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Noncalcemic adverse effects and withdrawals in randomized controlled trials of long-term vitamin D2 or D3 supplementation: a systematic review and meta-analysis.

  • Malihi, Zarintaj1
  • Wu, Zhenqiang1
  • Mm Lawes, Carlene1
  • Scragg, Robert1
  • 1 School of Population Health, University of Auckland, Auckland, New Zealand. , (New Zealand)
Published Article
Nutrition Reviews
Oxford University Press
Publication Date
Dec 01, 2017
DOI: 10.1093/nutrit/nux059
PMID: 29202186


Recent randomized controlled trials (RCTs) provide evidence for a possible beneficial impact of vitamin D supplementation on health outcomes beyond bone health, but there are few reviews of noncalcemic adverse effects from long-term supplementation. The aims of this systematic review of vitamin D supplementation in RCTs were as follows: to determine whether all adverse effects, when combined, are reported equally between treatment arms; to identify the most common noncalcemic adverse effects reported; and to ascertain whether withdrawal rates, as a marker of clinical adverse effects, differ between treatment arms. The MEDLINE Ovid, Embase, and Cochrane Library databases were searched systematically up to May 2016. Randomized controlled trials that met the following criteria were selected: administered vitamin D2 or D3 supplements for a minimum supplementation or follow-up period of 24 weeks, had a placebo/control group, and were conducted among adults (≥ 18 y). Two researchers independently screened studies for eligibility, extracted data, and carried out quality assessment of selected studies. A total of 128 studies with 52 297 participants were identified. A random-effects model was used to calculate risk ratios in a meta-analysis. Long-term vitamin D2 or D3 supplementation, compared with placebo, did not increase all adverse effects, when combined, as reported in 62 studies with 19 389 participants (relative risk [RR] = 0.97; 95%CI, 0.92-1.02). Vitamin D also did not increase the risk of the most common noncalcemic adverse effects: gastrointestinal symptoms were reported in 27 studies with 9189 participants (RR = 1.01; 95%CI, 0.87-1.17), and dermatological symptoms were reported in 8 studies with 1695 participants (RR = 1.33; 95%CI, 0.82-2.15). Vitamin D did not increase withdrawals from 123 studies with 41 861 participants (RR = 1.03; 95%CI, 0.96-1.09). However, participants given vitamin D were more likely to report withdrawals than those given placebo in studies in which calcium was given in both arms (RR = 1.16; 95%CI, 1.02-1.33) when compared with participants in studies in which calcium was not given in either arm (RR = 1.00; 95%CI, 0.95-1.06; P for interaction = 0.009). Overall, these findings suggest that vitamin D, by itself, does not increase the risk of noncalcemic adverse effects. © The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: [email protected]

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