Ortho­mol­e­c­u­lar Med­i­cine News Ser­vice, Jan­u­ary 17, 2013


by William B. Grant, Ph.D.

(OMNS Jan 17, 2013) There were 3600 pub­li­ca­tions with vit­a­min D in the title or abstract in 2012 accord­ing to This brings the total num­ber of pub­li­ca­tions on vit­a­min D listed at PubMed to 33,800 ( This total com­pares to 35,100 on vit­a­min C or ascor­bic acid, 21,700 on vit­a­min E, 19,100 on vit­a­min A, 17,600 on folate, and 12,000 on vit­a­min B12. How­ever, since the begin­ning of 2000, there have been 20,500 pub­li­ca­tions on vit­a­min D but only 16,300 pub­li­ca­tions on vit­a­min C or ascor­bic acid. Thus, vit­a­min D is the most pop­u­lar vit­a­min even though strictly speak­ing it is not a vit­a­min. Instead, it is a nec­es­sary hor­mone that can be made in the body through the action of ultraviolet-B (UVB) light. How­ever, it can also be obtained orally through the diet or supplements.


The fol­low­ing list of top vit­a­min D papers for 2012 was selected from a search at at the end of 2012. The list started out with 60 of can­di­date papers. This list was then sent to a panel of vit­a­min D researchers and advo­cates, who added a few more papers, then voted on the entire list. The final list has papers from a vari­ety of health effects. Many other fine papers could not be included due to space limitations.


A topic that gen­er­ated con­sid­er­able inter­est this year was the role of vit­a­min D dur­ing preg­nancy. In a pair of papers, researchers from the Med­ical Uni­ver­sity of South Car­olina dis­cussed the find­ings and impli­ca­tions of their ran­dom­ized con­trolled trial of vit­a­min D sup­ple­men­ta­tion dur­ing preg­nancy [Hol­lis et al., 2012; Wag­ner et al., 2012]. Over 300 women were enrolled in the study. Women were assigned to take sup­ple­ments con­tain­ing 400, 2000, or 4000 IU/d vit­a­min D3 or a placebo. No adverse effects were found such as hyper­cal­cemia or hyper­cal­cu­ria. This study found that it took 4000 IU/d to raise serum 25-hydroxyvitamin D [25(OH)D] lev­els to about 40 ng/ml (To con­vert to nmol/l, mul­ti­ple ng/ml by 2.5.), a nearly opti­mal level of 1,25-dihydroxyvitamin D. 1,25-dihydroxyvitamin D is the active or hor­monal metabo­lite of vit­a­min D which among other things con­trols the expres­sion of sev­eral hun­dred genes. (See Hossein-nezhad and Holick [2012] for a sum­mary of the effects of vit­a­min D on fetal devel­op­ment.) In the study, those tak­ing the higher vit­a­min D doses had sig­nif­i­cantly reduced risk of pri­mary Cesarean sec­tion deliv­ery and pre-eclampsia. Other adverse preg­nancy out­comes occur with vit­a­min D defi­ciency such as pre­ma­ture deliv­ery and low birth weight, but too few women were enrolled in this study to find sta­tis­ti­cally sig­nif­i­cant results on these conditions.


A study from Saudi Ara­bia exam­ined the rela­tion between serum 25(OH)D level and anti-myelin-associated gly­co­pro­tein (anti-MAG) auto-antibodies in autis­tic chil­dren near the age of eight years [Mostafa and Al-Ayadhi, 2012]. There was a very strong inverse rela­tion between the two lev­els (r = –0.86, p


A study in Perth, Aus­tralia mea­sured serum 25(OH)D lev­els at 18 weeks into preg­nancy, and then mea­sured lan­guage impair­ment of the off­spring at 5 and 10 years of age. It found that women with serum 25(OH)D lev­els below 18 ng/ml had chil­dren with twice the risk of clin­i­cally sig­nif­i­cant lan­guage dif­fi­cul­ties com­pared to those with 25(OH)D lev­els above 28 ng/ml. Exactly why is not cur­rently known, but there are many pos­si­bil­i­ties. It is noted that in the United States in the early 2000s, white women of child­bear­ing age had mean 25(OH)D level of 26 ng/ml while black women of child­bear­ing age had mean 25(OH)D level of 14 ng/ml. Both of these lev­els are low by cur­rent stan­dards. As explained below, skin color is directly rel­e­vant to serum vit­a­min D lev­els pro­duced by expo­sure to sunlight.


