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Association between vitamin D supplementation and mortality: systematic review and meta-analysis

BMJ 2019; 366 doi: (Published 12 August 2019) Cite this as: BMJ 2019;366:l4673

Rapid Response:

Re: Association between vitamin D supplementation and mortality: systematic review and meta-analysis

As the Corresponding Author for the above paper, I thank Mark J Bolland, Alison Avenell, and Andrew Grey for their comments. Dr Bolland and colleagues have published many important meta-analyses of vitamin D. [1-4] These great works have inspired me deeply.

A1. We acknowledge that the three, small trials, Lappe 2007, Prince 2008 and Zhu 2008, should not be included in the analysis of the second outcome, cancer mortality. This error occurred in the process of copying data from Excel to the software. After excluding the three trials, the conclusion of cancer mortality was not changed (RR 0.85, 95% CI [0.75, 0.97]) (originally RR 0.84, 95% CI [0.74, 0.95]).

A2. Dr Bolland et al firstly concerned that Ooms 1995 was not sub-study of Lips 1996. Though the two articles were reported by the same team, Ooms 1995 was like a prior trial but not a sub-study. The main difference between the two studies was that Ooms 1995 studied elderly women (Number=283); whereas Lips 1996 did elderly persons (No. of women/total=1916/2758). If Ooms 1995 was a sub-study focusing on women, the number of women in the study should be more. Furthermore, the two studies were included simultaneously by previous meta-analyses3 5, including Dr Bolland’s own meta-analysis (in Figure 5). [3] Secondly, we are not sure whether Reid 2017 (Number=452) was a sub-study of ViDA 2017 (Number=5108). The dose of vitamin D3 was different in Reid 2017 and ViDA 2017. Reid 2017 used vitamin D3 100 000IU monthly, however, ViDA 2017 did an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU. Even excluding Reid 2017, no result was changed (e.g. all-cause mortality RR 0.98, 95% CI [0.95, 1.02]) (originally RR 0.98, 95% CI [0.95, 1.02]). We will contact the corresponding authors of these studies to make sure whether they are sub-studies. After receiving the authors’ response, colleagues and I will discuss how to apply for correction, although there is no change in the overall direction of the effect or to the conclusions of the systematic review.

A3 Dr Bolland concerned the large study, RECORD 2012. We included the publication that reported the longest follow-up because effect of vitamin D on mortality usually takes a long time to show. RECORD 2012 was also included by The Cochrane reviews [5 6] of vitamin D on mortality, but Dr Bolland’s review included the early one.

B Discrepant subgroup and outcome analyses
Some subgroup analyses and outcomes were added retrospectively. Most of them were done by suggestions of reviewers. We think that they are important in the study. The retrospective analyses have been stated in the Method section.

C. Multiple statistical tests
We agree with Dr Bolland that multiple statistical analyses were associated with the possibility of false-positive results. However, the retrospective analyses of subgroup and outcome did not find positive results.

D. Implausible research timeline
“Sweatshop”. This is our secret. In China, we have sufficient manpower with little rest and pay to complete arduous tastes quickly. Dr Bolland may misunderstand other studies of our team. These works were published in 2019, but they were finished before the beginning of this study (Nov 2018). The first one [7] was submitted to JAMA on April 23, 2018 (ID JAMA18-3633), transferred to JAMA internal medicine and accepted on September 1, 2018. The second one [8] was submitted firstly to Thorax on June 29, 2018 (ID thoraxjnl-2018-212277), the Third [9] to BMC Medicine on September 29, 2018 (ID BMED-D-18-01451), the fourth [10] to Stroke on October 13, 2018 (ID STROKE/2018/023904).

E Authors’ conclusions
Dr Bolland did not agree with part of the conclusion "additional large clinical studies are needed to determine whether vitamin D3 supplementation is associated with lower all-cause mortality” because of inconsistent evidence. In conclusion, we have stated initially that “Vitamin D supplementation alone was not associated with all-cause mortality in adults compared with placebo or no treatment”. We think that the conclusions were balanced. Though current evidence did not support use vitamin D supplements to improve all-cause mortality, the positive effect may be found in special people with the use of vitamin D3.

1. Bolland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol 2018;6(11):847-58. doi: 10.1016/s2213-8587(18)30265-1 [published Online First: 2018/10/09]
2. Bolland MJ, Grey A, Gamble GD, et al. Vitamin D supplementation and falls: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014;2(7):573-80. doi: 10.1016/s2213-8587(14)70068-3 [published Online First: 2014/04/29]
3. Bolland MJ, Grey A, Gamble GD, et al. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014;2(4):307-20. doi: 10.1016/s2213-8587(13)70212-2 [published Online First: 2014/04/08]
4. Bolland MJ, Leung W, Tai V, et al. Calcium intake and risk of fracture: systematic review. BMJ (Clinical research ed) 2015;351:h4580. doi: 10.1136/bmj.h4580 [published Online First: 2015/10/01]
5. Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in adults. The Cochrane database of systematic reviews 2014(1):Cd007470. doi: 10.1002/14651858.CD007470.pub3 [published Online First: 2014/01/15]
6. Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of cancer in adults. The Cochrane database of systematic reviews 2014(6):CD007469. doi: 10.1002/14651858.CD007469.pub2 [published Online First: 2014/06/24]
7. Fang F, Zhang Y, Tang J, et al. Association of Corticosteroid Treatment With Outcomes in Adult Patients With Sepsis: A Systematic Review and Meta-analysis. JAMA internal medicine 2019;179(2):213-23. doi: 10.1001/jamainternmed.2018.5849 [published Online First: 2018/12/24]
8. Zhang Y, He J, Yuan Y, et al. Increased versus Stable Dose of Inhaled Corticosteroids for Asthma Exacerbations: A Systematic Review and Meta-analysis. Clin Exp Allergy 2019 doi: 10.1111/cea.13450 [published Online First: 2019/06/18]
9. Zhao Y, Yi C, Zhang Y, et al. Intensive follow-up strategies after radical surgery for nonmetastatic colorectal cancer: A systematic review and meta-analysis of randomized controlled trials. PLoS One 2019;14(7):e0220533. doi: 10.1371/journal.pone.0220533 [published Online First: 2019/07/31]
10. Zhang Y, Jia L, Fang F, et al. General Anesthesia Versus Conscious Sedation for Intracranial Mechanical Thrombectomy: A Systematic Review and Meta-analysis of Randomized Clinical Trials. Journal of the American Heart Association 2019;8(12):e011754. doi: 10.1161/JAHA.118.011754 [published Online First: 2019/06/12]

Competing interests: No competing interests

29 August 2019
Fang Fang
No. 37, Guo Xue Xiang