by William B. Grant, Ph.D.
Both the scientific evidence for and the awareness of vitamin D’s importance for optimal health are mounting. Originally, researchers considered vitamin D important only for preventing rickets and other bone diseases. Now, however, they recognize that vitamin D affects more than just the skeleton.
The skin naturally produces vitamin D3 (cholecalciferol) because ultraviolet-B (UVB) radiation acts on 7-dehydrocholesterol, after which a thermal reaction occurs. (Vitamin D also can be obtained from some foods and through taking supplements.) That vitamin D travels through the bloodstream to the liver, where it receives a hydroxyl (•OH) radical and becomes 25-dihydroxyvitamin D (calcidiol). The level of calcidiol measured in blood is one’s “vitamin D level.” Calcidiol then circulates in the blood and can be converted to 1,25-dihydroxyvitamin D (calcitriol), the active metabolite of vitamin D. Calcitriol helps regulate how much calcium the intestines absorb and the calcium concentration in the blood. Calcitriol acts as a key that can unlock vitamin D receptors (VDRs),which nearly every cell in the body has. VDRs are attached to chromosomes and, when activated, can affect the expression of hundreds of genes—making some more responsive and others less responsive. Other organs that need calcitriol can also produce it from calcidiol.
Scientifically, several ways exist to gauge vitamin D’s effects. Because solar UVB exposure is the main source of vitamin D for most people, studies of health outcomes and disease rates related to solar UVB doses are useful. Ecological studies offer one way to study how solar UVB affects health outcomes. In geographical ecological studies, researchers statistically compare average solar UVB doses with health outcomes for populations in geographically defined areas, such as states. Other disease risk–modifying factors also are included in such analyses. Such studies have helped to identify cancers for which UVB exposure and vitamin D reduce risk [Moukayed, 2013]. Temporal ecological studies also can be used. John Cannell proposed that the risk of influenza is highest in winter because of the lower solar UVB doses during that season [Cannell, 2006]. Ecological studies are often the first type of study to identify a beneficial effect of vitamin D. In general, observational and mechanism studies and clinical trials later support those findings [Grant, 2016]. Observational studies look at health outcomes with respect to vitamin D levels or sometimes UVB exposure history. Case–control studies use vitamin D levels measured when patients are diagnosed with a disease, such as breast cancer [Grant, 2015]. In prospective studies, researchers draw blood when participants enroll in a study and then look for changes in health over several years. Through laboratory investigations, scientists can determine how vitamin D reduces risk of adverse health outcomes. Although all those approaches are valid, our health care systems are designed around using pharmaceutical drugs, which require randomized controlled trials (RCTs) to show effectiveness and lack of harm. Unfortunately, many vitamin D RCTs have been poorly designed because they were based on the guidelines appropriate for drug trials. Such trials incorporate the assumption that the RCT is the only source of the agent in question and that a linear dose–response relation exists. They should be based on vitamin D levels [Heaney, 2014] as shown in a recent paper from a vitamin D RCT with pregnant women and preterm birth [Wagner, 2016]. Thus, for now, the other types of studies generally offer the best evidence for the benefits of UVB exposure and vitamin D.
Cancer cells survive by exploiting cellular differentiation; proliferation; and apoptosis, angiogenesis, and metastasis. UVB exposure and vitamin D reduce the risk of about 15–20 endothelial cancers [Moukayed, 2013]. The evidence is strongest for colorectal and breast cancer [Grant, 2015]. The risk reduces rapidly when the vitamin D level increases up to 20 ng/mL (50 nmol/L) and then more slowly to above 40 ng/mL. (For white Americans, the average annual level of vitamin D is around 25 ng/mL, whereas for black Americans it is near 16 ng/mL. Vitamin D levels are highest in summer, lowest in winter [Kroll, 2015].) In three RCTs, taking 1000–2000 IU/d vitamin D3 plus calcium reduced the risk of all-cancer incidence [Lappe, 2007; Bolland, 2011; Lappe, 2016]. People with vitamin D levels above 30 ng/mL tend to live much longer after cancer diagnosis [Tretli, 2012]. From the evidence to date, it seems reasonable to use vitamin D supplements and sensible solar UVB exposure to reduce the risk of, and treat, cancer [Grant, 2016].
