871 | doi = 10.1016/j.psyneuen.2009.07.003 | s2cid = 17462970 }} The relationship between serum calcifediol concentrations and all-cause mortality is "U-shaped": mortality is elevated at high and low calcifediol levels, relative to moderate levels. Harm from elevated calcifediol appears to occur at a lower level in dark-skinned Canadian and United States populations than in light-skinned populations.{{rp|424–435}}

{{Main|Rickets}}

File:XrayRicketsLegssmall.jpg

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. Maternal vitamin D deficiency can cause fetal bone defects from before birth and impairment of bone quality after birth.{{cite journal | vauthors = Elidrissy AT | title = The Return of Congenital Rickets, Are We Missing Occult Cases? | journal = Calcified Tissue International | volume = 99 | issue = 3 | pages = 227–236 | date = September 2016 | pmid = 27245342 | doi = 10.1007/s00223-016-0146-2 | type = Review | s2cid = 14727399 }}{{cite journal | vauthors = Paterson CR, Ayoub D | title = Congenital rickets due to vitamin D deficiency in the mothers | journal = Clinical Nutrition | volume = 34 | issue = 5 | pages = 793–798 | date = October 2015 | pmid = 25552383 | doi = 10.1016/j.clnu.2014.12.006 | type = Review }} Rickets typically appear between 3 and 18 months of age.{{cite journal | vauthors = Wagner CL, Greer FR | title = Prevention of rickets and vitamin D deficiency in infants, children, and adolescents | journal = Pediatrics | volume = 122 | issue = 5 | pages = 1142–1152 | date = November 2008 | pmid = 18977996 | doi = 10.1542/peds.2008-1862 | s2cid = 342161 | title-link = doi | doi-access = }} This condition can be caused by vitamin D, calcium or phosphorus deficiency.{{cite journal | vauthors = Lerch C, Meissner T | title = Interventions for the prevention of nutritional rickets in term born children | journal = The Cochrane Database of Systematic Reviews | volume = 2007 | issue = 4 | pages = CD006164 | date = October 2007 | pmid = 17943890 | pmc = 8990776 | doi = 10.1002/14651858.CD006164.pub2 | veditors = Lerch C }} Vitamin D deficiency remains the main cause of rickets among young infants in most countries because breast milk is low in vitamin D, and darker skin, social customs, and climatic conditions can contribute to inadequate sun exposure.{{cn|date=November 2024}} A post-weaning Western omnivore diet characterized by high intakes of meat, fish, eggs and vitamin D fortified milk is protective, whereas low intakes of those foods and high cereal/grain intake contribute to risk.{{cite journal |vauthors=Clements MR |title=The problem of rickets in UK Asians |journal=Journal of Human Nutrition and Dietetics |volume=2 |issue=2 |year=1989 |doi=10.1111/j.1365-277X.1989.tb00015.x |pages=105–16}}{{cite journal | vauthors = Pettifor JM | title = Nutritional rickets: deficiency of vitamin D, calcium, or both? | journal = The American Journal of Clinical Nutrition | volume = 80 | issue = 6 Suppl | pages = 1725S–1729S | date = December 2004 | pmid = 15585795 | doi = 10.1093/ajcn/80.6.1725S | title-link = doi | doi-access = free }}{{cite book|vauthors=Dupuis EM|title=Nature's Perfect Food: How Milk Became America's Drink|url=https://books.google.com/books?id=Nr1_u2DvDckC|date=1 February 2002|publisher=NYU Press|isbn=978-0-8147-1938-1|access-date=9 April 2017|archive-date=19 March 2023|archive-url=https://web.archive.org/web/20230319220637/https://books.google.com/books?id=Nr1_u2DvDckC|url-status=live}} For young children with rickets, supplementation with vitamin D plus calcium was superior to the vitamin alone for bone healing.{{cite journal | vauthors = Chibuzor MT, Graham-Kalio D, Osaji JO, Meremikwu MM | title = Vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 4 | pages = CD012581 | date = April 2020 | pmid = 32303107 | pmc = 7164979 | doi = 10.1002/14651858.CD012581.pub2 | collaboration = Cochrane Metabolic and Endocrine Disorders Group }}{{cite journal | vauthors = 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 | title = Global Consensus Recommendations on Prevention and Management of Nutritional Rickets | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 101 | issue = 2 | pages = 394–415 | date = February 2016 | pmid = 26745253 | pmc = 4880117 | doi = 10.1210/jc.2015-2175 }}

{{Main|Osteomalacia|Osteoporosis}}

File:RECALLED – Calcium 1200mg plus 1000 IU Vitamin D3 softgels (6711556801).jpg

Characteristics of osteomalacia are softening of the bones, leading to bending of the spine, bone fragility, and increased risk for fractures. Osteomalacia is usually present when 25-hydroxyvitamin D levels are less than about 10{{nbsp}}ng/mL.{{cite journal | vauthors = Holick MF | title = High prevalence of vitamin D inadequacy and implications for health | journal = Mayo Clinic Proceedings | volume = 81 | issue = 3 | pages = 353–373 | date = March 2006 | pmid = 16529140 | doi = 10.4065/81.3.353 | title-link = doi | doi-access = free }} Osteomalacia progress to osteoporosis, a condition of reduced bone mineral density with increased bone fragility and risk of bone fractures. Osteoporosis can be a long-term effect of calcium and/or vitamin D insufficiency, the latter contributing by reducing calcium absorption. In the absence of confirmed vitamin D deficiency there is no evidence that vitamin D supplementation without concomitant calcium slows or stops the progression of osteomalacia to osteoporosis.{{cite journal | vauthors = Reid IR, Bolland MJ, Grey A | title = Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis | journal = Lancet | volume = 383 | issue = 9912 | pages = 146–155 | date = January 2014 | pmid = 24119980 | doi = 10.1016/s0140-6736(13)61647-5 | s2cid = 37968189 }} 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.{{cite journal | vauthors = Avenell A, Mak JC, O'Connell D | title = Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 4 | pages = CD000227 | date = April 2014 | pmid = 24729336 | pmc = 7032685 | doi = 10.1002/14651858.CD000227.pub4 }}{{cite journal | vauthors = Bischoff-Ferrari HA, Willett WC, Orav 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 | title = A pooled analysis of vitamin D dose requirements for fracture prevention | journal = The New England Journal of Medicine | volume = 367 | issue = 1 | pages = 40–49 | date = July 2012 | pmid = 22762317 | doi = 10.1056/NEJMoa1109617 | url = https://research.vu.nl/ws/files/709966/300335.pdf | access-date = 17 July 2019 | url-status = live | s2cid = 24338997 | archive-date = 15 December 2020 | archive-url = https://web.archive.org/web/20201215140446/https://research.vu.nl/ws/files/709966/300335.pdf | hdl = 1871/48765 }} The reduced risk for fractures is not seen in healthier, community-dwelling elderly.{{cite journal | vauthors = Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA | title = 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 | journal = Annals of Internal Medicine | volume = 155 | issue = 12 | pages = 827–838 | date = December 2011 | pmid = 22184690 | doi = 10.7326/0003-4819-155-12-201112200-00005 | s2cid = 22380502 | title-link = doi | doi-access = }}{{cite journal | vauthors = Zhao JG, Zeng XT, Wang J, Liu L | title = Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis | journal = JAMA | volume = 318 | issue = 24 | pages = 2466–2482 | date = December 2017 | pmid = 29279934 | pmc = 5820727 | doi = 10.1001/jama.2017.19344 }} Low serum vitamin D levels have been associated with falls,{{cite journal | vauthors = 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 | title = Effectiveness and safety of vitamin D in relation to bone health | journal = Evidence Report/Technology Assessment | issue = 158 | pages = 1–235 | date = August 2007 | pmid = 18088161 | pmc = 4781354 }} but taking extra vitamin D does not appear to reduce that risk.{{cite journal | vauthors = Bolland MJ, Grey A, Gamble GD, Reid IR | title = Vitamin D supplementation and falls: a trial sequential meta-analysis | journal = The Lancet. Diabetes & Endocrinology | volume = 2 | issue = 7 | pages = 573–580 | date = July 2014 | pmid = 24768505 | doi = 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. Incremental decreases in risk are observed with rising serum 25(OH)D concentrations plateauing at 50{{nbsp}}ng/mL with no additional benefits seen in levels beyond this point.{{cite journal | vauthors = Shuler FD, Wingate MK, Moore GH, Giangarra C | title = Sports health benefits of vitamin d | journal = Sports Health | volume = 4 | issue = 6 | pages = 496–501 | date = November 2012 | pmid = 24179588 | pmc = 3497950 | doi = 10.1177/1941738112461621 }}

While serum low 25-hydroxyvitamin D status has been associated with a higher risk of cancer in observational studies,{{cite journal | vauthors = Sluyter JD, Manson JE, Scragg R | title = Vitamin D and Clinical Cancer Outcomes: A Review of Meta-Analyses | journal = JBMR Plus | volume = 5 | issue = 1 | pages = e10420 | date = January 2021 | pmid = 33553987 | pmc = 7839823 | doi = 10.1002/jbm4.10420 }}{{cite journal | vauthors = Zhao Y, Chen C, Pan W, Gao M, He W, Mao R, Lin T, Huang J | title = Comparative efficacy of vitamin D status in reducing the risk of bladder cancer: A systematic review and network meta-analysis | journal = Nutrition | volume = 32 | issue = 5 | pages = 515–523 | date = May 2016 | pmid = 26822497 | doi = 10.1016/j.nut.2015.10.023 }}{{cite journal | vauthors = Hernández-Alonso P, Boughanem H, Canudas S, Becerra-Tomás N, Fernández de la Puente M, Babio N, Macias-Gonzalez M, Salas-Salvadó J | title = Circulating vitamin D levels and colorectal cancer risk: A meta-analysis and systematic review of case-control and prospective cohort studies | journal = Critical Reviews in Food Science and Nutrition | volume = 63 | issue = 1 | pages = 1–17 | date = July 2021 | pmid = 34224246 | doi = 10.1080/10408398.2021.1939649 | hdl-access = free | s2cid = 235746547 | hdl = 10609/136992 }} the general conclusion is that there is insufficient evidence for an effect of vitamin D supplementation on the risk of cancer,{{Cite web |url=https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/vitamin-d-fact-sheet#q4 |title=Vitamin D and cancer prevention |publisher=National Cancer Institute, US National Institutes of Health |date=21 October 2013 |access-date=15 December 2016 |archive-date=13 February 2015 |archive-url=https://web.archive.org/web/20150213152515/http://www.cancer.gov/cancertopics/factsheet/prevention/vitamin-D#q4 |url-status=live }}{{cite journal | vauthors = Goulão B, Stewart F, Ford JA, MacLennan G, Avenell A | title = Cancer and vitamin D supplementation: a systematic review and meta-analysis | journal = The American Journal of Clinical Nutrition | volume = 107 | issue = 4 | pages = 652–663 | date = April 2018 | pmid = 29635490 | doi = 10.1093/ajcn/nqx047 | doi-access = free }} although there is some evidence for reduction in cancer mortality.{{cite journal | vauthors = Keum N, Lee DH, Greenwood DC, Manson JE, Giovannucci E | title = Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials | journal = Annals of Oncology | volume = 30 | issue = 5 | pages = 733–743 | date = May 2019 | pmid = 30796437 | pmc = 6821324 | doi = 10.1093/annonc/mdz059 }}

