Relative Efficacy of Vitamin D2 and Vitamin D3 in Improving Vitamin D Status: Systematic Review and Meta-Analysis

Abstract

Background: Widespread prevalence of vitamin D deficiency has been documented globally. Commonly used interventions to address this deficiency include supplementation and/or fortification with either ergocalciferol (vitamin D₂) or cholecalciferol (vitamin D₃), but the relative efficacy of these two vitamers is unclear. The current study aimed to evaluate the relative efficacy of ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃) for raising the serum levels of vitamin D metabolites and functional indicators including serum parathyroid (PTH) levels, isometric muscle strength, hand grip strength and bone mineral density.

Methods: Randomized and non-randomized controlled studies evaluating relative efficacy of ergocalciferol and cholecalciferol were systematically reviewed to synthesize quantitative and qualitative evidence as per the recommendations of according to "Preferred Reporting Items for Systematic reviews and Meta-analysis" guidelines. Search terms were constructed on the basis of the "participants", "intervention", "control", "outcome" and "study type" (PICOS) strategy to systematically search the popular electronic databases. Relevant data from studies meeting inclusion and exclusion criteria were extracted and analyzed. Meta-regression, subgroup and sensitivity analyses were performed to investigate the influence of study-level characteristics including intervention dosage, frequency of dosing, interval between the last dose and test for outcome assessment, participant characteristics and analytical methods.

Results: Apparently healthy human participants (n = 1277) from 24 studies were included for meta-analysis. The quantitative analysis suggested higher efficacy of cholecalciferol than ergocalciferol in improving total 25(OH)D (mean difference: 15.69, 95%CI: 9.46 to 21.93 nmol/L) and reducing PTH levels, consistently across variable participant demographics, dosage and vehicle of supplementation. Meta-regression suggested smaller differences in the efficacy of cholecalciferol and ergocalciferol at lower doses. Average daily dose was the single significant predictor of effect size, as revealed by multivariate meta-regression analysis.

Conclusions: Compared to ergocalciferol, cholecalciferol intervention was more efficacious in improving vitamin D status (serum levels of total 25(OH)D and 25(OH)D₃) and regulating PTH levels, irrespective of the participant demographics, dosage and vehicle of supplementation.

Keywords: cholecalciferol; ergocalciferol; parathyroid hormone; vitamin D; vitamin D2; vitamin D3.

Figure 1

Flow diagram as per PRISMA recommendations. Legend: The flow chart illustrates the number of articles included and excluded at various steps.

Figure 2

Forrest plot analysis of serum total 25(OH)D: sub-group analysis based on the frequency of doses. Legend: Forrest plot of random effect meta-analysis comparing the effects of cholecalciferol vs. ergocalciferol supplementation on net changes in 25(OH)D concentrations favored cholecalciferol. “Δ25(OH)D” denotes the change in total 25(OH)D concentrations from baseline (net change), “diamond” image denotes the mean differences (with 95% confidence interval). The pooled results indicate a mean difference of 15.69 nmol/L (95% confidence interval: 9.46–21.93 nmol/L) favoring cholecalciferol supplementation. Sub-group analyses in relation to the dosage frequency (single stat or bolus dose vs. daily dosage) are presented. Sub-group analyses show higher serum 25(OH)D levels among the cholecalciferol supplemented group as compared to ergocalciferol group. However, the studies are highly heterogeneous (I² > 65%).

Figure 3

Forrest plot analysis of serum total 25(OH)D: sub-group analysis based on daily dosage. Legend: Forrest plot of random effect meta-analysis comparing the effects of cholecalciferol vs. ergocalciferol supplementation on net changes in 25(OH)D concentrations favored cholecalciferol. Sub-group analyses in studies with daily dosage ≤ 1000 nmol/L, 1000–4000 nmol/L and ≥ 4000 nmol/L of the respective vitamin D forms showed higher serum 25(OH)D levels among the cholecalciferol group as compared to ergocalciferol group in all groups. The heterogeneity of the subgroup analysis was high (I² > 65%). The test of subgroup difference was statistically significant (p = 0.03).

Figure 4

Funnel plot for total 25(OH)D. Legend: Funnel plot with X axis representing the estimated measure (standardized mean difference) of the 25(OH)D and Y axis representing the precision of the measure (standard error). The funnel plot suggests relatively mixed quality studies (due to variations in the standard error/SE).

Figure 5

Forrest plot for 25(OH)D₂. Legend: Forrest plot of random effect meta-analysis comparing the effects of cholecalciferol vs. ergocalciferol supplementation on net changes in 25(OH)D₂ concentrations favored ergocalciferol. “Δ25(OH)D₂” denotes the change in 25(OH)D₂ concentrations from baseline (net change), squares denote the mean differences (with 95% confidence interval), i.e., the pooled results indicate mean difference of −27.5 nmol/L (95% confidence interval: −34.24 to −20.76 nmol/L), favoring ergocalciferol supplementation. However, the studies are highly heterogeneous (I² = 98%).

Figure 6

Forrest plot for 25(OH)D_3. Legend: Forrest plot of random effect meta-analysis comparing the effects of cholecalciferol vs. ergocalciferol supplementation on net changes in 25(OH)D₃ concentrations favored cholecalciferol. “Δ25(OH)D₃” denotes the change in 25(OH)D₃ concentrations from baseline (net change), squares denote the mean differences (with 95% confidence interval), i.e., the pooled results indicate mean difference of 40.85 nmol/L with 95% confidence interval of 31.52 to 50.17 nmol/L, favoring cholecalciferol supplementation. However, the studies are highly (significantly) heterogeneous (I² = 97%).

Figure 7

Forrest plot for parathyroid levels. Legend: Forrest plot of random effect meta-analysis comparing the effects of cholecalciferol vs. ergocalciferol supplementation on net changes in parathyroid (PTH) levels favored cholecalciferol. “ΔPTH” denotes the change in PTH concentrations from baseline (net change), squares denote the mean differences (with 95% confidence interval). The pooled results indicate a mean difference of 0.56 pmol/L (95% confidence interval 0.18–0.93 pmol/L), favoring cholecalciferol supplementation. Sub-group analyses in relation to dosage frequency (daily dosage vs. remaining studies) also demonstrated consistently higher PTH levels among the cholecalciferol-supplemented group as compared to the ergocalciferol group. However, the studies are moderately heterogeneous (I² = 42%).