Rates of cardiovascular disease (for example, congestive heart failure, coronary heart disease, and strokes) are higher in winter, when vitamin D levels are lowest, than in summer. Observational studies have associated lower vitamin D levels with higher risk of cardiovascular disease [Wang, 2012]. The mechanisms may be related to reducing infections, inflammation, and vascular calcification. The role of vitamin D in reducing risk of cardiovascular disease satisfies most of Hill’s criteria for causality in a biological system [Weyland, 2014]. Hill's criteria include strength of association, consistent findings in different populations, plausibility, and experiment [Hill, 1965]. However, clinical trials (RCTs) do not find that vitamin D supplementation reduces the risk of cardiovascular disease [Veloudi, 2016]. Thus, if the RCTs are correct, vitamin D levels may be associated with reduced risk of cardiovascular disease due to lower solar UVB exposure or elevated risk in winter when it is colder.
Vitamin D reduces the risk of several infectious diseases, both bacterial (e.g., pneumonia, sepsis) and viral (e.g., acute respiratory tract infections, influenza). At least two mechanisms are involved: (i) induction of cathelicidin and defensins and (ii) shifting the cytokine balance away from proinflammatory cytokines [Grant, 2009]. In RCTs, vitamin D supplementation reduced the risk of acute respiratory tract infections [Camargo, 2012] and influenza [Urashima, 2010]. In reducing the risk of influenza, vitamin D is probably at least as effective as vaccines. Vitamin D also can reduce tooth decay [Hujoel, 2012].
UVB exposure and vitamin D reduce both the risk and the symptoms of several autoimmune diseases. For multiple sclerosis, UVB exposure seems to have both effects from vitamin D production and from other, unknown mechanisms [DeLuca, 2016].
All-cause mortality rate:
The main question of vitamin D’s effects is whether higher levels are associated with lower mortality rates. One meta-analysis analyzed 32 prospective studies of both healthy and diseased individuals finding reduced mortality rates up to 36 ng/mL [Garland, 2014]. A recent study from Sweden found that people with the highest sun exposure had a life expectancy 0.6–2.1 years longer than that of sun avoiders [Lindqvist, 2016]. My earlier analysis of the benefits of increasing vitamin D levels in the population from 22 ng/mL (the average value in many countries) to 44 ng/mL would reduce mortality rates by about 15% and increase life expectancy by about 2 years [Grant, 2011].
Having high vitamin D levels during pregnancy and lactation is important for both mother and offspring. Genes control much of what happens during fetal development, and because vitamin D controls gene expression, having the optimal concentration is important. In a clinical trial in South Carolina, pregnant and nursing women needed 4000–6000 IU of vitamin D3per day to reach calcidiol levels of 40 ng/mL,at which calcitriol levels plateau [Hollis, 2011]. Observational studies linked higher levels of calcidiol during pregnancy to lower risk of birth requiring primary Cesarean delivery, preeclampsia, gestational diabetes, preterm delivery, and small-for-gestational-age delivery [Karras, 2016].
Other effects of vitamin D:
There are many effects attributed to vitamin D. For both the ones discussed here and additional ones, you may search the sources of information listed later.
Concerns about high vitamin D levels:
Several studies reported that people with vitamin D levels above 70–100 nmol/L had higher risks of adverse effects than people with vitamin D levels around 30 ng/mL. Reviewing the medical literature, my colleagues and I found that few of those findings could be considered definitive: many people showing adverse effects at higher vitamin D levels may have started supplementing with vitamin D shortly before entering the prospective studies, perhaps because their physician noticed a condition related to vitamin D deficiency. Thus, they were placed in the wrong vitamin D category [Grant, 2016].
Solar UVB exposure:
Because solar UVB exposure is the most important source of vitamin D for most people, examining the controversy surrounding UV exposure is worthwhile. Perhaps the best evidence that humans were meant to obtain vitamin D from solar UVB exposure is that skin pigmentation varies depending on where people have lived for many generations. Dark skin pigmentation, for example, protects against skin cancer and folate destruction but permits enough UVB to penetrate to generate vitamin D in the tropical plains. Light skin pigmentation, by contrast, is required at higher latitudes because of lower UVB doses there [Grant, 2016]. The time required to produce enough vitamin D depends on several factors such as the solar elevation angle, which varies during the day and with season [Engelsen, 2010];the amount of skin area exposed; and age (as people age, the skin makes less vitamin D). Although concern exists about the risk of skin cancer and melanoma from sun exposure, keep some facts in mind. First, the time people spend in the sun has decreased significantly during the past 70 years because of shifting work to largely indoor occupations. Melanoma incidence rates have risen dramatically during that period, but mortality rates have stayed nearly constant. Thus, much of the “increased” diagnosis of melanoma is probably due to nonlethal melanomas. Second, the risk of death from skin cancer and melanoma is much lower than that from internal cancers (3% vs. 97%), and sun exposure confers many other benefits.
