Vitamin D: Difference between revisions

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'''Vitamin D''' is a [[steroid]] and is [[vitamin]] that "includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone."<ref>{{MeSH}}</ref>
'''Vitamin D''' is a [[steroid]] and a [[vitamin]] that "includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone."<ref>{{MeSH}}</ref>


Vitamin D serves two classes of functions: (a) an '''endocrine''' function, in which a form of vitamin D, calcitriol, produced in the kidneys and secreted into the bloodstream, acts on target organs (gastrointestinal tract, bone, parathyroid glands) in such a way as to regulate aspects of calcium and phosphorus metabolism important to bone health and homeostasis of circulating calcium and phosphorus concentrations; and, (b) an '''autocrine''' function, in which the cells of numerous organs and tissues in the body (e.g., parts of the immune system, various epithelial tissues) generate calcitriol that functions in the cells that generate it, in intracellular signaling pathways (e.g., facilitation of the expression of specific genes) important to optimal functioning of those cells.<ref name=heaneycjasn>Heaney RP. (2008) [http://dx.doi.org/ 10.2215/CJN.01160308 Vitamin D in Health and Disease.] ''Clin. J. Am. Soc. Nephrol.'' (first published online June 4, 2008)</ref>  The autocrine mechanisms account for the preponderance of vitamin D utilized by body each day, and therefore tends to set the daily requirement for vitamin D.<ref name=heaneycjasn/>
Vitamin D serves two classes of functions: (a) an '''endocrine''' function, in which a form of vitamin D, calcitriol, produced in the kidneys and secreted into the bloodstream, acts on target organs (gastrointestinal tract, bone, parathyroid glands) in such a way as to regulate aspects of calcium and phosphorus [[metabolism]] important to bone health and homeostasis of circulating calcium and phosphorus concentrations; and, (b) an '''autocrine''' function, in which the cells of numerous organs and tissues in the body (e.g., parts of the immune system, various epithelial tissues) generate calcitriol that functions in the cells that generate it, in intracellular signaling pathways (e.g., facilitation of the expression of specific genes) important to optimal functioning of those cells.<ref name=heaneycjasn>Heaney RP. (2008) [http://dx.doi.org/ 10.2215/CJN.01160308 Vitamin D in Health and Disease.] ''Clin. J. Am. Soc. Nephrol.'' (first published online June 4, 2008)</ref>  The autocrine mechanisms account for the preponderance of vitamin D utilized by body each day, and therefore tends to set the daily requirement for vitamin D.<ref name=heaneycjasn/>


==Biochemistry==
==Biochemistry==
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Vitamin D<sub>2</sub> and vitamin D<sub>3</sub> are hydroxylated in the liver at the 25 position.<ref name="isbn0-8385-3684-0p645"/> This leads to calcitriol (1,25-Dihydroxyvitamin D3). Calcitriol is the "physiologically active form of vitamin D. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption."<ref>{{MeSH|Calcitriol}}</ref>
Vitamin D<sub>2</sub> and vitamin D<sub>3</sub> are hydroxylated in the liver at the 25 position.<ref name="isbn0-8385-3684-0p645"/> This leads to calcitriol (1,25-Dihydroxyvitamin D3). Calcitriol is the "physiologically active form of vitamin D. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption."<ref>{{MeSH|Calcitriol}}</ref>
Genetic variation in the vitamin D–binding protein level can affect the serum levels. "The T allele at rs7041 was associated with decreased levels of total 25-hydroxyvitamin D among blacks. In whites, the A allele at rs4588 was associated with decreased levels of total 25-hydroxyvitamin D."<ref>Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, et al. Vitamin D–Binding Protein and Vitamin D Status of Black Americans and White Americans. New England Journal of Medicine. 2013;369(21):1991–2000. {{doi|10.1056/NEJMoa1306357}}</ref>


==Deficiency==
==Deficiency==
Low levels of vitamin D are common in medical inpatients<ref name="pmid9504937">{{cite journal |author=Thomas MK, Lloyd-Jones DM, Thadhani RI, ''et al'' |title=Hypovitaminosis D in medical inpatients |journal=N. Engl. J. Med. |volume=338 |issue=12 |pages=777–83 |year=1998 |pmid=9504937 |doi=}}</ref> and some populations of patients with widespread musculoskeletal pain like fibromyalgia<ref name="pmid14661675">{{cite journal |author=Plotnikoff GA, Quigley JM |title=Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain |journal=Mayo Clin. Proc. |volume=78 |issue=12 |pages=1463–70 |year=2003 |pmid=14661675 |doi=}}</ref>.<ref name="pmid18331295">{{cite journal |author=Hicks GE, Shardell M, Miller RR, ''et al'' |title=Associations between vitamin D status and pain in older adults: the Invecchiare in Chianti study |journal=J Am Geriatr Soc |volume=56 |issue=5 |pages=785–91 |year=2008 |month=May |pmid=18331295 |doi=10.1111/j.1532-5415.2008.01644.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0002-8614&date=2008&volume=56&issue=5&spage=785 |issn=}}</ref> However, more recent studies make the associated between Vitamin D and non-specific pain doubtful.<ref name="pmid18431091">{{cite journal |author=Warner AE, Arnspiger SA |title=Diffuse musculoskeletal pain is not associated with low vitamin D levels or improved by treatment with vitamin D |journal=J Clin Rheumatol |volume=14 |issue=1 |pages=12–6 |year=2008 |month=February |pmid=18431091 |doi=10.1097/RHU.0b013e31816356a9 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00124743-200802000-00003 |issn=}}</ref><ref name="pmid18431091">{{cite journal |author=Warner AE, Arnspiger SA |title=Diffuse musculoskeletal pain is not associated with low vitamin D levels or improved by treatment with vitamin D |journal=J Clin Rheumatol |volume=14 |issue=1 |pages=12–6 |year=2008 |month=February |pmid=18431091 |doi=10.1097/RHU.0b013e31816356a9 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00124743-200802000-00003 |issn=}}</ref>
{{main|Vitamin D deficiency}}
 