Vitamin D supplementation is not associated with a reduced risk of stroke, cerebrovascular disease, myocardial infarction, or ischemic heart disease.{{cite journal | vauthors = Bolland MJ, Grey A, Gamble GD, Reid IR | title = The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis | journal = The Lancet. Diabetes & Endocrinology | volume = 2 | issue = 4 | pages = 307–320 | date = April 2014 | pmid = 24703049 | doi = 10.1016/S2213-8587(13)70212-2 | type = Meta-analysis }}{{cite journal | vauthors = Barbarawi M, Kheiri B, Zayed Y, Barbarawi O, Dhillon H, Swaid B, Yelangi A, Sundus S, Bachuwa G, Alkotob ML, Manson JE | title = Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83 000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis | journal = JAMA Cardiology | volume = 4 | issue = 8 | pages = 765–776 | date = August 2019 | pmid = 31215980 | pmc = 6584896 | doi = 10.1001/jamacardio.2019.1870 }}{{cite journal | vauthors = Nudy M, Krakowski G, Ghahramani M, Ruzieh M, Foy AJ | title = Vitamin D supplementation, cardiac events and stroke: A systematic review and meta-regression analysis | journal = International Journal of Cardiology. Heart & Vasculature | volume = 28 | pages = 100537 | date = June 2020 | pmid = 32462077 | pmc = 7240168 | doi = 10.1016/j.ijcha.2020.100537 }} Supplementation does not lower blood pressure in the general population.{{cite journal | vauthors = Beveridge LA, Struthers AD, Khan F, Jorde R, Scragg R, Macdonald HM, Alvarez JA, Boxer RS, Dalbeni A, Gepner AD, Isbel NM, Larsen T, Nagpal J, Petchey WG, Stricker H, Strobel F, Tangpricha V, Toxqui L, Vaquero MP, Wamberg L, Zittermann A, Witham MD | title = Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data | journal = JAMA Internal Medicine | volume = 175 | issue = 5 | pages = 745–754 | date = May 2015 | pmid = 25775274 | pmc = 5966296 | doi = 10.1001/jamainternmed.2015.0237 }}{{cite journal | vauthors = Zhang D, Cheng C, Wang Y, Sun H, Yu S, Xue Y, Liu Y, Li W, Li X | title = Effect of Vitamin D on Blood Pressure and Hypertension in the General Population: An Update Meta-Analysis of Cohort Studies and Randomized Controlled Trials | journal = Preventing Chronic Disease | volume = 17 | pages = E03 | date = January 2020 | pmid = 31922371 | pmc = 6977781 | doi = 10.5888/pcd17.190307 }}{{cite journal | vauthors = Abboud M, Al Anouti F, Papandreou D, Rizk R, Mahboub N, Haidar S | title = Vitamin D status and blood pressure in children and adolescents: a systematic review of observational studies | journal = Systematic Reviews | volume = 10 | issue = 1 | pages = 60 | date = February 2021 | pmid = 33618764 | pmc = 7898425 | doi = 10.1186/s13643-021-01584-x | doi-access = free }} One meta-analysis found a small increase in risk of stroke when calcium and vitamin D supplements were taken together.{{cite journal | vauthors = 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 | title = Effects of Nutritional Supplements and Dietary Interventions on Cardiovascular Outcomes: An Umbrella Review and Evidence Map | journal = Annals of Internal Medicine | volume = 171 | issue = 3 | pages = 190–198 | date = August 2019 | pmid = 31284304 | pmc = 7261374 | doi = 10.7326/m19-0341 }}

Vitamin D receptors are found in cell types involved in immunity. Functions are not understood. Some autoimmune and infectious diseases are associated with vitamin D deficiency, but either there is no evidence that supplementation has a benefit or not, or for some, evidence indicating there are no benefits.{{cite journal |vauthors=Al-Saoodi H, Kolahdooz F, Andersen JR, Jalili M |title=Effect of vitamin D on inflammatory and clinical outcomes in patients with rheumatoid arthritis: a systematic review and dose-response meta-analysis of randomized controlled trials |journal=Nutrition Reviews |volume=82 |issue=5 |pages=600–11 |date=April 2024 |pmid=37437898 |doi=10.1093/nutrit/nuad083}}{{cite journal |vauthors=Mahler JV, Solti M, Apóstolos-Pereira SL, Adoni T, Silva GD, Callegaro D |title=Vitamin D3 as an add-on treatment for multiple sclerosis: A systematic review and meta-analysis of randomized controlled trials |journal=Multiple Sclerosis and Related Disorders |volume=82 |issue= |pages=105433 |date=February 2024 |pmid=38211504 |doi=10.1016/j.msard.2024.105433|url=https://www.sciencedirect.com/science/article/abs/pii/S2211034824000129|url-access=subscription }}{{cite journal | vauthors = Goyal JP, Singh S, Bishnoi R, Bhardwaj P, Kaur RJ, Dhingra S, Yadav D, Dutta S, Charan J | title = Efficacy and safety of vitamin D in tuberculosis patients: a systematic review and meta-analysis | journal = Expert Review of Anti-Infective Therapy | volume = 20 | issue = 7 | pages = 1049–1059 | date = July 2022 | pmid = 35477334 | doi = 10.1080/14787210.2022.2071702 }}

Low plasma vitamin D concentrations have been reported for autoimmune thyroid diseases,{{cite journal |vauthors=Taheriniya S, Arab A, Hadi A, Fadel A, Askari G |title=Vitamin D and thyroid disorders: a systematic review and meta-analysis of observational studies |journal= BMC Endocrine Disorders|volume=21 |issue=1 |pages=171 |date=August 2021 |pmid=34425794 |pmc=8381493 |doi=10.1186/s12902-021-00831-5 |doi-access=free |url=}} lupus,{{cite journal |vauthors=Islam MA, Khandker SS, Alam SS, Kotyla P, Hassan R |title=Vitamin D status in patients with systemic lupus erythematosus (SLE): A systematic review and meta-analysis |journal=Autoimmunity Reviews |volume=18 |issue=11 |pages=102392 |date=November 2019 |pmid=31520805 |doi=10.1016/j.autrev.2019.102392 |url=}} myasthenia gravis,{{cite journal |vauthors=Bonaccorso G |title=Myasthenia gravis and vitamin D serum levels: A systematic review and meta-analysis |journal= CNS & Neurological Disorders Drug Targets|volume=22 |issue=5 |pages=752–60 |date=2023 |pmid=35796450 |doi=10.2174/1871527321666220707111344 |url=}} rheumatoid arthritis,{{cite journal |vauthors=Lee YH, Bae SC |title=Vitamin D level in rheumatoid arthritis and its correlation with the disease activity: a meta-analysis |journal=Clinical and Experimental Rheumatology |volume=34 |issue=5 |pages=827–33 |date=September 2016 |pmid=27049238 |doi= |url=}} and multiple sclerosis.{{cite journal |vauthors=Balasooriya NN, Elliott TM, Neale RE, Vasquez P, Comans T, Gordon LG |title=The association between vitamin D deficiency and multiple sclerosis: an updated systematic review and meta-analysis |journal=Multiple Sclerosis and Related Disorders |volume=90|pages=105804 |date=October 2024 |pmid=39180838 |doi=10.1016/j.msard.2024.105804 |url=https://www.msard-journal.com/article/S2211-0348(24)00381-X/fulltext|doi-access=free }} For multiple sclerosis and rheumatoid arthritis, intervention trials using vitamin D supplementation did not demonstrate therapeutic effects.{{cite journal |vauthors=Clasen JL, Cole R, Aune D, Sellon E, Heath AK |title=Vitamin D status and risk of rheumatoid arthritis: systematic review and meta-analysis |journal= BMC Rheumatology|volume=7 |issue=1 |pages=3 |date=March 2023 |pmid=36918989 |pmc=10015722 |doi=10.1186/s41927-023-00325-y|doi-access=free}}

Vitamin D supplementation does not reduce the risk of acute respiratory disease.{{cite journal |vauthors=Jolliffe DA, Camargo CA, Sluyter JD, Aglipay M, Aloia JF, Ganmaa D, Bergman P, Bischoff-Ferrari HA, Borzutzky A, Damsgaard CT, Dubnov-Raz G, Esposito S, Gilham C, Ginde AA, Golan-Tripto I, Goodall EC, Grant CC, Griffiths CJ, Hibbs AM, Janssens W, Khadilkar AV, Laaksi I, Lee MT, Loeb M, Maguire JL, Majak P, Mauger DT, Manaseki-Holland S, Murdoch DR, Nakashima A, Neale RE, Pham H, Rake C, Rees JR, Rosendahl J, Scragg R, Shah D, Shimizu Y, Simpson-Yap S, Trilok-Kumar G, Urashima M, Martineau AR |display-authors=6 |title=Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials |journal=Lancet Diabetes Endocrinol |volume=9 |issue=5 |pages=276–92 |date=May 2021 |pmid=33798465 |doi=10.1016/S2213-8587(21)00051-6 |url=|pmc=7709175 }} In general, vitamin D functions to activate the innate and dampen the adaptive immune systems with antibacterial, antiviral and anti-inflammatory effects.{{Cite book |vauthors=Hewison M |chapter=Vitamin D and innate and adaptive immunity |volume=86 |pages=23–62 |year=2011 |pmid=21419266 |doi=10.1016/B978-0-12-386960-9.00002-2 |isbn=978-0-12-386960-9 |series=Vitamins & Hormones|title=Vitamins and the Immune System |publisher=Academic Press }}{{cite journal | vauthors = Bishop EL, Ismailova A, Dimeloe S, Hewison M, White JH | title = Vitamin D and immune regulation: Antibacterial, antiviral, anti-Inflammatory | journal = Journal of Bone and Mineral Research Plus | volume = 5 | issue = 1 | pages = e10405 | date = January 2021 | pmid = 32904944 | pmc = 7461279 | doi = 10.1002/jbm4.10405 }} Low serum levels of vitamin D appear to be a risk factor for tuberculosis.{{cite journal | vauthors = Nnoaham KE, Clarke A | title = Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis | journal = International Journal of Epidemiology | volume = 37 | issue = 1 | pages = 113–119 | date = February 2008 | pmid = 18245055 | doi = 10.1093/ije/dym247 | citeseerx = 10.1.1.513.3969 }} However, supplementation trials showed no benefit.{{cite journal | vauthors = Cao Y, Wang X, Liu P, Su Y, Yu H, Du J | title = Vitamin D and the risk of latent tuberculosis infection: a systematic review and meta-analysis | journal = BMC Pulmonary Medicine| volume = 22 | issue = 1 | pages = 39 | date = January 2022 | pmid = 35045861 | pmc = 8772077 | doi = 10.1186/s12890-022-01830-5 | doi-access = free }}

Vitamin D deficiency has been linked to the severity of inflammatory bowel disease (IBD).{{cite journal | vauthors = Del Pinto R, Pietropaoli D, Chandar AK, Ferri C, Cominelli F | title = Association Between Inflammatory Bowel Disease and Vitamin D Deficiency: A Systematic Review and Meta-analysis | journal = Inflammatory Bowel Diseases | volume = 21 | issue = 11 | pages = 2708–2717 | date = November 2015 | pmid = 26348447 | pmc = 4615394 | doi = 10.1097/MIB.0000000000000546 }} However, whether vitamin D deficiency causes IBD or is a consequence of the disease is not clear.{{cite journal | vauthors = Wallace C, Gordon M, Sinopoulou V, Limketkai BN | title = Vitamin D for the treatment of inflammatory bowel disease | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 10 | pages = CD011806 | date = October 2023 | pmid = 37781953 | pmc = 10542962 | doi = 10.1002/14651858.CD011806.pub2 | collaboration = Cochrane Gut Group }} Supplementation leads to improvements in scores for clinical inflammatory bowel disease activity and biochemical markers,{{cite journal | vauthors = Guzman-Prado Y, Samson O, Segal JP, Limdi JK, Hayee B | title = Vitamin D Therapy in Adults With Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis | journal = Inflammatory Bowel Diseases | volume = 26 | issue = 12 | pages = 1819–1830 | date = November 2020 | pmid = 32385487 | doi = 10.1093/ibd/izaa087 }} and less frequent relapse of symptoms in IBD.

