Re: Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies
We cordially thank Dr Grant for his comments. We agree that while prior ecological studies are supportive of our current findings based on meta-analysis of observational studies; further work, especially those involving well-powered randomized intervention studies, is required. We would, however, like to add that the respective pooled risk ratios (RRs) that we reported by combining the primary and secondary prevention cohorts, are based on indirect comparison (ie, only a subset of studies provided mortality risk data on people with pre-existing disease).
We also thank Dr Bolland and colleagues for their observations and thoughts. The overall estimate from the vitamin D3 randomized controlled trials were indeed presented as a combination of both active and inactive vitamin D3 supplements, given a lack of power in each component in isolation. Additionally, we included the Campbell et al trial (1) as a study evaluating the effects of vitamin D3 alone without any concurrent administration of other pharmacological interventions (and was similarly kept as a vitamin D alone study in the earlier Cochrane report). Nonetheless, when this study and the other 3 calcitriol trials (2-4) were removed from the analyses, there was no significant effect of “any vitamin D supplementation” on mortality (which remains consistent with our original results). The pooled effect estimate for the 10 vitamin D3 trials became slightly attenuated (0.91 (95% CI 0.82-1.00) in our calculation), however, this apparent inverse effect differed significantly with the corresponding pooled estimate of vitamin D2 (P from meta-regression analysis=0.03, for a comparison between vitamin D3 and vitamin D2 trials). That said, we agree with Dr Bolland and colleagues that the selection criteria (eg, randomised vs. non-randomised, with vs. without calcium supplementation, etc.) and decisions on subgroup analyses vary across reviews on this topic, and may explain the differences of findings across these reports. However, as was discussed in our paper (and the accompanying editorial), all these reviews (including ours) are based on largely overlapping trials that principally included high risk, elderly populations (with an average age >75 years in all trials combined). Therefore, before any policy formulation, further large-scale and sufficiently prolonged trials involving sufficient samples derived from the general population will be required.
(1) Campbell AJ, Robertson MC, La Grow SJ, Kerse NM, Sanderson GF, Jacobs RJ, et al. Randomised controlled trial of prevention of falls in people aged > or =75 with severe visual impairment: the VIP trial. BMJ 2005;331:817.
(2) Grady D, Halloran B, Cummings S, Leveille S, Wells L, Black D, et al. 1,25-Dihydroxyvitamin D3 and muscle strength in the elderly: a randomized controlled trial. J Clin Endocrinol Metab 1991;73:1111-7.
(3) Gallagher JC. The effects of calcitriol on falls and fractures and physical performance tests. J Steroid Biochem Mol Biol 2004;89-90:497-501.
(4) Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 2007;25:669-74.
Rajiv Chowdhury[1]
cardiovascular epidemiologist
Oscar H Franco[2]
professor
On behalf of Setor Kunutsor, Anna Vitezova, Clare Oliver-Williams, Susmita Chowdhury, Jessica C Kiefte-de-Jong, Hassan Khan, Cristina P Baena, Dorairaj Prabhakaran, Moshe B Hoshen, Becca S Feldman, An Pan, Laura Johnson, Francesca Crowe, and Frank B Hu
[1] Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK
[2] Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands o.franco@erasmusmc.nl
Competing interests:
No competing interests
23 April 2014
Oscar Franco
Professor
Rajiv Chowdhury
ErasmusMC
Department of Epidemiology Erasmus MC, University Medical Center Rotterdam Office Na 29-16 PO Box 2040, 3000 CA Rotterdam, The Netherlands
Rapid Response:
Re: Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies
We cordially thank Dr Grant for his comments. We agree that while prior ecological studies are supportive of our current findings based on meta-analysis of observational studies; further work, especially those involving well-powered randomized intervention studies, is required. We would, however, like to add that the respective pooled risk ratios (RRs) that we reported by combining the primary and secondary prevention cohorts, are based on indirect comparison (ie, only a subset of studies provided mortality risk data on people with pre-existing disease).
We also thank Dr Bolland and colleagues for their observations and thoughts. The overall estimate from the vitamin D3 randomized controlled trials were indeed presented as a combination of both active and inactive vitamin D3 supplements, given a lack of power in each component in isolation. Additionally, we included the Campbell et al trial (1) as a study evaluating the effects of vitamin D3 alone without any concurrent administration of other pharmacological interventions (and was similarly kept as a vitamin D alone study in the earlier Cochrane report). Nonetheless, when this study and the other 3 calcitriol trials (2-4) were removed from the analyses, there was no significant effect of “any vitamin D supplementation” on mortality (which remains consistent with our original results). The pooled effect estimate for the 10 vitamin D3 trials became slightly attenuated (0.91 (95% CI 0.82-1.00) in our calculation), however, this apparent inverse effect differed significantly with the corresponding pooled estimate of vitamin D2 (P from meta-regression analysis=0.03, for a comparison between vitamin D3 and vitamin D2 trials). That said, we agree with Dr Bolland and colleagues that the selection criteria (eg, randomised vs. non-randomised, with vs. without calcium supplementation, etc.) and decisions on subgroup analyses vary across reviews on this topic, and may explain the differences of findings across these reports. However, as was discussed in our paper (and the accompanying editorial), all these reviews (including ours) are based on largely overlapping trials that principally included high risk, elderly populations (with an average age >75 years in all trials combined). Therefore, before any policy formulation, further large-scale and sufficiently prolonged trials involving sufficient samples derived from the general population will be required.
(1) Campbell AJ, Robertson MC, La Grow SJ, Kerse NM, Sanderson GF, Jacobs RJ, et al. Randomised controlled trial of prevention of falls in people aged > or =75 with severe visual impairment: the VIP trial. BMJ 2005;331:817.
(2) Grady D, Halloran B, Cummings S, Leveille S, Wells L, Black D, et al. 1,25-Dihydroxyvitamin D3 and muscle strength in the elderly: a randomized controlled trial. J Clin Endocrinol Metab 1991;73:1111-7.
(3) Gallagher JC. The effects of calcitriol on falls and fractures and physical performance tests. J Steroid Biochem Mol Biol 2004;89-90:497-501.
(4) Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 2007;25:669-74.
Rajiv Chowdhury[1]
cardiovascular epidemiologist
Oscar H Franco[2]
professor
On behalf of Setor Kunutsor, Anna Vitezova, Clare Oliver-Williams, Susmita Chowdhury, Jessica C Kiefte-de-Jong, Hassan Khan, Cristina P Baena, Dorairaj Prabhakaran, Moshe B Hoshen, Becca S Feldman, An Pan, Laura Johnson, Francesca Crowe, and Frank B Hu
[1] Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK
[2] Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
o.franco@erasmusmc.nl
Competing interests: No competing interests