Vitamin D: Difference between revisions

| Use = [[Rickets]], [[osteoporosis]], [[hypovitaminosisosteomalacia]], D|[[vitamin D deficiency]]

| Biological_target = [[calcitriol receptor|vitamin D receptor]]

'''Vitamin D''' is a group of [[Lipophilicity|fat-soluble]] [[secosteroid]]s responsible for increasing intestinal absorption of [[calcium]], [[magnesium]], and [[phosphate]], andalong forwith manynumerous other biological effectsfunctions.<ref name="lpi">{{cite web |title=Vitamin D |url=https://lpi.oregonstate.edu/mic/vitamins/vitamin-D |publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis |access-date=14 March 2022 |date=11 February 2021 |archive-date=8 April 2015 |archive-url=https://web.archive.org/web/20150408104559/http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD/ |url-status=live }}</ref><ref name="ods">{{cite web |title=Vitamin D |url=https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ |publisher=Office of Dietary Supplements, US National Institutes of Health |date=12 August 2022 |access-date=22 February 2022 |archive-date=9 April 2021 |archive-url=https://web.archive.org/web/20210409043137/https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ |url-status=live }}</ref><ref name="Norman_2008">{{cite journal | vauthors = Norman AW | title = From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health | journal = The American Journal of Clinical Nutrition | volume = 88 | issue = 2 | pages = 491S–9S | date = August 2008 | pmid = 18689389 | doi = 10.1093/ajcn/88.2.491S | doi-access = free | title-link = doi }}</ref> In humans, the most importantsignificant compounds inwithin this group are vitamin D₃ ([[cholecalciferol]]) and vitamin D₂ ([[ergocalciferol]]).<ref name="ods" /><ref name="Norman_2008" /><ref name=Bikle>{{cite journal | vauthors = Bikle DD | title = Vitamin D metabolism, mechanism of action, and clinical applications | journal = Chemistry & Biology | volume = 21 | issue = 3 | pages = 319–29 | date = March 2014 | pmid = 24529992 | pmc = 3968073 | doi = 10.1016/j.chembiol.2013.12.016 }}</ref>

The majorprimary natural source of vitamin D is the [[Chemical synthesis|synthesis]] of cholecalciferol in the [[Epidermis#Layers|lower layers of the skin’s epidermis]], oftriggered the skin, throughby a [[Photochemistry|photochemical]] reaction with [[Ultraviolet#Subtypes|Ultravioletultraviolet B (UV-B) radiation]] from [[Health effects of sunlight exposure|sun exposure]] or [[UV-B lamps]].<ref name=lpi/> Cholecalciferol and ergocalciferol can also be ingestedobtained from thethrough diet and [[dietary supplement|supplements]].<ref name=lpi/><ref name="ods" /> Only a few foods,Foods such as the flesh of fatty fish, naturallyare containgood significant amountssources of vitamin D, though there are few other foods where it naturally appears in significant amounts.<ref name="ods" /><ref>{{cite journal | vauthors = Lehmann U, Gjessing HR, Hirche F, Mueller-Belecke A, Gudbrandsen OA, Ueland PM, Mellgren G, Lauritzen L, Lindqvist H, Hansen AL, Erkkilä AT, Pot GK, Stangl GI, Dierkes J | title = Efficacy of fish intake on vitamin D status: a meta-analysis of randomized controlled trials | journal = The American Journal of Clinical Nutrition | volume = 102 | issue = 4 | pages = 837–47 | date = October 2015 | pmid = 26354531 | doi = 10.3945/ajcn.114.105395 | doi-access = free | title-link = doi }}</ref> In the U.S. and other countries, cow's milk and plant-derivedbased milk substitutes are fortified with vitamin D, as are many breakfast cereals.<ref name=lpi/> Mushrooms exposed to ultraviolet light contributealso provide useful amounts of vitamin D₂.<ref name="ods" /><ref>Cardwell, Glenn et al. “A Review of Mushrooms as a Potential Source of Dietary Vitamin D.” ''Nutrients'' vol. 10,10 1498. 13 Oct. 2018, doi:10.3390/nu10101498</ref> Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, becausegiven sunthe exposurevariability in thesunlight populationexposure isamong variablethe population and recommendationsuncertainties aboutregarding the[[Health amounteffects of sunsunlight exposure|safe thatlevels isof safesunlight areexposure]], uncertainparticularly indue view ofto the associated risksrisk of [[skin cancer]].<ref name="ods" />

Vitamin D obtained from the diet, or fromsynthesised skinin synthesis,the skin is biologically inactive. It isbecomes activatedactive by two protein enzymeenzymatic [[hydroxylation]] steps, the first occurring in the [[liver]] and the second in the [[Kidney|kidneys]].<ref name=lpi/><ref name=Bikle /> BecauseSince vitaminmost Dmammals can besynthesise synthesizedsufficient invitamin adequateD amountswith byadequate mostsunlight mammals if they get enough sunlightexposure, it is technically not essential andin thereforethe isdiet technicallyand thus not a true [[vitamin]].<ref name="Norman_2008"/> Instead it canfunctions be consideredas a [[hormone]],; withthe activation of the vitamin D pro-hormone resultingproduces in[[calcitriol]], the active form,. [[calcitriol]], whichCalcitriol then producesexerts its effects via the [[vitamin D receptor]], a [[nuclear receptor]] found in multiplevarious locationstissues throughout the body.<ref name="Norman_2008">{{cite journal | vauthors = Norman AW | title = From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health | journal = The American Journal of Clinical Nutrition | volume = 88 | issue = 2 | pages = 491S–9S | date = August 2008 | pmid = 18689389 | doi = 10.1093/ajcn/88.2.491S | doi-access = free | title-link = doi }}</ref>