Vitamin D supplementation does not help prevent asthma attacks or alleviate symptoms.{{cite journal | vauthors = Williamson A, Martineau AR, Sheikh A, Jolliffe D, Griffiths CJ | title = Vitamin D for the management of asthma | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 2 | pages = CD011511 | date = February 2023 | pmid = 36744416 | pmc = 9899558 | doi = 10.1002/14651858.CD011511.pub3 }}

{{See also|COVID-19 drug repurposing research#Vitamin D|COVID-19 misinformation#Vitamin D}}

In July 2020, the US National Institutes of Health stated "There is insufficient evidence to recommend for or against using vitamin D supplementation for the prevention or treatment of COVID-19."{{cite web | title=Vitamin D | work=Coronavirus Disease 2019 (COVID-19) Treatment Guidelines | date=17 July 2020 | url=https://www.covid19treatmentguidelines.nih.gov/supplements/vitamin-d/ | publisher=National Institutes of Health (NIH) | access-date=22 February 2021 | archive-date=21 February 2021 | archive-url=https://web.archive.org/web/20210221110534/https://www.covid19treatmentguidelines.nih.gov/supplements/vitamin-d/ | url-status=live }} {{PD-notice}} Same year, the UK National Institute for Health and Care Excellence (NICE) position was to not recommend to offer a vitamin D supplement to people solely to prevent or treat COVID-19.{{cite tech report | title=COVID-19 rapid guideline: vitamin D | publisher=National Institute for Health and Care Excellence (NICE) | date=December 2020 | url=https://www.nice.org.uk/guidance/ng187/resources/covid19-rapid-guideline-vitamin-d-pdf-66142026720709 | format=PDF | access-date=22 February 2021 | id=NG187 | isbn=978-1-4731-3942-8 | archive-date=3 December 2021 | archive-url=https://web.archive.org/web/20211203113126/https://www.nice.org.uk/guidance/ng187/resources/covid19-rapid-guideline-vitamin-d-pdf-66142026720709 | url-status=live }} NICE updated its position in 2022 to "Do not use vitamin D to treat COVID-19 except as part of a clinical trial."{{cite web |url=https://www.nice.org.uk/guidance/ng191 |title=COVID-19 rapid guideline: managing COVID-19 |date=8 May 2024 |website=National Institute for Health and Care Excellence (NICE) |access-date=18 January 2025}} Both organizations included recommendations to continue the previously established recommendations on vitamin D supplementation for other reasons, such as bone and muscle health, as applicable. Both organizations noted that more people may require supplementation due to lower amounts of sun exposure during the pandemic.

Vitamin D deficiency and insufficiency have been associated with adverse outcomes in COVID-19.{{cite journal | vauthors = Liu N, Sun J, Wang X, Zhang T, Zhao M, Li H | title = Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and meta-analysis | journal = International Journal of Infectious Diseases | volume = 104 | pages = 58–64 | date = March 2021 | pmid = 33401034 | pmc = 7833186 | doi = 10.1016/j.ijid.2020.12.077 }}{{cite journal | vauthors = Kazemi A, Mohammadi V, Aghababaee SK, Golzarand M, Clark CC, Babajafari S | title = Association of Vitamin D Status with SARS-CoV-2 Infection or COVID-19 Severity: A Systematic Review and Meta-analysis | journal = Advances in Nutrition | volume = 12 | issue = 5 | pages = 1636–1658 | date = October 2021 | pmid = 33751020 | pmc = 7989595 | doi = 10.1093/advances/nmab012 | title-link = doi | doi-access = free }}{{cite journal | vauthors = Petrelli F, Luciani A, Perego G, Dognini G, Colombelli PL, Ghidini A | title = Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and meta-analysis of 43 observational studies | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 211 | issue = | pages = 105883 | date = July 2021 | pmid = 33775818 | pmc = 7997262 | doi = 10.1016/j.jsbmb.2021.105883 }}{{cite journal | vauthors = Bassatne A, Basbous M, Chakhtoura M, El Zein O, Rahme M, El-Hajj Fuleihan G | title = The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis | journal = Metabolism | volume = 119 | issue = | pages = 154753 | date = June 2021 | pmid = 33774074 | pmc = 7989070 | doi = 10.1016/j.metabol.2021.154753 | type = Systematic review }}{{cite journal | vauthors = Dissanayake HA, de Silva NL, Sumanatilleke M, de Silva SD, Gamage KK, Dematapitiya C, Kuruppu DC, Ranasinghe P, Pathmanathan S, Katulanda P | title = Prognostic and Therapeutic Role of Vitamin D in COVID-19: Systematic Review and Meta-analysis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 107 | issue = 5 | pages = 1484–1502 | date = April 2022 | pmid = 34894254 | pmc = 8689831 | doi = 10.1210/clinem/dgab892 }} Supplementation trials, mostly large, single, oral dose upon hospital admission, reported lower subsequent transfers to intensive care and to all-cause mortality.{{cite journal |vauthors=Sartini M, Del Puente F, Carbone A, Schinca E, Ottria G, Dupont C, Piccinini C, Oliva M, Cristina ML |title=The Effect of Vitamin D Supplementation Post COVID-19 Infection and Related Outcomes: A Systematic Review and Meta-Analysis |journal=Nutrients |volume=16 |issue=22 |date=November 2024 |page=3794 |pmid=39599582 |pmc=11597733 |doi=10.3390/nu16223794 |doi-access=free |url=}}{{cite journal |vauthors=Kow CS, Ramachandram DS, Hasan SS, Wong Z, Thiruchelvam K |title=The impact of vitamin D administration on mortality in COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials |journal=Inflammopharmacology |volume=32 |issue=5 |pages=3205–12 |date=October 2024 |pmid=39225947 |doi=10.1007/s10787-024-01564-2 |url=}}{{cite journal |vauthors=Sobczak M, Pawliczak R |title=Effect of Vitamin D3 Supplementation on Severe COVID-19: A Meta-Analysis of Randomized Clinical Trials |journal=Nutrients |volume=16 |issue=10 |date=May 2024 |page=1402 |pmid=38794642 |pmc=11124475 |doi=10.3390/nu16101402 |doi-access=free |url=}}

Vitamin D supplementation substantially reduced the rate of moderate or severe exacerbations of chronic obstructive pulmonary disease (COPD).{{cite journal | vauthors = Jolliffe DA, Greenberg L, Hooper RL, Mathyssen C, Rafiq R, de Jongh RT, Camargo CA, Griffiths CJ, Janssens W, Martineau AR | title = Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials | journal = Thorax | volume = 74 | issue = 4 | pages = 337–345 | date = April 2019 | pmid = 30630893 | doi = 10.1136/thoraxjnl-2018-212092 | s2cid = 58548871 | title-link = doi | doi-access = free }}

A meta-analysis reported that vitamin D supplementation significantly reduced the risk of type 2 diabetes for non-obese people with prediabetes.{{cite journal | vauthors = Zhang Y, Tan H, Tang J, Li J, Chong W, Hai Y, Feng Y, Lunsford LD, Xu P, Jia D, Fang F | title = Effects of Vitamin D Supplementation on Prevention of Type 2 Diabetes in Patients With Prediabetes: A Systematic Review and Meta-analysis | journal = Diabetes Care | volume = 43 | issue = 7 | pages = 1650–1658 | date = July 2020 | pmid = 33534730 | doi = 10.2337/dc19-1708 | s2cid = 219897727 | doi-access = free }} Another meta-analysis reported that vitamin D supplementation significantly improved glycemic control [homeostatic model assessment-insulin resistance (HOMA-IR)], hemoglobin A1C (HbA1C), and fasting blood glucose (FBG) in individuals with type 2 diabetes.{{cite journal | vauthors = Sahebi R, Rezayi M, Emadzadeh M, Salehi M, Tayefi M, Parizadeh SM, Behboodi N, Rastgar-Moghadam A, Kharazmi Khorassani J, Khorassani SK, Mohammadi A, Ferns GA, Ghayour Mobarhan M | title = The effects of vitamin D supplementation on indices of glycemic control in Iranian diabetics: A systematic review and meta-analysis | journal = Complementary Therapies in Clinical Practice | volume = 34 | pages = 294–304 | date = February 2019 | pmid = 30712741 | doi = 10.1016/j.ctcp.2018.12.009 | s2cid = 57479957 }} In prospective studies, high versus low levels of vitamin D were respectively associated with a significant decrease in risk of type 2 diabetes, combined type 2 diabetes and prediabetes, and prediabetes.{{cite journal | vauthors = Mohammadi S, Hajhashemy Z, Saneei P | title = Serum vitamin D levels in relation to type-2 diabetes and prediabetes in adults: a systematic review and dose-response meta-analysis of epidemiologic studies | journal = Critical Reviews in Food Science and Nutrition | volume = 62 | issue = 29 | pages = 8178–8198 | date = June 2021 | pmid = 34076544 | doi = 10.1080/10408398.2021.1926220 | s2cid = 235295924 }} A systematic review included one clinical trial that showed vitamin D supplementation together with insulin maintained levels of fasting C-peptide after 12 months better than insulin alone.{{cite journal | vauthors = Brophy S, Davies H, Mannan S, Brunt H, Williams R | title = Interventions for latent autoimmune diabetes (LADA) in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2011 | issue = 9 | pages = CD006165 | date = September 2011 | pmid = 21901702 | pmc = 6486159 | doi = 10.1002/14651858.cd006165.pub3 }}

A meta-analysis of observational studies showed that children with ADHD have lower vitamin D levels and that there was a small association between low vitamin D levels at the time of birth and later development of ADHD.{{cite journal | vauthors = Khoshbakht Y, Bidaki R, Salehi-Abargouei A | title = Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies | journal = Advances in Nutrition | volume = 9 | issue = 1 | pages = 9–20 | date = January 2018 | pmid = 29438455 | pmc = 6333940 | doi = 10.1093/advances/nmx002 | title-link = doi | doi-access = free }} Several small, randomized controlled trials of vitamin D supplementation indicated improved ADHD symptoms such as impulsivity and hyperactivity.{{cite journal | vauthors = Gan J, Galer P, Ma D, Chen C, Xiong T | title = The Effect of Vitamin D Supplementation on Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Randomized Controlled Trials | journal = Journal of Child and Adolescent Psychopharmacology | volume = 29 | issue = 9 | pages = 670–687 | date = November 2019 | pmid = 31368773 | doi = 10.1089/cap.2019.0059 | s2cid = 199054851 }}

A 2014 systematic review concluded thay vitamin D supplementation does not reduce depressive symptoms overall but may have a moderate benefit for patients with clinically significant depression, though more high-quality studies were determined to be needed.{{cite journal | vauthors = Shaffer JA, Edmondson D, Wasson LT, Falzon L, Homma K, Ezeokoli N, Li P, Davidson KW | title = Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials | journal = Psychosomatic Medicine | volume = 76 | issue = 3 | pages = 190–196 | date = April 2014 | pmid = 24632894 | pmc = 4008710 | doi = 10.1097/psy.0000000000000044 }}

A systematic review of clinical studies found an association between low vitamin D levels with cognitive impairment and a higher risk of developing Alzheimer's disease. However, lower vitamin D concentrations are also associated with poor nutrition and spending less time outdoors. Therefore, alternative explanations for the increase in cognitive impairment exist and hence a direct causal relationship between vitamin D levels and cognition could not be established.{{cite journal | vauthors = Balion C, Griffith LE, Strifler L, Henderson M, Patterson C, Heckman G, Llewellyn DJ, Raina P | title = Vitamin D, cognition, and dementia: a systematic review and meta-analysis | journal = Neurology | volume = 79 | issue = 13 | pages = 1397–1405 | date = September 2012 | pmid = 23008220 | pmc = 3448747 | doi = 10.1212/WNL.0b013e31826c197f }}

People diagnosed with schizophrenia tend to have lower serum vitamin D concentrations compared to those without the condition. This may be a consequence of the disease rather than a cause, due, for example, to low dietary vitamin D and less time spent exposed to sunlight.{{cite journal | vauthors = Cui X, McGrath JJ, Burne TH, Eyles DW | title = Vitamin D and schizophrenia: 20 years on | journal = Molecular Psychiatry | volume = 26 | issue = 7 | pages = 2708–2720 | date = July 2021 | pmid = 33500553 | pmc = 8505257 | doi = 10.1038/s41380-021-01025-0 }}{{cite journal | vauthors = Zhu JL, Luo WW, Cheng X, Li Y, Zhang QZ, Peng WX | title = Vitamin D deficiency and Schizophrenia in Adults: A Systematic Review and Meta-analysis of Observational Studies | journal = Psychiatry Research | volume = 288 | issue = | pages = 112959 | date = June 2020 | pmid = 32335466 | doi = 10.1016/j.psychres.2020.112959 }} Results from supplementation trials have been inconclusive.