==Administration==
The best treatment may be calciferol (ergocalciferol or colecalciferol).<ref name="pmid20064851">{{cite journal| author=Pearce SH, Cheetham TD| title=Diagnosis and management of vitamin D deficiency. | journal=BMJ | year= 2010 | volume= 340 | issue=  | pages= b5664 | pmid=20064851 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&[email protected]&retmode=ref&cmd=prlinks&id=20064851 | doi=10.1136/bmj.b5664 }} </ref> For every 100 IU of vitamin D taken, the serum level rises about 1 ng/ml.<ref name="doi10.1056/NEJMcp1009570">{{Cite journal | doi = 10.1056/NEJMcp1009570 | issn = 0028-4793 | volume = 364 | issue = 3 | pages = 248-254 | last = Rosen | first = Clifford J. | title = Vitamin D Insufficiency
| journal = New England Journal of Medicine | date = 2011-01-20 }}</ref>&nbsp;For 1000 IU daily, a [[randomized controlled trial]] found that consuming orange juice fortified with either vitamin D<sub>3</sub> or vitamin D<sub>2</sub> was not significantly different than consuming the corresponding capsules of the vitamins in respect of increasing 25-hydroxyvitamin D blood levels.<ref>Biancuzzo RM, Young A, Bibuld D et al. (2010) [http://dx.doi.org/10.3945/ajcn.2009.27972 Fortification of orange juice with vitamin D2 or vitamin D3 is as effective as an oral supplement in maintaining vitamin D status in adults]. ''The American Journal of Clinical Nutrition'' 91:1621-6.</ref>
 
In a prior study of healthy adults, Vitamin D<sub>2</sub> and vitamin D<sub>3</sub> are equally effective in maintaining serum 25-hydroxyvitamin D levels.<ref name="pmid18089691">{{cite journal |author=Holick MF, Biancuzzo RM, Chen TC, ''et al'' |title=Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D |journal=J. Clin. Endocrinol. Metab. |volume=93 |issue=3 |pages=677-81 |year=2008 |pmid=18089691 |doi=10.1210/jc.2007-2308 |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=18089691}}</ref>
 
==Clinical uses==
[[Clinical practice guideline]]s by the [http://www.endo-society.org/ Endocrine Society] are available.<ref name="pmid21646368">{{cite journal| author=Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP et al.| title=Evaluation, treatment, and prevention of vitamin d deficiency: an endocrine society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2011 | volume= 96 | issue= 7 | pages= 1911-30 | pmid=21646368 | doi=10.1210/jc.2011-0385 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21646368  }} </ref>
 
[[Clinical practice guideline]]s by the [[U.S. Preventive Services Task Force]] recommend (italics are added):
* "recommends exercise or physical therapy and vitamin D supplementation to  prevent [[accidental fall|falls]] in community-dwelling adults aged 65 years or older who  are at increased risk for falls"
* "recommends ''against'' daily supplementation with ≤400 IU of vitamin D3 and 1,000 mg of calcium carbonate for the primary prevention of fractures in ''noninstitutionalized'' postmenopausal women" (draft recommendation)
* "the current evidence is insufficient to assess the balance of the  benefits and harms of vitamin D supplementation, with or without  calcium, for the primary prevention of cancer in adults" (draft recommendation)
* "the current evidence is  insufficient to assess the balance of the  benefits and harms of combined  vitamin D and calcium supplementation  for the primary prevention of fractures  in ''premenopausal women or in men''"  (draft recommendation)
* "the current evidence is insufficient to assess the balance of the  benefits and harms of daily supplementation with >400 IU of vitamin  D3 and 1,000 mg of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women" (draft recommendation)
 
===Mortality===
"Vitamin D in the form of vitamin  D(3) seems to decrease mortality in predominantly elderly women who are  mainly in institutions and dependent care" according to the [[Cochrane Collaboration]]. <ref  name="pmid21735411">{{cite journal| author=Bjelakovic G, Gluud LL,  Nikolova D, Whitfield K, Wetterslev J, Simonetti RG et al.|  title=Vitamin D supplementation for prevention of mortality in adults. |  journal=Cochrane Database Syst Rev | year= 2011 | volume= 7 | issue= | pages= CD007470 | pmid=21735411 | doi=10.1002/14651858.CD007470.pub2 | pmc= | url= }} </ref>
 
A recent [[randomized controlled trial]] found no benefit.<ref name="pmid22112804">{{cite journal| author=Avenell A, MacLennan GS, Jenkinson DJ, McPherson GC, McDonald AM, Pant PR et al.| title=Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial). | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 2 | pages= 614-22 | pmid=22112804 | doi=10.1210/jc.2011-1309 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22112804  }} </ref>
 
===Accidental falls===
The American Geriatrics Society recommends regarding vitamin D for prevention of [[accidental fall]]s in [[geriatrics]]:<ref>AGS/BGS Clinical Practice Guideline (2011). [http://www.americangeriatrics.org/health_care_professionals/clinical_practice/clinical_guidelines_recommendations/prevention_of_falls_summary_of_recommendations Prevention of Falls in Older Persons]</ref>
# "Vitamin D supplements of at least 800 IU per day should be provided to older persons with proven vitamin D deficiency."
# "Vitamin D supplements of at least 800 IU per day should be considered for people with suspected vitamin D deficiency or who are otherwise at increased risk for falls."
 