Cholecalciferol is converted in the liver to [[calcifediol]] (also known as calcidiol or 25-hydroxycholecalciferol);, while [[ergocalciferol]] is converted to ercalcidiol (25-hydroxyergocalciferol).<ref name=lpi/> These two vitamin D metabolites, (calledcollectively referred to as 25-hydroxyvitamin D or 25(OH)D), are measured in serum to determineassess a person's vitamin D status.<ref>{{cite web |title=Vitamin D Tests |url=http://labtestsonline.org/understanding/analytes/vitamin-d/tab/sample |work=Lab Tests Online (USA) |publisher=American Association for Clinical Chemistry |access-date=23 June 2013 |archive-date=7 November 2017 |archive-url=https://web.archive.org/web/20171107113730/https://labtestsonline.org/understanding/analytes/vitamin-d/tab/sample |url-status=live }}</ref><ref name="Hollis_1996">{{cite journal | vauthors = Hollis BW | title = Assessment of vitamin D nutritional and hormonal status: what to measure and how to do it | journal = Calcified Tissue International | volume = 58 | issue = 1 | pages = 4–5 | date = January 1996 | pmid = 8825231 | doi = 10.1007/BF02509538 | s2cid = 35887181 }}</ref> Calcifediol is further hydroxylated by the kidneys and some of thecertain immune system cells to form [[calcitriol]] (1,25-dihydroxycholecalciferol), the biologically active form of vitamin D.<ref name="pmid4323790" /><ref name="pmid4325863" /> Calcitriol circulates in the blood as a hormone in the blood, havingplaying a major role in regulating the concentration of [[calcium]] and [[phosphate]] concentrations, andas promotingwell theas healthypromoting growth[[bone health]] and remodeling of [[bone remodeling]].<ref name=lpi/> CalcitriolAdditionally, alsocalcitriol has other effects, including some oninfluencing cell growthdifferentiation, neuromuscular and immune functions, and reduction ofreducing inflammation.<ref name="ods" />

Vitamin D has a significant role in [[calcium homeostasis]] and metabolism.<ref name=lpi/> Its discovery was due to effort to findidentify the dietary substance lackingdeficiency in children with [[rickets]], (the childhood form of [[osteomalacia]]).<ref name="Wolf_2004">{{cite journal | vauthors = Wolf G | title = The discovery of vitamin D: the contribution of Adolf Windaus | journal = The Journal of Nutrition | volume = 134 | issue = 6 | pages = 1299–302 | date = June 2004 | pmid = 15173387 | doi = 10.1093/jn/134.6.1299 | doi-access = free | title-link = doi }}</ref> Vitamin D supplements are givencommonly used to treat or to prevent osteomalacia and rickets.<ref name=lpi/> The evidence for other health effectsbenefits of vitamin D supplementation in individuals who are already vitamin D–repleteD individualssufficient is inconsistent.<ref name="ods" /> The effect of vitamin D supplementation on morbidity and mortality is notalso clearunclear, with one meta-analysis finding a small decrease in mortality in elderly people.<ref name=Bj2014/> Except for the prevention of rickets and osteomalacia in high-risk groups, any benefit of vitamin D supplements to musculoskeletal or general health may be small and in some cases, may have adverse effects on health.<ref name=reid/><ref name=Futil2014/><ref name="Lancet_2018">{{Cite web|title=The Lancet Diabetes & Endocrinology: Vitamin D supplementation in adults does not prevent fractures, falls or improve bone mineral density|url=https://www.eurekalert.org/news-releases/808633|access-date=23 February 2022|website=EurekAlert!|quote=The authors conclude that there is therefore little reason to use vitamin D supplements to maintain or improve musculoskeletal health, except for the prevention of rare conditions such as rickets and osteomalacia in high risk groups, which can be caused by vitamin D deficiency after long lack of exposure to sunshine.|archive-date=24 March 2022|archive-url=https://web.archive.org/web/20220324065454/https://www.eurekalert.org/news-releases/808633|url-status=live}}</ref>

| style="text-align: center;" |[[File:Ergocalciferol.svg|70px|class=skin-invert-image|Note [[double bond]] at top center.]]

| style="text-align: center;"|[[File:Cholecalciferol.svg|70px|class=skin-invert-image]]

| style="text-align: center;"|[[File:22-Dihydroergocalciferol.svg|70px|class=skin-invert-image]]

| style="text-align: center;"|[[File:Vitamin D5 structure.svg|70px|class=skin-invert-image]]

Several forms ([[vitamer]]s) of vitamin D exist.<ref, name=lpi/>with Thethe two major forms arebeing vitamin D₂ or ergocalciferol, and vitamin D₃ or cholecalciferol.<ref name=lpi/> VitaminThe Dterm without'vitamin a subscriptD' refers to either D₂ or D₃, or both, and is known collectively as calciferol.<ref>{{citationCite journal |last=Alayed Albarri |first=Esmail Mohammad |last2=Sameer Alnuaimi |first2=Ahmed |last3=Abdelghani |first3=Doaa needed|date=April2022-08-04 2023|title=Effectiveness of vitamin D2 compared with vitamin D3 replacement therapy in a primary healthcare setting: a retrospective cohort study |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9372493/ |journal=Qatar Medical Journal |volume=2022 |issue=3 |pages=29 |doi=10.5339/qmj.2022.35 |issn=0253-8253 |pmc=9372493 |pmid=35974883 |quote=Vitamin D is a fat-soluble vitamin consisting of vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol)}}</ref>

Vitamin D₂ was chemically characterized in 1931. In 1935, the [[chemical structure]] of vitamin D₃ was defined and shown to result from the [[ultraviolet|ultraviolet irradiation]] of 7-dehydrocholesterol. AAlthough a chemical nomenclature for vitamin D forms was recommended in 1981,<ref name=nomen-d>{{cite journal | 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 = 223–7 | date = May 1982 | pmid = 7094913 | doi = 10.1111/j.1432-1033.1982.tb06581.x | doi-access = free | title-link = doi }}</ref> but alternative names remain in commoncommonly useused.<ref name=Bikle />