Erectile dysfunction can be a consequence of vitamin D deficiency. Mechanisms may include the regulation of vascular stiffness, the production of vasodilating nitric oxide, and the regulation of vessel permeability. However, the clinical trial literature does not yet contain sufficient evidence that supplementation treats the problem. Part of the complexity is that vitamin D deficiency is also linked to morbidities that are associated with erectile dysfunction, such as obesity, hypertension, diabetes mellitus, hypercholesterolemia, chronic kidney disease and hypogonadism.{{cite journal | vauthors = Crafa A, Cannarella R, Barbagallo F, Leanza C, Palazzolo R, Flores HA, La Vignera S, Condorelli RA, Calogero AE | title = Mechanisms Suggesting a Relationship between Vitamin D and Erectile Dysfunction: An Overview | journal = Biomolecules | volume = 13 | issue = 6 | page = 930 | date = June 2023 | pmid = 37371510 | pmc = 10295993 | doi = 10.3390/biom13060930 | doi-access = free }}{{cite journal | vauthors = Canguven O, Al Malki AH | title = Vitamin D and Male Erectile Function: An Updated Review | journal = The World Journal of Men's Health | volume = 39 | issue = 1 | pages = 31–37 | date = January 2021 | pmid = 32009309 | pmc = 7752519 | doi = 10.5534/wjmh.190151 }}

In women, vitamin D receptors are expressed in the superficial layers of the urogenital organs. There is an association between vitamin D deficiency and a decline in sexual functions, including sexual desire, orgasm, and satisfaction in women, with symptom severity correlated with vitamin D serum concentration. The clinical trial literature does not yet contain sufficient evidence that supplementation reverses these dysfunctions or improves other aspects of vaginal or urogenital health.{{cite journal | vauthors = Hassanein MM, Huri HZ, Abduelkarem AR, Baig K | title = Therapeutic Effects of Vitamin D on Vaginal, Sexual, and Urological Functions in Postmenopausal Women | journal = Nutrients | volume = 15 | issue = 17 | page = 3804 | date = August 2023 | pmid = 37686835 | pmc = 10490181 | doi = 10.3390/nu15173804 | doi-access = free }}

Pregnant women often do not take the recommended amount of vitamin D.{{cite journal | vauthors = Wagner CL, Taylor SN, Dawodu A, Johnson DD, Hollis BW | title = Vitamin D and its role during pregnancy in attaining optimal health of mother and fetus | journal = Nutrients | volume = 4 | issue = 3 | pages = 208–230 | date = March 2012 | pmid = 22666547 | pmc = 3347028 | doi = 10.3390/nu4030208 | title-link = doi | doi-access = free }} Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small for gestational age infants.{{cite journal | vauthors = Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O'Beirne M, Rabi DM | title = Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies | journal = BMJ | volume = 346 | pages = f1169 | date = March 2013 | pmid = 23533188 | doi = 10.1136/bmj.f1169 | title-link = doi | doi-access = free }} Although taking vitamin D supplements during pregnancy raises blood levels of vitamin D in the mother at term, the full extent of benefits for the mother or baby is unclear.{{cite journal | vauthors = Roth DE, Leung M, Mesfin E, Qamar H, Watterworth J, Papp E | title = Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials | journal = BMJ | volume = 359 | pages = j5237 | date = November 2017 | pmid = 29187358 | pmc = 5706533 | doi = 10.1136/bmj.j5237 }}{{cite journal | vauthors = Palacios C, Kostiuk LL, Cuthbert A, Weeks J | title = Vitamin D supplementation for women during pregnancy | journal = The Cochrane Database of Systematic Reviews | volume = 2024 | issue = 7 | pages = CD008873 | date = July 2024 | pmid = 39077939 | pmc = 11287789 | doi = 10.1002/14651858.CD008873.pub5 | pmc-embargo-date = July 30, 2025 }}

Obesity increases the risk of having low serum vitamin D. Supplementation does not lead to weight loss, but weight loss increases serum vitamin D. The theory is that fatty tissue sequesters vitamin D.{{cite journal | vauthors = Mallard SR, Howe AS, Houghton LA | title = Vitamin D status and weight loss: a systematic review and meta-analysis of randomized and nonrandomized controlled weight-loss trials | journal = The American Journal of Clinical Nutrition | volume = 104 | issue = 4 | pages = 1151–1159 | date = October 2016 | pmid = 27604772 | doi = 10.3945/ajcn.116.136879 }} Bariatric surgery as a treatment for obesity can lead to vitamin deficiencies. Long-term follow-up reported deficiencies for vitamins D, E, A, K and B12, with D the most common at 36%.{{cite journal | vauthors = Chen L, Chen Y, Yu X, Liang S, Guan Y, Yang J, Guan B | title = Long-term prevalence of vitamin deficiencies after bariatric surgery: a meta-analysis | journal = Langenbeck's Archives of Surgery | volume = 409 | issue = 1 | pages = 226 | date = July 2024 | pmid = 39030449 | doi = 10.1007/s00423-024-03422-9 }}

There is evidence that the pathogenesis of uterine fibroids is associated with low serum vitamin D and that supplementation reduces the size of fibroids.{{cite journal | vauthors = Alsharif SA, Baradwan S, Alshahrani MS, Khadawardi K, AlSghan R, Badghish E, Bukhari IA, Alyousef A, Khuraybah AM, Alomar O, Abu-Zaid A | title = Effect of Oral Consumption of Vitamin D on Uterine Fibroids: A Systematic Review and Meta-Analysis of Randomized Clinical Trials | journal = Nutrition and Cancer | volume = 76 | issue = 3 | pages = 226–235 | date = 2024 | pmid = 38234246 | doi = 10.1080/01635581.2023.2288716 }}{{cite journal | vauthors = Combs A, Singh B, Nylander E, Islam MS, Nguyen HV, Parra E, Bello A, Segars J | title = A Systematic Review of Vitamin D and Fibroids: Pathophysiology, Prevention, and Treatment | journal = Reproductive Sciences | volume = 30 | issue = 4 | pages = 1049–1064 | date = April 2023 | pmid = 35960442 | doi = 10.1007/s43032-022-01011-z }}

Governmental regulatory agencies stipulate for the food and dietary supplement industries certain health claims as allowable as statements on packaging.

Europe: European Food Safety Authority (EFSA)

• normal function of the immune system{{cite journal |author=((European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies (NDA) )) |title=Scientific opinion on the substantiation of health claims related to vitamin D and normal function of the immune system and inflammatory response (ID 154, 159), maintenance of normal muscle function (ID 155) and maintenance of normal cardiovascular function (ID 159) according to Article 13(1) of Regulation (EC) No 1924/2006 |journal=EFSA Journal |volume=8 |issue=2 |pages=1468–85 |year=2010 |doi=10.2903/j.efsa.2010.1468|doi-access=free }}
• normal inflammatory response
• normal muscle function
• reduced risk of falling in people over age 60{{cite journal |author=((European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies (NDA) )) |title=Scientific opinion on the substantiation of a health claim related to vitamin D and risk of falling according to Article 14 of Regulation (EC) No 1924/2006 |journal=EFSA Journal |volume=9 |issue=9 |pages=2382–2400 |year=2011 |doi=10.2903/j.efsa.2011.2382 |url=http://orbit.dtu.dk/files/6355745/prod11324398702885.Scientific.pdf |doi-access=free |access-date=20 August 2019 |archive-date=20 August 2019 |archive-url=https://web.archive.org/web/20190820154317/https://orbit.dtu.dk/files/6355745/prod11324398702885.Scientific.pdf |url-status=live }}

US: Food and Drug Administration (FDA)

• "Adequate calcium and vitamin D, as part of a well-balanced diet, along with physical activity, may reduce the risk of osteoporosis."{{cite web |url=https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-food-labeling-guide |publisher=Food and Drug Administration (FDA) |title=Guidance for Industry: Food Labeling Guide |date=January 2013 |access-date=17 July 2019 |archive-date=22 December 2020 |archive-url=https://web.archive.org/web/20201222015608/https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-food-labeling-guide |url-status=live }} {{PD-notice}}

Canada: Health Canada

• "Adequate calcium and regular exercise may help achieve strong bones in children and adolescents and reduce the risk of osteoporosis in older adults. An adequate intake of vitamin D is also necessary."{{cite web |url=http://www.hc-sc.gc.ca/fn-an/label-etiquet/claims-reclam/assess-evalu/calcium_osteo-eng.php |publisher=Bureau of Nutritional Sciences Food Directorate, Health Products and Food Branch Health Canada |title=Health Canada Scientific Summary on the U. S. Health Claim Regarding Calcium and Osteoporosis |date=1 May 2000 |access-date=29 January 2012 |archive-date=3 December 2016 |archive-url=https://web.archive.org/web/20161203155930/http://www.hc-sc.gc.ca/fn-an/label-etiquet/claims-reclam/assess-evalu/calcium_osteo-eng.php |url-status=live }}

Japan: Foods with Nutrient Function Claims (FNFC)

• "Vitamin D is a nutrient which promotes the absorption of calcium in the gut intestine and aids in the development of bone."{{cite journal | vauthors = Shimizu T | title = Newly established regulation in Japan: foods with health claims | journal = Asia Pacific Journal of Clinical Nutrition | volume = 11 | issue = 2 | pages = S94–S96 | date = 2002 | pmid = 12074195 | doi = 10.1046/j.1440-6047.2002.00007.x }}

Various government institutions have proposed different recommendations for the amount of daily intake of vitamin D. These vary according to age, pregnancy, or lactation, and the extent assumptions are made regarding skin synthesis. Older recommendations were lower. For example, the US Adequate Intake recommendations from 1997 were 200 IU/day for infants, children, adults to age 50, and women during pregnancy or lactation, 400 IU/day for ages 51–70, and 600 IU/day for 71 and older.{{cite book|chapter-url=https://nap.nationalacademies.org/read/5776/chapter/9 |title=Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride |last1=Institute of Medicine|author-link=Institute of Medicine|publisher=The National Academies Press|year=1997|isbn=0-309-06403-1|location=Washington, DC|pages=250–87|chapter=Vitamin D |access-date=28 December 2024}}

Conversion: 1{{nbsp}}μg (microgram) = 40{{nbsp}}IU (international unit). For dietary recommendation and food labeling purposes government agencies consider vitamin D₃ and D₂ bioequivalent.

The UK National Health Service (NHS) recommends that people at risk of vitamin D deficiency, breast-fed babies, formula-fed babies taking less than 500{{nbsp}}ml/day, and children aged 6 months to 4 years, should take daily vitamin D supplements throughout the year to ensure sufficient intake.{{cite web |url=http://www.nhs.uk/Conditions/vitamins-minerals/Pages/Vitamin-D.aspx |title=Vitamins and minerals – Vitamin D |website=National Health Service |date=3 August 2020 |access-date=15 November 2020 |archive-date=30 October 2017 |archive-url=https://web.archive.org/web/20171030213854/https://www.nhs.uk/Conditions/vitamins-minerals/Pages/Vitamin-D.aspx |url-status=live }} This includes people with limited skin synthesis of vitamin D, who are not often outdoors, are frail, housebound, living in a care home, or usually wearing clothes that cover up most of the skin, or with dark skin, such as having an African, African-Caribbean or south Asian background. Other people may be able to make adequate vitamin D from sunlight exposure from April to September. The NHS and Public Health England recommend that everyone, including those who are pregnant and breastfeeding, consider taking a daily supplement containing 10{{nbsp}}μg (400 IU) of vitamin D during autumn and winter because of inadequate sunlight for vitamin D synthesis.{{cite web |url=https://www.gov.uk/government/news/phe-publishes-new-advice-on-vitamin-d |title=PHE publishes new advice on vitamin D |publisher=Public Health England |date=21 July 2016 |access-date=15 November 2020 |archive-date=3 January 2021 |archive-url=https://web.archive.org/web/20210103142730/https://www.gov.uk/government/news/phe-publishes-new-advice-on-vitamin-d |url-status=live }}

The dietary reference intake for vitamin D issued in 2011 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|362–394}} 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|424–446}} 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|404}}{{rp|439–440}}

For US 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 in May 2016, it was revised to 800{{nbsp}}IU (20{{nbsp}}μg) to bring it into agreement with the recommended dietary allowance (RDA).{{Cite web|url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf|title=Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels. FR page 33982.|access-date=20 August 2019|archive-date=8 August 2016|archive-url=https://web.archive.org/web/20160808164651/https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf|url-status=live}} {{PD-notice}}{{cite web | title=Daily Value Reference of the Dietary Supplement Label Database (DSLD) | website=Dietary Supplement Label Database (DSLD) | url=https://www.dsld.nlm.nih.gov/dsld/dailyvalue.jsp | access-date=16 May 2020 | archive-date=7 April 2020 | archive-url=https://web.archive.org/web/20200407073956/https://dsld.nlm.nih.gov/dsld/dailyvalue.jsp | url-status=dead }} A table of the old and new adult daily values is provided at Reference Daily Intake.

