Correspondence
concerns on the authors’ arguments against the efficacy of vitamin D in the prevention of fractures and mortality, we believe that the same concerns apply to the other outcomes. In view of the small risk and cost of vitamin D supplementation, we believe that it is too early to recommend the cessation of trials and certainly too early to stop treatment with vitamin D. HAB-F reports investigator initiated funding by MSD, DSM, Nestle, Roche Diagnostics, WILD, and Pfizer. We declare that we have no further competing interests.
Heike A Bischoff-Ferrari, Endel J Orav, Walter C Willett, Bess Dawson-Hughes heikeabischoff@aol.com Department of Geriatrics and Aging Research, University of Zurich, Zurich, Switzerland (HAB-F), Department of Medicine, Harvard Medical School, MA, USA (EJO), Department of Nutrition, Harvard School of Public Health, MA, USA (WCW), Jean Mayer USDA Human Nutrition Research Centre on Aging, Tufts University Boston, MA, USA (BD-H) 1
2
3
Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014; published online Jan 24. http:// dx.doi.org/10.1016/S2213-8587(13)70212-2. Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebocontrolled trial. Lancet 2005; 365: 1621–28. Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C. Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial. Rheumatology (Oxford) 2007; 46: 1852–57.
The recent report by Bolland and colleagues1 noted that results of randomised controlled trials of vitamin D supplementation for community-dwelling people do not reduce skeletal, vascular, or cancer outcomes greater than 15%. Part of the reason for this finding might be that nearly all of the trials reviewed used between daily averaged values of 400 and 1000 IU vitamin D. Worldwide, population averaged serum 25-hydroxyvitamin D (25OHD) concentrations are about 54 nmol/L.2 From meta-analysis of observational studies of cardiovascular disease incidence versus serum 25OHD 364
concentrations, an increase of serum 25OHD concentrations from 54 to 105 nmol/L was associated with a 15% reduced incidence rate.2 A similar analysis for breast and colorectal cancer found a 30% reduction.3 To raise the mean population serum 25OHD concentration from 54 to 105 nmol/L would take 2500–3000 IU per day vitamin D3.4 The estimated health benefit for this action is a 15% reduction in all-cause mortality rate and a 2 year increase in life expectancy.2 It should also be noted that there are two general types of randomised controlled trials of vitamin D. Most of these trials, including most referenced by Bolland and colleagues, enrolled community-dwelling people without regard for serum 25OHD concentrations, and gave 400–1000 IU per day vitamin D. Another type of vitamin D randomised controlled trial is required to assess the effects of serum 25OHD on health outcomes. In such trials, the relation between serum 25OHD concentrations and the health outcome of interest should be known from observational studies, those enrolled in the study should have serum 25OHD concentrations low enough that vitamin D supplementation will provide health benefits, serum 25OHD concentrations should be measured after supplementation, and conutrient status should be optimised.5 For both types of trials, sufficient numbers of people should be enrolled so that the 95% confidence intervals are smaller than the expected vitamin D supplementation effects. This requirement makes vitamin D randomised controlled trial very expensive. Until these guidelines are incorporated, observational studies with short follow-up times will probably provide better evidence of the health benefits of vitamin D than will the trials. I receive funding from Bio-Tech Pharmacal (Fayetteville, AR), and the Sunlight Research Forum (Veldhoven), and have received funding from the UV
Foundation (McLean, VA), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada). I declare that I have no further competing interests.
William B Grant wbgrant@infionline.net Sunlight, Nutrition, and Health Research Center, San Francisco, CA 94164-1603, USA 1
2
3
4
5
Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014; published online Jan 24. http:// dx.doi.org/10.1016/S2213-8587(13)70212-2. Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr 2011; 65: 1016–26. Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B 2010; 101: 130–36. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011; 31: 617–22. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev 2014; 72: 48–54.
