To our knowledge, our reported work is the first-ever systematic review and meta-analysis of the comparative effectiveness of ergocalciferol compared with cholecalciferol in the raising of serum 25(OH)D concentrations. We consider this study to be a key investigation because of the widespread perception that ergocalciferol and cholecalciferol are equally efficacious in their respective abilities to raise serum 25(OH)D concentrations (21
). As shown in our meta-analysis results, after we reviewed all known studies, there was a clear favoring of cholecalciferol supplementation in the raising of serum 25(OH)D concentrations compared with that of ergocalciferol supplementation (). We have also shown that, regardless of whether supplementation with vitamin D was in small daily doses or in larger and more infrequent bolus dosages, the favoring toward cholecalciferol was still evident. The reasons why cholecalciferol is much more proficient than ergocalciferol at raising serum 25(OH)D concentrations must be examined. Evidence has been accumulating that specifically looks at the metabolism of vitamin D, especially that focuses on the hydroxylation steps at the liver and kidney that were required to convert the inert ergocalciferol and cholecalciferol to the active calcitriol (1,25-dihydroxyvitamin D). As described in the review of Houghton and Vieth (8
) of the evidence in 2006, it is clear that there are stark differences in the metabolic fates of ergocalciferol and cholecalciferol that should not be ignored. By centering on the differences in side chains between the 2 forms of vitamin D [ergocalciferol has an additional methyl group on carbon 24 (22
)], there have been reports that this difference directly affects the rate of ergocalciferol conversion to serum 25(OH)D (9
) and also its affinity for vitamin D binding protein and VDR (8
), which are all critical steps involved in the activation of vitamin D. Once the 2-step 25-hydroxylation process has been completed and 1,25-dihydroxyvitamin D has been formed, an additional step occurs that involves 24-hydroxylation at the kidney to form 1,24,25(OH)3
D [1,24,25-trihydroxyvitamin D; 25(OH)D can also be converted to 24,25-dihydroxyvitamin D at this point] (8
). As reported by Horst et al (25
), it is this 24-hydroxylation step that truly demarcates the impact of ergocalciferol compared with that of cholecalciferol. This differentiation between ergocalciferol and cholecalciferol is due to the fact that once 1,24,25(OH)3
has been formed, ergocalciferol has been deactivated and, therefore, is irretrievable (25
). In contrast, cholecalciferol [now 1,24,25(OH)3
] retains its capacity to bind to the VDR (8
) and still requires an additional side-chain oxidation to become deactivated (25
). Thus, this additional step gives a vast advantage and potential for cholecalciferol to remain biologically active and, thus, maintain vitamin D status, which only strengthen the hypothesis that cholecalciferol is the preferred substrate compared with ergocalciferol.
This complication in the hydroxylation and deactivation processes of ergocalciferol and cholecalciferol that could impact efficacy is explored to some degree in a small number of the clinical trials included in this review. Armas et al (13
) and Heaney et al (17
) showed that, over a time course, cholecalciferol induced a quicker response in the production of serum 25(OH)D that was sustained for longer and at higher concentrations than did ergocalciferol. In Heaney et al (17
), weekly doses of 50,000 IU (for 12 wk) induced AUC values for cholecalciferol that were significantly higher than those for ergocalciferol; Heaney et al (17
) also noted that, once the doses of vitamin D were stopped at week 12, there was evidence of far greater rates of degradation of serum 25(OH)D2
(ergocalciferol) than serum 25(OH)D3
(cholecalciferol) over a 6-wk time period. Armas et al (13
) chose a single bolus of 50,000 IU that again showed a significantly greater AUC for cholecalciferol than for ergocalciferol, with serum 25(OH)D2
concentrations that fell rapidly back to baseline after only 14 d, whereas serum 25(OH)D3
concentrations peaked at the same time point and had not returned to baseline at the end of the 28-d intervention.
When the evidence from the studies that focused on vitamin D metabolism at the cellular level is compared with the evidence from clinical trials, it is clear that, overall, there was consistency in the results that shows cholecalciferol appears to have advantageous biological qualities that allows it to sustain its systemic influence for far longer and at far greater concentrations than does ergocalciferol. However, not all the clinical trials agree with this outcome, and 2 clinical trials showed no difference in the efficacy of ergocalciferol compared with cholecalciferol (6
), which indicated the possibility that the not all possible influences on vitamin D metabolism have been accounted for in the research completed to date.
The main limitation of this review was the small number of studies available within the literature, which, in turn, limited, to some degree, the ability to extrapolate the outcomes of this review toward realistic public health recommendations when referring to ergocalciferol and cholecalciferol supplementation. In addition, as described previously, the small number of studies also limited, to some degree, the confidence in our knowledge of the metabolism of vitamin D and whether all influences have been examined and quantified.
The intervention strategy across all studies was diverse with respect to the chosen dosage of vitamin D, the frequency of supplementation, and the method of administration used (oral compared with intramuscular), which inevitably contributed to the high levels of heterogeneity (). In addition, there were recurring issues across all studies in terms of the depth and detail of reporting. Many omissions were shown in the reporting of the randomization strategy, power calculations, and subject compliance. In scientific reporting, this lack of detail is unacceptable, especially given the crucial role of such studies in establishing key data within the vitamin D field. A lack of serious bias was only assured because of the clear detail that referred to the blinding of subjects and investigators and the overall attention to detail when methodologies were reported.
It was also noted that all studies gave ergocalciferol and cholecalciferol supplementation dosages far above the amount currently recommended [Recommended Dietary Allowance of 600 IU for males and females aged 1–70 y (26
)]. Although this strategy can be a useful methodology to force a physiologic change (and, thus, to possibly piece together a mechanism of action), these studies offered little information for lower doses, which are more realistic in terms of what individuals are likely to be able to consume within their daily diet and gain from sunlight exposure and the concentrations of ergocalciferol and cholecalciferol available in commercial supplements. Thus, in combination with the small and underpowered study populations (n
= 19–89) and lack of data in lower doses, there is a clear need for additional research to ascertain whether the results obtained within the studies included in this review translate across the entire dose-response curve.
In conclusion, our results suggest a favoring toward cholecalciferol rather than ergocalciferol supplementation with respect to the more effective improvement of vitamin D status. When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a bolus dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation. Far larger, more robust trials are now required that not only monitor serum 25(OH)D concentrations but also explore much further the potential mechanism behind this apparent discrepancy in effectiveness between the 2 forms of vitamin D available. This mechanistic approach should encompass the obvious need for a description of genetic polymorphisms linked to vitamin D metabolism and, also, the critical enzymes involved in the hydroxylation process. These studies would provide an ideal opportunity to identify the levels of enzymatic activity (microsomal cytochrome P450 2R1, mitochondrial cytochrome P450 27A1, and cytochrome P450 27B1) and the spectrum of vitamin D metabolites that are produced as part of the hydroxylation process that would be able to account for the deactivation process of ergocalciferol and cholecalciferol that appears to be the central cause for the discrepancy between efficacies at this point in time.