Abstract
BACKGROUNDTwo previous meta-analyses showed smaller differences between vitamin D3 (D3) and vitamin D2 (D2) in raising serum 25-hydroxy-vitamin D [25(OH)D] and a consistently high heterogeneity, when only including daily dosing studies. OBJECTIVETo compare more frequently dosed D2 and D3 in improving total 25(OH)D and to determine the concomitant effect of response modifiers on heterogeneity, and secondly to compare the D2-associated change in 25(OH)D2 with the D3-associated change in 25(OH)D3 (PROSPERO 2021 CRD42021272674). METHODSPubMed, EMBASE, Cochrane and the Web of Science Core collection were searched for RCTs of D2 versus D3, daily or once/twice weekly dosed. After screening for eligibility, relevant data were extracted for meta-analyses to determine the standardized mean difference (SMD) when different methods of 25(OH)D analyses were used. Otherwise, the weighted mean difference (WMD) was determined. RESULTSOverall, the results based on 20 comparative studies showed D3 to be superior to D2 in raising total 25(OH)D concentrations, but D2 and D3 had a similar positive impact on their corresponding 25(OH)D hydroxylated forms. The WMD in change in total 25(OH)D based on twelve, all daily dosed D2-D3 comparisons, analyzed using LCMS/MS, was 10.39 nmol/l (40%) lower for the D2 group compared to D3 group (95% CI -14.62, -6.16; I2=64%; p<00001). BMI appeared to be the strongest response modifier, reducing heterogeneity to 0% in both subgroups. The D2- and D3-induced change in total 25(OH)D lost significance in the predominantly subjects with a BMI>25kg/m2 (p=0.99). However, information on BMI was only available in 13/17 daily dosed comparisons. CONCLUSIONSD3 leads to a greater increase of 25(OH)D than D2, even if limited to daily dose studies, but D2 and D3 had similar positive impacts on their corresponding 25(OH)D hydroxylated forms. BMI should be considered when comparing the effect of daily vitamin D2 and vitamin D3 supplementation on total 25(OH)D concentration. STATEMENT OF SIGNIFICANCEPrevious meta-analyses suggest that vitamin D3 may be more potent in increasing serum 25(OH)D concentrations than vitamin D2. In addition, it appeared that with daily dosing this difference is smaller compared to other doses, e.g. monthly/bolus. Our meta-analysis confirms this when comparing the commonly recommended more frequent dosing regimens, daily versus weekly, although residual heterogeneity remained high. BMI and baseline 25(OH)D concentration may contribute to this residual variability and may therefore be considered when recommending a daily intervention with vitamin D2 or D3.