Research Article: Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data

Date Published: July 7, 2017

Publisher: Public Library of Science

Author(s): Lars Rejnmark, Lise Sofie Bislev, Kevin D. Cashman, Gudny Eiríksdottir, Martin Gaksch, Martin Grübler, Guri Grimnes, Vilmundur Gudnason, Paul Lips, Stefan Pilz, Natasja M. van Schoor, Mairead Kiely, Rolf Jorde, Andrzej T Slominski.


A large number of observational studies have reported harmful effects of low 25-hydroxyvitamin D (25OHD) levels on non-skeletal outcomes. We performed a systematic quantitative review on characteristics of randomized clinical trials (RCTs) included in meta-analyses (MAs) on non-skeletal effects of vitamin D supplementation.

We identified systematic reviews (SR) reporting summary data in terms of MAs of RCTs on selected non-skeletal outcomes. For each outcome, we summarized the results from available SRs and scrutinized included RCTs for a number of predefined characteristics. We identified 54 SRs including data from 210 RCTs. Most MAs as well as the individual RCTs reported null-findings on risk of cardiovascular diseases, type 2 diabetes, weight-loss, and malignant diseases. Beneficial effects of vitamin D supplementation was reported in 1 of 4 MAs on depression, 2 of 9 MAs on blood pressure, 3 of 7 MAs on respiratory tract infections, and 8 of 12 MAs on mortality. Most RCTs have primarily been performed to determine skeletal outcomes, whereas non-skeletal effects have been assessed as secondary outcomes. Only one-third of the RCTs had low level of 25OHD as a criterion for inclusion and a mean baseline 25OHD level below 50 nmol/L was only present in less than half of the analyses.

Published RCTs have mostly been performed in populations without low 25OHD levels. The fact that most MAs on results from RCTs did not show a beneficial effect does not disprove the hypothesis suggested by observational findings on adverse health outcomes of low 25OHD levels.

Partial Text

In recent years the number of studies exploring effects of vitamin D beyond its well-known effects on the musculo-skeletal system have increased markedly. The vitamin D receptor (VDR) and the enzyme (the 1α-hydroxylase) needed to hydroxylate 25-hydroxyvitamin D (25OHD) to its active form 1,25-dihydroxyvitamin D (1,25(OH)2D) has been identified in a large number of different cells. This widespread expression of the 1α-hydroxylase suggests that local production and action of 1,25(OH)2D to regulate VDR-directed gene expression may be of importance to the function of many tissues [1]. Moreover, gene array studies have shown that vitamin D may be involved in the regulation of as much as 5% of the human genome [1–3].

The present paper is a part of a collaborative study between a number of European research institutions within a project on food-based solutions for eradication of vitamin D deficiency and health promotion throughout the life cycle (ODIN project, funded by the European Commission as part of the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities.

We identified 54 SRs reporting summary data in terms of a formal MA on effects of vitamin D supplementation on selected outcomes (Table 1). Included SRs had a mean AMSTAR score of 8.8 (range 6–11) suggesting an overall moderate to good quality. Within each group of studied non-skeletal health outcomes, mean AMSTAR score varied between 8.4 to 9.8 (Table 1). For each outcome, number of RCTs included in one or more of the MAs varied from four to 69 trials. A total of 210 RCTs were included in the MAs.

Overall, 16 of the 54 MAs suggested beneficial effects of vitamin D supplementation on different extra-skeletal outcomes among which eight of 12 MAs (66%) reported a decreased mortality. Beneficial effects were also suggested by MAs on blood pressure (2 of 9 [22%] MAs), birth weight (2 of 6 [33%] MAs), RTIs (3 of 7 [43%] MAs), and depression (1 of 4 [25%] MAs). No beneficial effects were reported in any of the MAs on CVD, T2D, body weight, or malignant diseases.




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