A topic of inter­est at the other end of life was the rela­tion of mor­tal­ity rate to serum 25(OH)D lev­els. A meta-analysis of 11 obser­va­tional stud­ies and 60,000 indi­vid­u­als found a reduc­tion in risk over about 10 years for high­est vs. low­est cat­e­gory of 25(OH)D level of mor­tal­ity of 29% [Zit­ter­mann et al., 2012]. Com­par­ing graded lev­els of intake, the reduc­tion in risk was 14% for an increase of 5 ng/ml, 23% for an increase of 10 ng/ml, and 39% for an increase of 20 ng/ml in plasma lev­els of 25(OH)D, start­ing from a median of ~11 ng/ml. The par­tic­i­pants start­ing with the low­est lev­els of serum 25(OH)D received the great­est ben­e­fits. Those who started with higher serum lev­els, closer to opti­mal (30–40 ng/ml), received less ben­e­fit from addi­tional vit­a­min D. This rela­tion between start­ing serum 25(OH)D lev­els and health out­come is not sur­pris­ing because it is sim­i­lar to many other health stud­ies. Since 25(OH)D lev­els likely changed over the dura­tion of the stud­ies, and some par­tic­i­pants died of unre­lated causes, the actual effect of serum 25(OH)D level on mor­tal­ity rate is greater than these estimates.


Car­dio­vas­cu­lar dis­ease is an impor­tant con­trib­u­tor to mor­tal­ity rates. A study of 11,000 patients in Kansas was reported. The patients had a mean age of 58±15 years, a body mass index of 30±8 kg/m2, and a mean serum 25(OH)D level of 24±14 ng/ml [Vacek et al., 2012]. Serum 25(OH)D lev­els below 30 ng/ml was sig­nif­i­cantly asso­ci­ated with sev­eral cardiovascular-related dis­eases, includ­ing hyper­ten­sion, coro­nary artery dis­ease, car­diomy­opa­thy, and dia­betes. After a period of 5.5 years, those with serum 25(OH)D lev­els below 30 ng/ml had twice the mor­tal­ity rate of those with higher 25(OH)D levels.


In a 2.7-year study of 2000 pre­di­a­bet­ics, par­tic­i­pants with the high­est third of 25(OH)D lev­els (median, 30.1 ng/ml) had a reduc­tion in risk of 28% for devel­op­ing dia­betes mel­li­tus type 2 com­pared with par­tic­i­pants in the low­est third (median, 12.8 ng/ml) [Pit­tas, 2012].


An obser­va­tional study on insulin-dependent dia­betes mel­li­tus (T1DM) was based on 1000 U.S. mil­i­tary ser­vice per­son­nel who devel­oped this dis­ease between 2002 and 2011 [Gorham et al., 2012]. They had pro­vided blood sam­ples between one and ten years prior to devel­op­ing T1DM. They were care­fully matched with another thou­sand ser­vice per­son­nel who did not develop T1DM. There was a reduc­tion in risk of 78% for devel­op­ing T1DM for those with serum 25(OH)D lev­els above 24 ng/ml com­pared to those with lev­els above 24 ng/ml. This find­ing is highly sta­tis­ti­cally sig­nif­i­cant and is one of the strongest stud­ies of its type.


