Editorial
Ongoing randomised clinical trials assessing the ability of vitamin D supplementation to reduce the risk of several non-skeletal disorders involve a population larger than that of Cambridge, UK, and will cost millions of research dollars. VITAL, for example, will enroll 20 000 participants and has US$22 million in funding. This vast investment of effort by patients, researchers, and funders is laudable, as it is almost certain that it will be sufficient to answer a question that has long kept the medical community in the dark. Vitamin D first became a medical success story when its importance in bone health and calcium homoeostasis was proven decades ago. Since then, epidemiological evidence has been accumulating to support a role for vitamin D in the protection of individuals from various non-skeletal disorders including cancer, cardiovascular diseases, autoimmune and inflammatory diseases, dementia, and diabetes; it might also reduce allcause mortality. Many of these studies show a strong association between low vitamin D concentrations and disease. However, the results of myriad recent small randomised controlled trials are almost unanimous in concluding that vitamin D supplementation provides protection from few, if any, of these outcomes. Vitamin D is a steroid hormone with pleiotropic and tissue-specific effects owing to the wide expression of the nuclear vitamin D receptor in many different tissues, and the many genes that are targeted by its actions. In the skeletal system, vitamin D promotes healthy development and remodelling of bone. In other tissues, vitamin D is postulated to mediate potentially beneficial effects via a wide variety of mechanisms: some evidence suggests that it exerts anticancer activity by limiting hyperproliferation of certain cell types, that it promotes metabolic health by regulating lipid metabolism in adipocytes, and that it limits autoimmunity by suppressing inappropriate immune responses. In a systematic review in The Lancet Diabetes & Endocrinology, Philippe Autier and colleagues discuss a large number of observational studies suggesting that high serum concentrations of vitamin D might be protective. For example, those with high vitamin D had decreased risk of cardiovascular events (by up to 58%), diabetes (by up to 38%), colorectal cancer (by up to 33%), and all-cause mortality (by www.thelancet.com/diabetes-endocrinology Vol 2 January 2014
up to 29%). However, they also compare these findings with the results of randomised clinical trials, which reveal a very different picture: no reduction in risk was found, even in trials involving adequate supplementation of participants with low vitamin D levels at baseline (less than 50 nmol/L). Autier and colleagues also did a new meta-analysis of 16 trials that assessed the effects of vitamin D supplementation on blood HbA1c, a biomarker mainly used for monitoring disorders of glucose metabolism. Although type 2 diabetes is associated with low vitamin D, the results show that vitamin D supplementation does not reduce HbA1c. Thus, it looks increasingly likely that low vitamin D is not a cause but a consequence of ill health. Despite the growing body of evidence indicating that vitamin D is unlikely to prevent non-skeletal disorders, there is strong support for its use from many prominent members of the research community, which is fuelled by the relatively low toxicity of vitamin D, the glimmer of positivity from some trials, and the large body of evidence from prospective observational studies. For those who ‘believe’, the lack of benefit found in most trials completed thus far can be attributed to issues including inadequate supplementation, testing of a population not sufficiently vitamin D deficient at baseline, incorrect formulation, underpowering, or insufficient follow-up. Vitamin D might not be safe in all settings, however. Supplementing at high doses could cause harm in people with already high concentrations of serum vitamin D, particularly in those with liver, kidney, or vascular problems. This is a concern, given the large number of people taking vitamin D supplements (up to 50% of adults in the USA). Large clinical trials to assess the effects of vitamin D on non-skeletal health outcomes are therefore justified. It would be a real boon to patients if the results are positive, but unless effect sizes for clinically important outcomes are large, the results will only confirm the neutral effect reported by most clinical trials thus far. Although this investment might therefore have little effect on current guidelines, the results will at least allow the research community to move on. ■ The Lancet Diabetes & Endocrinology
Eduardo Contreras/ZUMA Press/Corbis
Vitamin D: chasing a myth?