Chemically, the various forms of vitamin D are [[secosteroids]], meaning that is, [[steroid]]s in which one of the bonds in the [[steroid]] rings is broken.<ref name=PKIN2020VitD>{{cite book |vauthors=Fleet JC, Shapses SA |title = Present Knowledge in Nutrition, Eleventh Edition |chapter = Vitamin D |editor=BP Marriott |editor2=DF Birt |editor3=VA Stallings|editor4=AA Yates |publisher = Academic Press (Elsevier) |year=2020 |location = London, United Kingdom |pages = 93–114 |isbn=978-0-323-66162-1}}</ref> The structural difference between vitamin D₂ and vitamin D₃ islies in the [[side chain]],: whichvitamin containsD₂ has a [[double bond]], between carbons 22 and 23, and a [[methyl group]] on carbon 24 in vitamin D₂.<ref name=Bikle /> ManyNumerous [[vitamin D analogues]] have also been synthesized.<ref name=Bikle />

[[File:Calcium regulation.png|thumb|[[CalciumThe metabolism|Calciumrole regulation]]of active vitamin D or calcitriol (orange) in calcium metabolism in the human body.<ref name="BoronBoulpaep2016">{{cite book|vauthors=Boron WF, Boulpaep EL|title=Medical Physiology E-Book|url=https://books.google.com/books?id=6QzhCwAAQBAJ|date=29 March 2016|publisher=Elsevier Health Sciences|isbn=978-1-4557-3328-6|access-date=9 April 2017|archive-date=19 March 2023|archive-url=https://web.archive.org/web/20230319220722/https://books.google.com/books?id=6QzhCwAAQBAJ|url-status=live}}</ref> The role of active vitamin D (1,25-dihydroxyvitamin D, calcitriol) is shown in orange.]]

The active vitamin D metabolite, calcitriol, mediatesexerts its biological effects by binding to the [[vitamin D receptor]] (VDR), which is principallyprimarily located in the [[Cell nucleus|nuclei]] of target cells.<ref name=lpi/><ref name=PKIN2020VitD /> TheWhen bindingcalcitriol of calcitriolbinds to the VDR, it allowsenables the VDRreceptor to act as a [[transcription factor]], that modulatesmodulating the [[gene expression]] of [[Transport protein|transport proteins]] involved in calcium absorption in the intestine, (such as [[TRPV6]] and [[calbindin]]), which are involved in calcium absorption in the intestine.<ref name=Bouillon2003>{{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 = 332–9 | date = February 2003 | pmid = 12520535 | doi = 10.1002/jcb.10360 | s2cid = 9853381 }}</ref> The vitaminVDR Dis receptorpart belongs toof the [[nuclear receptor]] superfamily of [[steroid hormone receptor|steroid/thyroid hormone receptors]], and VDRswhich are expressedhormone-dependent byregulators cellsof ingene mostexpression. [[organThese (biology)|organs]],receptors includingare theexpressed brain,in heart,cells skin,across gonads,most prostate and breastorgans.

VDRActivation activationof VDR in the intestine, bone, kidney, and [[parathyroid gland]] cells leadsplays toa thecrucial maintenancerole ofin [[Calcium homeostasis|maintaining calcium and phosphorus levels]] in the blood, (witha theprocess assistancethat ofis assisted by [[parathyroid hormone]] and [[calcitonin]]), andthereby to the maintenance ofsupporting [[bone contenthealth]].<ref name=lpi/><ref name="Holick 2004">{{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–88S | date = December 2004 | pmid = 15585788 | doi = 10.1093/ajcn/80.6.1678S | doi-access = free | title-link = doi }}</ref>

One of the most important rolesfunctions of vitamin D is to maintain skeletal calcium balance by promoting [[Calcium metabolism|calcium absorption]] in the intestines, promoting [[bone resorption]] by increasing [[osteoclast]] numbernumbers, maintaining [[calcium]] and [[phosphate]] levels necessary for [[bone formation]], and allowingfacilitating the proper functioningfunction of parathyroid hormone to maintainsustain serum calcium levels.<ref name=lpi/> [[Vitamin D deficiency]] can resultlead into lowerdecreased [[bone mineral density]], andincreasing an increasedthe risk of reduced bone density ([[osteoporosis]]) orand [[Fracture (bone)|bone fracturefractures]] becausedue ato lackits ofimpact vitamin D alterson mineral metabolism in the body.<ref name=lpi/><ref name="Bell">{{cite journal | vauthors = Bell TD, Demay MB, Burnett-Bowie SA | title = The biology and pathology of vitamin D control in bone | journal = Journal of Cellular Biochemistry | volume = 111 | issue = 1 | pages = 7–13 | date = September 2010 | pmid = 20506379 | pmc = 4020510 | doi = 10.1002/jcb.22661 }}</ref> ThusConsequently, vitamin D is also criticalimportant for [[bone remodeling]], through its roleacting as a potent stimulator of [[bone resorption]].<ref name=Bell/>

The VDR also regulates [[cell proliferation]] and [[cellularCellular differentiation|differentiation]]. VitaminAdditionally, vitamin D also affectsinfluences the immune system, andwith VDRs arebeing expressed in several [[white blood cell]]scells, including [[monocytemonocytes]]s and activated [[T cell|T]] and [[B cellcells]]s.<ref name="PDR">{{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 = 363–8 | date = May 2015 | pmid = 25741906 | doi = 10.1139/cjpp-2014-0352 }}</ref> In vitro, studies indicate that vitamin D increases the [[Expression (genetics)|expression]] of the [[tyrosine hydroxylase]] gene in [[adrenal]] [[Adrenal medulla|medullaadrenal medullary]]ry cells, and affects the synthesis of [[neurotrophic factorfactors]]s, [[nitric oxide synthase]], and [[glutathione]], which may control the body's response and adaption to [[Stress (biology)|stress]].<ref name="pmid9011759">{{cite journal | vauthors = Puchacz E, Stumpf WE, Stachowiak EK, Stachowiak MK | title = Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells | journal = Brain Research. Molecular Brain Research | volume = 36 | issue = 1 | pages = 193–6 | date = February 1996 | pmid = 9011759 | doi = 10.1016/0169-328X(95)00314-I }}</ref>