Authors’ reply All the correspondents suggest that vitamin D supplementation had no effect on skeletal or nonskeletal endpoints because the doses studied were too low. The goal of vitamin D supplementation is to increase 25-hydroxyvitamin D (25OHD) in the hope that higher 25OHD concentrations will lead to fewer events. 70% of the trials in our analyses reported baseline 25OHD concentrations lower than 50 nmol/L and 90% of these studies achieved 25OHD of 60–75 nmol/L with vitamin D supplementation. Data from observational studies suggest a continuous U-shaped relationship between 25OHD and non-skeletal outcomes.1,2 If this relationship is causal, such studies would predict that increasing 25OHD from less than 50 nmol/L to 60-75 nmol/L would reduce event rates. Findings of our analyses showed that this did not happen, suggesting that the association between 25OHD and health outcomes in observational studies is not causal; rather, low 25OHD might be a marker of ill
www.thelancet.com/diabetes-endocrinology Vol 2 May 2014
Correspondence
health.3 Trials that increase 25OHD to still higher concentrations are unlikely to find different results to our analyses; in fact, higher concentrations of 25OHD might be harmful.4 We disagree with Bischoff-Ferrari and colleagues that our trial inclusion criteria were too broad. All the trials were included in previous metaanalyses, and the populations and doses studied are consistent with existing recommendations for vitamin D supplementation. Many of the criticisms of these trials seem somewhat arbitrary, and consistent with responses to evidence constituting medical reversal,5 wherein fault is found with the trials and there is unwillingness to consider that the intervention might be ineffective. Trial durations are unlikely to have been too short to show effects, as suggested by Anagnostis and colleagues and Bischoff-Ferrari and colleagues because each analysis included at least four large trials (n>1000) lasting 4 years or longer. Anagnostis and colleagues regard the continuing VITAL trial to be pivotal, but it might report similar results to previous trials. Despite its size, it has limited power to detect small effects (200 000). We disagree with Bischoff-Ferrari and colleagues that the small benefits of co-administered vitamin D with calcium on fracture make them suitable as a public health intervention, because any benefits are outweighed by the risk of adverse effects (kidney stones, cardiovascular events, and acute gastrointestinal symptoms).7 Our results suggest that whether vitamin D supplements reduce mortality remains uncertain, and any absolute benefit is very small, suggesting no present public health indication for mortality reduction.
www.thelancet.com/diabetes-endocrinology Vol 2 May 2014
MB is funded by the Health Research Council of New Zealand and is the recipient of a Sir Charles Hercus Health Research Fellowship. MB, IRR, GDG, and AG received grants from the Health Research Council of New Zealand during the study. We declare that we have no further competing interests.
Mark J Bolland, Andrew Grey, Greg D Gamble, Ian R Reid [email protected] Department of Medicine, University of Auckland, Auckland 1142, New Zealand (MJB, AG, GDG, IRR) 1
2
3
4
5
6
7
Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008; 168: 1629–37. Michaelsson K, Baron JA, Snellman G, et al. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr 2010; 92: 841–48. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2014; 2: 76–89. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010; 303: 1815–22. Prasad V, Cifu A, Ioannidis JP. Reversals of established medical practices: evidence to abandon ship. JAMA 2012; 307: 37–38. Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials 2012; 33: 159–71. Bolland MJ, Grey A, Reid IR. Benefits of calcium supplements are too small for clinical equipoise to exist. J Bone Miner Res 2014; published online April 3. DOI:10.1002/ jbmr.2235.
365
concerns on the authors’ arguments against the efficacy of vitamin D in the prevention of fractures and mortality, we believe that the same concerns apply to the other outcomes. In view of the small risk and cost of vitamin D supplementation, we believe that it is too early to recommend the cessation of trials and certainly too early to stop treatment with vitamin D. HAB-F reports investigator initiated funding by MSD, DSM, Nestle, Roche Diagnostics, WILD, and Pfizer. We declare that we have no further competing interests.
Heike A Bischoff-Ferrari, Endel J Orav, Walter C Willett, Bess Dawson-Hughes heikeabischoff@aol.com Department of Geriatrics and Aging Research, University of Zurich, Zurich, Switzerland (HAB-F), Department of Medicine, Harvard Medical School, MA, USA (EJO), Department of Nutrition, Harvard School of Public Health, MA, USA (WCW), Jean Mayer USDA Human Nutrition Research Centre on Aging, Tufts University Boston, MA, USA (BD-H) 1
2
3
Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014; published online Jan 24. http:// dx.doi.org/10.1016/S2213-8587(13)70212-2. Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebocontrolled trial. Lancet 2005; 365: 1621–28. Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C. Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial. Rheumatology (Oxford) 2007; 46: 1852–57.
The recent report by Bolland and colleagues1 noted that results of randomised controlled trials of vitamin D supplementation for community-dwelling people do not reduce skeletal, vascular, or cancer outcomes greater than 15%. Part of the reason for this finding might be that nearly all of the trials reviewed used between daily averaged values of 400 and 1000 IU vitamin D. Worldwide, population averaged serum 25-hydroxyvitamin D (25OHD) concentrations are about 54 nmol/L.2 From meta-analysis of observational studies of cardiovascular disease incidence versus serum 25OHD 364
concentrations, an increase of serum 25OHD concentrations from 54 to 105 nmol/L was associated with a 15% reduced incidence rate.2 A similar analysis for breast and colorectal cancer found a 30% reduction.3 To raise the mean population serum 25OHD concentration from 54 to 105 nmol/L would take 2500–3000 IU per day vitamin D3.4 The estimated health benefit for this action is a 15% reduction in all-cause mortality rate and a 2 year increase in life expectancy.2 It should also be noted that there are two general types of randomised controlled trials of vitamin D. Most of these trials, including most referenced by Bolland and colleagues, enrolled community-dwelling people without regard for serum 25OHD concentrations, and gave 400–1000 IU per day vitamin D. Another type of vitamin D randomised controlled trial is required to assess the effects of serum 25OHD on health outcomes. In such trials, the relation between serum 25OHD concentrations and the health outcome of interest should be known from observational studies, those enrolled in the study should have serum 25OHD concentrations low enough that vitamin D supplementation will provide health benefits, serum 25OHD concentrations should be measured after supplementation, and conutrient status should be optimised.5 For both types of trials, sufficient numbers of people should be enrolled so that the 95% confidence intervals are smaller than the expected vitamin D supplementation effects. This requirement makes vitamin D randomised controlled trial very expensive. Until these guidelines are incorporated, observational studies with short follow-up times will probably provide better evidence of the health benefits of vitamin D than will the trials. I receive funding from Bio-Tech Pharmacal (Fayetteville, AR), and the Sunlight Research Forum (Veldhoven), and have received funding from the UV
Foundation (McLean, VA), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada). I declare that I have no further competing interests.
