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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:

Vitamin D supplementation, cancer death and NNT

“If you torture the data long enough, it will confess.” Ronald Coase.

The conclusion of Zhang and colleagues’ meta-analysis of randomised controlled trials comparing vitamin D supplementation with a placebo or no treatment , “Vitamin D supplementation reduced the risk of cancer death by 16%” and the box “WHAT THIS STUDY ADDS” highlighting “Vitamin D supplementation reduced the risk of cancer death” deserve comment.(1)

First, from Fig 3. (1) cancer mortality was 428/22,793 with vitamin D vs 511/22,785 without. This is an absolute reduction of 0,37 death from cancer when treating 100 healthy persons. Considering the median follow-up of 5.3 years in VITAL,(2) this means treating 1,452 healthy persons during one year for avoiding one death from cancer. Statistical significance does not mean clinically relevant.

Second, Zhang and colleagues’ tested heterogeneity (p=.82) of the trials they mixed. However, they obviously mixed trials with flawed design with a robust one. Indeed, among basic prerequisites for quality is an a priori sample size calculation.(3) Half a dozen of the trials among the 11 pooled recruited fewer than 500 subjects by group. The only one (VITAL) which recruited more than 10 000 per group, the adequate amount when considering observational data and previous trials, failed to observed a significant result.

Third, translation of results from trials in the real life setting is a challenge. Among many barriers, subjects participating in trials are more compliant.(4) This is a most critical issue when dealing with healthy subjects or asymptomatic patients. Further, in the real life setting excessive consumption of vitamin D through dietary supplements may lead to vitamin D intoxication, even without developing hypervitaminosis D, (4) and medical conditions with “hypersensitivity” to vitamin D, although rare, must not be overlooked. Potential harms must always be a concern, even more when dealing with healthy subjects. A slight, although non-significant, increase in non-cancer mortality with vitamin D supplementation is a concern (Fig 3 in 1).

Last, this critical evaulation must be balanced by the fact that male smoking prevalence is 50% in China. As smokers have lower 25(OH)D levels, (7) and as lower plasma 25(OH)D is associated with higher risk of tobacco-related cancers, (8) vitamin D supplementation in Zhang and colleagues’ country may have relevant benefit at the population level.

1 Zhang Y, Fang F, Tang J, Jia L, Feng Y, Xu P, Faramand A. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ. 2019;366:l4673.

2 Manson JE, Cook NR, Lee IM et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380:33-44.

3 Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995;310:452.

4 Charles P, Giraudeau B, Dechartres A, Baron G, Ravaud P. Reporting of sample size calculation in randomised controlled trials: review. BMJ 2009;338:b1732.

5 Britten N. Does a prescribed treatment match a patient's priorities? BMJ 2003;327:840.

6 Razzaque MS. Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis D? J Steroid Biochem Mol Biol 2018;180:81-86.

7 Tønnesen R, Hovind PH, Jensen LT, Schwarz P. Determinants of vitamin D status in young adults: influence of lifestyle, sociodemographic and anthropometric factors. BMC Public Health 2016:16:385.

8 Afzal S, Bojesen SE, Nordestgaard BG. Low plasma 25-hydroxyvitamin D and risk of tobacco-related cancer. Clin Chem 2013;59:771-80.

Competing interests: No competing interests

14 August 2019
alain braillon
senior consultant
University Hospital. 80000 Amiens. France