Vitamin D receptorVDR expression decreases with age.<ref name=lpi/>

A diet with insufficient in vitamin D, in conjunctioncombined with inadequate sunsunlight exposure, can lead causesto vitamin D deficiency, which is defined as a blood 25-hydroxyvitamin D or 25(OH)D level below 12{{nbsp}} ng/mL (30{{nbsp}} nmol/liter),. whereas vitaminVitamin D insufficiency, on the other hand, is characterized by a blood 25(OH)D level ofbetween 12–20{{nbsp}} ng/mL (30–50{{nbsp}} nmol/liter).<ref name=ods/><ref name=holick2011>{{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 = 1911–30 | date = July 2011 | pmid = 21646368 | doi = 10.1210/jc.2011-0385 | doi-access = free | title-link = doi }}</ref> AnIt is estimated that one billion adults worldwide are either vitamin D insufficient or deficient,<ref name="Holick_2007">{{citeincluding journal | vauthors = Holick MF | title = Vitamin D deficiency | journal = The New England Journal of Medicine | volume = 357 | issue = 3 | pages = 266–81 | date = July 2007 | pmid = 17634462 | doi = 10.1056/NEJMra070553 | s2cid = 18566028 }}</ref> includingthose in developed countries inacross Europe.<ref>{{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 = 1033–44 | date = April 2016 | pmid = 26864360 | pmc = 5527850 | doi = 10.3945/ajcn.115.120873 }}</ref> Severe vitamin D deficiency in children, aalthough rare disease in the developed world, causescan cause a softening and weakening of growing bones, andleading to a condition calledknown as [[rickets]].<ref>{{cite web |date=8 March 2012 |title=Rickets |publisher=[[National Health Service]] |url=http://www.nhs.uk/conditions/Rickets/Pages/Introduction.aspx |access-date=9 July 2012 |archive-date=11 October 2017 |archive-url=https://web.archive.org/web/20171011165432/http://www.nhs.uk/Conditions/Rickets/Pages/Introduction.aspx |url-status=live }}</ref>

Vitamin D deficiency is foundprevalent worldwideglobally, inparticularly among the elderly, and remains common in both children and adults.<ref>{{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 |date=February title2016 |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 |pmc=4880117 |pmid=26745253}}</ref><ref name="pmid12014847">{{cite journal | vauthors = Eriksen EF, Glerup H |year=2002 |title = Vitamin D deficiency and aging: implications for general health and osteoporosis | journal = Biogerontology | volume = 3 | issue=1–2 |pages=73–7 1–2|doi=10.1023/A:1015263514765 |pmid=12014847 pages|s2cid=22112344}}</ref><ref name="Holick_2007">{{cite 73–7journal |vauthors=Holick yearMF |date=July 20022007 |title=Vitamin pmidD deficiency |journal=The 12014847New England Journal of Medicine |volume=357 doi|issue=3 |pages=266–81 |doi=10.10231056/A:1015263514765NEJMra070553 |pmid=17634462 |s2cid = 22112344 18566028}}</ref><ref name="Holick_2007"/>This Deficiencydeficiency results in impairedimpairs [[bone mineralization]] and causes bone damage, which leadsleading to bone-softening diseases, such as rickets in children and osteomalacia in adults.<ref name="Brown_2008">{{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}}</ref> including rickets in children and [[osteomalacia]] in adults. Low blood calcifediol (25-hydroxy-vitaminhydroxyvitamin D₃) levels can result from avoidinglimited thesun sunexposure.<ref name="pmid18234141">{{cite journal | vauthors = Schoenmakers I, Goldberg GR, Prentice A | title = Abundant sunshine and vitamin D deficiency | journal = The British Journal of Nutrition | volume = 99 | issue = 6 | pages = 1171–3 | date = June 2008 | pmid = 18234141 | pmc = 2758994 | doi = 10.1017/S0007114508898662 }}</ref> BeingWhen deficientvitamin inD Vitaminlevels Dare can causedeficient, the total absorption of dietary calcium tocan falldecrease from the normal fractionrange (betweenof 60 and 80 percent)60–80% to as little as 15 percent%.<ref name="Holick 2004" />

Dark-skinned peopleindividuals living in temperate climates haveare beenmore shownlikely to have low vitamin D levels.<ref name="pmid28620422">{{cite journal | vauthors = Lowe NM, Bhojani I |date=June 2017 |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 = 137–44 | date doi= June 201710.1177/1759720X17704430 | pmid = 28620422 | pmc = 5466148 | doi pmid= 10.1177/1759720X17704430 28620422}}</ref><ref name="pmid24267433">{{cite journal | vauthors = O'Connor MY, Thoreson CK, Ramsey NL, Ricks M, Sumner AE |year=2013 |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 = 261–9 | year = 2013 | pmid = 24267433 | pmc = 3894250 | doi = 10.1016/j.pcad.2013.10.015 |pmc=3894250 |pmid=24267433}}</ref><ref name="pmid22688752">{{cite journal | vauthors = Freedman BI, Register TC |date=June title2012 |title= Effect of race and genetics on vitamin D metabolism, bone and vascular health | journal = Nature Reviews. Nephrology | volume = 8 | issue = 8 | pages = 459–66 | date = June 2012 | pmid = 22688752 | doi = 10.1038/nrneph.2012.112 | pmc = 10032380 |pmid=22688752 |s2cid = 29026212 }}</ref> Dark-skinnedThis peopleis arebecause less[[melanin]] efficientin atthe makingskin, which hinders vitamin D becausesynthesis, melaninmakes indark-skinned theindividuals skinless hindersefficient at producing vitamin D synthesis.<ref name="pmid28467404">{{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 = 444–51 | date = September 2017 | pmid = 28467404 | pmc = 5570640 | doi = 10.1038/pr.2017.114 }}</ref> VitaminIn the U.S., vitamin D deficiency is particularly common inamong Hispanic and African-AmericansAmerican in the United Statespopulations, with levels dropping significantly in the winter.<ref name=holick2011/> This is due to the levels of melanin in the skin, as it acts as amelanin’s naturalprotective protectanteffect fromagainst sun exposure.<ref name=holick2011/>

Vitamin D deficiency ishas also been associated with an increased risk of development ofdeveloping various types of cancer, including [[melanoma]].<ref name="pmid38672780">{{cite journal |vauthors=Ben-Eltriki M, Gayle EJ, Paras JM, Nyame-Addo L, Chhabra M, Deb S |title=Vitamin D in Melanoma: Potential Role of Cytochrome P450 Enzymes |journal=Life (Basel) |volume=14 |issue=4 |date=April 2024 |page=510 |pmid=38672780 |doi=10.3390/life14040510|doi-access=free |pmc=11050855 |bibcode=2024Life...14..510B }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref>

