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Vitamin D status and ill health Philippe Autier and colleagues recently concluded that the frequently observed inverse associations between 25-hydroxyvitamin D (25[OH]D) and various health outcomes result from low 25(OH)D being a marker of ill health because putative benefits of vitamin D have generally not been supported by randomised controlled trials (RCTs). 1 However, the same authors use solely observational and mechanistic evidence to support a causal association between sunbed use and cutaneous melanoma, with conclusions compelling enough to warrant “nationwide prohibition of the public use of tanning devices”.2 In this case, the degree of evidence necessary for public policy did not require RCT evidence. Why does this imbalance exist? To advise people not to do or prohibit them from doing something that might be harmful— eg, stop smoking, avoid sunbeds— seems warranted. However, before the public are advised to do something potentially beneficial (increase vitamin D intake), the potential of adverse effects, however small, must be excluded. The fear of these potential effects can become paralysing—eg, it generally takes decades for the genotoxic effects of tobacco, ionising radiation, and arsenic to manifest. Based largely on observational data and mechanistic understanding, laws are formulated to limit exposure. If decades are needed for genotoxic events to manifest as cancer, a similar timescale is expected for genoprotective agents. If we are required to have RCT data on cancer endpoints, we are effectively precluded from ever harnessing potential anti-cancer benefits of micronutrients that protect genomic integrity. The biological evidence that deficiency of some micronutrients (eg, folate) is genotoxic is compelling,3 and observational studies suggest

low folate increases cancer risk, but after at least 15 years. RCTs have been constrained to fit the typical 5 year grant cycle. Moreover, instead of testing whether relative deficiency of a micronutrient might increase risk decades in the future, the short trial durations are often compensated by megadoses. Biologically, this makes as much sense as advising an elderly person who has been sedentary his entire life to immediately start intensive physical training after having developed angina. Regarding vitamin D, most RCTs have lasted only months or several years. For protection against acute respiratory infections, many RCTs have supported a short-term benefit of vitamin D. 4 Not all RCTs are positive, but this is expected in view of the heterogeneity of respiratory infections. For some diseases possibly linked to vitamin D deficiency, present biological understanding suggests a more complex timing relationship. For multiple sclerosis, for example, Autier and colleagues discount a role of vitamin D on the basis of equivocal results from RCTs designed to examine whether high doses would acutely reverse established disease. Yet the evidence for vitamin D effect on multiple sclerosis suggests a long process, possibly beginning as early as in utero, and is supported by ecological data on latitudinal gradient (UV-B), case-control studies on sun exposure, studies of vitamin D intake and 25(OH)D concentrations, and genetic studies of vitamin D pathway genes.5 When RCTs are not designed to test the relevant biological hypothesis, they should not be used to nullify all other types of evidence. I declare that I have no competing interests.

Edward Giovannucci [email protected] Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02135, USA 1

Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2014; 2: 76–89.

www.thelancet.com/diabetes-endocrinology Vol 2 April 2014

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Boniol M, Autier P, Boyle P, Gandini S. Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ 2012; 345: e4757. Fenech M. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat Res 2012; 733: 21–33. Bergman P, Lindh AU, Bjorkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One 2013; 8: e65835. Simon KC, Munger KL, Ascherio A. Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics. Curr Opin Neurol 2012; 25: 246–51.

In their article, Autier and colleagues1 argued that the beneficial effects of vitamin D have not been shown because RCTs have not supported the observational studies. Furthermore, they suggest that low blood concentrations of 25-hydroxyvitamin D (25[OH]D) recorded in many association studies was due to the inflammation associated with the chronic disease. This approach to assessment of the evidence of the health benefits of vitamin D is based on the medical model of evidence, which is not necessarily appropriate for natural compounds. As pointed out recently,2 most vitamin D RCTs were not only poorly designed but had poor compliance, so would probably not record a beneficial effect. The more appropriate way to establish causality is through application of Hill’s criteria for causality in a biological system.3 These criteria have been largely satisfied for breast cancer, especially when case-control and ecological studies, and one RCT for women who were not taking vitamin D or calcium supplements before entering the trial, are considered. 3 The mechanisms by which vitamin D reduces risk of cancer are well known. The authors1 proposed “the hypothesis that variations in 25(OH)D concentrations would essentially be a result, and not a cause, of ill health and inflammation”. The authors would also have to hypothesise inverse correlations between solar UVB doses 273

