Correspondence
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
2
3
4
5
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
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
2
3
4
5
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