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. Rickets typically appearsappear between 3 and 18 months of age.<ref name=Wagner2008>{{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 = 1142–52 |date = November 2008 |pmid = 18977996 |doi = 10.1542/peds.2008-1862 |doi-access = | title-link = doi |s2cid = 342161 }}</ref> Cases continue to be reported in North American and other Western Countries and is primarily seen in breastfed infants and those with darker skin complexions.<ref name=Wagner2008/> This condition is characterized by bow legs,<ref name="Brown_2008"/> which can be caused by calcium or phosphorus deficiency, as well as a lack of vitamin D; in the 21st century, it is largely found in low-income countries in Africa, Asia, or the Middle East<ref name="pmid17943890">{{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 |issue = 4 |pages = CD006164 |date = October 2007 |volume = 2010 |pmid = 17943890 |doi = 10.1002/14651858.CD006164.pub2 |pmc = 8990776 |veditors = Lerch C }}</ref> and in those with genetic disorders such as pseudo-vitamin-D-deficiency rickets.<ref>{{cite journal |vauthors = Zargar AH, Mithal A, Wani AI, Laway BA, Masoodi SR, Bashir MI, Ganie MA |title = Pseudovitamin D deficiency rickets—a report from the Indian subcontinent |journal = Postgraduate Medical Journal |volume = 76 |issue = 896 |pages = 369–72 |date = June 2000 |pmid = 10824056 |pmc = 1741602 |doi = 10.1136/pmj.76.896.369 }}</ref>

[[Osteomalacia]] is a disease in adults that results from vitamin D deficiency.<ref name=lpi/> Characteristics of this disease are softening of the bones, leading to bending of the spine, [[Anatomical terms of location#Proximal and distal|proximal]] muscle weakness, bone fragility, and increased risk for fractures.<ref name=lpi/> Osteomalacia reduces calcium absorption and increases calcium loss from bone, which increases the risk for bone fractures. Osteomalacia is usually present when 25-hydroxyvitamin D levels are less than about 10{{nbsp}}ng/mL.<ref name="Holick_2006">{{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 = 353–73 | date = March 2006 | pmid = 16529140 | doi = 10.4065/81.3.353 | doi-access = free | title-link = doi }}</ref> Although the effects of osteomalacia are thought to contribute to chronic [[musculoskeletal]] [[pain]], there is no persuasive evidence of lower vitamin D levels in people with chronic pain<ref>{{cite journal | vauthors = Straube S, Andrew Moore R, Derry S, McQuay HJ | title = Vitamin D and chronic pain | journal = Pain | volume = 141 | issue = 1–2 | pages = 10–3 | date = January 2009 | pmid = 19084336 | doi = 10.1016/j.pain.2008.11.010 | s2cid = 17244398 }}</ref> or that supplementation alleviates chronic nonspecific musculoskeletal pain.<ref>{{cite journal | vauthors = Gaikwad M, Vanlint S, Mittinity M, Moseley GL, Stocks N | title = Does vitamin D supplementation alleviate chronic nonspecific musculoskeletal pain? A systematic review and meta-analysis | journal = Clinical Rheumatology | volume = 36 | issue = 5 | pages = 1201–08 | date = May 2017 | pmid = 26861032 | doi = 10.1007/s10067-016-3205-1 | url = https://www.researchgate.net/publication/293637550 | s2cid = 30189971 }}</ref> 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.<ref name="ods"/>

Vitamin D₃ supplementation has been tentatively found to lead to a reduced risk of death in the elderly,<ref name=Bj2014/><ref name=Aut2013/> but the effect has not been deemed pronounced, or certain enough, to make taking supplements recommendable.<ref name=Futil2014/> Other forms (vitamin D₂, alfacalcidol, and calcitriol) do not appear to have any beneficial effects with regard to the risk of death.<ref name=Bj2014>{{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 = 1 | issue = 1 | pages = CD007470 | date = January 2014 | pmid = 24414552 | doi = 10.1002/14651858.CD007470.pub3 | type = Systematic review | pmc = 11285307 }}</ref> High blood levels appear to be associated with a lower risk of death, but it is unclear if supplementation can result in this benefit.<ref>{{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 }}</ref> Both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging.<ref>{{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 }}</ref><ref>{{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 = S278–86 | date = December 2009 | pmid = 19660871 | doi = 10.1016/j.psyneuen.2009.07.003 | s2cid = 17462970 }}</ref><ref name="pmid20590845">{{cite journal | vauthors = Manya H, Akasaka-Manya K, Endo T | title = Klotho protein deficiency and aging | journal = Geriatrics & Gerontology International | volume = 10 | issue = Suppl 1 | pages = S80-7 | date = July 2010 | pmid = 20590845 | doi = 10.1111/j.1447-0594.2010.00596.x | s2cid = 36692930 | doi-access = free | title-link = doi }}</ref> 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.<ref name="Ross_2011"/> Harm from vitamin D appears to occur at a lower vitamin D level in the blackdark populationskinned Canadian and United States populations which have been studied than in the whitelight skinned Canadian and United States populations which have been studied. Whether this is so with dark skinned populations in other parts of the world is populationunknown.<ref name="Ross_2011" />{{rp|435}}

