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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
  1. Evropi Theodoratou, research fellow1,
  2. Ioanna Tzoulaki, lecturer23,
  3. Lina Zgaga, associate professor4,
  4. John P A Ioannidis, professor56
  1. 1Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK
  2. 2Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK
  3. 3Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece
  4. 4Department of Public Health and Primary Care, Trinity College Dublin, Dublin 24, Ireland
  5. 5Stanford Prevention Research Center, Departments of Medicine and Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305-5411, USA
  6. 6Department of Statistics, Stanford University School of Humanities and Sciences, Stanford
  1. Correspondence to: E Theodoratou e.theodoratou{at}
  • Accepted 24 February 2014


Objective To evaluate the breadth, validity, and presence of biases of the associations of vitamin D with diverse outcomes.

Design Umbrella review of the evidence across systematic reviews and meta-analyses of observational studies of plasma 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D concentrations and randomised controlled trials of vitamin D supplementation.

Data sources Medline, Embase, and screening of citations and references.

Eligibility criteria Three types of studies were eligible for the umbrella review: systematic reviews and meta-analyses that examined observational associations between circulating vitamin D concentrations and any clinical outcome; and meta-analyses of randomised controlled trials assessing supplementation with vitamin D or active compounds (both established and newer compounds of vitamin D).

Results 107 systematic literature reviews and 74 meta-analyses of observational studies of plasma vitamin D concentrations and 87 meta-analyses of randomised controlled trials of vitamin D supplementation were identified. The relation between vitamin D and 137 outcomes has been explored, covering a wide range of skeletal, malignant, cardiovascular, autoimmune, infectious, metabolic, and other diseases. Ten outcomes were examined by both meta-analyses of observational studies and meta-analyses of randomised controlled trials, but the direction of the effect and level of statistical significance was concordant only for birth weight (maternal vitamin D status or supplementation). On the basis of the available evidence, an association between vitamin D concentrations and birth weight, dental caries in children, maternal vitamin D concentrations at term, and parathyroid hormone concentrations in patients with chronic kidney disease requiring dialysis is probable, but further studies and better designed trials are needed to draw firmer conclusions. In contrast to previous reports, evidence does not support the argument that vitamin D only supplementation increases bone mineral density or reduces the risk of fractures or falls in older people.

Conclusions Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.


  • Contributors: ET, IT, and JPAI conceived the study. ET and IT did the systematic reviews. ET, IT, and LZ did the data abstraction. ET did the statistical analysis. All authors contributed to writing and reviewing the manuscript. ET and JPAI are the guarantors.

  • Funding: No specific funding.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not needed.

  • Data sharing: No additional data available.

  • Transparency declaration: The lead authors (the manuscript’s guarantors) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

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