Vitamin D Supplementation and Fractures in Adults

A Systematic Umbrella Review of Meta-Analyses of Controlled Trials

Marlene Chakhtoura; Dania S. Bacha; Charbel Gharios; Sara Ajjour; Mariam Assaad; Yara Jabbour; Francesca Kahale; Aya Bassatne; Stephanie Antoun; Elie A. Akl; Roger Bouillon; Paul Lips; Peter R. Ebeling; Ghada El-Hajj Fuleihan

Disclosures

J Clin Endocrinol Metab. 2022;107(3):882-898. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

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.[3] This deficiency may contribute to the observed steep rise in the risk of fractures with older age, particularly at the hip.[4] This is of particular importance given that the estimated 1-year mortality following hip fracture is around 30%.[5]

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.[6] A recent review in 2017 identified more than 40 international vitamin D guidelines with highly variable recommendations.[7] 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.

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