Meta-analyses supports these recommendations.<ref name="pmid21795448">{{cite journal| author=Murad MH, Elamin KB, Abu Elnour NO, Elamin MB, Alkatib AA, Fatourechi MM et al.| title=The effect of vitamin d on falls: a systematic review and meta-analysis. | journal=J Clin Endocrinol Metab | year= 2011 | volume= 96 | issue= 10 | pages= 2997-3006 | pmid=21795448 | doi=10.1210/jc.2011-1193 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21795448  }} </ref><ref name="pmid19797342">{{cite journal| author=Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R et al.| title=Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. | journal=BMJ | year= 2009 | volume= 339 | issue= | pages= b3692 | pmid=19797342 | doi=10.1136/bmj.b3692 | pmc=PMC2755728 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19797342  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20083818 Review in: Ann Intern Med. 2010 Jan 19;152(2):JC1-3] </ref> especially if the level of vitamin D achieved is over 24 ng/ml (60 nmol/l).<ref name="pmid19797342"/>


About a quarter of older adults have levels below 20 ng/mL.<ref name="pmid19174492">{{cite journal |author=Orwoll E, Nielson CM, Marshall LM, ''et al'' |title=Vitamin D deficiency in older men |journal=J. Clin. Endocrinol. Metab. |volume=94 |issue=4 |pages=1214–22 |year=2009 |month=April |pmid=19174492 |doi=10.1210/jc.2008-1784 |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=19174492 |issn=}}</ref>
===Fracture prevention===
Vitamin D, if given with<ref name="pmid22184690">{{cite journal| author=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=Ann Intern Med | year= 2011 | volume= 155 | issue= 12 | pages= 827-38 | pmid=22184690 | doi=10.1059/0003-4819-155-12-201112200-00005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22184690  }} </ref><ref name="pmid17720017">{{cite journal| author=Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A| title=Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. | journal=Lancet | year= 2007 | volume= 370 | issue= 9588 | pages= 657-66 | pmid=17720017 | doi=10.1016/S0140-6736(07)61342-7 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17720017  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18364429 Review in: Evid Based Nurs. 2008 Apr;11(2):59]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18375706 Review in: Evid Based Med. 2008 Apr;13(2):53]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18311871 Review in: ACP J Club. 2008 Mar-Apr;148(2):41] </ref><ref name="pmid19307517">{{cite journal| author=Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin  HB, Orav EJ et al.| title=Prevention of nonvertebral fractures with oral  vitamin D and dose dependency: a meta-analysis of randomized controlled  trials. | journal=Arch Intern Med | year= 2009 | volume= 169 | issue= 6  | pages= 551-61 | pmid=19307517 | doi=10.1001/archinternmed.2008.600 |  pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19307517  }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19687482 Review in: Ann Intern Med. 2009 Aug 18;151(4):JC2-8]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19794024 Review in: Evid Based Med. 2009 Oct;14(5):149] </ref> or without<ref name="pmid19307517"/> calcium, may prevent fractures.


==Administration==
Vitamin D levels below 20 ng/ml predicts fractures in anglo women, but not in African-American women.<ref name="pmid21710614">{{cite journal| author=Cauley JA, Danielson ME, Boudreau R, Barbour KE, Horwitz MJ, Bauer DC et al.| title=Serum 25-hydroxyvitamin D and clinical fracture risk in a multiethnic cohort of women: the Women's Health Initiative (WHI). | journal=J Bone Miner Res | year= 2011 | volume= 26 | issue= 10 | pages= 2378-88 | pmid=21710614 | doi=10.1002/jbmr.449 | pmc=PMC3304434 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21710614  }} </ref>
In health adults, Vitamin D<sub>2</sub> and vitamin D<sub>3</sub> are equally effective in maintaining serum 25-hydroxyvitamin D levels.<ref name="pmid18089691">{{cite journal |author=Holick MF, Biancuzzo RM, Chen TC, ''et al'' |title=Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D |journal=J. Clin. Endocrinol. Metab. |volume=93 |issue=3 |pages=677-81 |year=2008 |pmid=18089691 |doi=10.1210/jc.2007-2308 |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=18089691}}</ref>
 
