Comparison of the Effect of Daily Vitamin D2 and Vitamin D3 Supplementation on Serum 25-Hydroxyvitamin D Concentration (Total 25(OH)D, 25(OH)D2, and 25(OH)D3) and Importance of Body Mass Index: A Systematic Review and Meta-Analysis

Abstract

Background: Two previous meta-analyses showed smaller differences between vitamin D3 and vitamin D2 in raising serum 25-hydroxyvitamin D [25(OH)D] and a consistently high heterogeneity when only including daily dosing studies.

Objective: This study aimed to compare more frequently dosed vitamin D2 and vitamin D3 in improving total 25(OH)D and determine the concomitant effect of response modifiers on heterogeneity, and secondly, to compare the vitamin D2-associated change in 25(OH)D2 with the vitamin D3-associated change in 25(OH)D3.

Methods: PubMed, EMBASE, Cochrane, and the Web of Science Core collection were searched for randomized controlled trials of vitamin D2 compared with vitamin D3, daily or once/twice weekly dosed. After screening for eligibility, relevant data were extracted for meta-analyses to determine the standardized mean difference when different methods of 25(OH)D analyses were used. Otherwise, the weighted mean difference (WMD) was determined.

Results: Overall, the results based on 20 comparative studies showed vitamin D3 to be superior to vitamin D2 in raising total 25(OH)D concentrations, but vitamin D2 and vitamin 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 12 daily dosed vitamin D2-vitamin D3 comparisons, analyzed using liquid chromatography-tandem mass spectrometry, was 10.39 nmol/L (40%) lower for the vitamin D2 group compared with the vitamin D3 group (95% confidence interval: -14.62, -6.16; I² = 64%; P < 00001). Body mass index (BMI) appeared to be the strongest response modifier, reducing heterogeneity to 0% in both subgroups. The vitamin D2- and vitamin D3-induced change in total 25(OH)D lost significance predominantly in subjects with a BMI >25 kg/m² (P = 0.99). However, information on BMI was only available in 13/17 daily dosed comparisons.

Conclusions: Vitamin D3 leads to a greater increase of 25(OH)D than vitamin D2, even if limited to daily dose studies, but vitamin D2 and vitamin D3 had similar positive impacts on their corresponding 25(OH)D hydroxylated forms. Next to baseline 25(OH)D concentration, BMI should be considered when comparing the effect of daily vitamin D2 and vitamin D3 supplementation on total 25(OH)D concentration. This study was registered in PROSPERO as CRD42021272674.

Keywords: 25(OH)D; bioavailability; cholecalciferol; ergocalciferol; healthy adults; meta-analysis; systematic review; vitamin D response.

FIGURE 1

Funnel plot of all included studies comparing vitamin D2 and D2 in changing serum concentration of total 25(OH)D. ◊, weekly treatment; ○, daily treatment.

FIGURE 2

Random-effects meta-analysis comparing the effects of daily and weekly supplementation of D2 with that of D3 on net changes in serum 25(OH)D concentrations. The forest plot indicates that the absolute change in 25(OH)D from baseline favored the D3 intervention. In the figure, “vitamin D2” and “vitamin D3” denotes the change in serum 25(OH)D concentrations from baseline (net change) in the D2 and D3 group respectively, and “Total” denotes the cumulative n from all included comparisons. Using a random-effects model, there was generally a significantly smaller effect in the raising of serum 25 (OH)D concentrations over time for D2 supplementation than for D3 supplementation, which was more striking when vitamin D was administered less often (P < 0.00001). Excluding the low-quality studies [25,27,[32], [33], [34],36,39], the SMD of the subgroup consisting of studies with a daily dosing schedule was −0.49 (95% CI: −0.80, −0.18; I² = 67%; P = 0.002). IV, inverse variance; t25(OH)D, total 25(OH)D concentration.

FIGURE 3

Random-effects meta-analysis comparing the effects of daily supplementation of D2 with that of D3 on the D2-induced change in 25(OH)D2 with the D3-induced change in 25(OH)D3 concentrations. The forest plot indicates that no difference in the absolute change in 25(OH)D2/3 was observed. In the figure, “25(OH)D2 due to D2” and “25(OH)D3 due to D3” denotes the vitamin D2-induced change in 25(OH)D2 and the vitamin D3-induced change in 25(OH)D3 concentrations from baseline (net change), and “Total” denotes the cumulative n from all included comparisons. As shown in Supplementary Figure S4D4, excluding the low-quality studies [32,33,36,39], the SMD was −0.07 (95% CI: −0.43, 0.28; I² = 51%; P = 0.69). IV, inverse variance.

FIGURE 4

Random-effects meta-analysis comparing the effects of average BMI > 25 vs. BMI < 25 on net changes in serum 25(OH)D concentrations. In the figure, “vitamin D2” and “vitamin D3” denotes the change in serum 25(OH)D concentrations from baseline (net change) in the daily dosed D2 and D3 group respectively, and “Total” denotes the cumulative number of all included comparisons. Using a random-effects model, no significant difference was found between the raising of serum 25 (OH)D concentrations over time for D2 supplementation and for D3 supplementation in subjects with overweight or obesity, whereas in subjects with a healthy weight a significantly smaller effect was found in the raising of serum 25 (OH)D concentrations over time for D2 supplementation than for D3 supplementation. The test for subgroup differences suggests that there is a statistically significant subgroup effect (P < 0.00001), meaning that BMI significantly modifies the effect of the intervention. Excluding the low-quality studies [33,34,36,39] the SMD in the D2-D3 comparison in predominantly subjects with healthy weight was −0.88 (95% CI: −1.12, −0.64; I² = 0%; P < 0.00001) with no impact on the other subgroup or the P value of the difference. IV, inverse variance; t25(OH)D, total 25(OH)D concentration.