Influence of vitamin D supplementation on fracture risk, bone mineral density and bone biochemistry in Mongolian schoolchildren: multicenter double-blind randomised placebo-controlled trial.

BackgroundRandomized controlled trials (RCT) of vitamin D supplementation to reduce fracture risk in children are lacking. MethodsWe conducted a Phase 3 RCT of weekly oral supplementation with 14,000 IU vitamin D3 for 3 years in Mongolian schoolchildren aged 6-13 years. Serum 25-hydroxyvitamin D (25[OH]D) concentrations and the proportion of participants reporting [&ge;]1 fracture were secondary outcomes for the main trial. Radial bone mineral density (BMD) was assessed in a nested sub-study, with serum concentrations of parathyroid hormone (PTH) and bone-specific alkaline phosphatase (BALP) determined in a subset of participants. Findings8851 children were enrolled in the main trial, of whom 1465 also participated in the sub-study. Vitamin D deficiency was prevalent at baseline (25[OH]D <20 ng/mL in 90.1%). The intervention elevated 25(OH)D concentrations (adjusted inter-arm mean difference [aMD] 20.3 ng/mL, 95% CI 19.9 to 20.6) and suppressed PTH concentrations (aMD -13.6 pmol/L, 95% CI -23.5 to -3.7), but it did not influence fracture risk (adjusted risk ratio 1.10, 95% CI 0.93 to 1.29, P=0.27) or radial BMD z-score (aMD -0.06, 95% CI -0.18 to 0.07, P=0.36). Vitamin D suppressed serum BALP concentrations more among participants with baseline 25(OH)D concentrations <10 vs. [&ge;]10 ng/mL (Pinteraction=0.04). However, effects of the intervention on fracture risk and radial BMD were not modified by baseline vitamin D status (Pinteraction[&ge;]0.67). InterpretationWeekly oral vitamin D supplementation elevated serum 25(OH)D concentrations and suppressed PTH concentrations in vitamin D-deficient schoolchildren in Mongolia. However, this was not associated with reduced fracture risk or increased radial BMD. FundingNational Institutes of Health RESEARCH IN CONTEXTO_ST_ABSEVIDENCE BEFORE THIS STUDYC_ST_ABSWe searched PubMed from inception to 31st December 2022 for randomized controlled trials (RCT) evaluating effects of vitamin D supplementation on bone mineral content (BMC), bone mineral density (BMD) and fracture risk in HIV-uninfected schoolchildren. A meta-analysis of data from 884 participants in six RCT reported no statistically significant effects of vitamin D on total body BMC, hip BMD, or forearm BMD, but a trend towards a small positive effect on lumbar spine BMD. RCT investigating fracture outcomes were lacking, as were RCT investigating effects of vitamin D on bone outcomes in children with baseline serum 25-hydroxyvitamin D (25[OH]D) concentrations <20 ng/mL. ADDED VALUE OF THIS STUDYThis is the first RCT to investigate effects of vitamin D supplementation on fracture risk and BMD in Mongolian schoolchildren. Vitamin D deficiency was prevalent among the study population at baseline, and weekly oral supplementation with 14,000 IU vitamin D3 for 3 years elevated serum 25(OH)D concentrations into the physiologic range and suppressed serum PTH concentrations. However, the intervention did not influence fracture risk or radial BMD, either in the study population as a whole or in the large sub-group of participants with baseline serum 25(OH)D concentrations <10 ng/mL. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCETaken together with null findings from another recenty-completed phase 3 RCT of weekly oral vitamin D supplementation conducted in South African schoolchildren, our findings do not support a role for vitamin D supplementation to reduce fracture risk or increase BMD in primary schoolchildren.