===Cancer prevention===
A secondary analysis of a [[randomized controlled trial]] originally designed to study fractures suggests that cholecalciferol (vitamin D<sub>3</sub>) combined with calcium may reduce risk of [[cancer]].<ref name=lappe2007>Lappe,J.M.; Travers-Gustafson,D.; Davies,K.M.; Recker,R.R.; Heaney,R.P. (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. ''Am J. Clin Nutr.'' 85(6):1586-1591. [http://www.ajcn.org/cgi/content/full/85/6/1586 Full Text].</ref> They reported that 1100 IU of vitamin D (cholecalciferol) combined with 1500 mg of calcium per day administered for four years greatly reduced the risk for new cancers compared with placebo controls (p < 0.005). They also noted that the concentrations of serum 25-hydroxy-vitamin D (25[OH]D) levels, both pre-treatment and during treatment independently predicted cancer risk. The treatment group achieved mean concentrations of serum 25-hydroxy-vitamin D (25[OH]D) of 96 nmol/L (38 ng/ml). Natural levels for people who live and work in the sun: ~50-70 ng/ml (~125-175 nmol/L). <ref name=vieth2006>Vieth R. (2006) What is the optimal vitamin D status for health? ''Prog. Biophys. Mol. Biol.'' 92(1):26-32. [http://dx.doi.org/10.1016/j.pbiomolbio.2006.02.003 Full Text]</ref>
 
A [[randomized controlled trial]] found no benefit on [[colorectal cancer]] prevention.<ref name="pmid16481636">{{cite journal| author=Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O'Sullivan MJ et al.| title=Calcium plus vitamin D supplementation and the risk of colorectal cancer. | journal=N Engl J Med | year= 2006 | volume= 354 | issue= 7 | pages= 684-96 | pmid=16481636 | doi=10.1056/NEJMoa055222 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16481636  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17076014 Review in: Evid Based Nurs. 2006 Oct;9(4):114]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16813354 Review in: ACP J Club. 2006 Jul-Aug;145(1):4-5] </ref>
 
An observational analysis of a randomized controlled trial found no benefit for [[prostate cancer]].<ref name="pmid20693267">{{cite journal| author=Kristal AR, Arnold KB, Neuhouser ML, Goodman P, Platz EA, Albanes D et al.| title=Diet, supplement use, and prostate cancer risk: results from the prostate cancer prevention trial. | journal=Am J Epidemiol | year= 2010 | volume= 172 | issue= 5 | pages= 566-77 | pmid=20693267 | doi=10.1093/aje/kwq148 | pmc=PMC2950820 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20693267  }} </ref>
 
A recent [[randomized controlled trial]]  found no benefit.<ref name="pmid22112804"/>
 
===Cardiovascular disease===
Vitamin D supplementation may reduce cardiovascular disease according to a [[systematic review]]<ref name="pmid20194238">{{cite journal| author=Wang L, Manson JE, Song Y, Sesso HD| title=Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. | journal=Ann Intern Med | year= 2010 | volume= 152 | issue= 5 | pages= 315-23 | pmid=20194238 | doi=10.1059/0003-4819-152-5-201003020-00010 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20194238  }} </ref> although some [[randomized controlled trial]]s are negative.<ref name="pmid12609940">{{cite journal| author=Trivedi DP, Doll R, Khaw KT| title=Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. | journal=BMJ | year= 2003 | volume= 326 | issue= 7387 | pages= 469 | pmid=12609940 | doi=10.1136/bmj.326.7387.469 | pmc=PMC150177 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12609940  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14577395 Review in: Evid Based Nurs. 2003 Oct;6(4):113]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12791218 Review in: J Fam Pract. 2003 Jun;52(6):431-5] </ref><ref name="pmid17309935">{{cite journal| author=Hsia J, Heiss G, Ren H, Allison M, Dolan NC, Greenland P et al.| title=Calcium/vitamin D supplementation and cardiovascular events. | journal=Circulation | year= 2007 | volume= 115 | issue= 7 | pages= 846-54 | pmid=17309935 | doi=10.1161/CIRCULATIONAHA.106.673491 | pmc= | url=http://www.annals.org/content/152/5/315  }} </ref>
 
A recent [[randomized controlled trial]]  found no benefit.<ref name="pmid22112804"/>
 
===Cognition===
Vitamin D may help [[cognition]].<ref name="pmid19940269">{{cite journal| author=Miller JW| title=Vitamin D and cognitive function in older adults: are we concerned about vitamin D-mentia? | journal=Neurology | year= 2010 | volume= 74 | issue= 1 | pages= 13-5 | pmid=19940269 | doi=10.1212/WNL.0b013e3181c719a2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19940269  }} </ref>
 
===Diabetes mellitus type 2===
Vitamin D supplementation does not appear to prevent [[diabetes mellitus type 2]].<ref name="pmid20194237">{{cite journal| author=Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K et al.| title=Systematic review: Vitamin D and cardiometabolic outcomes. | journal=Ann Intern Med | year= 2010 | volume= 152 | issue= 5 | pages= 307-14 | pmid=20194237 | doi=10.1059/0003-4819-152-5-201003020-00009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20194237  }} </ref>
 
===Chronic pain===
Vitamin D supplementation does not seem to reduce chronic [[pain]].<ref name="pmid20091647">{{cite journal| author=Straube S, Derry S, Moore RA, McQuay HJ| title=Vitamin D for the treatment of chronic painful conditions in adults. | journal=Cochrane Database Syst Rev | year= 2010 | volume=  | issue= 1 | pages= CD007771 | pmid=20091647 | doi=10.1002/14651858.CD007771.pub2 | pmc= | url= }} </ref>
 
===Muscle function===
Vitamin D supplementation for individuals with less than  24 ng/mL may improve muscle function according to a [[randomized controlled trial]].<ref name="pmid21054285">{{cite journal| author=Zhu K, Austin N, Devine A, Bruce D, Prince RL| title=A randomized controlled trial of the effects of vitamin D on muscle strength and mobility in older women with vitamin D insufficiency. | journal=J Am Geriatr Soc | year= 2010 | volume= 58 | issue= 11 | pages= 2063-8 | pmid=21054285 | doi=10.1111/j.1532-5415.2010.03142.x | pmc= | url= }} </ref>
 
