Meta-Analysis of European Clinical Trials Characterizing the Healthy-Adult Serum 25-hydroxyvitamin D Response to Vitamin D Supplementation

Abstract

To obtain reliable data that allow health authorities to re-evaluate recommendations for oral vitamin D uptake, we conducted a meta-analysis to investigate the impact of supplementation on serum 25-hydroxyvitamin D (25(OH)D) levels in healthy adults in Europe. Of the publications identified (n = 4005) in our literature search (PUBMED, through 2 January 2022), 49 primary studies (7320 subjects, 73 study arms) were eligible for inclusion in our meta-analysis. The risk of bias was assessed using the Cochrane RoB tool based on seven categories, according to which each study is rated using three grades, and overall was rated as rather low. The median duration of intervention was 136.78 days (range, 1088 days); the mean weighted baseline 25(OH)D concentration and mean age were 33.01 vs. 33.84 nmol/L and 46.8 vs. 44.8 years in the vitamin D and placebo groups, respectively. Using random-effects models, 25(OH)D levels were increased by 36.28 nmol/L (95% CI 31.97-40.59) in the vitamin D group compared to the placebo, with a relative serum increment of 1.77 nmol/L per 2.5 μg of vitamin D daily. Notably, the relative serum 25(OH)D increment was affected by various factors, including the dosage and baseline serum 25(OH)D concentration, decreasing with increasing vitamin D doses and with increasing baseline serum levels. We estimate that supplementation in all healthy adults in Europe with appr. 25 μg of vitamin D (1000 IU) daily would raise serum 25(OH)D levels in 95% of the population to ≥50 nmol/L. Our work provides health authorities with reliable data that can help to re-evaluate recommendations for oral vitamin D supplementation.

Keywords: Europe; adults; healthy; supplementation; vitamin D; vitamin D deficiency.

Figure 1

Flow chart according to PRISMA guidelines [11] showing the structured process, from PUBMED search results to title and abstract screening against inclusion/exclusion criteria to full-text reading of prior positively screened studies for further alignment with inclusion/exclusion criteria for the final inclusion of studies for systematic review and meta-analysis.

Figure 2

Risk-of-bias assessment—overall summary.

Figure 3

Forest plot of all included studies (arms). Created with Review Manager v.5.4.1 [17]. The effect of vitamin D supplementation (right side of the graph) on serum 25(OH)D increment compared with placebo was demonstrated in all studies [26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74]. With the exception of 6 studies that crossed the zero line, this effect was also statistically significant [43,61,68,72,73].

Figure 4

Subgroups of vitamin D variants 25(OH)D and D2. The effect of serum 25(OH)D increment vs. placebo was stronger in the studies with 25(OH)D supplements than in those with D2. The vitamin D2 study, furthermore, could not show a statistically significant serum increment over placebo due to crossing the zero line [33,43,67].

Figure 5

Within each box, horizontal lines denote median values; boxes extend from the 25th to the 75th percentile of each group’s distribution of values; vertically extending lines denote adjacent values (i.e., the most extreme values within 1.5 interquartile range of the 25th and 75th percentiles of each group); dots denote observations outside the range of adjacent values. The relative serum 25(OH)D increment per 2.5 μg daily vitamin D dependent on baseline 25(OH)D levels <50 and ≥50 nmol/L are shown for (A) age 18–59 years with <38 μg/day vitamin D, (B) age 18–59 years with ≥38–<75 μg/day vitamin D, (C) age 18–59 years with ≥75 μg/day vitamin D, and (D) age ≥60 years with <38 μg/day vitamin D. On the one hand, it was shown that baseline 25(OH)D levels <50 nmol/L achieved a greater serum increment per 2.5 μg of vitamin D (100 IU) per day regardless of the supplemented vitamin D dose. On the other hand, however, it also appeared that this relative serum increment was most pronounced in the low-dose category and always decreased with higher doses. In addition, it was also shown that the older population achieved a greater serum increment per 2.5 mcg of daily vitamin D compared to the younger population with low-dose vitamin D.

Figure 6

Subgroup analysis of women with low dose, 18–59 vs. ≥60 years. Created with Review Manager v.5.4.1 [17]. Both subgroups showed significant weighted mean difference between vitamin D supplementation versus placebo (both p < 0.00001), despite significant and substantial heterogeneity. The serum increase with vitamin D supplementation was significantly greater in the older population than in the younger population (p = 0.03), although the heterogeneity in the results of the studies of both subgroups could not be explained by this subgroup analysis [27,29,30,41,43,60,61].

Figure 7

Estimation of serum 25(OH)D concentration reasonably assured for adults taking the doses used in European clinical trials of vitamin D supplementation using cholecalciferol (circles) or calcidiol (triangles). The data points shown in this scatter plot each show the values of the mean minus 2 SD for serum 25(OH)D in all vitamin D studies included in this meta-analysis versus the daily doses of vitamin D in those studies. That is, each data point represents the lowest serum 25(OH)D value estimated for the study’s daily dose.