Peter Ebeling, Robert Adler, Glenville Jones, Uri A Liberman, Gherando Mazziotti, Salvatore Minisola, Craig Munns, Nicola Napoli, Anastassios Pittas, Andrea Giustina, John P Bilezikian, Rene Rizzoli

Research output: Contribution to journalReview articlepeer-review


Objective: The central role of vitamin D in bone health is well recognized. However, controversies regarding its clinical application remain. We therefore aimed to review the definition of hypovitaminosis D, the skeletal and extra-skeletal effects of vitamin D and the available therapeutic modalities.

Design: Narrative and systematic literature review.

Methods: An international working group that reviewed the current evidence linking bone and extra-skeletal health and vitamin D therapy to identify knowledge gaps for future research.

Results: Findings from observational studies and randomized controlled trials (RCTs) in vitamin D deficiency are discordant, with findings of RCTs being largely negative. This may be due to reverse causality with the illness itself contributing to low vitamin D levels. The results of many RCTs have also been inconsistent. However, overall evidence from RCTs shows vitamin D reduces fractures (when administered with calcium) in the institutionalized elderly. Although controversial, vitamin D reduces acute respiratory tract infections (if not given as bolus monthly or annual doses) and may reduce falls in those with the lowest serum 25-hydroxyvitamin D (25OHD) levels. However, despite large ongoing RCTs with 21 000–26 000 participants not recruiting based on baseline 25OHD levels, they will contain a large subset of participants with vitamin D deficiency and are adequately powered to meet their primary end-points.

Conclusions: The effects of long-term vitamin D supplementation on non-skeletal outcomes, such as type 2 diabetes mellitus (T2DM), cancer and cardiovascular disease (CVD) and the optimal dose and serum 25OHD level that balances extra-skeletal benefits (T2DM) vs risks (e.g. CVD), may soon be determined by data from large RCTs.

Original languageEnglish
Pages (from-to)R239-R259
JournalEuropean Journal of Endocrinology
Issue number5
Publication statusPublished - Oct 12 2018


  • Dietary Supplements
  • Hormone Replacement Therapy
  • Humans
  • Vitamin D/analogs & derivatives
  • Vitamin D Deficiency/blood


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