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Does vitamin D supplementation improve bone density in vitamin D-deficient children? Protocol for an individual patient data meta-analysis
  1. Tania Winzenberg1,2,
  2. Christel Lamberg-Allardt3,
  3. Ghada El-Hajj Fuleihan4,
  4. Christian Mølgaard5,
  5. Kun Zhu6,7,
  6. Feitong Wu1,
  7. Richard D Riley8
  1. 1 Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  2. 2 Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia
  3. 3 Calcium Research Unit, Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland
  4. 4 Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, Division of Endocrinology and Metabolism, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
  5. 5 Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
  6. 6 Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
  7. 7 School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
  8. 8 Research Institute for Primary Care and Health Sciences, Keele University, Staffordshire, UK
  1. Correspondence to Professor Tania Winzenberg; Tania.Winzenberg{at}


Introduction Our previous study-level (aggregate data) meta-analysis suggested that vitamin D supplements may be beneficial for bone density specifically in children with vitamin D deficiency. However, the misclassification of vitamin D status inherent in study-level data means that the results are not definitive and cannot provide an accurate assessment of the size of any effect. Therefore, we propose to undertake an individual patient data (IPD) meta-analysis to determine whether the effect of vitamin D supplementation on bone density in children differs according to baseline vitamin D status, and to specifically estimate the effect of vitamin D in children who are vitamin D deficient.

Methods and analysis This study has been designed to adhere to the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement. We will include randomised placebo-controlled trials of vitamin D supplementation reporting bone density outcomes at least 6 months after the study commenced in children and adolescents (aged <20 years) without coexistent medical conditions or treatments causing osteoporosis. We will update the search of the original review to cover the period 2009–2017, using the same methods as the original review. Fully anonymised data on all randomised patients will be requested. Outcomes will be femoral neck, total hip, lumbar spine and proximal and distal forearm bone mineral density, and total body bone mineral content. A two-stage IPD meta-analysis will be used to examine the effect of baseline serum 25-hydroxyvitamin D (25(OH)D) on treatment effect for each bone density outcome. Restricted maximum likelihood will be used to estimate the random-effects meta-analysis models, with 95% CI for summary effects. Heterogeneity will be assessed by I2 and potential publication bias (small-study effects) and availability bias by funnel plots, Egger’s test and Peter’s test.

Ethics and dissemination Ethics approval will not be required as the data are to be used for the primary purpose for which they were collected and all original individual studies had ethics approval. Results of the IPD meta-analysis will be submitted for publication in a peer-reviewed journal.

PROSPERO registration number CRD42017068772.

  • paediatric endocrinology
  • rheumatology
  • preventive medicine

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  • Contributors Study design: TW and RDR with input from CL-A, GE-HF, CM, KZ and FW. Contributors of data to underpin design of the protocol: TW, CL-A, GE-HF, CM and KZ. These authors will also contribute data to the IPD meta-analysis itself. Drafting manuscript: TW and FW. Revising manuscript content: TW, CL-A, GE-HF, CM, KZ, FW, RDR. Approving final version of manuscript: TW, CL-A, GE-HF, CM, KZ, FW, RDR.

  • Funding The original RCT was financially supported by the European Commission’s Framework V Programme, OPTIFORD (QLK1-CT-2000-00623).

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.