==Secondary hyperparathyroidism==
Vitamin D can lower levels of parathyroid hormone in patients with secondary hyperparathryoidism from chronic kidney disease.<ref name="pmid19821446">{{cite journal| author=Palmer SC, McGregor DO, Craig JC, Elder G, Macaskill P, Strippoli GF| title=Vitamin D compounds for people with chronic kidney disease not requiring dialysis. | journal=Cochrane Database Syst Rev | year= 2009 | volume=  | issue= 4 | pages= CD008175 | pmid=19821446 | doi=10.1002/14651858.CD008175 | pmc= | url= }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20404369 Review in: Ann Intern Med. 2010 Apr 20;152(8):JC4-12] </ref>


==Vitamin D and risk of internal cancers==
===Vascular disease prevention===
Vitamin D may help prevent [[vascular disease]].<ref name="pmid20194238"/>


In 2007 in the ''American Journal of Clinical Nutrition'', Lappe and coworkers  published the first population-based, double-blind, randomised, placebo-controlled, interventional trial of cholecalciferol (vitamin D<sub>3</sub>) taking internal cancer prevention as their principal secondary end point, with fractures as their primary end point.<ref name=lappe2007>Lappe,J.M.; Travers-Gustafson,D.; Davies,K.M.; Recker,R.R.; Heaney,R.P. (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. ''Am J. Clin Nutr.'' 85(6):1586-1591. [http://www.ajcn.org/cgi/content/full/85/6/1586 Full Text]
==Drug toxicity==
:*<b><u>Abstract:</u></b>&nbsp;BACKGROUND: Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers. However, interventional studies to test this effect are lacking. OBJECTIVE: The purpose of this analysis was to determine the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk of all types. DESIGN: This was a 4-y, population-based, double-blind, randomized placebo-controlled trial. The primary outcome was fracture incidence, and the principal secondary outcome was cancer incidence. The subjects were 1179 community-dwelling women randomly selected from the population of healthy postmenopausal women aged >55 y in a 9-county rural area of Nebraska centered at latitude 41.4 degrees N. Subjects were randomly assigned to receive 1400-1500 mg supplemental calcium/d alone (Ca-only), supplemental calcium plus 1100 IU vitamin D3/d (Ca + D), or placebo. RESULTS: When analyzed by intention to treat, cancer incidence was lower in the Ca + D women than in the placebo control subjects (P < 0.03). With the use of logistic regression, the unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were 0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the Ca-only group. In multiple logistic regression models, both treatment and serum 25-hydroxyvitamin D concentrations were significant, independent predictors of cancer risk. CONCLUSIONS: Improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00352170.</ref> They reported that 1100 IU of vitamin D (cholecalciferol) combined with 1500 mg of calcium per day administered for four years greatly reduced the risk for new cancers compared with placebo controls (p < 0.005). They also noted that the concentrations of serum 25-hydroxy-vitamin D (25[OH]D) levels, both pre-treatment and during treatment independently predicted cancer risk. The treatment group achieved mean concentrations of serum 25-hydroxy-vitamin D (25[OH]D) of 96 nmol/L (38 ng/ml). Natural levels for people who live and work in the sun: ~50-70 ng/ml (~125-175 nmol/L). <ref name=vieth2006>Vieth R. (2006) What is the optimal vitamin D status for health? ''Prog. Biophys. Mol. Biol.'' 92(1):26-32. [http://dx.doi.org/10.1016/j.pbiomolbio.2006.02.003 Full Text]
Vitamin D, when combined with calcium, may increase [[nephrolithiasis]].<ref name="pmid16481635">{{cite journal| author=Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE et al.| title=Calcium plus vitamin D supplementation and the risk of fractures. | journal=N Engl J Med | year= 2006 | volume= 354 | issue= 7 | pages= 669-83 | pmid=16481635 | doi=10.1056/NEJMoa055218 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16481635  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16813354 Review in: ACP J Club. 2006 Jul-Aug;145(1):4-5]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17076014 Review in: Evid Based Nurs. 2006 Oct;9(4):114] </ref>
:*<b><u>Abstract:</u></b>&nbsp;The most objectively substantiated health-related reason for tanning is that it improves vitamin D status. The serum 25-hydroxyvitamin D concentration (25(OH)D) is the measure of vitamin D nutrition status. Human biology was probably optimized through natural selection for a sun-rich environment that maintained serum 25(OH)D higher than 100 nmol/L. These levels are now only prevalent in people who spend an above-average amount of time outdoors, with the sun high in the sky. The best-characterized criteria for vitamin D adequacy are based on randomized clinical trials that show fracture prevention and preservation of bone mineral density. Based upon these studies, 25(OH)D concentrations should exceed 75 nmol/L. This concentration is near the upper end of the 25(OH)D reference ("normal") range for populations living in temperate climates, or for people who practice sun-avoidance, or who wear head coverings. Officially mandated nutrition guidelines restrict vitamin D intake from fortified food and supplements to less than 25 mcg/day, a dose objectively shown to raise serum 25(OH)D in adults by about 25 nmol/L. The combined effect of current nutrition guidelines and current sun-avoidance advice is to ensure that adults who follow these recommendations will have 25(OH)D concentrations lower than 75 nmol/L. Therefore, advice to avoid UVB light should be accompanied by encouragement to supplement with vitamin D in an amount that will correct for the nutrient deficit that sun-avoidance will cause.</ref>