The effect of vit­a­min D in reduc­ing risk of infec­tions is a topic of increas­ing inter­est. Vit­a­min D reduces risk of infec­tions pri­mar­ily by strength­en­ing the innate immune sys­tem, pri­mar­ily by induc­ing pro­duc­tion of cathe­li­cidin, a polypep­tide with antimi­cro­bial and antien­do­toxin prop­er­ties. It also shifts pro­duc­tion of cytokines, a type of cell sig­nal­ing mol­e­cule, away from proin­flam­ma­tory ones, and has a num­ber of other actions on both the innate and adap­tive immune sys­tem [Lang et al., 2012]. While the effects of vit­a­min D have been found mostly for bac­te­r­ial infec­tions, some have also been reported for viral infec­tions such as influenza, HIV, and hepati­tis C [Lang et al., 2012]. In a sup­ple­men­ta­tion study in Swe­den involv­ing 140 patients with fre­quent res­pi­ra­tory tract infec­tions (RTIs) using 4000 IU/d vit­a­min D3, those in the sup­ple­men­ta­tion group increased their serum 25(OH)D level to 53 ng/ml while those in the placebo group had lev­els near 27 ng/ml [Bergman et al., 2012]. Those tak­ing vit­a­min D3 had a 23% reduc­tion in RTIs and a 50% reduc­tion in the num­ber of days using antibiotics.


One of the impor­tant and well-documented effects of vit­a­min D is reduced risk of can­cer and increased sur­vival after can­cer diag­no­sis. There were 400 pub­li­ca­tions on vit­a­min D and can­cer in 2012 accord­ing to Evi­dence from eco­log­i­cal, obser­va­tional and lab­o­ra­tory stud­ies have iden­ti­fied over 15 types of can­cer for which higher solar UVB light and/or serum 25(OH)D lev­els are asso­ci­ated with reduced risk. Two of the papers are espe­cially note­wor­thy. One, a study from Nor­way involv­ing 658 patients with either breast, colon, lung, or lym­phoma with serum 25(OH)D lev­els deter­mined within 90 days of can­cer diag­no­sis were fol­lowed for up to nine years [Tretli et al., 2012]. Com­pared to those with levels32 ng/ml had a reduc­tion in risk for dying from can­cer of 66%. To a can­cer patient, this would be a lifeline.

Another can­cer paper reported the results of sup­ple­men­ta­tion with 4000 IU/d vit­a­min D3 of those with low-grade biopsy-assayed prostate can­cer [Mar­shall et al., 2012]. Forty four patients suc­cess­fully com­pleted the one-year study. Twenty four of the sub­jects (55%) showed a decrease in the amount of can­cer; five sub­jects (11%) showed no change; 15 sub­jects (34%) showed an increase. In com­par­i­son, with a his­tor­i­cal group of 19 patients, only 4 (21%) had reduc­tions in the amount of can­cer, 3 (16%) showed no changes, and 12 (63%) showed an increase in can­cer. Thus opti­mal vit­a­min D sup­ple­men­ta­tion appears to be use­ful for treat­ing those with cancer.


The clas­si­cal role of vit­a­min D is to reg­u­late cal­cium and phos­phate absorp­tion and metab­o­lism, lead­ing to strong bones. A pooled analy­sis of 31,000 per­sons (mean age, 76 years; 91% women) par­tic­i­pat­ing in ran­dom­ized con­trolled tri­als of vit­a­min D sup­ple­men­ta­tion who devel­oped ~1000 inci­dent hip frac­tures and ~3800 non­ver­te­bral frac­tures found that those with the high­est intake (median 800 IU/d; range 792‑2000) had a 30% reduc­tion in risk of hip frac­ture and a 14% reduced risk of non­ver­te­bral frac­ture [Bischoff-Ferrari et al., 2012]. The role of vit­a­min D in neu­ro­mus­cu­lar con­trol also plays an impor­tant role in reduc­ing risk of falls and fractures.