Health Canada published recommended dietary intakes (DRIs) and tolerable upper intake levels (ULs) for vitamin D.{{cite web |url=https://www.canada.ca/en/health-canada/services/food-nutrition/healthy-eating/vitamins-minerals/vitamin-calcium-updated-dietary-reference-intakes-nutrition.html |title=Vitamin D and Calcium: Updated Dietary Reference Intakes |work=Nutrition and Healthy Eating |publisher=Health Canada |access-date=28 April 2018 |date=5 December 2008 |archive-date=14 June 2017 |archive-url=https://web.archive.org/web/20170614125403/http://www.hc-sc.gc.ca/fn-an/nutrition/vitamin/vita-d-eng.php |url-status=live }}

Australia and New Zealand published nutrient reference values including guidelines for dietary vitamin D intake in 2006.{{cite book |url=https://www.nhmrc.gov.au/about-us/publications/nutrient-reference-values-australia-and-new-zealand-including-recommended-dietary-intakes#block-views-block-file-attachments-content-block-1 |title=Nutrient Reference Values for Australia and New Zealand Including Recommended Dietary Intakes |year=2006 | publisher = National Health and Medical Research Council |isbn=1-86496-243-7 |location=Canberra |access-date=19 March 2023 |archive-date=3 March 2023 |archive-url= https://web.archive.org/web/20230303184505/https://www.nhmrc.gov.au/about-us/publications/nutrient-reference-values-australia-and-new-zealand-including-recommended-dietary-intakes#block-views-block-file-attachments-content-block-1 |url-status=live }} About a third of Australians have vitamin D deficiency.{{cite web |vauthors=Salleh A |title=Vitamin D food fortification on the table |date=12 June 2012 |publisher=Australian Broadcasting Corporation |url=http://www.abc.net.au/science/articles/2012/06/12/3522708.htm |access-date=12 June 2012 |archive-date=22 December 2020 |archive-url=https://web.archive.org/web/20201222015352/http://www.abc.net.au/science/articles/2012/06/12/3522708.htm |url-status=live }}{{cite web | title=Australian Health Survey: Biomedical Results for Nutrients, 2011–12 | website=Australian Bureau of Statistics | date=21 December 2011 | url=https://www.abs.gov.au/statistics/health/health-conditions-and-risks/australian-health-survey-biomedical-results-nutrients/latest-release | access-date=19 March 2023 | archive-date=10 March 2023 | archive-url=https://web.archive.org/web/20230310191806/https://www.abs.gov.au/statistics/health/health-conditions-and-risks/australian-health-survey-biomedical-results-nutrients/latest-release | url-status=live }}

The European Food Safety Authority (EFSA) in 2016{{Cite journal |last1=EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) |title=Dietary reference values for vitamin D |journal=EFSA Journal |volume=14 |issue=10 |pages=e04547 |doi=10.2903/j.efsa.2016.4547 |date=29 June 2016|doi-access=free |hdl=11380/1228918 |hdl-access=free }} 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 intake 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).

On the other hand, the EU Commission defined nutrition labelling for foodstuffs as regards recommended daily allowances (RDA) for vitamin D to 5 μg/day (200 IU) as 100%.{{Cite web |date=28 October 2008 |title=nutrition labelling for foodstuffs as regards recommended daily allowances, energy conversion factors, and definitions |url=https://eur-lex.europa.eu/legal-content/En/TXT/PDF/?uri=CELEX:32008L0100}}

The EFSA reviewed safe levels of intake in 2012,{{Cite journal |last1=EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) |title=Scientific Opinion on the Tolerable Upper Intake Level of vitamin D |journal=EFSA Journal |volume=10 |issue=7 |doi=10.2903/j.efsa.2012.2813 |year=2012 |type=Submitted manuscript |pages=2813 |doi-access=free |hdl=2434/257871 |hdl-access=free}} setting the tolerable upper limit for adults at 100{{nbsp}}μg/day (4000{{nbsp}}IU), a similar conclusion as the IOM.

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.{{Cite web |url=https://www.livsmedelsverket.se/livsmedel-och-innehall/naringsamne/vitaminer-och-antioxidanter/d-vitamin |title=Vitamin D (translated) |publisher=Swedish National Food Agency |language=sv |access-date=19 October 2018 |archive-date=26 October 2020 |archive-url=https://web.archive.org/web/20201026192059/https://www.livsmedelsverket.se/livsmedel-och-innehall/naringsamne/vitaminer-och-antioxidanter/d-vitamin |url-status=live }}

Non-government organisations in Europe have made their own recommendations. The German Society for Nutrition recommends 20{{nbsp}}μg.[//www.dge.de/modules.php?name=Content&pa=showpage&pid=4&page=12 Vitamin-D-Bedarf bei fehlender endogener Synthese] Deutsche Gesellschaft für Ernährung, January 2012 The European Menopause and Andropause Society recommends postmenopausal women consume 15{{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.{{cite journal | vauthors = Pérez-López FR, Brincat M, Erel CT, Tremollieres F, Gambacciani M, Lambrinoudaki I, Moen MH, Schenck-Gustafsson K, Vujovic S, Rozenberg S, Rees M | title = EMAS position statement: Vitamin D and postmenopausal health | journal = Maturitas | volume = 71 | issue = 1 | pages = 83–88 | date = January 2012 | pmid = 22100145 | doi = 10.1016/j.maturitas.2011.11.002 | doi-access = free }}

{{see also|Ergocalciferol#Biosynthesis}}

Few foods naturally contain vitamin D. Cod liver oil as a dietary supplement contains 450 IU/teaspoon. Fatty fish (but not lean fish such as tuna) are the best natural food sources of vitamin D₃. Beef liver, eggs, and cheese have modest amounts. Mushrooms provide variable amounts of vitamin D₂, as mushrooms can be treated with UV light to greatly increase their content.{{cite web |vauthors=Haytowitz DB |title=Vitamin D in mushrooms |url=https://www.ars.usda.gov/ARSUserFiles/80400525/Articles/AICR09_Mushroom_VitD.pdf |publisher=Nutrient Data Laboratory, US Department of Agriculture |access-date=16 April 2018 |date=2009 |archive-date=1 February 2021 |archive-url=https://web.archive.org/web/20210201181749/https://www.ars.usda.gov/ARSUserFiles/80400525/Articles/AICR09_Mushroom_VitD.pdf |url-status=live }} In certain countries, breakfast cereals, dairy milk and plant milk products are fortified. Infant formulas are fortified with 400 to 1000 IU per liter,{{cite journal | vauthors = Schmid A, Walther B | title = Natural vitamin D content in animal products | journal = Advances in Nutrition | volume = 4 | issue = 4 | pages = 453–462 | date = July 2013 | pmid = 23858093 | pmc = 3941824 | doi = 10.3945/an.113.003780 }} a normal volume for a full-term infant after the first month. Cooking only minimally decreases vitamin content.

In the early 1930s, the United States and countries in northern Europe began to fortify milk with vitamin D in an effort to eradicate rickets. This, plus medical advice to expose infants to sunlight, effectively ended the high prevalence of rickets. The proven health benefit of vitamin D led to fortification to many foods, even foods as inappropriate as hot dogs and beer. In the 1950s, due to some highly publicized cases of hypercalcemia and birth defects, vitamin D fortification became regulated, and in some countries discontinued.{{cite journal | vauthors = Wacker M, Holick MF | title = Sunlight and Vitamin D: A global perspective for health | journal = Dermato-Endocrinology | volume = 5 | issue = 1 | pages = 51–108 | date = January 2013 | pmid = 24494042 | pmc = 3897598 | doi = 10.4161/derm.24494 }} As of 2024, governments have established mandated or voluntary food fortification programs to combat deficiency in, respectively, 15 and 10 countries.{{cite web|url=https://fortificationdata.org/map-number-of-nutrients/|title=Map: Count of Nutrients In Fortification Standards|website=Global Fortification Data Exchange |date=2024 |access-date=16 December 2024 }} Depending on the country, manufactured foods fortified with either vitamin D₂ or D₃ may include dairy milk and other dairy foods, fruit juices and fruit juice drinks, meal replacement food bars, soy protein-based beverages, wheat flour or corn meal products, infant formulas, breakfast cereals and 'plant milks',{{cite web |url=https://www.fda.gov/food/food-additives-petitions/vitamin-d-milk-and-milk-alternatives |title=Vitamin D for Milk and Milk Alternatives |date=15 July 2016 |publisher=Food and Drug Administration (FDA) |access-date=22 February 2017 |archive-date=22 December 2020 |archive-url=https://web.archive.org/web/20201222015435/https://www.fda.gov/food/food-additives-petitions/vitamin-d-milk-and-milk-alternatives |url-status=dead }} {{PD-notice}}{{cite journal | vauthors = de Lourdes Samaniego-Vaesken M, Alonso-Aperte E, Varela-Moreiras G | title = Vitamin food fortification today | journal = Food & Nutrition Research | volume = 56 | pages = 5459 | year = 2012 | pmid = 22481896 | pmc = 3319130 | doi = 10.3402/fnr.v56i0.5459 }}{{cite journal | vauthors = Spiro A, Buttriss JL | title = Vitamin D: An overview of vitamin D status and intake in Europe | journal = Nutrition Bulletin | volume = 39 | issue = 4 | pages = 322–350 | date = December 2014 | pmid = 25635171 | pmc = 4288313 | doi = 10.1111/nbu.12108 }} the last described as beverages made from soy, almond, rice, oats and other plant sources intended as alternatives to dairy milk.{{Cite web|url=https://health.clevelandclinic.org/what-you-need-to-know-when-choosing-milk-and-milk-alternatives |title=What You Need to Know When Choosing Milk and Milk Alternatives |date=11 November 2021 |website=Cleveland Clinic|access-date=3 January 2025 |vauthors = }}

File:Skinlayers.png

File:Vitamin D biosynthesis.svg

Synthesis of vitamin D in nature is dependent on the presence of UV radiation and subsequent activation in the liver and the kidneys. Many animals synthesize vitamin D₃ from 7-dehydrocholesterol, and many fungi synthesize vitamin D₂ from ergosterol.

Vitamin D₃ is produced photochemically from 7-dehydrocholesterol in the skin of most vertebrate animals, including humans.{{cite journal | vauthors = Crissey SD, Ange KD, Jacobsen KL, Slifka KA, Bowen PE, Stacewicz-Sapuntzakis M, Langman CB, Sadler W, Kahn S, Ward A | title = Serum concentrations of lipids, vitamin d metabolites, retinol, retinyl esters, tocopherols and selected carotenoids in twelve captive wild felid species at four zoos | journal = The Journal of Nutrition | volume = 133 | issue = 1 | pages = 160–6 | date = January 2003 | pmid = 12514284 | doi = 10.1093/jn/133.1.160 | doi-access = free | title-link = doi }} The skin consists of two primary layers: the inner layer called the dermis, and the outer, thinner epidermis. Vitamin D is produced in the keratinocytes of two innermost strata of the epidermis, the stratum basale and stratum spinosum, which also can produce calcitriol and express the vitamin D receptor.{{cite journal | vauthors = Bikle DD | title = Vitamin D and the skin | journal = Journal of Bone and Mineral Metabolism | volume = 28 | issue = 2 | pages = 117–30 | date = March 2010 | pmid = 20107849 | doi = 10.1007/s00774-009-0153-8 | s2cid = 6072459 }} The 7-dehydrocholesterol reacts with UVB light at wavelengths of 290–315 nm. 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.{{cite book | vauthors = Holick MF | title = Sunlight, Vitamin D and Skin Cancer | chapter = Sunlight, UV Radiation, Vitamin D, and Skin Cancer: How Much Sunlight do We Need? | series = Advances in Experimental Medicine and Biology | volume = 1268 | pages = 19–36 | date = 2020 | publisher = Springer | pmid = 32918212 | doi = 10.1007/978-3-030-46227-7_2 | isbn = 978-3-030-46226-0 | quote = 108 references | s2cid = 221636019 }} In skin, either permanently in dark skin or temporarily due to tanning, melanin is located in the stratum basale, where it blocks UVB light and thus inhibits vitamin D synthesis.