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and cancer incidence and mortality rates noted in ecological studies were due to confounding factors. However, most such ecological studies have accounted for the important cancer risk-modifying factors such as alcohol consumption, ethnic background, occupation, smoking, socioeconomic status, and urban or rural residence.3 Their hypothesis connecting ill health and inflammation as the cause for reduction in blood concentrations of 25(OH)D is not only flawed but the authors misrepresented the published work regarding their statement that “25(OH)D concentrations drop substantially during acute health episodes characterised by severe inflammation”. The two references cited do not support this hypothesis. Lee and colleagues4 reported a high incidence of vitamin D deficiency in patients in intensive care units that was associated with adverse outcomes independent of hypocalcaemia and hypoalbuminaemia. They suggested the cause was multifactorial—ie, little sun exposure and altered vitamin D and parathyroid hormone metabolism. Van den Berghe and colleagues5 reported that critically ill patients were vitamin D deficient and that 200 or 500 IUs of vitamin D₃ were inadequate to normalise vitamin D status, and that these patients had a striking increase in bone resorption and impaired osteoblast function. They also reported that raised markers of inflammation, CRP and interleukin 6, decreased significantly with time in the study groups receiving either 200 or 500 IUs of vitamin D3 daily, and that these changes seemed to be dose-related, with a more significant decrease for those receiving 500 IUs of vitamin D3. Neither of these reports suggests that serum 25(OH)D concentrations abruptly decreased, nor is there any suggestion that inflammation caused the vitamin D deficiency, in critically ill patients. Therefore, the veracity of the hypothesis and conclusions in this Article are open to question. 274

We declare that we have no competing interests.

Michael F Holick, William B Grant [email protected] Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, and the Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, Boston, MA, USA (MFH); and Sunlight, Nutrition, and Health Research Center, PO Box 641603, San Francisco, CA 94164-1603, USA (WBG) 1

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Autier P, Boniol M, Pizot C, Mullie, P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2014; 2: 76–89. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev 2014; 72: 48054. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients 2013; 5: 3993–4023. Lee P, Eisman JA, Center JR. Vitamin D deficiency in critically ill patients. N Engl J Med 2009; 360: 1912–14. Van den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq L, Bouillon R. Bone turnover in prolonged critical illness: effect of vitamin D. J Clin Endocrinol Metab 2003; 88: 4623–32.

We read with interest the recent review by Autier and colleagues1 of the considerable number of studies that have reported attempts to associate vitamin D deficiency, and efforts to restore normal concentrations via supplementation, with ill health. The outcomes partly mirror an earlier survey of meta-analyses of vitamin D supplement studies that showed no association with disease onset or progression.2 However, limitations of the focus of many vitamin D studies might be the overarching issue. The absence of a resolution between inherent and supplemented vitamin D concentrations with disease can be attributed to various experimental factors: deficiencies in assays (including the inability to differentiate and separately quantify active and inactive forms); the target of assays being the circulating forms, usually with no discrimination between forms, including epimers; absence of correlation between the usually measured circulating forms and the active form;3–5 administration of an individual supplemental form that is inactive without further enzymemediated activation; and absence of

understanding of the in-vivo roles of some forms. With the advent of more powerful vitamin D assays, recent studies attest to emerging roles of various forms of vitamin D stretching beyond the frequently measured circulating forms, among other factors.4,5 In view of the complexity of vitamin D metabolism, it is possible that vitamin D metabolites have myriad effects, through multiple mechanisms of action and crossregulation. Thus, supplementation might have significant benefits by enhancing concentrations of particular metabolites, and their functions might be dominant. However, this dominance—through competitive binding to activating enzymes, transport proteins, or receptors— might hinder roles of minor, nonsupplemented forms. A better understanding of the roles of different vitamin D forms could benefit patients through enabling targeted supplementation. Thus, it is recommended that further investigations involve application of modern assays that can accurately measure several forms of vitamin D, and potential roles of the full range of metabolites are considered in experimental design.5 Recent reports point to a role for hitherto largely ignored epimers in establishing maternal-affected neonate concentrations of vitamin D forms and associations with serious diseases such as rheumatoid arthritis, type 1 diabetes, and Alzheimer’s disease.4,5 In our view, it is premature to come to association-based conclusions about such a complex set of metabolites until investigations capture the roles of several forms, and supplementation with several forms. We declare that we have no competing interests.

Declan Naughton, *Andrea Petroczi [email protected] Faculty of Science, Engineering and Computing, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey KT1 2EE (DN, AP)

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Vitamin D status and ill health.

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