==References==
==References==
<References/>
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Vitamin D is a steroid and a vitamin that "includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone."[1]

Vitamin D serves two classes of functions: (a) an endocrine function, in which a form of vitamin D, calcitriol, produced in the kidneys and secreted into the bloodstream, acts on target organs (gastrointestinal tract, bone, parathyroid glands) in such a way as to regulate aspects of calcium and phosphorus metabolism important to bone health and homeostasis of circulating calcium and phosphorus concentrations; and, (b) an autocrine function, in which the cells of numerous organs and tissues in the body (e.g., parts of the immune system, various epithelial tissues) generate calcitriol that functions in the cells that generate it, in intracellular signaling pathways (e.g., facilitation of the expression of specific genes) important to optimal functioning of those cells.[2] The autocrine mechanisms account for the preponderance of vitamin D utilized by body each day, and therefore tends to set the daily requirement for vitamin D.[2]

Biochemistry

Ergocalciferols (vitamin D2) is formed in plants. Ergocalciferols are "derivatives of ergosterol formed by ultraviolet rays breaking of the C9-C10 bond. They differ from cholecalciferol in having a double bond between C22 and C23 and a methyl group at C24."[3]

Cholecalciferol (vitamin D3) is formed in the skin of animals from 7-dehydrocholesterol by sunlight. Cholecalciferol is a "derivative of 7-dehydroxycholesterol formed by ultraviolet rays breaking of the C9-C10 bond. It differs from ergocalciferol in having a single bond between C22 and C23 and lacking a methyl group at C24."[4]

Vitamin D2 and vitamin D3 are of equal potency.[5]

Vitamin D2 and vitamin D3 are hydroxylated in the liver at the 25 position.[5] This leads to calcitriol (1,25-Dihydroxyvitamin D3). Calcitriol is the "physiologically active form of vitamin D. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption."[6]

Genetic variation in the vitamin D–binding protein level can affect the serum levels. "The T allele at rs7041 was associated with decreased levels of total 25-hydroxyvitamin D among blacks. In whites, the A allele at rs4588 was associated with decreased levels of total 25-hydroxyvitamin D."[7]

Deficiency

For more information, see: Vitamin D deficiency.


Administration

The best treatment may be calciferol (ergocalciferol or colecalciferol).[8] For every 100 IU of vitamin D taken, the serum level rises about 1 ng/ml.[9] For 1000 IU daily, a randomized controlled trial found that consuming orange juice fortified with either vitamin D3 or vitamin D2 was not significantly different than consuming the corresponding capsules of the vitamins in respect of increasing 25-hydroxyvitamin D blood levels.[10]

In a prior study of healthy adults, Vitamin D2 and vitamin D3 are equally effective in maintaining serum 25-hydroxyvitamin D levels.[11]

Clinical uses

Clinical practice guidelines by the Endocrine Society are available.[12]

Clinical practice guidelines by the U.S. Preventive Services Task Force recommend (italics are added):

  • "recommends exercise or physical therapy and vitamin D supplementation to prevent falls in community-dwelling adults aged 65 years or older who are at increased risk for falls"
  • "recommends against daily supplementation with ≤400 IU of vitamin D3 and 1,000 mg of calcium carbonate for the primary prevention of fractures in noninstitutionalized postmenopausal women" (draft recommendation)
  • "the current evidence is insufficient to assess the balance of the benefits and harms of vitamin D supplementation, with or without calcium, for the primary prevention of cancer in adults" (draft recommendation)
  • "the current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men" (draft recommendation)
  • "the current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with >400 IU of vitamin D3 and 1,000 mg of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women" (draft recommendation)

Mortality

"Vitamin D in the form of vitamin D(3) seems to decrease mortality in predominantly elderly women who are mainly in institutions and dependent care" according to the Cochrane Collaboration. [13]

A recent randomized controlled trial found no benefit.[14]

Accidental falls

The American Geriatrics Society recommends regarding vitamin D for prevention of accidental falls in geriatrics:[15]

  1. "Vitamin D supplements of at least 800 IU per day should be provided to older persons with proven vitamin D deficiency."
  2. "Vitamin D supplements of at least 800 IU per day should be considered for people with suspected vitamin D deficiency or who are otherwise at increased risk for falls."

Meta-analyses supports these recommendations.[16][17] especially if the level of vitamin D achieved is over 24 ng/ml (60 nmol/l).[17]

Fracture prevention

Vitamin D, if given with[18][19][20] or without[20] calcium, may prevent fractures.