The transformation in the skin that converts 7-dehydrocholesterol to vitamin D₃ occurs in two steps. 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) via a [1,7]-sigmatropic hydrogen shift. In fungi, the conversion from ergosterol to vitamin D₂ follows a similar procedure, forming previtamin{{nbsp}}D₂ by UVB photolysis, which isomerizes to vitamin D₂ (ergocalciferol).

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{{VitaminDSynthesis_WP1531|highlight=Calcidiol|align=left|width=600|height=300}}

For at least 1.2 billion years, eukaryotes - a classification of life forms that includes single-cell species, fungi, plants, and animals, but not bacteria - have been able to synthesize 7-dehydrocholesterol. When this molecule is exposed to UVB light from the sun it absorbs the energy in the process of being converted to vitamin D. The function was to prevent DNA damage, the converted molecule being an end product without vitamin function. Present day, phytoplankton in the ocean photosynthesize vitamin D without any calcium management function. Ditto some species of algae, lichen, fungi, and plants.{{cite journal | vauthors = Jäpelt RB, Jakobsen J | title = Vitamin D in plants: a review of occurrence, analysis, and biosynthesis | journal = Frontiers in Plant Science | volume = 4 | pages = 136 | date = May 2013 | pmid = 23717318 | pmc = 3651966 | doi = 10.3389/fpls.2013.00136 | doi-access = free | bibcode = 2013FrPS....4..136J }}{{cite journal | vauthors = Göring H | title = Vitamin D in Nature: A Product of Synthesis and/or Degradation of Cell Membrane Components | journal = Biochemistry. Biokhimiia | volume = 83 | issue = 11 | pages = 1350–1357 | date = November 2018 | pmid = 30482146 | doi = 10.1134/S0006297918110056 | s2cid = 53437216 }}{{cite journal | vauthors = Björn LO, Wang T | title = Vitamin D in an ecological context | journal = International Journal of Circumpolar Health | volume = 59 | issue = 1 | pages = 26–32 | date = January 2000 | pmid = 10850004 }} Only circa 500 million years ago, when animals began to leave the oceans for land, did the UV-converted molecule take on a hormone function as a promoter of calcium regulation. This function required the development of a nuclear vitamin D receptor (VDR) that binds the biologically active vitamin D metabolite 1α,25-dihydroxyvitamin (D₃), plasma transport proteins, and vitamin D metabolizing CYP450 enzymes regulated by calciotropic hormones. The triumvirate of receptor protein, transport and metabolizing enzymes are found only in vertebrates.{{cite journal | vauthors = Bouillon R, Suda T | title = Vitamin D: calcium and bone homeostasis during evolution | journal = BoneKEy Reports | volume = 3 | pages = 480 | date = January 2014 | pmid = 24466411 | pmc = 3899559 | doi = 10.1038/bonekey.2013.214 }}

The initial vitamin function evolved for control of metabolic genes supporting innate and adaptive immunity. Only later did the VDR system start to function as an important regulator of calcium supply for a calcified skeleton in land-based vertebrates. From amphibians onward, bone management is biodynamic, with bone functioning as internal calcium reservoir under the control of osteoclasts via the combined action of parathyroid hormone and 1α,25-dihydroxyvitamin D₃.

Most land-based vertebrates - mammals, reptiles, birds, and amphibians - produce vitamin D in response to ultraviolet light. Carnivores and omnivores also get the vitamins from their diets, and herbivores can get some vitamins from fungi that are consumed along with plant foods.{{cite journal | vauthors = Uhl EW | title = The pathology of vitamin D deficiency in domesticated animals: An evolutionary and comparative overview | journal = International Journal of Paleopathology | volume = 23 | issue = | pages = 100–09 | date = December 2018 | pmid = 29544996 | doi = 10.1016/j.ijpp.2018.03.001 | doi-access = free | bibcode = 2018IJPal..23..100U }} In the wild, reptiles require either exposure to sunlight or consumption of prey, or both. In captivity, artificial lighting that provides UVB light is preferred to fortified food.{{cite web |url=https://www.merckvetmanual.com/management-and-nutrition/nutrition-exotic-and-zoo-animals/nutrition-in-reptiles |title=Nutrition in Reptiles: Vitamin D and Ultraviolet Light |first=Joeke |last= Nijboer |date=September 2024 |website=Merck Veterinary Manual |access-date=10 February 2025}} The same holds true for birds{{cite web |url=https://www.merckvetmanual.com/exotic-and-laboratory-animals/pet-birds/nutritional-diseases-of-pet-birds |title=Nutritional Diseases of Pet Birds: Phosphorus and vitamin D3 imbalance |first=Sharman |last=Hoppes |date=September 2024 |website=Merck Veterinary Manual |access-date=10 February 2025}} and amphibians.{{cite journal |vauthors=Antwis RE, Browne RK |title=Ultraviolet radiation and Vitamin D3 in amphibian health, behaviour, diet and conservation |journal=Comp Biochem Physiol A |volume=154 |issue=2 |pages=184–90 |date=October 2009 |pmid=19555772 |doi=10.1016/j.cbpa.2009.06.008 |url=http://usir.salford.ac.uk/id/eprint/36713/1/Ultraviolet%20radiation%20and%20Vitamin%20D3%20in%20amphibian.pdf}} There are some exceptions. Feline species and dogs are practically incapable of vitamin D synthesis due to the high activity of 7-dehydrocholesterol reductase, which converts any 7-dehydrocholesterol in the skin to cholesterol before it can be UVB light-modified, but instead get vitamin D from diet.{{cite journal | vauthors = Zafalon RV, Risolia LW, Pedrinelli V, Vendramini TH, Rodrigues RB, Amaral AR, Kogika MM, Brunetto MA | title = Vitamin D metabolism in dogs and cats and its relation to diseases not associated with bone metabolism | journal = Journal of Animal Physiology and Animal Nutrition | volume = 104 | issue = 1 | pages = 322–42 | date = January 2020 | pmid = 31803981 | doi = 10.1111/jpn.13259 | title-link = doi | doi-access = free }}{{cite journal |vauthors=Zafalon RV, Ruberti B, Rentas MF, Amaral AR, Vendramini TH, Chacar FC, Kogika MM, Brunetto MA |title=The Role of Vitamin D in Small Animal Bone Metabolism |journal=Metabolites |volume=10 |issue=12 |date=December 2020 |page=496 |pmid=33287408 |pmc=7761812 |doi=10.3390/metabo10120496 |doi-access=free |url=}}

Fish do not synthesize vitamin D from exposure to ultraviolet light. Wild-caught fish obtain vitamin D via a diet of phytoplankton, zooplankton, and the aquatic food chain. Commercially raised fish are fed D₃ fortified diets. As with land-based vertebrates, the vitamin is transported by vitamin D binding protein to cellular receptors. Aquaculture research shows that the vitamin is needed for bone health, optimizing growth, reducing fatty liver problems and supporting immune health. Unlike land-based vertebrates, large amounts of vitamin D₃ are stored in the liver and fatty tissues, making fish a good dietary source for human consumption.{{cite journal |journal=Reviews in Aquaculture |vauthors=Cheng K, Huang Y, Wang C, Ali W, Karrow NA |title=Physiological function of vitamin D3 in fish |date= March 2023 |volume=15 |issue=4 |pages=1732–1748 |doi=10.1111/raq.12814|bibcode=2023RvAq...15.1732C }}

During the long period between one and three million years ago, hominids, including ancestors of homo sapiens, underwent several evolutionary changes. A long-term climate shift toward drier conditions promoted life changes from sedentary forest-dwelling with a primarily plant-based diet toward upright walking/running on open terrain and more meat consumption. One consequence of the shift to a culture that included more physically active hunting was a need for evaporative cooling from sweat, which to be functional, meant an evolutionary shift toward less body hair, as evaporation from sweat-wet hair would have cooled the hair but not the skin underneath.{{Cite news | vauthors = Wade N |date=19 August 2003 |title=Why Humans and Their Fur Parted Ways |url=https://www.nytimes.com/2003/08/19/science/why-humans-and-their-fur-parted-ways.html |access-date=24 August 2019 |work=The New York Times |language=en-US |issn=0362-4331 |archive-date=18 June 2009 |archive-url=https://web.archive.org/web/20090618134300/http://www.nytimes.com/2003/08/19/science/why-humans-and-their-fur-parted-ways.html |url-status=live }} A second consequence was darker skin.{{cite journal | vauthors = Jarrett P, Scragg R | title = Evolution, Prehistory and Vitamin D | journal = International Journal of Environmental Research and Public Health | volume = 17 | issue = 2 | page = 646 | date = January 2020 | pmid = 31963858 | pmc = 7027011 | doi = 10.3390/ijerph17020646 | doi-access = free }} The early humans who evolved in the regions of the globe near the equator had permanent large quantities of the skin pigment melanin in their skins, resulting in brown/black skin tones. For people with light skin tone, exposure to UV radiation induces the synthesis of melanin causing the skin to darken, i.e., sun tanning. Either way, the pigment can protect by dissipating up to 99.9% of absorbed UV radiation. In this way, melanin protects skin cells from UVA and UVB radiation damage that causes photoaging and the risk of malignant melanoma, a cancer of melanin cells.{{cite journal | vauthors = Brenner M, Hearing VJ | title = The protective role of melanin against UV damage in human skin | journal = Photochemistry and Photobiology | volume = 84 | issue = 3 | pages = 539–549 | year = 2008 | pmid = 18435612 | pmc = 2671032 | doi = 10.1111/j.1751-1097.2007.00226.x }} Melanin also protects against photodegradation of the vitamin folate in skin tissue, and in the eyes, preserves eye health.

The dark-skinned humans who had evolved in Africa populated the rest of the world through migration some 50,000 to 80,000 years ago.{{Cite news |date=22 September 2016 |title=A Single Migration From Africa Populated the World, Studies Find |url=https://www.nytimes.com/2016/09/22/science/ancient-dna-human-history.html |work=The New York Times |access-date=2 March 2017 |archive-date=2 May 2019 |archive-url=https://web.archive.org/web/20190502133043/https://www.nytimes.com/2016/09/22/science/ancient-dna-human-history.html |url-status=live }} Following settlement in northward regions of Asia and Europe which seasonally get less sunlight, the selective pressure for radiation-protective skin tone decreased while a need for efficient vitamin D synthesis in skin increased, resulting in low-melanin, lighter skin tones in the rest of the prehistoric world.{{cite journal | vauthors = Carlberg C | title = Vitamin D in the Context of Evolution | journal = Nutrients | volume = 14 | issue = 15 | page = 3018 | date = July 2022 | pmid = 35893872 | pmc = 9332464 | doi = 10.3390/nu14153018 | doi-access = free }}{{cite journal | vauthors = Hanel A, Carlberg C | title = Vitamin D and evolution: Pharmacologic implications | journal = Biochemical Pharmacology | volume = 173 | issue = | pages = 113595 | date = March 2020 | pmid = 31377232 | doi = 10.1016/j.bcp.2019.07.024 }} For people with low skin melanin, moderate sun exposure to the face, arms and lower legs several times a week is sufficient.{{cite journal | vauthors = Young AR, Morgan KA, Harrison GI, Lawrence KP, Petersen B, Wulf HC, Philipsen PA | title = A revised action spectrum for vitamin D synthesis by suberythemal UV radiation exposure in humans in vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 118 | issue = 40 | date = October 2021 | pmid = 34580202 | pmc = 8501902 | doi = 10.1073/pnas.2015867118 | bibcode = 2021PNAS..11815867Y | doi-access = free }} However, for recent cultural changes such as indoor living and working, UV-blocking skin products to reduce the risk of sunburn and emigration of dark-skinned people to countries far from the equator have all contributed to an increased incidence of vitamin D insufficiency and deficiency that need to be addressed by food fortification and vitamin D dietary supplements.