Potential associations have been found between low vitamin D levels and the risk of developing several types of cancer.<ref name="pmid38672780"/><ref name="Zhao">{{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 }}</ref><ref name="Hernandez-Alonso">{{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 | pages = 1–17 | date = July 2021 | volume = 63 | issue = 1 | pmid = 34224246 | doi = 10.1080/10408398.2021.1939649 | s2cid = 235746547 | hdl = 10609/136992 | hdl-access = free }}</ref> Meta-analyses of [[observational study|observational studies]] have found reduced risk of cancer incidence related to vitamin D intake and 25(OH)D levels, particularly for [[colorectal cancer]], although the strength of the associations was classified as weak.<ref name=Hernandez-Alonso/><ref name="pmid33553987">{{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 }}</ref> [[Vitamin D receptor]] and [[SNAI2]] are found to be involved in the [[metastasis|metastastic]] process of [[osteosarcoma]].<ref>{{cite journal |vauthors=Seraphin G, Rieger S, Hewison M, Capobianco E, Lisse TS |title=The impact of vitamin D on cancer: A mini review |journal=J Steroid Biochem Mol Biol |volume=231 |issue= |pages=106308 |date=July 2023 |pmid=37054849 |doi=10.1016/j.jsbmb.2023.106308|pmc=10330295 |pmc-embargo-date=July 1, 2024 }}</ref> While [[randomized controlled trial]]s have not confirmed that vitamin D supplements reduce the risk of cancer incidence, the relative risk of cancer deaths was lower by up to 16% in several meta-analyses.<ref name="Keum">{{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 | doi = 10.1093/annonc/mdz059| pmc=6821324 }}</ref><ref name="pmid33553987" />

Vitamin D supplementation is not associated with a reduced risk of stroke, [[cerebrovascular disease]], [[myocardial infarction]], or [[coronary artery disease|ischemic heart disease]].<ref name=Futil2014>{{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 = 307–20 | date = April 2014 | pmid = 24703049 | doi = 10.1016/S2213-8587(13)70212-2 | type = Meta-analysis }}</ref><ref>{{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 = 765–76 | date = August 2019 | pmid = 31215980 | pmc = 6584896 | doi = 10.1001/jamacardio.2019.1870 }}</ref><ref>{{Cite journal |vauthors=Nudy M, Krakowski G, Ghahramani M, Ruzieh M, Foy AJ |year=2020 |title=Vitamin D supplementation, cardiac events and stroke: A systematic review and meta-regression analysis |journal=Int J Cardiol Heart Vasc |volume=28 |pages=100537 |doi=10.1016/j.ijcha.2020.100537 |pmid=32462077|pmc=7240168 }}</ref> Supplementation does not lower [[blood pressure]] in the general population.<ref>{{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 = 745–54 | date = May 2015 | pmid = 25775274 | pmc = 5966296 | doi = 10.1001/jamainternmed.2015.0237}}</ref><ref>{{Cite journal |vauthors=Zhang D, Cheng C, Wang Y, Sun H, Yu S, Xue Y, Liu Y, Li W, Li X |year=2020 |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=Prev Chronic Dis |volume=17 |pages=E03 |doi=10.5888/pcd17.190307 |pmid=31922371|pmc=6977781 }}</ref><ref>{{cite journal|vauthors=Abboud M, Al Anouti F, Papandreou D|year=2021|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|pmid=33618764|doi=10.1186/s13643-021-01584-x|pmc=7898425 |doi-access=free }}</ref>

There is some evidence that vitamin D supplementation therapy for people with inflammatory bowel disease may be associated with improvements in scores for clinical inflammatory bowel disease activity and biochemical markers.<ref>{{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 | date = May 2020 | volume = 26 | issue = 12 | pages = 1819–1830 | pmid = 32385487 | doi = 10.1093/ibd/izaa087 }}</ref><ref name="Wallace_2023" /> Vitamin D treatment may be associated with less frequent relapse of symptoms in IBD.<ref name="Wallace_2023" /> It is not clear if this treatment improves the person's quality of life or what the clinical response to vitamin D treatment.<ref name="Wallace_2023" /> The ideal treatment regime and dose of vitamin D therapy has not been well enough studied.<ref name="Wallace_2023" />

A meta-analysis of observational studies showed that children with [[Attention deficit hyperactivity disorder|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.<ref>{{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 | doi-access = free | title-link = doi }}</ref> Several small, randomized controlled trials of vitamin D supplementation indicated improved ADHD symptoms such as impulsivity and hyperactivity.<ref>{{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 = 670–87 | date = November 2019 | pmid = 31368773 | doi = 10.1089/cap.2019.0059 | s2cid = 199054851 }}</ref>

A systematic review of clinical studies found an association between low vitamin D levels with [[cognitive deficit|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.<ref name="pmid23008220">{{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 = 1397–405 | date = September 2012 | pmid = 23008220 | pmc = 3448747 | doi = 10.1212/WNL.0b013e31826c197f }}</ref>

Though hypothesized that vitamin D supplementation may be an effective treatment for [[obesity]] apart from [[calorie restriction]], one systematic review found no association of supplementation with body weight or [[adipose tissue|fat mass]].<ref>{{cite journal | vauthors = Pathak K, Soares MJ, Calton EK, Zhao Y, Hallett J | title = Vitamin D supplementation and body weight status: a systematic review and meta-analysis of randomized controlled trials | journal = Obesity Reviews | volume = 15 | issue = 6 | pages = 528–37 | date = June 2014 | pmid = 24528624 | doi = 10.1111/obr.12162 | s2cid = 8660739 }}</ref> A 2016 meta-analysis found that circulating vitamin D status was improved by weight loss, indicating that fat mass may be inversely associated with blood levels of vitamin D.<ref name="mallard">{{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 | doi-access = free | title-link = doi }}</ref>

Various institutions have proposed different recommendations for the amount of [[Reference Daily Intake|daily intake]]<ref>{{Cite web |title=Office of Dietary Supplements – Vitamin D |url=https://ods.od.nih.gov/factsheets/VitaminD-Consumer/ |access-date=14 April 2022 |website=National Institutes of Health Office of Dietary Supplements |archive-date=23 July 2020 |archive-url=https://web.archive.org/web/20200723193356/https://ods.od.nih.gov/factsheets/VitaminD-Consumer/ |url-status=live }} {{PD-notice}}</ref> of vitamin D. These vary according to precise definition, age, pregnancy or lactation, and the extent assumptions are made regarding skin synthesis of vitamin D.<ref name = "NHSVDRoss_2011" /><ref name="Ross_2011AusNZ"/><ref name = "HCanadaNHSVD" /><ref name="AusNZHCanada"/><ref name="EFSA-vitD"/>

