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Table of contents Evidence category (from the study)
Forest plots (from the study)
MethodsStructure of umbrella review
Eligibility criteria and appraisal of included studies
ResultsVitamin D concentrations and health outcomes: systematic reviews of observational studies
Vitamin D concentrations and health outcomes: meta-analyses of observational studies
Summary effects, heterogeneity, and bias tests for meta-analyses of observational associations
Significant observational associations without hints of bias
Meta-analyses of randomised controlled trials of vitamin D supplementation
Comparison of findings from observational studies and clinical trials
DiscussionStrengths and weaknesses of study and in relation to other studies
Possible explanations and implications for clinicians and policy makers
Conclusions, unanswered questions, and future researchReferences
What is already known on this topic
What this study addsEditorial on the study: Vitamin D and chronic disease prevention
Vitamin D trials use inadequate doses
New York Times article on the study - with selected comments
See also VitaminDWiki
BMJ2014;348:g2035 doi: 10.1136/bmj.g2035 (Published 1 April 2014)Evropi Theodoratou research fellow John P A Ioannidis professor56Ioanna Tzoulaki lecturer23, Lina Zgaga associate professor4,1Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK; 2Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; 3Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece; "Department of Public Health and Primary Care, Trinity College Dublin, Dublin 24, Ireland; 5Stanford Prevention Research Center, Departments of Medicine and Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305-5411, USA; 6Department of Statistics, Stanford University School of Humanities and Sciences, Stanford
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.
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.
IntroductionThe associations between vitamin D concentrations and various conditions and diseases have been assessed in a large and rapidly expanding literature. In addition to observational studies, numerous randomised trials have examined the effect of vitamin D supplementation on a range of outcomes. Historically, vitamin D had been linked to skeletal disease including calcium, phosphorus, and bone metabolism,12 osteoporosis,3 fractures,4 5 muscle strength,6 and falls.7 In the 2000s, growing scientific attention turned to non-skeletal chronic diseases as vitamin D deficiency was linked to cancer,8 cardiovascular diseases,910 metabolic disorders,11 infectious diseases,12 and autoimmune diseases,13-15 as well as mortality.16 If causal, these associations might be of great importance for public health, as vitamin D deficiency has been found to be highly prevalent in populations residing at high latitudes or leading an indoors oriented lifestyle.17 However, the composite literature is often confusing and has led to heated debates about the optimal concentrations of vitamin D and related guidelines for supplementation.18-20RESEARCHTo provide an overview of the breadth and validity of the claimed associations of vitamin D with diverse outcomes, we have done an umbrella review of the evidence across existing systematic reviews and meta-analyses. We aimed to do a comprehensive evaluation of systematic reviews and meta-analyses of observational studies that examined associations of vitamin D concentrations with a range of clinical outcomes, as well as meta-analyses of randomised controlled trials of vitamin D supplementation. We also compared the findings of the observational studies with those from meta-analyses of randomised controlled trials of vitamin D supplementation, whenever these could be juxtaposed. We sought to summarise the health outcomes that have been associated with vitamin D concentrations, evaluate whether evidence exists of biases in this literature, identify health outcomes without evidence of biases, and examine the consistency of inferences from the meta-analyses of observational studies and of randomised controlled trials.
An umbrella review systematically collects and evaluates information from multiple systematic reviews and meta-analyses on all clinical outcomes for which these have been performed.21 Here, for evidence on observational associations between vitamin D concentrations and any health outcome, we sought to collect information from systematic reviews regardless of whether they also included quantitative syntheses (meta-analyses). Given the very large heterogeneity that may be encountered in observational studies, often meta-analysis may not be done in systematic reviews of observational studies, whereas this problem occurs much less frequently in systematic reviews of randomised controlled trials, for which meta-analysis is the norm, especially when interventions are drugs or vitamins.22 Where available, we also evaluated in more depth the quantitative results of the meta-analyses of observational associations and potential hints of bias in these meta-analyses.23-25 For evidence on randomised controlled trials of vitamin D supplementation, we considered only formal quantitative meta-analyses. We compared results from meta-analyses of observational studies and randomised controlled trials, whenever data were available for the same outcome.
Two reviewers (IT, ET) searched Medline and Embase in duplicate, using the search algorithm in supplementary table A, from inception to 11 October 2013 (last update) and limited the search to humans and English language, as the overwhelming majority of review studies are published in English language, peer reviewed journals. Any discrepancies were resolved with discussion. We firstly perused the title and abstract of each of these citations and then retrieved potentially eligible articles for perusal in full text. 041b061a72