Vitamin D Food Fortification and Biofortification Increases Serum 25-Hydroxyvitamin D Concentrations in Adults and Children: An Updated and Extended Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Low vitamin D status is a global public health issue that vitamin D food fortification and biofortification may help to alleviate. Objectives: We investigated the effect of vitamin D food fortification and biofortification on circulating 25-hydroxyvitamin D (25(OH)D) concentrations. We expanded the scope of earlier reviews to include adults and children, to evaluate effects by vitamin D vitamer, and investigate linear and nonlinear dose-response relations. Methods: We conducted a systematic review and meta-analysis. We searched CINAHL, MEDLINE, PubMed, Embase, the Cochrane Library, and gray and unpublished literature sites for randomized controlled trials, including people of all ages, with the criteria: absence of illness affecting vitamin D absorption, duration ≥4 wk, equivalent placebo food control, dose quantification, dose ≥5 μg/d, baseline and endpoint or absolute change in 25(OH)D concentrations reported, random allocation, and participant blinding. Quality was assessed using the Jadad Scale. Results: Data from 34 publications (2398 adults: 1345 intervention, 1053 controls; 1532 children: 970 intervention, 562 controls) were included. Random-effects meta-analysis of all studies combined (mean dose 16.2 μg/d) indicated a pooled treatment effect of 21.2 nmol/L (95% CI: 16.2, 26.2), with a greater effect for studies using cholecalciferol than ergocalciferol. Heterogeneity was high (I2 > 75%). Metaregression analyses for all studies combined suggested positive effect differences for baseline circulating 25(OH)D concentrations <50 nmol/L, dose ≥10 μg/d and a negative effect difference when the intervention arm included a calcium dose ≥500 mg/d greater than the control arm. Dose-response rates were found to be nonlinear (Wald test for nonlinearity P < 0.001). For all studies combined, a threshold occurred at ∼26 nmol/L for a dose of ∼21 μg/d. Conclusions: These results support use of vitamin D food fortification to improve circulating 25(OH)D circulations in populations. This work was registered with PROSPERO as CRD42020145497.