Although vitamin D is present naturally in only a few foods,<ref name="ods" /> it is commonly [[food additive|added]] as a [[Food fortification|fortification]] in manufactured foods. In some countries, staple foods are [[Food fortification|artificially fortified]] with vitamin D.<ref name="IoM250">{{cite book |title=DRI, Dietary reference intakes: for calcium, phosphorus, magnesium, vitamin D, and fluoride |publisher=National Academy Press |location=Washington, D.C. |year=1997 |pages=250 |isbn=978-0-309-06350-0 |url=http://www.nap.edu/openbook.php?isbn=0-309-06350-7&page=250 |doi=10.17226/5776 |pmid=23115811 |author1=Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes |access-date=11 April 2010 |archive-date=2 April 2015 |archive-url=https://web.archive.org/web/20150402201104/http://www.nap.edu/openbook.php?isbn=0-309-06350-7&page=250 |url-status=live }}</ref>

| rowspan="2" | ''[[Cladonia|Cladonia arbuscula]]'' (lichen), [[thallus|thalli]], dry<ref name="pmid11693362">{{cite journal | vauthors = Wang T, Bengtsson G, Kärnefelt I, Björn LO | title = Provitamins and vitamins D₂and D₃in Cladina spp. over a latitudinal gradient: possible correlation with UV levels | journal = Journal of Photochemistry and Photobiology B: Biology | volume = 62 | issue = 1–2 | pages = 118–22 | date = September 2001 | pmid = 11693362 | doi = 10.1016/S1011-1344(01)00160-9 | url = http://lup.lub.lu.se/record/133512 | type = | access-date = 31 October 2018 | archive-date = 28 May 2020 | archive-url = https://web.archive.org/web/20200528231009/https://lup.lub.lu.se/search/publication/133512 | url-status = live }}</ref>

* 240 μg/day (10k IU), over 5 months have been showshown not to cause toxicity.<ref name="Holick_2007" />

* Over 18% of the population exceeds the [[National Institutes of Health|NIH]] daily recommended allowance ([[Recommended Daily Allowance|RDA]]) of 600–800 IU,<ref name="ods" /> by taking over 1000 IU, which suggests intentional supplement intake.<ref name="Rooney_2017">{{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 | doi = 10.1001/jama.2017.4392 | pmc = 5587346 }}</ref>

[[File:Vitamin D biosynthesis in fungi and animals.svg|thumb|upright=1.35|class=skin-invert-image|The photochemistry of vitamin D biosynthesis in animal and fungi]]

[[File:Calcitriol-Biosynthese 2.svg|thumb|upright=1.35|class=skin-invert-image|Thermal isomerization of [[previtamin D3|previtamin{{nbsp}}D₃]] to vitamin D₃]]

The skin consists of two primary layers: the inner layer called the [[dermis]], and the outer, thinner [[epidermis (skin)|epidermis]]. Vitamin D is produced in the [[keratinocytes]] of two innermost strata of the epidermis, the stratum basale and stratum spinosum, which also are able to produce calcitriol and express the VDR.<ref name="Bikle2010">{{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 }}</ref>

Vitamin D₃ (cholecalciferol) is produced industrially by exposing [[7-dehydrocholesterol]] to UVB and UVC light, followed by purification.<ref name="Holick05">{{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–48S2739S–2748S | date = November 2005 | pmid = 16251641 | doi = 10.1093/jn/135.11.2739S | url = http://jn.nutrition.org/content/135/11/2739S.full.pdf | access-date = 24 November 2011 | url-status = live | 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 | doi-access = free | title-link = doi | doi-access-date = 24 November 2011 | archive-date = 18 November 2017free | archive-url = https://web.archive.org/web/20171118043538/http://jn.nutrition.org/content/135/11/2739S.full.pdf | urlarchive-statusdate = live18 November 2017 }}</ref><ref name="keegan" /> The 7-dehydrocholesterol is a natural substance in fish organs, especially the liver,<ref>{{cite journal | vauthors = Takeuchi A, Okano T, Sayamoto M, Sawamura S, Kobayashi T, Motosugi M, Yamakawa T | title = Tissue distribution of 7-dehydrocholesterol, vitamin D3 and 25-hydroxyvitamin D3 in several species of fishes | journal = Journal of Nutritional Science and Vitaminology | volume = 32 | issue = 1 | pages = 13–22 | date = February 1986 | pmid = 3012050 | doi = 10.3177/jnsv.32.13 | url = https://www.jstage.jst.go.jp/article/jnsv1973/32/1/32_1_13/_pdf | doi-access-date = free20 August 2019 | titleurl-linkstatus = doilive | accesstitle-datelink = 20 August 2019doi | archivedoi-dateaccess = 1 November 2018free | archive-url = https://web.archive.org/web/20181101013656/https://www.jstage.jst.go.jp/article/jnsv1973/32/1/32_1_13/_pdf | urlarchive-statusdate = live1 November 2018 }}</ref> in wool grease ([[lanolin]]) from sheep and in some plants,<ref>{{cite likejournal | 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 }}</ref> and lichen ([[Cladonia rangiferina]]).<ref>{{cite journal |last1 vauthors = Göring |first1=HorstH | title = Vitamin D in Nature: A Product of Synthesis and/or Degradation of Cell Membrane Components |url=https://www.researchgate.net/publication/328961025 |date=November 2018 |journal =Biokhimiya (Moscow)Biochemistry. Biokhimiia | volume = 83 | issue = 11 | pages = 1350–1357 | date = November 2018 | pmid = 30482146 | doi = 10.1134/S0006297918110056 |pmid=30482146 |s2cid=53437216 |access-date=2 December53437216 2023}}</ref><ref name="Björn Wang 2000 pp. 26–32">{{cite journal |last1=JäpeltBjörn |first1=RieL. BO. |last2=JakobsenWang |first2=JetteT. |date=2000 |title=Vitamin D in plants:an aecological review of occurrence, analysis, and biosynthesiscontext |journal=FrontiersInternational inJournal Plantof ScienceCircumpolar |date=May 2013Health |volume=459 |pageissue=1361 |doipages=10.3389/fpls.2013.0013626–32 |pmidissn=237173181239-9736 |pmcpmid=3651966 |doi-access=free 10850004}}</ref> Vitamin D₂ (ergocalciferol) is produced in a similar way using ergosterol from yeast or mushrooms as a starting material.<ref name="Holick05"/><ref name=keegan/>

