FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, September 16, 2011

Why You Need More Vitamin D. A Lot More.

by William B. Grant, Ph.D.

(OMNS, Sept 16, 2011) Vitamin D has emerged as the nutrient of the decade. Numerous studies have found benefits for nearly 100 types of health conditions. These health benefits include reduced risk of bone diseases, many types of cancer, cardiovascular disease (CVD), diabetes mellitus, bacterial and viral infectious diseases, and autoimmune diseases such as multiple sclerosis,[1] neurological conditions such as cognitive dysfunction,[2] and improved athletic and physical performance.[3]

Sunshine, Skin, Sunburn, and Sunscreen

The primary source of vitamin D for most people is solar ultraviolet-B (UVB) light. Skin pigmentation has adapted to where a population lives for a thousand years or more as those with skin too dark or light do not survive as well as those with the appropriate skin pigmentation.[4] Dark skin protects against the harmful effects of UV, but also blocks the UVB from penetrating deeply enough into the skin to produce vitamin D from 7-dehydrocholesterol. Those with lighter skin can produce vitamin D more rapidly, but are more prone to melanoma and other skin cancer. Sunscreens block UVB and thus limit vitamin D production. While sunscreens are useful in reducing risk of sunburning, they do not block the long wave UV (UVA) as well as UVB. UVA is linked to risk of melanoma. Wearing sunscreen when there is no danger of burning can actually increase the risk of melanoma.[5]

Understanding Vitamin D Research

Since vitamin D production is the primary source of vitamin D, ecological and observational studies have been very useful in teasing out the effects of vitamin D on health. There are two types of ecological studies, based on geographical and temporal (over time) variations. In geographical studies, populations are defined geographically and both health outcome and risk-modifying factors are averaged for each geographical unit. Statistical analyses are then used to determine the relative importance of each factor. The first paper linking UVB and vitamin D to reduced risk of colon cancer was published in 1980.[6] This link has now been extended to about 15 types of cancer in the United States with respect to average noontime solar UVB doses in July.[7] Solar UVB doses in July are highest in the Southwest and lowest in the Northeast.[8] Mortality rates are generally lowest in the Southwest and highest in the Northeast.[9] Similar results have been found in Australia, China, France, Japan, Russia, and Spain, and the entire world.[10]

In temporal studies, seasonal variations in health outcomes are sought. A good example of a seasonal effect linked to solar UVB doses and vitamin D is influenza, which peaks in winter.[11]

Observational studies are generally of three types: case-control, cohort, and cross-sectional. In case-control studies, those diagnosed with a disease have serum 25-hydroxyvitamin D [25(OH)D] level or oral vitamin D intake determined at that time and are compared statistically with others with similar characteristics but without that disease. In cohort studies, people are enrolled in the study and the vitamin D index determined at that time. The cohort is followed for a number of years and those who develop a specific disease are compared statistically with matched controls who did not. The main problem with cohort studies is that the single value of the vitamin D index may not relate to the time in the individual's life when vitamin D had the most impact on the disease outcome. Cross-sectional studies are essentially snapshots of a population and look at various factors in relation to the prevalence of health conditions. As biochemistry can be affected by health status, such studies provide less reliable information on the role of UVB and vitamin D on health outcome.

The role of vitamin D in CVD and diabetes mellitus type 2 have largely been studied using cohort studies. Significantly reduced risk of CVD and diabetes mellitus incidence have been reported in a number of studies in the past three years.[12]

Health policy officials like to see randomized controlled trials (RCTs) reporting health benefits with limited adverse effects. RCTs are certainly appropriate for pharmaceutical drugs which, by definition, are artificial substances that the human body has no experience with. RCTs with vitamin D are problematic for a number of reasons. For one, many RCTs used only 400 IU/day vitamin D3, which is much lower than the 10,000 IU/day that can be produced with whole-body exposure to the midday sun in summer, or 1500 IU/day from casual sunlight exposure in summer.[13] For another, there are both oral and UVB sources of vitamin D, so the amount taken in the study will compete with the other sources. There is considerable individual variation in serum 25(OH)D for a given oral vitamin D intake.[14] Unfortunately, serum 25(OH)D levels are generally not measured in oral vitamin D RCTs.

Nonetheless, there have been several vitamin D RCTs that found significant health benefits beyond preventing falls and fractures.[15] These include ones for cancer,[16],[17] influenza and colds,[18] type A influenza,[19] and pneumonia.[20]

Important Benefits of Vitamin D

The evidence of beneficial roles of UVB and vitamin D for a large number of health conditions have recently been posted at the Vitamin D Council's website: http://www.vitamindcouncil.org/health-conditions/

In addition to an overview of the literature, the website also includes a feature to pull up a large number of titles on each condition from www.pubmed.gov .