Vitamin D levels below 20 ng/ml predicts fractures in anglo women, but not in African-American women.[21]

Cancer prevention

A secondary analysis of a randomized controlled trial originally designed to study fractures suggests that cholecalciferol (vitamin D3) combined with calcium may reduce risk of cancer.[22] They reported that 1100 IU of vitamin D (cholecalciferol) combined with 1500 mg of calcium per day administered for four years greatly reduced the risk for new cancers compared with placebo controls (p < 0.005). They also noted that the concentrations of serum 25-hydroxy-vitamin D (25[OH]D) levels, both pre-treatment and during treatment independently predicted cancer risk. The treatment group achieved mean concentrations of serum 25-hydroxy-vitamin D (25[OH]D) of 96 nmol/L (38 ng/ml). Natural levels for people who live and work in the sun: ~50-70 ng/ml (~125-175 nmol/L). [23]

A randomized controlled trial found no benefit on colorectal cancer prevention.[24]

An observational analysis of a randomized controlled trial found no benefit for prostate cancer.[25]

A recent randomized controlled trial found no benefit.[14]

Cardiovascular disease

Vitamin D supplementation may reduce cardiovascular disease according to a systematic review[26] although some randomized controlled trials are negative.[27][28]

A recent randomized controlled trial found no benefit.[14]

Cognition

Vitamin D may help cognition.[29]

Diabetes mellitus type 2

Vitamin D supplementation does not appear to prevent diabetes mellitus type 2.[30]

Chronic pain

Vitamin D supplementation does not seem to reduce chronic pain.[31]

Muscle function

Vitamin D supplementation for individuals with less than 24 ng/mL may improve muscle function according to a randomized controlled trial.[32]

Secondary hyperparathyroidism

Vitamin D can lower levels of parathyroid hormone in patients with secondary hyperparathryoidism from chronic kidney disease.[33]

Vascular disease prevention

Vitamin D may help prevent vascular disease.[26]

Drug toxicity

Vitamin D, when combined with calcium, may increase nephrolithiasis.[34]