[[File:Cholecalciferol_to_calcidiol_CH3.svg|thumb|upright=1.35|class=skin-invert-image|Liver hydroxylation of [[cholecalciferol]] to [[calcifediol]] ]]

[[File:Calcidiol_to_calcitriol_CH3.svg|thumb|upright=1.35|class=skin-invert-image|Kidney hydroxylation of calcifediol to [[calcitriol]] ]]

Whether synthesized in the skin or ingested, vitamin D is [[hydroxylated]] in the [[liver]] at position 25 (upper right of the molecule) to form 25-hydroxycholecalciferol (calcifediol or 25(OH)D).<ref name=Bikle /> This reaction is catalyzed by the [[Microsome|microsomal]] enzyme [[vitamin D 25-hydroxylase]], the product of the ''CYP2R1'' human gene, and expressed by [[hepatocytes]].<ref>{{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 = 7711–5 | date = May 2004 | pmid = 15128933 | pmc = 419671 | doi = 10.1073/pnas.0402490101 | bibcode = 2004PNAS..101.7711C | doi-access = free | title-link = doi }}</ref> Once made, the product is released into the [[blood plasma|plasma]], where it is bound to an α-globulin carrier protein named the [[vitamin D-binding protein]].<ref>{{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 }}</ref>

In 1925,<ref name="Wolf_2004"/> it was established that when 7-dehydrocholesterol is irradiated with light, a form of a [[fat-soluble]] substance is produced (now known as D₃). [[Alfred Fabian Hess]] stated: "Light equals vitamin D."<ref>{{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 }}</ref> [[Adolf Otto Reinhold Windaus|Adolf Windaus]], at the [[University of Göttingen]] in Germany, received the [[Nobel Prize in Chemistry]] in 1928 for his work on the constitution of sterols and their connection with vitamins.<ref>{{cite web |url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1928/windaus-bio.html |title=Adolf Windaus&nbsp;– 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 }}</ref> In 1929, a group at [[National Institute for Medical Research|NIMR]] in Hampstead, London, were working on the structure of vitamin D, which was still unknown, as well as the structure of steroids. A meeting took place with [[J.B.S. Haldane]], [[John Desmond Bernal|J.D. Bernal]], and [[Dorothy Hodgkin|Dorothy Crowfoot]] to discuss possible structures, which contributed to bringing a team together. X-ray crystallography demonstrated the sterol molecules were flat, not as proposed by the German team led by Windaus. In 1932, Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids which found immediate acceptance.<ref>{{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}}</ref> The informal academic collaboration between the team members [[Robert Benedict Bourdillon]], Otto Rosenheim, Harold King, and [[Kenneth Callow]] was very productive and led to the isolation and characterization of vitamin D.<ref>{{ 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 }}</ref> At this time, the policy of the [[Medical Research Council (United Kingdom)|Medical Research Council]] was not to patent discoveries, believing the results of medical research should be open to everybody. In the 1930s, Windaus clarified further the chemical structure of vitamin D.<ref name=Hirsch2011>{{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 }}</ref>

In 1969, a specific binding protein for vitamin D called the [[calcitriol receptor|vitamin D receptor]] was identified.<ref>{{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 = 155–62 | date = January 1969 | pmid = 5253652 | pmc = 285968 | doi = 10.1073/pnas.62.1.155 | bibcode = 1969PNAS...62..155H | doi-access = free | title-link = doi }}</ref> Shortly thereafter, the conversion of vitamin D to calcifediol and then to calcitriol, the biologically active form, was confirmed.<ref name="pmid4323790">{{cite journal | vauthors = Holick MF, Schnoes HK, DeLuca HF | title = Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D₃ metabolically active in the intestine | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 68 | issue = 4 | pages = 803–4 | date = April 1971 | pmid = 4323790 | pmc = 389047 | doi = 10.1073/pnas.68.4.803 | bibcode = 1971PNAS...68..803H | doi-access = free | title-link = doi }}</ref><ref name="pmid4325863">{{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 = 51–4 | date = July 1971 | pmid = 4325863 | doi = 10.1126/science.173.3991.51 | s2cid = 35236666 | bibcode = 1971Sci...173...51N }}</ref><ref>{{cite journal | vauthors = Holick MF, DeLuca HF, Avioli LV | title = Isolation and identification of 25-hydroxycholecalciferol from human plasma | journal = Archives of Internal Medicine | volume = 129 | issue = 1 | pages = 56–61 | date = January 1972 | pmid = 4332591 | doi = 10.1001/archinte.1972.00320010060005 }}</ref> The photosynthesis of vitamin D₃ in skin via previtamin D₃ and its subsequent metabolism was described in 1980.<ref>{{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 = 203–5 | date = October 1980 | pmid = 6251551 | doi = 10.1126/science.6251551 | bibcode = 1980Sci...210..203H | jstor = 1685024 }}</ref>

Fish do not synthesise vitamin D in a natural setting and rely on dietary sources. As with mammals, vitamin D₃ is more bioavailable than vitamin D₂.<ref name="Cheng-2023">{{Cite journal |last1 vauthors = Cheng |first1=KeK, |last2=Huang |first2=YanqingY, |last3=Wang |first3=ChunfangC, |last4=Ali |first4=WajeehaW, |last5=Karrow |first5=Niel A.NA |date=September 2023 |title=Physiological function of vitamin D 3 in fish |url=https://onlinelibrary.wiley.com/doi/10.1111/raq.12814 |journal=Reviews in Aquaculture |language=en |volume=15 |issue=4 |pages=1732–1748 |doi=10.1111/raq.12814 |bibcode=2023RvAq...15.1732C |issn=1753-5123}}</ref> Unlike mammals, both hydroxylation steps from vitamin D₃ to the active form 1,25 hydroxyvitamin D₃ occur in the liver, so plasma levels of 25 hydroxyvitamin D₃ is not an accurate measure of vitamin D₃ levels.<ref name="Cheng-2023" />