Vitamin D and Muscle Health: A Systematic Review and Metaanalysis of Randomized Placebo-Controlled Trials

Abstract Background: Data regarding effects of vitamin D on muscle function are inconsistent. Discrepancies between observational and placebo-controlled studies are an indisputable fact. Objective: To investigate effects of vitamin D supplementation vs placebo on muscle health. Data Sources: A systematic research of published randomized controlled trials published until October 2020 has been conducted on Medline, Cochrane Database of Systematics Reviews, Embase and Google Scholar. Study Selection: Participants treated with vitamin D2 or vitamin D3 supplementation vs placebo, with or without calcium co-supplementation. All studies despite administration form (daily, bolus and duration) and populations, except athletes, were included. The pre-defined end-points were maximum muscle strength (Newton) measured as handgrip, elbow flexion, elbow extension, knee flexion, and knee extension. Physical performance reported as Timed Up and Go test (s), Chair Rising Test (s), 6 minutes walking distance (m) and Standard Physical Performance Battery (points). Finally, muscle mass in term of total lean mass (kg) was included. As the end-point measures were standardized, we apriori used random model effects and mean difference. Data Synthesis: In total, 51 randomized controlled trials involving 7798 individuals were included. Of included studies, 14 studies included participants with vitamin D insufficiency (25(OH)D<50 nmol/l) as inclusion criteria (19% of individuals). Outlier studies (N=1) were excluded. Analyses revealed a significant negative effect of vitamin D supplementation on knee flexion strength, mean difference -3.3 N, 95% CI (-6.63 to -0.03), I2=0%, n=765. The majority (8/12) of the studies used dosages > 2800 IU/day. Time spend performing the TUG test was also significant longer in individuals treated with vitamin D as compared with placebo, mean difference at 0.15 s (95% CI 0.04 to 0.26), I2=0%, n=5175. Excluding studies using bolus therapy or daily dosages > 2800 IU, the negative findings were no longer significant. No significant effect was found on the other measures of muscle strength, physical performance or muscle mass. In the minority of studies using vitamin D insufficiency as inclusion criteria, subgroup analysis revealed comparable effects of vitamin D and placebo. Conclusions: Overall, vitamin D do not have a beneficial effect on muscle health in non-athletes and may in some cases even have a negative effect. Subgroup analysis suggest that this finding may be dose-dependent. Our data do not support a beneficial effect on muscle health in vitamin D insufficient individuals, albeit only a minority of included studies investigated individuals suffering from vitamin D insufficiency. As an increasing number of studies report negative musculoskeletal effects including an increased fall risk, this study support the theory, that vitamin D should be dosed with care.