Sufficient information is currently available from observational studies with support from ecological studies and RCTs to determine relationships between serum 25(OH)D levels and incidence rates for breast and colorectal cancer,[21] CVD,[22] and influenza.[23] Risk decreases rapidly for small increases in 25(OH)D for those with initial values below 10 ng/ml (25 nmol/L), then decrease at a slower rate to levels above 40 ng/ml (100 nmol/L). These relations have been used to estimate the change in mortality rates and life expectancy if population mean serum 25(OH)D levels were raised from current levels of 20-25 ng/ml (50-63 nmol/L) to 45 ng/ml (113 nmol/L). For the U.S., it was estimated that 400,000 deaths/year could be delayed,[24] which is about 15% of all deaths/year. For the entire world, it was estimated that the reduction in all-cause mortality rates would correspond to an increased life expectancy of two years.[22]

The mechanisms whereby vitamin D reduces the risk of disease are largely understood. For cancer, they include effects on cellular differentiation and proliferation, angiogenesis and metastasis.[25] For infectious diseases, they include induction of cathelicidin and defensins [26] and shifting cytokine production from proinflammatory T-helper 1 (Th1) cytokines to Th2 cytokines.[27] For CVD, they may include reducing blood pressure and keeping calcium in the bones and teeth and out of the vascular tissues.[28] For diabetes mellitus type 2, they may include improving insulin sensitivity.[29]

Current Government-Sponsored Recommendations are Too Low

In spite of the large and expanding body of scientific evidence that vitamin D has many health benefits, the US Institute of Medicine issued a report in November 2010 claiming that the evidence was strong only for effects on bones.[30],[31] The reason given was lack of convincing randomized controlled trials on other health conditions. The one on cancer showing a 77% reduced risk of all-cancer incidence between the ends of the first and fourth years involved 1100 IU/day vitamin D plus 1450 mg/day calcium.[16] However, the IOM Committee relied on the findings from the start of the study, which was not statistically significant. In addition, the IOM Committee pointed to observational studies reporting a U-shaped serum 25(OH)D-disease incidence relation as a reason to be concerned about higher doses of vitamin D. However, these studies used a single serum 25(OH)D value from the time of enrollment followed by follow-up times as long as 17 years. Two studies reported that the sign of the correlation between disease outcome and serum 25(OH)D level changes from negative to positive after seven-to-15 years.[32],[33] Thus, the U-shaped relations are not reliable and should not be used as the basis for policy decisions, especially since the Committee refused to consider the largely beneficial findings from observational studies.

How Much Vitamin D Do We REALLY Need?

The IOM committee set the recommended vitamin D intake at 600 IU/day for those under the age of 70 years and 800 IU/day for those over 70, and stated that 20 ng/ml (50 nmol/L) was an adequate level. The scientific consensus is that oral intake should be 1000-5000 IU/day vitamin D with a goal of 30-40 ng/ml (75-100 nmol/L).[34] The vitamin D research community has responded to the IOM report on vitamin D with over 60 letters and articles in peer-reviewed journals pointing out the absurdity and illogic of the IOM report.[35] The Endocrine Society published a paper recommending 1500-2000 IU/day and 30 ng/ml.[36] Meanwhile, members of the IOM Committee have been publishing articles in mainstream journals promoting their report.

(William Grant, PhD, is the director of the Sunlight, Nutrition, and Health Research Center (SUNARC) in San Francisco, California. www.sunarc.org . The author receives funding from the UV Foundation, the Sunlight Research Forum, Bio-Tech-Pharmacal, the Vitamin D Council, and the Vitamin D Society of Canada.)

References:

1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-81.

2. Llewellyn DJ, Lang IA, Langa KM, Melzer D. Vitamin D and cognitive impairment in the elderly U.S. population. J Gerontol A Biol Sci Med Sci. 2011;66(1):59-65.

3. Cannell JJ, Hollis BW, Sorenson MB, Taft TN, Anderson JJ. Athletic performance and vitamin D. Med Sci Sports Exerc. 2009;41(5):1102-10.

4. Jablonski NG, Chaplin G. Colloquium paper: human skin pigmentation as an adaptation to UV radiation. Proc Natl Acad Sci U S A. 2010;107 Suppl 2:8962-8.

5. Gorham ED, Mohr SB, Garland CF, Chaplin G, Garland FC. Do sunscreens increase risk of melanoma in populations residing at higher latitudes? Ann Epidemiol. 2007;17(12):956-63.

6. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980;9(3):227-31.

7. Grant WB, Garland CF. The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res. 2006;26(4A):2687-99.

8. Leffell DJ and Brash DE: Sunlight and skin cancer. Sci Am. 275(1): 52-53, 56-59, 1996. http://toms.gsfc.nasa.gov/ery_uv/dna_exp.gif (accessed March 9, 2011).

9. Devesa SS, Grauman DJ, Blot WJ, Pennello GA, Hoover RN, Fraumeni JF Jr: Atlas of Cancer Mortality in the United States, 1950-1994. NIH Publication No. 99-4564, 1999. http://ratecalc.cancer.gov/ratecalc//

10. Grant WB, Mohr SB. Ecological studies of ultraviolet B, vitamin D and cancer since 2000. Ann Epidemiol. 2009;19(7):446-54.

11. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134(6):1129-40.

12. Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala NB, Clarke A, Franco OH. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas. 2010;65(3):225-36.

13. Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr. 2007;85(3):860-8.

14. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011:31:617-22.

15. Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ, Thoma A, Kiel DP, Henschkowski J. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169(6):551-61.

16. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85(6):1586-91.

17. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr. 2011 Aug 31. [Epub ahead of print]

18. Aloia JF, Li-Ng M. Re: epidemic influenza and vitamin D. Epidemiol Infect. 2007;135(7):1095-6; author reply 1097-8.

19. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010;91(5):1255-60.

20. Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, Walraven G. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med Int Health. 2010;15(10):1148-55.

21. Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B, 2010;101:130-136.

22. Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr, 2011;65:1016-1026.

23. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5(6):e11088.

24. Grant WB. In defense of the sun: An estimate of changes in mortality rates in the United States if mean serum 25-hydroxyvitamin D levels were raised to 45 ng/mL by solar ultraviolet-B irradiance. Dermato-Endocrinology, 2009;1(4):207-14.

25. Krishnan AV, Feldman D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol. 2011;51:311-36.

26. Liu PT, Stenger S, Tang DH, Modlin RL. Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol. 2007;179(4):2060-3.

27. Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med (Maywood). 2004;229(11):1136-42.

28. Zagura M, Serg M, Kampus P, Zilmer M, Eha J, Unt E, Lieberg J, Cockcroft JR, Kals J. Aortic stiffness and vitamin D are independent markers of aortic calcification in patients with peripheral arterial disease and in healthy subjects. Eur J Vasc Endovasc Surg. 2011 Aug 24. [Epub ahead of print]

29. Alvarez JA, Ashraf AP, Hunter GR, Gower BA. Serum 25-hydroxyvitamin D and parathyroid hormone are independent determinants of whole-body insulin sensitivity in women and may contribute to lower insulin sensitivity in African Americans. Am J Clin Nutr. 2010;92(6):1344-9.

30. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, Del Valle HB, editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011.

31. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53-8.

32. Lim U, Freedman DM, Hollis BW, Horst RL, Purdue MP, Chatterjee N, Weinstein SJ, Morton LM, Schatzkin A, Virtamo J, Linet MS, Hartge P, Albanes D. A prospective investigation of serum 25-hydroxyvitamin D and risk of lymphoid cancers. Int J Cancer. 2009;124(4):979-86.

33. Robien K, Cutler GJ, Lazovich D. Vitamin D intake and breast cancer risk in postmenopausal women: the Iowa Women's Health Study. Cancer Causes Control. 2007;18(7):775-82.

34. Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, Bischoff-Ferrari HA, Cavalier E, Ebeling PR, Fardellone P, Gandini S, Gruson D, Guérin AP, Heickendorff L, Hollis BW, Ish-Shalom S, Jean G, von Landenberg P, Largura A, Olsson T, Pierrot-Deseilligny C, Pilz S, Tincani A, Valcour A, Zittermann A. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev 2010;9:709-15.

35. Heaney RP, Grant WB, Holick MF, Amling M. The IOM Report on Vitamin D misleads. J Clin Endocrinol Metab. eLetter. (4 March 2011) http://jcem.endojournals.org/cgi/eletters/96/1/53

36. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2011;96(7):1911-30.

For More Information:

For additional information on vitamin D, the reader is directed to PubMed at http://www.ncbi.nlm.nih.gov/pubmed or www.pubmed.gov to search "vitamin D" along with any keyword of interest. Some representative papers found there, with free access, are listed below. Papers published in the Journal of Orthomolecular Medicine are (still) not listed on PubMed. Reasons for this are presented at http://orthomolecular.org/resources/omns/v06n03.shtml and http://orthomolecular.org/resources/omns/v06n07.shtml . All J Orthomolecular Med papers may all be accessed at the Journal's free archive: http://orthomolecular.org/library/jom/index.shtml .

Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab. 2010 Feb;95(2):471-8. Review. http://jcem.endojournals.org/content/95/2/471.full.pdf+html

Bikle DD. Vitamin D: newly discovered actions require reconsideration of physiologic requirements. Trends Endocrinol Metab. 2010 Jun;21(6):375-84. Epub 2010 Feb 10. Review. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880203/pdf/nihms-170960.pdf

Herr C, Greulich T, Koczulla RA, Meyer S, Zakharkina T, Branscheidt M, Eschmann R, Bals R. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respir Res. 2011 Mar 18;12:31. Review. http://respiratory-research.com/content/pdf/1465-9921-12-31.pdf

Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Endocrinol Metab Clin North Am. 2010 Jun;39(2):365-79, table of contents. Review. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879394/pdf/nihms180153.pdf

Raman M, Milestone AN, Walters JR, Hart AL, Ghosh S. Vitamin D and gastrointestinal diseases: inflammatory bowel disease and colorectal cancer. Therap Adv Gastroenterol. 2011 Jan;4(1):49-62. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3036961/pdf/10.1177_1756283X10377820.pdf

Zhang R, Naughton DP. Vitamin D in health and disease: current perspectives. Nutr J. 2010 Dec 8;9:65. Review. http://www.nutritionj.com/content/pdf/1475-2891-9-65.pdf

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