William B Grant wbgrant@infionline.net Sunlight, Nutrition, and Health Research Center, San Francisco, CA 94164-1603, USA 1
2
3
4
5
Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014; published online Jan 24. http:// dx.doi.org/10.1016/S2213-8587(13)70212-2. Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr 2011; 65: 1016–26. Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B 2010; 101: 130–36. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011; 31: 617–22. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev 2014; 72: 48–54.
Authors’ reply All the correspondents suggest that vitamin D supplementation had no effect on skeletal or nonskeletal endpoints because the doses studied were too low. The goal of vitamin D supplementation is to increase 25-hydroxyvitamin D (25OHD) in the hope that higher 25OHD concentrations will lead to fewer events. 70% of the trials in our analyses reported baseline 25OHD concentrations lower than 50 nmol/L and 90% of these studies achieved 25OHD of 60–75 nmol/L with vitamin D supplementation. Data from observational studies suggest a continuous U-shaped relationship between 25OHD and non-skeletal outcomes.1,2 If this relationship is causal, such studies would predict that increasing 25OHD from less than 50 nmol/L to 60-75 nmol/L would reduce event rates. Findings of our analyses showed that this did not happen, suggesting that the association between 25OHD and health outcomes in observational studies is not causal; rather, low 25OHD might be a marker of ill
www.thelancet.com/diabetes-endocrinology Vol 2 May 2014
Correspondence
health.3 Trials that increase 25OHD to still higher concentrations are unlikely to find different results to our analyses; in fact, higher concentrations of 25OHD might be harmful.4 We disagree with Bischoff-Ferrari and colleagues that our trial inclusion criteria were too broad. All the trials were included in previous metaanalyses, and the populations and doses studied are consistent with existing recommendations for vitamin D supplementation. Many of the criticisms of these trials seem somewhat arbitrary, and consistent with responses to evidence constituting medical reversal,5 wherein fault is found with the trials and there is unwillingness to consider that the intervention might be ineffective. Trial durations are unlikely to have been too short to show effects, as suggested by Anagnostis and colleagues and Bischoff-Ferrari and colleagues because each analysis included at least four large trials (n>1000) lasting 4 years or longer. Anagnostis and colleagues regard the continuing VITAL trial to be pivotal, but it might report similar results to previous trials. Despite its size, it has limited power to detect small effects (200 000). We disagree with Bischoff-Ferrari and colleagues that the small benefits of co-administered vitamin D with calcium on fracture make them suitable as a public health intervention, because any benefits are outweighed by the risk of adverse effects (kidney stones, cardiovascular events, and acute gastrointestinal symptoms).7 Our results suggest that whether vitamin D supplements reduce mortality remains uncertain, and any absolute benefit is very small, suggesting no present public health indication for mortality reduction.
www.thelancet.com/diabetes-endocrinology Vol 2 May 2014
MB is funded by the Health Research Council of New Zealand and is the recipient of a Sir Charles Hercus Health Research Fellowship. MB, IRR, GDG, and AG received grants from the Health Research Council of New Zealand during the study. We declare that we have no further competing interests.
Mark J Bolland, Andrew Grey, Greg D Gamble, Ian R Reid [email protected] Department of Medicine, University of Auckland, Auckland 1142, New Zealand (MJB, AG, GDG, IRR) 1
2
3
4
5
6
7
Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008; 168: 1629–37. Michaelsson K, Baron JA, Snellman G, et al. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr 2010; 92: 841–48. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2014; 2: 76–89. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010; 303: 1815–22. Prasad V, Cifu A, Ioannidis JP. Reversals of established medical practices: evidence to abandon ship. JAMA 2012; 307: 37–38. Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials 2012; 33: 159–71. Bolland MJ, Grey A, Reid IR. Benefits of calcium supplements are too small for clinical equipoise to exist. J Bone Miner Res 2014; published online April 3. DOI:10.1002/ jbmr.2235.
365