Vitamin D₃ (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB and UVC light, followed by purification. The 7-dehydrocholesterol is sourced as an extraction from lanolin, a waxy skin secretion in sheep's wool.{{cite journal | vauthors = Holick MF | title = The vitamin D epidemic and its health consequences | journal = The Journal of Nutrition | volume = 135 | issue = 11 | pages = 2739S–2748S | date = November 2005 | pmid = 16251641 | doi = 10.1093/jn/135.11.2739S | url = http://jn.nutrition.org/content/135/11/2739S.full.pdf | quote = 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 | title-link = doi | doi-access = free | archive-url = https://web.archive.org/web/20171118043538/http://jn.nutrition.org/content/135/11/2739S.full.pdf | archive-date = 18 November 2017 }} Vitamin D₂ (ergocalciferol) is produced in a similar way using ergosterol from yeast as a starting material.{{cite book | vauthors = Hirsch AL |chapter-url= https://books.google.com/books?id=w7hMAFmsM84C&pg=PA79 |chapter= Chapter 6: Industrial Aspects of Vitamin D |title= Vitamin D: Two-Volume Set |veditors= Feldman D, Pike JW, Adam JS |publisher= Academic Press |date= 12 May 2011 |isbn= 978-0123819789}}

File:Cholecalciferol_to_calcidiol_CH3.svg to calcifediol ]]

File:Calcidiol_to_calcitriol_CH3.svg ]]

Whether synthesized in the skin or ingested, vitamin D is hydroxylated in the liver at position 25 (upper right of the molecule) to form the prohormone calcifediol, also referred to as 25(OH)D). This reaction is catalyzed by the microsomal enzyme vitamin D 25-hydroxylase, the product of the CYP2R1 human gene.{{cite journal | vauthors = Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW | title = Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 20 | pages = 7711–15 | date = May 2004 | pmid = 15128933 | pmc = 419671 | doi = 10.1073/pnas.0402490101 | title-link = doi | doi-access = free | bibcode = 2004PNAS..101.7711C }} Once made, the product is released into the blood where it is bound to vitamin D-binding protein.{{cite book |vauthors=Laing CJ, Cooke NE |chapter=Section I: Ch. 8: Vitamin D Binding Protein |veditors=Feldman D, Glorieux FH, Pike JW |title=Vitamin D |volume=1 |publisher=Academic Press |edition=2 |year=2004 |isbn=978-0-12-252687-9 |pages=117–134 |chapter-url=https://books.google.com/books?id=5c66r0KrPUMC |access-date=9 April 2017 |archive-date=19 March 2023 |archive-url=https://web.archive.org/web/20230319220639/https://books.google.com/books?id=5c66r0KrPUMC |url-status=live }}

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, also referred to as 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 plasma 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. 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.{{cite journal | vauthors = Adams JS, Hewison M | title = Update in vitamin D | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 95 | issue = 2 | pages = 471–478 | date = February 2010 | pmid = 20133466 | pmc = 2840860 | doi = 10.1210/jc.2009-1773 }}

The bioactivity of calcitriol is terminated by hydroxylation at position 24 by vitamin D3 24-hydroxylase, coded for by gene CYP24A1, forming calcitetrol. Further metabolism yields calcitroic acid, an inactive water-soluble compound that is excreted in bile.

Vitamin{{nbsp}}D₂ (ergocalciferol) and vitamin{{nbsp}}D₃ (cholecalciferol) share a similar but not identical mechanism of action. Metabolites produced by vitamin D₂ are named with an er- or ergo- prefix to differentiate them from the D₃-based counterparts (sometimes with a chole- prefix).

• 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, an enzyme coded for by gene CYP27A1, but vitamin{{nbsp}}D₂ cannot.
• Ergocalciferol can be directly hydroxylated at position 24 by the enzyme coded for by CYP27A1. This hydroxylation also leads to a greater degree of inactivation: the activity of calcitriol decreases to 60% of original after 24-hydroxylation, whereas ercalcitriol undergoes a 10-fold decrease in activity on conversion to ercalcitetrol.

File:Vitamin D mechanism of action.svg

{{See also|Vitamin D receptor | Calcitriol | Parathyroid hormone}}

Calcitriol exerts its effects primarily by binding to the vitamin D receptor (VDR), which leads to the upregulation of gene transcription.{{cite book | vauthors = Bikle DD | chapter = Vitamin D: Production, Metabolism and Mechanisms of Action | date = 31 December 2021 | veditors = Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP | display-editors = 3 | title = Endotext [Internet] | location = South Dartmouth (MA) | publisher = MDText.com, Inc. | orig-date = 1st published 2000 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK278935/ | pmid = 25905172 }} In the absence of calcitriol, the VDR is mainly located in the cytoplasm of cells. Calcitriol enters cells and binds to the VDR which forms a complex with its coreceptor RXR and the activated VDR/RXR complex is translocated into the nucleus. The VDR/RXR complex subsequently binds to vitamin D response elements (VDRE) which are specific DNA sequences adjacent to genes, numbers estimated as being in the thousands. The VDR/RXR/DNA complex recruits other proteins that transcribe the downstream gene into mRNA which in turn is translated into protein causing a change in cell function.

In addition to calcitriol, other vitamin D metabolites may contribute to vitamin D's biological effects. For example, CYP11A1, an enzyme chiefly known for its role in steroidogenesis, has been found to hydroxylate vitamin D3 at several positions, including C-20, C-22, and C-23, without cleaving the side chain. The resulting metabolites, such as 20-hydroxyvitamin D3 and 20,23-dihydroxyvitamin D3, act as inverse agonists for RORα and RORγ2. This interaction leads to effects such as the downregulation of IL-17 signaling, which influences the immune system.{{cite book | vauthors=Slominski AT, Tuckey RC, Jenkinson C, Li W, Jetten AM | chapter=Alternative pathways for vitamin D metabolism | veditors=Hewison M, Bouillon R, Giovanucci E, Goltzman D, Meyer M, Welsh J | title=Feldman and Pike's Vitamin D | date=January 2024 | pages=85–109 | publisher=Academic Press | isbn=978-0-323-91390-4 | doi=10.1016/B978-0-323-91386-7.00001-5 }} Finally, some effects of vitamin D occur too rapidly to be explained by its influence on gene transcription. For example, calcitriol triggers rapid calcium uptake (within 1-10 minutes) in a variety of cells. These non-genomic actions may involve membrane-bound receptors like PDIA3.{{cite journal | vauthors = Doroudi M, Schwartz Z, Boyan BD | title = Membrane-mediated actions of 1,25-dihydroxy vitamin D3: a review of the roles of phospholipase A2 activating protein and Ca(2+)/calmodulin-dependent protein kinase II | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 147 | pages = 81–84 | date = March 2015 | pmid = 25448737 | pmc = 4323845 | doi = 10.1016/j.jsbmb.2014.11.002 }}{{cite journal | vauthors = Hii CS, Ferrante A | title = The Non-Genomic Actions of Vitamin D | journal = Nutrients | volume = 8 | issue = 3 | pages = 135 | date = March 2016 | pmid = 26950144 | pmc = 4808864 | doi = 10.3390/nu8030135 | title-link = doi | doi-access = free }}{{cite journal | vauthors = Żmijewski MA | title = Nongenomic Activities of Vitamin D | journal = Nutrients | volume = 14 | issue = 23 | date = December 2022 | page = 5104 | pmid = 36501134 | pmc = 9737885 | doi = 10.3390/nu14235104 | doi-access = free }}

Genes regulated by the vitamin D receptor influence a wide range of physiological processes beyond calcium homeostasis and bone metabolism. They play a significant role in immune function, cellular signaling, and even blood coagulation, demonstrating the broad impact of vitamin D-regulated genes on human physiology. Examples of these genes are outlined below.

Vitamin D receptor-regulated genes involved in vitamin D metabolism are CYP27B1, which encodes the enzyme that produces active vitamin D. and CYP24A1, which encodes the enzyme responsible for degrading active vitamin D,{{cite journal | vauthors = Pike JW, Meyer MB | title = The vitamin D receptor: new paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D(3) | journal = Endocrinology and Metabolism Clinics of North America | volume = 39 | issue = 2 | pages = 255–69, table of contents | date = June 2010 | pmid = 20511050 | pmc = 2879406 | doi = 10.1016/j.ecl.2010.02.007 }}{{cite journal | vauthors = Kato S | title = The function of vitamin D receptor in vitamin D action | journal = Journal of Biochemistry | volume = 127 | issue = 5 | pages = 717–22 | date = May 2000 | pmid = 10788778 | doi = 10.1093/oxfordjournals.jbchem.a022662 }} In the area of calcium homeostasis and bone metabolism, several genes are regulated by vitamin D. These include TNFSF11 (RANKL), crucial for bone metabolism;{{cite journal | vauthors = Khammissa RA, Fourie J, Motswaledi MH, Ballyram R, Lemmer J, Feller L | title = The Biological Activities of Vitamin D and Its Receptor in Relation to Calcium and Bone Homeostasis, Cancer, Immune and Cardiovascular Systems, Skin Biology, and Oral Health | journal = BioMed Research International | volume = 2018 | issue = | pages = 9276380 | date = 2018 | pmid = 29951549 | pmc = 5987305 | doi = 10.1155/2018/9276380 | doi-access = free }} SPP1 (Osteopontin), which is important for bone metabolism; and BGLAP (Osteocalcin), which is involved in bone mineralization. Additional genes include TRPV6, a calcium channel critical for intestinal calcium absorption;{{cite journal | vauthors = Carlberg C | title = Vitamin D and Its Target Genes | journal = Nutrients | volume = 14 | issue = 7 | date = March 2022 | page = 1354 | pmid = 35405966 | pmc = 9003440 | doi = 10.3390/nu14071354 | doi-access = free | url = }} S100G (Calbindin-D9k), a calcium-binding protein that facilitates calcium translocation in enterocytes; ATP2B1 (PMCA1b), a plasma membrane calcium ATPase involved in calcium extrusion from the cell; and the S100A family of genes, which encode calcium-binding proteins involved in various cellular processes.

Vitamin D also plays a role in immune function, influencing genes such as CAMP (Cathelicidin Antimicrobial Peptide), which is involved in innate immune responses; CD14, which participates in innate immune responses; and HLA class II genes, which are important for adaptive immune function. Cytokines such as IL2 and IL12, crucial for T cell responses, are also regulated by vitamin D.{{cite journal | vauthors = Fleet JC | title = The role of vitamin D in the endocrinology controlling calcium homeostasis | journal = Molecular and Cellular Endocrinology | volume = 453 | issue = | pages = 36–45 | date = September 2017 | pmid = 28400273 | pmc = 5529228 | doi = 10.1016/j.mce.2017.04.008 }} In the domain of blood coagulation, vitamin D regulates the expression of THBD (Thrombomodulin), a key gene involved in the coagulation process. Vitamin D also affects genes involved in cell differentiation and proliferation, including p21 and p27, which regulate the cell cycle,{{cite journal | vauthors = Lu M, Taylor BV, Körner H | title = Genomic Effects of the Vitamin D Receptor: Potentially the Link between Vitamin D, Immune Cells, and Multiple Sclerosis | journal = Frontiers in Immunology | volume = 9 | issue = | pages = 477 | date = 2018 | pmid = 29593729 | pmc = 5857605 | doi = 10.3389/fimmu.2018.00477 | doi-access = free }} as well as transcription factors such as c-fos and c-myc, which are involved in cell proliferation.

File:Calcium regulation.png

Calcitriol plays a key role in regulating vitamin D levels through a negative feedback mechanism. It strongly upregulates the expression of the enzyme CYP24A1, which inactivates vitamin D. This activation happens through binding of the activated vitamin D receptor (VDR) to two vitamin D response elements (VDREs) in the CYP24A1 gene. VDR also recruits proteins like histone acetyltransferases and RNA polymerase II to enhance this process. At the same time, calcitriol suppresses the production of CYP27B1, another enzyme involved in vitamin D metabolism, by modifying its gene's promoter region through an epigenetic mechanism. Together, these actions help tightly control vitamin D levels in the kidney.

