Abstract and Introduction
Context: The growing number of systematic reviews/meta-analyses (SR/MAs) on vitamin D (± calcium) for fracture prevention has led to contradictory guidelines.
Objective: This umbrella review aims to assess the quality and explore the reasons for the discrepancy of SR/MAs of trials on vitamin D supplementation for fracture risk reduction in adults.
Methods: We searched 4 databases (2010–2020), Epistemonikos, and references of included SRs/MAs, and we contacted experts in the field. We used A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR-2) for quality assessment. We compared results and investigated reasons for discordance using matrices and subgroup analyses (PROSPERO registration: CRD42019129540). We included 13 SR/MAs on vitamin D and calcium (Ca/D) and 19 SR/MAs on vitamin D alone, compared to placebo/control.
Results: Only 2 from 10 SRs/MAs on Ca/D were of moderate quality. Ca/D reduced the risk of hip fractures in 8 of 12 SRs/MAs (relative risk [RR] 0.61–0.84), and any fractures in 7 of 11 SR/MAs (RR 0.74–0.95). No fracture risk reduction was noted in SRs/MAs exclusively evaluating community-dwelling individuals or in those on vitamin D alone compared to placebo/control. Discordance in results between SRs/MAs stems from inclusion of different trials, related to search periods and eligibility criteria, and varying methodology (using intention to treat, per-protocol, or complete case analysis from individual trials).
Conclusion: Ca/D reduces the risk of hip and any fractures, possibly driven by findings from institutionalized individuals. Individual participant data meta-analyses of patients on Ca/D with sufficient follow-up periods, and subgroup analyses, would unravel determinants for a beneficial response to supplementation.
Vitamin D plays a critical role in musculoskeletal health through its effects on mineral homeostasis and bone metabolism.[1,2] Vitamin D deficiency is common among older individuals because of reduced cholecalciferol synthesis in the skin, reduced intestinal calcium (Ca) absorption, and changes in lifestyle favoring lower exposure to ultraviolet radiation. This deficiency may contribute to the observed steep rise in the risk of fractures with older age, particularly at the hip. This is of particular importance given that the estimated 1-year mortality following hip fracture is around 30%.
The benefit of vitamin D supplementation on fracture prevention has been extensively assessed, with an exponential rise in the number of systematic reviews/meta-analyses (SRs/MAs) reporting discordant conclusions. A recent review in 2017 identified more than 40 international vitamin D guidelines with highly variable recommendations. There is still conflicting evidence with regards to the extent of vitamin D's benefit in fracture prevention, the target population likely to benefit the most, the desirable serum 25-hydroxyvitamin D (25[OH]D) concentration, the optimal vitamin D dose, and the need for coadministration of Ca.[7–9]
We therefore conducted an umbrella review of SRs/MAs of vitamin D supplementation randomized clinical trials (RCTs) evaluating fracture risk reduction in adults, to assess the quality of each SR/MA, explore similarities and differences between them, investigate the reasons for any discrepancy, and formulate a reliable conclusion on the topic. Such an approach would bring clarity to much confusion, paving the path for the formulation of informed population-tailored conclusions regarding the benefit of vitamin D supplementation in preventing fractures.
J Clin Endocrinol Metab. 2022;107(3):882-898. © 2022 Endocrine Society