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Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials

BMJ 2014; 348 doi: (Published 01 April 2014) Cite this as: BMJ 2014;348:g2035

Re: Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials

To the Editor

The report, “Vitamin D and multiple outcomes; umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials”, and related comment [1a,b], suggests that benefits from higher vitamin D repletion are limited. However, the findings may have been affected by a number of factors that were not adjusted for such as,
1) the likely inclusion of reported data in more than one of the meta-analyses examined,
2) not allowing for the fact that some benefits appear only at higher intakes, e.g., >800 IU/day for fracture reductions in older women[2].
3) that improvements are often seen only in initially deficient subjects, as for muscle strength[3] or
4) that ‘threshold’ 25(OH)D concentrations are reported for the appearance of some benefits, e.g. >80nmol/l for reductions in insulin resistance,[4] and
5) non-exclusion of studies using huge interval doses with initial adverse effects[5], though such problems are mentioned in the Discussion section[1].

Furthermore, failure of supplementation to achieve repletion, or being replete before supplementation, affects nutrient RCT outcomes,[6] but this is not discussed. Though the authors refer to the importance of calcium intakes in studying vitamin D efficacy, they do not discuss the interactions of other nutrients known to interact with vitamin D in humans, e.g., vitamin A[7], vitamin K[8] and magnesium[9] - intakes of vitamin A are woefully inadequate in many developing countries[10] and excessive in most affluent communities, circulating retinoids being in the potentially toxic range in 34% of Europeans.[11] Thus, confounding by lack of data on vitamin A intakes is likely to be considerable.

In addition, the degree of tissue damage when RCTs start matters, since irreversible changes cannot be corrected, (as long known for bony deformity in rickets and already suspected for islet insulin secretion in 1995[12]), and recently highlighted as a potential problem for vitamin D and target soft tissues since health benefits from adequate provision of vitamin D may well require life-long repletion,[13] a concept which has recently been provided with considerable support.[14,15]

It is also surprising that Ioannidis and colleagues do not appear to have allowed for all the problems inherent in nutritional research in humans since a recent BMJ editorial by Ioannidis discusses the many specific problems of nutrient intake studies, including RCTs, and clearly identifies many factors that need to be allowed for in RCTs of nutrients, as compared to RCTs of pharmaceuticals, detailing also why varying intakes of single nutrients can only be expected to produce relatively small (<10%) effects on health.[16] However, Chowdury et al this week report 35% increases in mortality with low vitamin D status on meta-analysis of 73 observational cohorts (n= 849,412 subjects) together with an 11% reduction in overall mortality (from cardiovascular, cancer and non-vascular and non-cancer deaths) after supplementation in 22 randomised intervention studies using solely vitamin D3 (n=30,716 subjects) but not with vitamin D2.

Overall, the available evidence appears to suggest that the possibility of causality of vitamin D insufficiency for human ill health should not be dismissed.

1 (a). Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014. Apr1;348:g2035. doi: 10.1136/bmj.g2035. (b), Kmietowicz Z. Vitamin D shows no clear evidence of benefits despite hundreds of studies BMJ. 2014 Apr 1;348:g2489. doi: 10.1136/bmj.g2489.

2. Bergman GJ, Fan T, McFetridge JT, Sen SS. Efficacy of vitamin D3 supplementation in preventing fractures in elderly women: a meta-analysis. Curr Med Res Opin. 2010 26:1193-201.

3. Muir SW, Montero-Odasso M. Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis. J Am Geriatr Soc. 2011 59:2291-300. Review

4. von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised, placebo-controlled trial. Br J Nutr. 2010 103:549-55

5. Hansen KE. High-dose vitamin D: helpful or harmful? Curr Rheumatol Rep. 2011 13:257-64.

6. Lappe JM1, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrinol. 2012 ;4:95-100.

7. Carlberg C. Lipid soluble vitamins in gene regulation. Biofactors. 1999;10:91-7. Review.

8. Torbergsen AC, Watne LO2, Wyller TB3, Frihagen F4, Strømsøe K5, Bøhmer T6, Mowe M7. Vitamin K1 and 25(OH)D are independently and synergistically associated with a risk for hip fracture in an elderly population: A case control study. Clin Nutr. 2014.01.016. [Epub ahead of print]

9. Matsuzaki H, Katsumata S, Kajita Y, Miwa M. Magnesium deficiency regulates vitamin D metabolizing enzymes and type II sodium-phosphate co-transporter mRNA expression in rats. Magnes Res. 2013;26:83-6.

10. Ahmed T, Hossain M, Sanin KI. Global burden of maternal and child undernutrition and micronutrient deficiencies. Ann Nutr Metab. 2012;61 Suppl 1:8-17.

11. Flynn A, Hirvonen T, Mensink GB, Ocké MC, Serra-Majem L, Stos K, Szponar L, Tetens I, Turrini A, Fletcher R, Wildemann T. Intake of selected nutrients from foods, from fortification and from supplements in various European countries. Food Nutr Res. 2009; 12;53.

12. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83:191-201. Review.

13. Afzal S, Brøndum-Jacobsen P, Bojesen SE, Nordestgaard B. Vitamin D concentration, obesity and risk of diabetes: a Mendelian randomisation study. Lancet Diabetes & Endoctinology. 2014;2:2298-306

14. Pilz S, Gaksch M, Tomaschitz A. 28 Jan 2014 - Vitamin D and prevention of diabetes: is lifelong endogenous vitamin D needed? Lancet Diabetes & Endocrinology. 2014;2:267 - 268

15. Ioannidis JPA. Implausible results in human nutrition research. BMJ. 2014;347:7

16. Chowdury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ; 2014:11

Competing interests: No competing interests

08 April 2014
Barbara J Boucher
Honorary Professor
Bart's & The London School of Medicine & Dentistry, Queen Mary University of London
Blizard Institute, Newark SDtreet, London E1 2AT, UK