Vitamin D metabolism is regulated not only by the negative feedback mechanism of calcitriol but also by two hormones: parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). These hormones are essential for maintaining the body's calcium and phosphate balance.

Parathyroid hormone (PTH) regulates serum calcium through its effects on bone, kidneys, and the small intestine. Bone remodeling, a constant process throughout life, involves bone mineral content being released by osteoclasts (bone resorption) and deposited by osteoblasts. PTH enhances the release of calcium from the large reservoir contained in the bones. It accomplishes this by binding to osteoblasts, in this way inhibiting the cells responsible for adding mineral content to bones, thus favoring the actions of osteoclasts.{{cite journal | vauthors = Poole KE, Reeve J | title = Parathyroid hormone - a bone anabolic and catabolic agent | journal = Current Opinion in Pharmacology | volume = 5 | issue = 6 | pages = 612–7 | date = Dec 2005 | pmid = 16181808 | doi = 10.1016/j.coph.2005.07.004 }} In the kidneys, around 250 mmol of calcium ions are filtered into the glomerular filtrate per day, with the great majority reabsorbed and the remainder excreted in the urine.{{cite journal | vauthors = Blaine J, Chonchol M, Levi M | title = Renal control of calcium, phosphate, and magnesium homeostasis | journal = Clinical Journal of the American Society of Nephrology | volume = 10 | issue = 7 | pages = 1257–72 | year = 2015 | pmid = 25287933 | doi = 10.2215/CJN.09750913 | pmc = 4491294 }} PTH inhibits reabsorption of phosphate (HPO₄²⁻) by the kidneys, resulting in a decrease in plasma phosphate concentration. Given that phosphate ions form water-insoluble salts with calcium, a decrease in the phosphate concentration in plasma (for a given total calcium concentration) increases the amount of ionized (free) calcium. A third important effect of PTH on the kidneys is stimulation of the conversion of 25-hydroxy vitamin D into 1,25-dihydroxy vitamin D (calcitriol). This form of vitamin D is the active hormone which promotes calcium uptake from the intestine via the action of calbindin.{{cite book | vauthors = Wasserman RH, Fullmer CS | title = Mineral Absorption in the Monogastric GI Tract | chapter = On the Molecular Mechanism of Intestinal Calcium Transport | series = Advances in Experimental Medicine and Biology | volume = 249 | pages = 45–65 | year = 1989 | pmid = 2543194 | doi = 10.1007/978-1-4684-9111-1_5 | isbn = 978-1-4684-9113-5 }} Calcitriol also reduces calcium loss to urine.

Per the diagram, calcitriol suppresses the parathyroid hormone gene, thus creating a negative feedback loop that combines to tightly maintain plasma calcium in a normal range of 2.1-2.6 mmol/L for total calcium and 1.1-1.3 mmol/L for ionized calcium. However, there are also vitamin D receptors in bone cells, so that with serum vitamin D in great excess, osteoclastic bone resorption is promoted regardless of PTH, resulting in hypercalcemia and its symptomology.{{cite journal |vauthors=Nakamichi Y, Liu Z, Mori T, He Z, Yasuda H, Takahashi N, Udagawa N |title=The vitamin D receptor in osteoblastic cells but not secreted parathyroid hormone is crucial for soft tissue calcification induced by the proresorptive activity of 1,25(OH)2D3 |journal=J Steroid Biochem Mol Biol |volume=232 |issue= |pages=106351 |date=September 2023 |pmid=37352941 |doi=10.1016/j.jsbmb.2023.106351 |url=|doi-access=free }}

{{Further|Vitamin#History}}

File:A Modern Village School- Education in Cambridgeshire, England, UK, 1944 D23618.jpg

File:Scott’s Emulsion of Pure Cod Liver Oil Trade Card 1994.ARC.0112.jpg

In northern European countries, cod liver oil had a long history of folklore medical uses, including applied to the skin and taken orally as a treatment for rheumatism and gout.{{cite journal | vauthors = Hernigou P, Auregan JC, Dubory A | title = Vitamin D: part II; cod liver oil, ultraviolet radiation, and eradication of rickets | journal = International Orthopaedics | volume = 43 | issue = 3 | pages = 735–749 | date = March 2019 | pmid = 30627846 | doi = 10.1007/s00264-019-04288-z }} There were several extraction processes. Fresh livers cut to pieces and suspended on screens over pans of boiling water would drip oil that could be skimmed off the water, yielding a pale oil with a mild fish odor and flavor. For industrial purposes such as a lubricant, cod livers were placed in barrels to rot, with the oil skimmed off over months. The resulting oil was light to dark brown, and exceedingly foul smelling and tasting. In the 1800s, cod liver oil became popular as a bottled medicinal product for oral consumption - a teaspoon a day - with both pale and brown oils being used. The trigger for the surge in oral use was the observation made in several European countries starting with Holland in the 1820s and spreading to other countries into the 1860s that young children fed cod liver oil did not develop rickets. In northern Europe and the United States, the practice of giving children cod liver oil to prevent rickets persisted well in the 1950s. This overlapped with the fortification of cow's milk with vitamin D, which began in the early 1930s.

Knowledge of cod liver oil being rickets-preventive in humans carried over to treating animals. In 1899, London surgeon John Bland-Sutton was asked to investigate why litters of lion cubs at the London Zoo were dying with a presentation that included rickets. He recommended that the diets of the pregnant and nursing females and the weaned cubs be switched from lean horse meat to goat - including calcium- and phosphorus-containing bones - and cod liver oil, solving the problem. Subsequently, researchers realized that animal models such as dogs and rats could be used for rickets research,{{cite journal |vauthors=Chesney RW, Hedberg G |title=Metabolic bone disease in lion cubs at the London Zoo in 1889: the original animal model of rickets |journal=J Biomed Sci |volume=17 Suppl 1 |issue=Suppl 1 |pages=S36 |date=August 2010 |pmid=20804612 |pmc=2994403 |doi=10.1186/1423-0127-17-S1-S36 |doi-access=free |url=}} leading to the identification and naming of the responsible vitamin in 1922.{{cite journal | vauthors = Jones G | title = 100 YEARS OF VITAMIN D: Historical aspects of vitamin D | journal = Endocrine Connections | volume = 11 | issue = 4 | date = April 2022 | pmid = 35245207 | pmc = 9066576 | doi = 10.1530/EC-21-0594 }}

In 1914, American researchers Elmer McCollum and Marguerite Davis had discovered a substance in cod liver oil which later was named "vitamin A". Edward Mellanby, a British researcher, observed that dogs that were fed cod liver oil did not develop rickets, and (wrongly) concluded that vitamin A could prevent the disease. In 1922, 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.{{cite news |url=https://www.thestar.com/printarticle/239341 |title=Age-old children's disease back in force | vauthors = Carere S |work=Toronto Star |date=25 July 2007 |access-date=24 August 2010 |url-status=dead |archive-url=https://web.archive.org/web/20080517044348/http://www.thestar.com/printArticle/239341 |archive-date=17 May 2008 }}{{cite book |vauthors=McClean FC, Budy AM |chapter=Vitamin A, Vitamin D, Cartilage, Bones, and Teeth |title=Vitamins and Hormones |chapter-url=https://books.google.com/books?id=gGb7vm2SapcC |date= January 1964 |publisher=Academic Press |volume=21 |pages=51–52 |access-date=19 March 2023 |archive-date=19 March 2023 |archive-url=https://web.archive.org/web/20230319220727/https://books.google.com/books?id=gGb7vm2SapcC |url-status=live }}

In 1925, it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble substance is produced, now known as vitamin D₃. Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928 "...for the services rendered through his research into the constitution of the sterols and their connection with the vitamins."{{cite web |url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1928/windaus-bio.html |title=Adolf Windaus – Biography |publisher=Nobelprize.org |date=25 March 2010 |access-date=25 March 2010 |archive-date=24 July 2018 |archive-url=https://web.archive.org/web/20180724002502/https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1928/windaus-bio.html |url-status=live }} Alfred Fabian Hess, his research associate, stated: "Light equals vitamin D."{{cite web |url=http://vitamind.ucr.edu/about/ |title=History of Vitamin D |publisher=University of California at Riverside |date=2011 |access-date=9 May 2014 |archive-date=16 October 2017 |archive-url=https://web.archive.org/web/20171016014311/http://vitamind.ucr.edu/about/ |url-status=dead }} In 1932, Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids,{{cite journal |vauthors=Rosenheim O, King H |title=The Ring-system of sterols and bile acids. Part II |journal=J. Chem. Technol. Biotechnol. |volume=51 |pages=954–7 |year=1932 |doi=10.1002/jctb.5000514702 |issue=47}} and soon thereafter collaborated with Kenneth Callow and others on the isolation and characterization of vitamin D.{{ cite journal | vauthors = Askew FA, Bourdillon RB, Bruce HM, Callow RK, ((St. L. Philpot J)), Webster TA | title = Crystalline Vitamin D |journal = Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character |volume = 109 | issue = 764 | pages = 488–506 | doi = 10.1098/rspb.1932.0008 | year = 1932 | jstor=81571| doi-access = free | title-link = doi }} Windaus further clarified the chemical structure of vitamin D.{{cite book |vauthors=Hirsch AL |chapter=Industrial aspects of vitamin D |title=Vitamin D |year=2011 |veditors=Feldman DJ, Pike JW, Adams JS |publisher=Academic Press |pages=73 |chapter-url=https://books.google.com/books?id=w7hMAFmsM84C |isbn=978-0-12-387035-3 |access-date=19 March 2023 |archive-date=19 March 2023 |archive-url=https://web.archive.org/web/20230319220640/https://books.google.com/books?id=w7hMAFmsM84C |url-status=live }}

In 1969, a specific binding protein for vitamin D called the vitamin D receptor was identified.{{cite journal | vauthors = Haussler MR, Norman AW | title = Chromosomal receptor for a vitamin D metabolite | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 62 | issue = 1 | pages = 155–162 | date = January 1969 | pmid = 5253652 | pmc = 285968 | doi = 10.1073/pnas.62.1.155 | title-link = doi | doi-access = free | bibcode = 1969PNAS...62..155H }} Shortly thereafter, the conversion of vitamin D to calcifediol and then to calcitriol, the biologically active form, was confirmed.{{cite journal | vauthors = Norman AW, Myrtle JF, Midgett RJ, Nowicki HG, Williams V, Popják G | title = 1,25-dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine | journal = Science | volume = 173 | issue = 3991 | pages = 51–54 | date = July 1971 | pmid = 4325863 | doi = 10.1126/science.173.3991.51 | s2cid = 35236666 | bibcode = 1971Sci...173...51N }} The photosynthesis of vitamin D₃ in skin via previtamin D₃ and its subsequent metabolism was described in 1980.{{cite journal | vauthors = Holick MF, MacLaughlin JA, Clark MB, Holick SA, Potts JT, Anderson RR, Blank IH, Parrish JA, Elias P | title = Photosynthesis of previtamin D3 in human skin and the physiologic consequences | journal = Science | volume = 210 | issue = 4466 | pages = 203–205 | date = October 1980 | pmid = 6251551 | doi = 10.1126/science.6251551 | bibcode = 1980Sci...210..203H | jstor = 1685024 }}

{{reflist}}

• Feldman and Pike's Vitamin D (5th Edition) Volume One: Biochemistry, Physiology and Diagnostics; Editors: Hewison M, Bouillon R, Giovannucci E, Goltzman D,Meyer MB, Welsh J. Academic Press (October 2023) ISBN 978-0-32-391386-7
• Feldman and Pike's Vitamin D (5th Edition) Volume Two: Diseases and Therapeutics; Editors: Hewison M, Bouillon R, Giovannucci E, Goltzman D,Meyer MB, Welsh J. Academic Press (January 2024) ISBN 978-0-32-391338-6
• Dietary Reference Intakes for Vitamin D and Calcium Editors: Ross AC, Taylor CL, Yaktine AL, Del Valle HB. National Academies Press (US) (2011) ISBN 978-0-30-916394-1 Available from: https://www.ncbi.nlm.nih.gov/books/NBK56070/ doi: 10.17226/13050

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