Vitamin D as in different

Preventive Medicine 51 (2010) 195-196 (PDF is attached)

Randomized studies have now essentially debunked the naive vision of all vitamins as being good for health no matter what the dose. The first shock came from the demonstration that high doses of beta-carotene compared to placebo increased lung cancer risk among smokers in Finland (ATBC, 1994) and in the US (Hennekens et al., 1996; Omenn et al., 1996). Then came the evidence that vitamin E was ineffective for preventing cardiovascular diseases (Sesso et al., 2008) or cancer (Lin et al., 2009), and at high doses could even be life-threatening (Miller et al., 2005). Finally there are the continuing sobering negative results about the potential benefits of high doses of multivitamin, multimineral supplements, vitamin C, for all types of indications (e.g., Douglas et al., 2007; Lin et al., 2009; Mulholland and Bedford, 2007; Huang et al., 2006), even though there seem to be no major side effects in the case of vitamin C.

Vitamins A, C, and E are all anti-oxidants. They are believed to trap free radicals and thus protect cells from their damaging oxidative effects. We definitely need them, they are indispensable for our metabolism, but they should not and need not be used beyond the daily dietary recommended doses. Indeed, a too-neglected positive message came from the French large community trial SU.VI. MAX, in which a cocktail-pill of vitamins A, E, and C and of anti-oxidant minerals, not exceeding the dietary recommended doses, was found to have a protective effect against cancer in men, but not women (Hercberg et al., 2004).

Vitamin D is different. First, it is not an anti-oxidant. The more we learn about vitamin D, the more healthful it seems to be. Most tissues and cells in the body have a vitamin D receptor involved in the regulation of cellular proliferation, differentiation, and death (Holick, 2007). Its effects on bone mass, osteoporosis, and fractures are well known and established, but vitamin D also has beneficial effects on many chronic illnesses, including autoimmune and infectious diseases (Holick, 2007). Dietary supplementation with vitamin D appears to reduce the risks of cancer (Lappe et al., 2007) and overall mortality (Autier and Gandini, 2007).

What about cardiovascular diseases, the most common cause of death in many regions of the world (WHO, 2008)? A deficit of vitamin D seems to be detrimental in this major health domain too. This issue of Preventive Medicine includes a study by Grandi et al. reporting the results of a systematic review and meta-analysis of cohort studies relating serum vitamin D (25-hydro- xyvitamin D, abbreviated 25-OH-D) to cardiovascular disease incidence and mortality (Grandi et al., 2010). Compared to those in the highest category of vitamin D intake, defined either by quartiles or quintiles, those in the lowest categories of serum vitamin D had an increased meta-analytic risk of cardiovascular events of 1.5 for incidence and of 1.8 for death.

Vitamin D is different from vitamins A and E in another way which can be decisively important when designing community interventions. It has been used at very high doses for many months without toxic effects. This makes sense if you will permit us a small speculative digression. Vitamins are molecules that are so common in our environment that there was no evolutionary pressure for humans to self-synthesize them. There is a limited natural supply of vitamins A and E, so there was no selection advantage of consuming doses superior to those that we can reasonably found in our food. But we get vitamin D from exposure to sunlight, which our ancestors had in huge amounts. We are therefore likely to be configured to stand high daily doses of vitamin D over long periods.

Dependence on sunlight also makes vitamin D intake different from that of other vitamins, because protecting ourselves from UV exposure has resulted in widespread vitamin D deficiency in many regions of the world (Holick, 2007).

Doesn't vitamin D appear as the perfect candidate for community supplementation trials? Its deficit is prevalent. It seems associated with increased risk for common chronic diseases. To our knowledge, there is a good dose margin before it can become toxic, at least among people free of kidney diseases. Too good to be true? We would welcome in Preventive Medicine data or ideas that would take us further in this direction.

References

• ATBC (The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group), 1994. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330, 1029-1035.
• Autier, P., Gandini, S., 2007. Vitamin D supplementaion and total mortality: a meta-analysis of randomized controlled trials. Arch. Int. Med. 167, 1730-1737.
• Douglas, R.M., Hemilä, H., Chalker, E., Treacey, B., 2007. Vitamin C for preventing and treating the common cold. Cochrane Database of Syst. Rev. (Issue 3) doi:10.1002/14651858.CD000980.pub3 Art. No. CD000980.
• Grandi, N.C., Breitling, L.P., Brenner, H., 2010. Vitamin D and cardiovascular disease: Systematic review of prospective studies. Prev. Med. 51 228-233.
• Hennekens, C.H., Buring, J.E., Manson, J.E., et al., 1996. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N. Engl. J. Med. 334, 1145-1149.
• Hercberg, S., Galan, P., Preziosi, P., et al., 2004. The SU.VI.MAX study: a randomized, placebo-controlled trial of the health effects of anti-oxidant vitamins and minerals. Arch. Intern. Med. 164, 2335-2342.
• Holick, M.F., 2007. Vitamin D deïfciency. New Engl. J. Med. 357, 266-281.
• Huang, H.Y., Caballero, B., Chang, S., et al., 2006. The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference. Ann. Intern. Med. 145, 372-385.
• Lappe, J.M., Travers-Guftafson, 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, 1586-1591.
• Lin, J., Cook, N.R., Albert, C., et al., 2009. Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. J. Natl. Cancer Inst. 101, 14-23.
• Miller, E.R., Pastor-Barriuso, R., Dalal, D., Riemersma, R.A., Appel, L.J., Guallar, E., 2005. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann. Intern. Med. 142, 37-46.
• Mulholland, C.A., Benford, D.J., 2007. What is known about the safety of multivitamin-multimineral supplements for the generally healthy population? Theoretical basis for harm. Am. J. Clin. Nutr. 85, 318S-322S.
• Omenn, G.S., Goodman, G.E., Thornquist, M.D., et al., 1996. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334, 1150-1155.
• Sesso, H.D., Buring, J.E., Christen, W.G., et al., 2008. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA 300, 2123-2133.
• WHO (World Health Organization), 2008. The top ten causes of death Fact sheet No 310 http://www.who.int/mediacentre/factsheets/fs310/en/2008(accessed 16 August 2010).

Alfredo Morabia

Center for the Biology of Natural Systems, Queens College-CUNY,
163-03 Horace Harding Expressway, Flushing, NY 11365, USA

Michael C. Costanza

6 Newbury Close, Rushden, Northamptonshire NN10 0EU, UK Preventive.Medicine at qc.cuny.edu.