Jablon­ski and Chap­lin have pub­lished a series of papers on human skin pig­men­ta­tion and its rela­tion to solar ultra­vi­o­let radi­a­tion (UVR) [Jablon­ski and Chap­lin, 2012]. Their pri­mary the­sis is that human skin pig­men­ta­tion has adapted to UVR con­di­tions where a group of peo­ple live for 50 gen­er­a­tions, or about a thou­sand years. UVR from mid-day sun­light pro­duces vit­a­min D, which pro­vides impor­tant pro­tec­tion against many dis­eases, but sun­light also causes skin can­cer and destruc­tion of folate. Dark skin pro­tects against free rad­i­cal pro­duc­tion, dam­age to DNA, can­cer, and loss of folate. Thus, dark skin is best in the trop­i­cal planes regions while pale skin is best at high lat­i­tude regions. Those with skin adapted to UVB between 23° and 46° have the abil­ity to tan, which is an adap­ta­tion to sea­sonal changes in solar UVB doses. How­ever, in recent times, peo­ple have moved or trav­eled to regions where their skin pig­men­ta­tion is not suited to the local UVR con­di­tions. They dis­cuss three exam­ples: nutri­tional rick­ets, mul­ti­ple scle­ro­sis and melanoma. Their abstract con­cludes with this obser­va­tion: “Low UVB lev­els and vit­a­min D defi­cien­cies pro­duced by changes in loca­tion and lifestyle pose some of the most seri­ous dis­ease risks of the twenty-first century.”


A study on tra­di­tion­ally liv­ing Africans near the equa­tor pro­vides infor­ma­tion on “nor­mal” 25(OH)D lev­els. A paper was pub­lished on serum 25(OH)D lev­els of the Masai and the Hadz­abe liv­ing near 4° S in Tan­za­nia [Lux­wolda et al., 2012]. They have skin type VI (very dark), wear a mod­er­ate amount of cloth­ing, spend the major part of the day out­doors, but avoid direct expo­sure to sun­light when pos­si­ble. The mean serum 25(OH)D lev­els of Maa­sai and Hadz­abe were 48 (range 23–67) ng/ml and 44 (range 28–68) ng/ml, respec­tively. This find­ing sug­gests that serum 25(OH)D lev­els in the range of 40–50 ng/ml may be opti­mal for human health, which is gen­er­ally con­sis­tent with obser­va­tional stud­ies for a num­ber of health outcomes.

Vit­a­min D is made by expo­sure to sun­light to a sig­nif­i­cant degree only when the sun is 45 degrees or more above the hori­zon. At the lat­i­tudes of North Amer­ica and Europe, this is sum­mer mid­day sun­light between the hours of 11 a.m. and 3 p.m. In the early morn­ing or late after­noon, light-skinned indi­vid­u­als may tan but they hardly get any vit­a­min D from sun­light. And in the win­ter, nobody gets much vit­a­min D from the sun. This explains the health ben­e­fits of tak­ing sup­ple­ments of vit­a­min D.


Thus, the evi­dence that serum 25(OH)D lev­els above 30–40 ng/ml are required for opti­mal health con­tin­ues to mount. It takes 1000–4000 IU/d vit­a­min D3 to reach these lev­els in the absence of sig­nif­i­cant UVB expo­sure. The evi­dence comes from a vari­ety of stud­ies includ­ing obser­va­tional and lab­o­ra­tory stud­ies and ran­dom­ized con­trolled tri­als (RCTs). While RCTs are required to demon­strate effec­tive­ness and lack of harm for phar­ma­ceu­ti­cal drugs which, by def­i­n­i­tion, are arti­fi­cial com­pounds, they should not be required for vit­a­min D since it is a nat­ural com­pound impor­tant for all ani­mal life includ­ing humans. In addi­tion, RCTs on vit­a­min D are dif­fi­cult to con­duct due to other sources of vit­a­min D and reduced con­ver­sion of vit­a­min D to 25(OH)D level at higher serum lev­els. It will take five years or more before large-scale RCTs test­ing vit­a­min D sup­ple­ments are com­pleted and reported. The adverse effects of oral intake of up to 4000 IU/d vit­a­min D3 and serum 25(OH)D lev­els up to 100 ng/ml are prac­ti­cally non-existent except for those indi­vid­u­als with con­di­tions that may lead to hyper­cal­cemia. How­ever, some peo­ple have expe­ri­enced hyper­ten­sion, irri­ta­tion and tachy­car­dia at doses above 4000 IU/d. Thus, there seems to be lit­tle rea­son to wait for the RCTs before imple­ment­ing vit­a­min D poli­cies of higher oral intake and/or mod­er­ate UVB expo­sure and serum 25(OH)D lev­els. Every­one in North Amer­ica and Europe should take a sup­ple­ment of 1000–4000 IU/d of vit­a­min D in the win­ter, and those with dark skin or office jobs should take vit­a­min D all year long. Sup­ple­men­ta­tion with vit­a­min D is an inex­pen­sive and very effec­tive way to pro­duce huge health benefits.