References

  1. ↑ Anonymous (2024), Vitamin D (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. ↑ 2.0 2.1 Heaney RP. (2008) 10.2215/CJN.01160308 Vitamin D in Health and Disease. Clin. J. Am. Soc. Nephrol. (first published online June 4, 2008)
  3. ↑ Anonymous (2024), Ergocalciferols (English). Medical Subject Headings. U.S. National Library of Medicine.
  4. ↑ Anonymous (2024), Cholecalciferol (English). Medical Subject Headings. U.S. National Library of Medicine.
  5. ↑ 5.0 5.1 Harper, Harold W.; Murray, Robert F. (2000). “Structure and Function of the Lipid-Soluble Vitamins”, Harper's Biochemistry. Norwalk, CT: Appleton & Lange, 645. ISBN 0-8385-3684-0. 
  6. ↑ Anonymous (2024), Calcitriol (English). Medical Subject Headings. U.S. National Library of Medicine.
  7. ↑ Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, et al. Vitamin D–Binding Protein and Vitamin D Status of Black Americans and White Americans. New England Journal of Medicine. 2013;369(21):1991–2000. DOI:10.1056/NEJMoa1306357
  8. ↑ Pearce SH, Cheetham TD (2010). "Diagnosis and management of vitamin D deficiency.". BMJ 340: b5664. DOI:10.1136/bmj.b5664. PMID 20064851. Research Blogging.
  9. ↑ Rosen, Clifford J. (2011-01-20). "Vitamin D Insufficiency". New England Journal of Medicine 364 (3): 248-254. DOI:10.1056/NEJMcp1009570. ISSN 0028-4793. Research Blogging.
  10. ↑ Biancuzzo RM, Young A, Bibuld D et al. (2010) Fortification of orange juice with vitamin D2 or vitamin D3 is as effective as an oral supplement in maintaining vitamin D status in adults. The American Journal of Clinical Nutrition 91:1621-6.
  11. ↑ Holick MF, Biancuzzo RM, Chen TC, et al (2008). "Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D". J. Clin. Endocrinol. Metab. 93 (3): 677-81. DOI:10.1210/jc.2007-2308. PMID 18089691. Research Blogging.
  12. ↑ Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP et al. (2011). "Evaluation, treatment, and prevention of vitamin d deficiency: an endocrine society clinical practice guideline.". J Clin Endocrinol Metab 96 (7): 1911-30. DOI:10.1210/jc.2011-0385. PMID 21646368. Research Blogging.
  13. ↑ Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG et al. (2011). "Vitamin D supplementation for prevention of mortality in adults.". Cochrane Database Syst Rev 7: CD007470. DOI:10.1002/14651858.CD007470.pub2. PMID 21735411. Research Blogging.
  14. ↑ 14.0 14.1 14.2 Avenell A, MacLennan GS, Jenkinson DJ, McPherson GC, McDonald AM, Pant PR et al. (2012). "Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial).". J Clin Endocrinol Metab 97 (2): 614-22. DOI:10.1210/jc.2011-1309. PMID 22112804. Research Blogging.
  15. ↑ AGS/BGS Clinical Practice Guideline (2011). Prevention of Falls in Older Persons
  16. ↑ Murad MH, Elamin KB, Abu Elnour NO, Elamin MB, Alkatib AA, Fatourechi MM et al. (2011). "The effect of vitamin d on falls: a systematic review and meta-analysis.". J Clin Endocrinol Metab 96 (10): 2997-3006. DOI:10.1210/jc.2011-1193. PMID 21795448. Research Blogging.
  17. ↑ 17.0 17.1 Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R et al. (2009). "Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials.". BMJ 339: b3692. DOI:10.1136/bmj.b3692. PMID 19797342. PMC PMC2755728. Research Blogging. Review in: Ann Intern Med. 2010 Jan 19;152(2):JC1-3
  18. ↑ Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA (2011). "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.". Ann Intern Med 155 (12): 827-38. DOI:10.1059/0003-4819-155-12-201112200-00005. PMID 22184690. Research Blogging.
  19. ↑ Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A (2007). "Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis.". Lancet 370 (9588): 657-66. DOI:10.1016/S0140-6736(07)61342-7. PMID 17720017. Research Blogging. Review in: Evid Based Nurs. 2008 Apr;11(2):59 Review in: Evid Based Med. 2008 Apr;13(2):53 Review in: ACP J Club. 2008 Mar-Apr;148(2):41
  20. ↑ 20.0 20.1 Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ et al. (2009). "Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials.". Arch Intern Med 169 (6): 551-61. DOI:10.1001/archinternmed.2008.600. PMID 19307517. Research Blogging. Review in: Ann Intern Med. 2009 Aug 18;151(4):JC2-8 Review in: Evid Based Med. 2009 Oct;14(5):149
  21. ↑ Cauley JA, Danielson ME, Boudreau R, Barbour KE, Horwitz MJ, Bauer DC et al. (2011). "Serum 25-hydroxyvitamin D and clinical fracture risk in a multiethnic cohort of women: the Women's Health Initiative (WHI).". J Bone Miner Res 26 (10): 2378-88. DOI:10.1002/jbmr.449. PMID 21710614. PMC PMC3304434. Research Blogging.
  22. ↑ Lappe,J.M.; Travers-Gustafson,D.; Davies,K.M.; Recker,R.R.; Heaney,R.P. (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J. Clin Nutr. 85(6):1586-1591. Full Text.
  23. ↑ Vieth R. (2006) What is the optimal vitamin D status for health? Prog. Biophys. Mol. Biol. 92(1):26-32. Full Text
  24. ↑ Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O'Sullivan MJ et al. (2006). "Calcium plus vitamin D supplementation and the risk of colorectal cancer.". N Engl J Med 354 (7): 684-96. DOI:10.1056/NEJMoa055222. PMID 16481636. Research Blogging. Review in: Evid Based Nurs. 2006 Oct;9(4):114 Review in: ACP J Club. 2006 Jul-Aug;145(1):4-5
  25. ↑ Kristal AR, Arnold KB, Neuhouser ML, Goodman P, Platz EA, Albanes D et al. (2010). "Diet, supplement use, and prostate cancer risk: results from the prostate cancer prevention trial.". Am J Epidemiol 172 (5): 566-77. DOI:10.1093/aje/kwq148. PMID 20693267. PMC PMC2950820. Research Blogging.
  26. ↑ 26.0 26.1 Wang L, Manson JE, Song Y, Sesso HD (2010). "Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events.". Ann Intern Med 152 (5): 315-23. DOI:10.1059/0003-4819-152-5-201003020-00010. PMID 20194238. Research Blogging.
  27. ↑ Trivedi DP, Doll R, Khaw KT (2003). "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.". BMJ 326 (7387): 469. DOI:10.1136/bmj.326.7387.469. PMID 12609940. PMC PMC150177. Research Blogging. Review in: Evid Based Nurs. 2003 Oct;6(4):113 Review in: J Fam Pract. 2003 Jun;52(6):431-5
  28. ↑ Hsia J, Heiss G, Ren H, Allison M, Dolan NC, Greenland P et al. (2007). "Calcium/vitamin D supplementation and cardiovascular events.". Circulation 115 (7): 846-54. DOI:10.1161/CIRCULATIONAHA.106.673491. PMID 17309935. Research Blogging.
  29. ↑ Miller JW (2010). "Vitamin D and cognitive function in older adults: are we concerned about vitamin D-mentia?". Neurology 74 (1): 13-5. DOI:10.1212/WNL.0b013e3181c719a2. PMID 19940269. Research Blogging.
  30. ↑ Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K et al. (2010). "Systematic review: Vitamin D and cardiometabolic outcomes.". Ann Intern Med 152 (5): 307-14. DOI:10.1059/0003-4819-152-5-201003020-00009. PMID 20194237. Research Blogging.
  31. ↑ Straube S, Derry S, Moore RA, McQuay HJ (2010). "Vitamin D for the treatment of chronic painful conditions in adults.". Cochrane Database Syst Rev (1): CD007771. DOI:10.1002/14651858.CD007771.pub2. PMID 20091647. Research Blogging.
  32. ↑ Zhu K, Austin N, Devine A, Bruce D, Prince RL (2010). "A randomized controlled trial of the effects of vitamin D on muscle strength and mobility in older women with vitamin D insufficiency.". J Am Geriatr Soc 58 (11): 2063-8. DOI:10.1111/j.1532-5415.2010.03142.x. PMID 21054285. Research Blogging.
  33. ↑ Palmer SC, McGregor DO, Craig JC, Elder G, Macaskill P, Strippoli GF (2009). "Vitamin D compounds for people with chronic kidney disease not requiring dialysis.". Cochrane Database Syst Rev (4): CD008175. DOI:10.1002/14651858.CD008175. PMID 19821446. Research Blogging. Review in: Ann Intern Med. 2010 Apr 20;152(8):JC4-12
  34. ↑ Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE et al. (2006). "Calcium plus vitamin D supplementation and the risk of fractures.". N Engl J Med 354 (7): 669-83. DOI:10.1056/NEJMoa055218. PMID 16481635. Research Blogging. Review in: ACP J Club. 2006 Jul-Aug;145(1):4-5 Review in: Evid Based Nurs. 2006 Oct;9(4):114
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