Published Online December 6, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70164-5 See Review page 76 For more background on non-skeletal effects of vitamin D see Endocr Rev 2012; 33: 456–92 For the 2011 Endocrine Society vitamin D deficiency guidelines see http://www.endocrine.org/~/ media/endosociety/Files/ Publications/Clinical%20 Practice%20Guidelines/FINALStandalone-Vitamin-DGuideline.pdf
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Ongoing randomised clinical trials assessing the ability of vitamin D supplementation to reduce the risk of several non-skeletal disorders involve a population larger than that of Cambridge, UK, and will cost millions of research dollars. VITAL, for example, will enroll 20 000 participants and has US$22 million in funding. This vast investment of effort by patients, researchers, and funders is laudable, as it is almost certain that it will be sufficient to answer a question that has long kept the medical community in the dark. Vitamin D first became a medical success story when its importance in bone health and calcium homoeostasis was proven decades ago. Since then, epidemiological evidence has been accumulating to support a role for vitamin D in the protection of individuals from various non-skeletal disorders including cancer, cardiovascular diseases, autoimmune and inflammatory diseases, dementia, and diabetes; it might also reduce allcause mortality. Many of these studies show a strong association between low vitamin D concentrations and disease. However, the results of myriad recent small randomised controlled trials are almost unanimous in concluding that vitamin D supplementation provides protection from few, if any, of these outcomes. Vitamin D is a steroid hormone with pleiotropic and tissue-specific effects owing to the wide expression of the nuclear vitamin D receptor in many different tissues, and the many genes that are targeted by its actions. In the skeletal system, vitamin D promotes healthy development and remodelling of bone. In other tissues, vitamin D is postulated to mediate potentially beneficial effects via a wide variety of mechanisms: some evidence suggests that it exerts anticancer activity by limiting hyperproliferation of certain cell types, that it promotes metabolic health by regulating lipid metabolism in adipocytes, and that it limits autoimmunity by suppressing inappropriate immune responses. In a systematic review in The Lancet Diabetes & Endocrinology, Philippe Autier and colleagues discuss a large number of observational studies suggesting that high serum concentrations of vitamin D might be protective. For example, those with high vitamin D had decreased risk of cardiovascular events (by up to 58%), diabetes (by up to 38%), colorectal cancer (by up to 33%), and all-cause mortality (by www.thelancet.com/diabetes-endocrinology Vol 2 January 2014
up to 29%). However, they also compare these findings with the results of randomised clinical trials, which reveal a very different picture: no reduction in risk was found, even in trials involving adequate supplementation of participants with low vitamin D levels at baseline (less than 50 nmol/L). Autier and colleagues also did a new meta-analysis of 16 trials that assessed the effects of vitamin D supplementation on blood HbA1c, a biomarker mainly used for monitoring disorders of glucose metabolism. Although type 2 diabetes is associated with low vitamin D, the results show that vitamin D supplementation does not reduce HbA1c. Thus, it looks increasingly likely that low vitamin D is not a cause but a consequence of ill health. Despite the growing body of evidence indicating that vitamin D is unlikely to prevent non-skeletal disorders, there is strong support for its use from many prominent members of the research community, which is fuelled by the relatively low toxicity of vitamin D, the glimmer of positivity from some trials, and the large body of evidence from prospective observational studies. For those who ‘believe’, the lack of benefit found in most trials completed thus far can be attributed to issues including inadequate supplementation, testing of a population not sufficiently vitamin D deficient at baseline, incorrect formulation, underpowering, or insufficient follow-up. Vitamin D might not be safe in all settings, however. Supplementing at high doses could cause harm in people with already high concentrations of serum vitamin D, particularly in those with liver, kidney, or vascular problems. This is a concern, given the large number of people taking vitamin D supplements (up to 50% of adults in the USA). Large clinical trials to assess the effects of vitamin D on non-skeletal health outcomes are therefore justified. It would be a real boon to patients if the results are positive, but unless effect sizes for clinically important outcomes are large, the results will only confirm the neutral effect reported by most clinical trials thus far. Although this investment might therefore have little effect on current guidelines, the results will at least allow the research community to move on. ■ The Lancet Diabetes & Endocrinology
Eduardo Contreras/ZUMA Press/Corbis
Vitamin D: chasing a myth?
Published Online December 6, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70164-5 See Review page 76 For more background on non-skeletal effects of vitamin D see Endocr Rev 2012; 33: 456–92 For the 2011 Endocrine Society vitamin D deficiency guidelines see http://www.endocrine.org/~/ media/endosociety/Files/ Publications/Clinical%20 Practice%20Guidelines/FINALStandalone-Vitamin-DGuideline.pdf
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