For fur­ther infor­ma­tion on vit­a­min D, the inter­ested reader is directed to these web­sites:,, and Dr. Grant is direc­tor of .

Appre­ci­a­tion is expressed to all the sci­en­tists who have reviewed and con­tributed to this paper:

Bar­bara J. Boucher, M.D., Queen Mary Uni­ver­sity of Lon­don, Cen­tre for Dia­betes, Blizard Insti­tute, London

John J. Can­nell, M.D., Vit­a­min D Coun­cil, San Luis Obispo, CA

Brant Cebulla, Vit­a­min D Coun­cil, San Luis Obispo, CA

Cedric F. Gar­land, Dr. P.H., pro­fes­sor of Fam­ily and Pre­ven­tive Med­i­cine in the UCSD School of Med­i­cine, and mem­ber of the Moores UC San Diego Can­cer Cen­ter, LaJolla, CA

Afrozul Haq, Ph.D., Insti­tutes of Pedi­atrics and Lab­o­ra­tory Med­i­cine; Sheikh Khal­ifa Med­ical City; Abu Dhabi, United Arab Emirates

Robert P. Heaney, M.D., Osteo­poro­sis Research Cen­ter, Creighton Uni­ver­sity Med­ical Cen­ter, Omaha, NE.

Perry Hol­man, Vit­a­min D Soci­ety, Canada

Johan E. Moan, M.D., Ph.D., Depart­ment of Radi­a­tion Biol­ogy, The Nor­we­gian Radium Hos­pi­tal, Uni­ver­sity of Oslo, Oslo, Norway

Ste­fan Pilz, M.D., Depart­ment of Inter­nal Med­i­cine, Divi­sion of Endocrinol­ogy and Metab­o­lism, Med­ical Uni­ver­sity of Graz, Graz, Austria

Jörg Reichrath, M.D., Ph.D., Depart­ment of Der­ma­tol­ogy; The Saar­land Uni­ver­sity Hos­pi­tal; Homburg/Saar, Germany.

And, the Edi­to­r­ial Review Board of the Ortho­mol­e­c­u­lar Med­i­cine News Ser­vice, listed fur­ther below.


1. Bergman P, Nor­lin AC, Hansen S, Rekha RS, Ager­berth B, Bj”rkhem-Bergman L, Ekstr”m L, Lindh JD, Ander­s­son J. Vit­a­min D3 sup­ple­men­ta­tion in patients with fre­quent res­pi­ra­tory tract infec­tions: a ran­domised and double-blind inter­ven­tion study. BMJ Open. 2012;2(6). pii: e001663.

2. Bischoff-Ferrari HA, Wil­lett WC, Orav EJ, Lips P, Meu­nier PJ, Lyons RA, Flicker L, Wark J, Jack­son RD, Cauley JA, Meyer HE, Pfeifer M, Sanders KM, St„helin HB, Theiler R, Dawson-Hughes B. A pooled analy­sis of vit­a­min D dose require­ments for frac­ture pre­ven­tion. N Engl J Med. 2012;367(1):40–9.

3. Gorham ED, Gar­land CF, Burgi AA, Mohr SB, Zeng K, Hof­flich H, Kim JJ, Ricordi C. Lower pre­di­ag­nos­tic serum 25-hydroxyvitamin D con­cen­tra­tion is asso­ci­ated with higher risk of insulin-requiring dia­betes: a nested case-control study. Dia­betolo­gia. 2012 Dec;55(12):3224–7.