Determined largely from observational studies, the optimal vitamin D level is above 30 ng/mL [Holick, 2011; Pludowski, 2012], but 40 ng/mL is even better [Garland, 2014; Lappe, 2016; McDonnell, 2016]. The Institute of Medicine recommended 20 ng/mL and daily supplementation with 600–800 IU of vitamin D3. Those values are based primarily on clinical studies related to bone health and a deeply flawed analysis of data from Germany on bone condition with respect to vitamin D level [Heaney, 2011]. The U.S. Food and Drug Administration, the National Institutes of Health, and Health Canada sponsored that review. Although uncertainty regarding vitamin D’s beneficial and harmful effects certainly exists, nearly all the evidence supports beneficial effects. The fact that existing health systems require RCTs before accepting vitamin D is a very high bar that I believe is set to protect the status quo. As German philosopher Arthur Schopenhauer said, “All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident.” Vitamin D is now in the middle of the second stage. Think of vitamin D as inexpensive health and life insurance. A year’s supply can cost $10-$20. A look back at changes in public health policies indicates that beneficial changes happen slowly. For example, going from understanding how to prevent scurvy to carrying citrus fruits aboard ships took about a century. And doctors took decades to start washing their hands between autopsies and examinations of pregnant women after Semmelweis showed that doing so reduced deaths.
Sources of information on vitamin D:
The standard sources of the peer-reviewed journal literature on vitamin D are the National Library of Medicine’s PubMed database (https://www.ncbi.nlm.nih.gov/pubmed/) and Google Scholar (https://scholar.google.com/). Publications can be searched by topic, title, or author. The full text is often available for free, especially from Google Scholar or by e-mailing the authors. In addition, several vitamin D organizations stay abreast of and often update the benefits of UVB exposure and vitamin D. The first two also offer blood spot tests of vitamin D level at a nominal cost of about $60. They recommend measuring your vitamin D level prior to starting to supplement, then again after a few months of supplementation. There is considerable variation in the response to both UVB exposure and oral vitamin D.
- Grassroots Health has an advisory panel of about 50 leading vitamin D researchers, offers many videos by those researchers, and sponsors vitamin D supplementation programs for pregnant women.
- The Vitamin D Council is a vitamin D advocacy organization that offers summaries of the benefits of vitamin D for many health conditions and more than a dozen podcasts by leading vitamin D researchers.
- The Vitamin D Society is a Canadian organization interested in both UV exposure and vitamin D.
- The Vitamin D Wiki offers papers that can be translated into more than 90 languages.
For evidence-based research on the benefits of vitamin D, visit the GreenMedInfo.com Research Dashboard.
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 Oct;94(4):1144-9. http://ajcn.nutrition.org/content/94/4/1144.long
Camargo CA Jr, Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, Sumberzul N, Rich-Edwards JW. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012 Sep;130(3):e561-7. http://pediatrics.aappublications.org/content/pediatrics/130/3/e561.full.pdf
Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect. 2006 Dec;134(6):1129-40. http://xa.yimg.com/kq/groups/27664726/279293356/name/Epidemic+influenza+and+vitamin+D+Review.pdf
DeLuca HF, Plum L. UVB radiation, vitamin D and multiple sclerosis. Photochem Photobiol Sci. 2016 Dec 2. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27910985
Engelsen O. The relationship between ultraviolet radiation exposure and vitamin D status. Nutrients. 2010 May;2(5):482-95. http://www.mdpi.com/2072-6643/2/5/482/htm
Grant WB, Karras SN, Bischoff-Ferrari HA, Annweiler C, Boucher BJ, Juzeniene A, Garland CF, Holick MF. Do studies reporting ‘U’-shaped serum 25-hydroxyvitamin D–health outcome relationships reflect adverse effects? Dermato-Endocrinology, 2016;8(1): e1187349. http://www.tandfonline.com/doi/full/10.1080/19381980.2016.1187349
Grant WB. 25-Hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case–control versus nested case–control studies. Anticancer Res. 2015;35(2):1153-60. http://ar.iiarjournals.org/content/35/2/1153.short
Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr. 2011 September;65(9):1016-26. http://www.nature.com/ejcn/journal/v65/n9/pdf/ejcn201168a.pdf
Grant WB. Roles of solar UVB and vitamin D in reducing cancer risk and increasing survival. Anticancer Res. 2016;36(3):1357-1370. http://ar.iiarjournals.org/content/36/3/1357.full.pdf+html
Grant WB. The Role of geographical ecological studies in identifying diseases linked to UVB exposure and/or vitamin D. Dermato-Endocrinology. 2016 Jan 8;8(1):e1137400 http://www.tandfonline.com/doi/full/10.1080/19381980.2015.1137400
Grant WB. The UVB-vitamin D3-skin pigmentation is alive and well. Am J Phys Anthro. 2016 Dec; 61(4):752-755.
Heaney RP, Holick MF. Why the IOM recommendations for vitamin D are deficient. J Bone Miner Res. 2011;26(3):455-7. http://onlinelibrary.wiley.com/doi/10.1002/jbmr.328/epdf
Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014 Jan;72(1):48-54. https://www.ncbi.nlm.nih.gov/pubmed/24330136
Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965 May;58:295-300. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1898525/pdf/procrsmed00196-0010.pdf
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 Jul;96(7):1911-30. http://press.endocrine.org/doi/pdf/10.1210/jc.2011-0385
Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011 Oct;26(10):2341-57. http://onlinelibrary.wiley.com/doi/10.1002/jbmr.463/epdf
Hujoel PP. Vitamin D and dental caries in controlled clinical trials: systematic review and meta-analysis. Nutrition Reviews. 2013 Feb;71(2):88-97. http://nutritionreviews.oxfordjournals.org/content/71/2/88.short
Karras S, Fakhoury H, Muscogiuri G, Grant WB, van den Ouweland JM, Colao AM, Kotsa K Maternal Vitamin D status in pregnancy and neonatal health: evidence to date and clinical implications. Ther Adv Musculoskelet Dis. 2016 Aug;8(4):124-35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959630/pdf/10.1177_1759720X16656810.pdf
Kroll MH, Bi C, Garber CC, Kaufman HW, Liu D, Caston-Balderrama A, Zhang K, Clarke N, Xie M, Reitz RE, Suffin SC, Holick MF. Temporal Relationship between Vitamin D Status and Parathyroid Hormone in the United States. PLoS One. 2015 Mar 4;10(3):e0118108. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118108
Lindqvist PG, Epstein E, Nielsen K, Landin-Olsson M, Ingvar C, Olsson H. Avoidance of sun exposure as a risk factor for major causes of death: a competing risk analysis of the Melanoma in Southern Sweden cohort. J Intern Med. 2016 Oct;280(4):375-87. http://onlinelibrary.wiley.com/doi/10.1111/joim.12496/full
McDonnell SL, Baggerly C, French CB, Baggerly LL, Garland CF, Gorham ED, Lappe JM, Heaney RP. Serum 25-hydroxyvitamin D concentrations ≥40 ng/ml are associated with >65% lower cancer risk: Pooled analysis of randomized trial and prospective cohort study. PLoS One. 2016 Apr 6;11(4):e0152441. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152441
Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023. http://www.mdpi.com/2072-6643/5/10/3993
Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, Shoenfeld Y, Lerchbaum E, Llewellyn DJ, Kienreich K, Soni M. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality- a review of recent evidence. Autoimmun Rev. 2013 Aug;12(10):976-89. https://www.ncbi.nlm.nih.gov/pubmed/23542507
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 Jan;96(1):53-8. http://press.endocrine.org/doi/pdf/10.1210/jc.2010-2704
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 May;91(5):1255-60. http://ajcn.nutrition.org/content/91/5/1255.full.pdf+html
Veloudi P, Jones G, Sharman JE. Effectiveness of vitamin D supplementation for cardiovascular health outcomes. Pulse 2016;4:193-207. https://www.karger.com/Article/FullText/452742
Wagner CL, Baggerly C, McDonnell S, Baggerly KA, French CB, Baggerly L, Hamilton SA, Hollis BW. Post-hoc analysis of vitamin D status and reduced risk of preterm birth in two vitamin D pregnancy cohorts compared with South Carolina March of Dimes 2009-2011 rates. J Steroid Biochem Mol Biol. 2016 Jan;155(Pt B):245-51. https://www.ncbi.nlm.nih.gov/pubmed/26554936