4. Hol­lis BW, Wag­ner CL. Vit­a­min D and preg­nancy: Skele­tal effects, nonskele­tal effects, and birth out­comes. Cal­cif Tis­sue Int. 2012 May 24. [Epub ahead of print]

5. Hossein-nezhad A, Holick MF. Opti­mize dietary intake of vit­a­min D: an epi­ge­netic per­spec­tive. Curr Opin Clin Nutr Metab Care. 2012;15(6):567–79.

6. Jablon­ski NG, Chap­lin G. Human skin pig­men­ta­tion, migra­tion and dis­ease sus­cep­ti­bil­ity. Phi­los Trans R Soc Lond B Biol Sci. 2012;367(1590):785–92.

7. Lang PO, Sama­ras N, Sama­ras D, Aspinall R. How impor­tant is vit­a­min D in pre­vent­ing infec­tions? Osteo­poros Int. 2012 Nov 17. [Epub ahead of print]

8. Lux­wolda MF, Kuipers RS, Kema IP, Jan­neke Dijck-Brouwer DA, Muskiet FA. Tra­di­tion­ally liv­ing pop­u­la­tions in East Africa have a mean serum 25-hydroxyvitamin D con­cen­tra­tion of 115 nmol/l. Br J Nutr. 2012;108(9):1557–61.

9. Mar­shall DT, Sav­age SJ, Garrett-Mayer E, Keane TE, Hol­lis BW, Host RL, Ambrose LH, Kindy MS, Gattoni-Celli S. Vit­a­min D3 sup­ple­men­ta­tion at 4000 inter­na­tional units per day for one year results in a decrease of pos­i­tive cores at repeat biopsy in sub­jects with low-risk prostate can­cer under active sur­veil­lance. J Clin Endocrinol Metab. 2012;97(7):2315–24.

10. Mostafa GA, Al-Ayadhi LY. Reduced serum con­cen­tra­tions of 25-hydroxy vit­a­min D in chil­dren with autism: rela­tion to autoim­mu­nity. J Neu­roin­flam­ma­tion. 2012;9:201.

11. Pit­tas AG, Nel­son J, Mitri J, Hill­mann W, Gar­ganta C, Nathan DM, Hu FB, Dawson-Hughes B; Dia­betes Pre­ven­tion Pro­gram Research Group. Plasma 25-hydroxyvitamin D and pro­gres­sion to dia­betes in patients at risk for dia­betes: an ancil­lary analy­sis in the Dia­betes Pre­ven­tion Pro­gram. Dia­betes Care. 2012;35(3):565–73.

12. Tretli S, Schwartz GG, Tor­je­sen PA, Rob­sahm TE. Serum lev­els of 25-hydroxyvitamin D and sur­vival in Nor­we­gian patients with can­cer of breast, colon, lung, and lym­phoma: a population-based study. Can­cer Causes Con­trol. 2012;23(2):363–70.

13. Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA. Vit­a­min D defi­ciency and sup­ple­men­ta­tion and rela­tion to car­dio­vas­cu­lar health. Am J Car­diol. 2012;109(3):359–63.

14. Wag­ner CL, Tay­lor SN, Dawodu A, John­son DD, Hol­lis BW. Vit­a­min D and its role dur­ing preg­nancy in attain­ing opti­mal health of mother and fetus. Nutri­ents. 2012;4(3):208–30.

15. White­house AJ, Holt BJ, Ser­ralha M, Holt PG, Kusel MM, Hart PH. Mater­nal serum vit­a­min D lev­els dur­ing preg­nancy and off­spring neu­rocog­ni­tive devel­op­ment. Pedi­atrics. 2012;129(3):485–93.

16. Zit­ter­mann A, Iodice S, Pilz S, Grant WB, Bag­nardi V, Gan­dini S. Vit­a­min D defi­ciency and mor­tal­ity risk in the gen­eral pop­u­la­tion: A meta-analysis of prospec­tive cohort stud­ies. Am J Clin Nutr. 2012;95(1):91–100.

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