The case against ergocalciferol (vitamin D2) as a vitamin supplement

Supplemental vitamin D is available in 2 distinct forms: ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃). Pharmacopoeias have officially regarded these 2 forms as equivalent and interchangeable, yet this presumption of equivalence is based on studies of rickets prevention in infants conducted 70 y ago. The emergence of 25-hydroxyvitamin D as a measure of vitamin D status provides an objective, quantitative measure of the biological response to vitamin D administration. As a result, vitamin D₃ has proven to be the more potent form of vitamin D in all primate species, including humans. Despite an emerging body of evidence suggesting several plausible explanations for the greater bioefficacy of vitamin D₃, the form of vitamin D used in major preparations of prescriptions in North America is vitamin D₂. The case that vitamin D₂ should no longer be considered equivalent to vitamin D₃ is based on differences in their efficacy at raising serum 25-hydroxyvitamin D, diminished binding of vitamin D₂ metabolites to vitamin D binding protein in plasma, and a nonphysiologic metabolism and shorter shelf life of vitamin D₂. Vitamin D₂, or ergocalciferol, should not be regarded as a nutrient suitable for supplementation or fortification.

Vitamin D₂, if given in high enough doses, prevents infantile rickets and is capable of healing adult osteomalacia. However, the inefficiency of vitamin D₂ compared with vitamin D₃, on a per mole basis, at increasing 25(OH)D is now well documented, and no successful clinical trials to date have shown that vitamin D₂ prevents fractures (19-21, 47). Given the assumption that the intake of any nutrient will deliver defined effects [ie, supplementation with vitamin D will lead to an increase in 25(OH)D or fracture prevention], it is clear that vitamin D₂ does not fit this current nutritional notion. This is not to suggest that vitamin D₂ is not efficacious, but, because the units of the 2 forms is clearly not equivalent, likely due to its distinct metabolic features and diminished binding of vitamin D₂ metabolites to DBP in plasma, continual application of vitamin D₂ in clinical use, including in research trials, only serves to confound our understanding of optimal vitamin D dosing recommendations. Furthermore, the public expects to derive the equivalent effect per unit dose of vitamin D, whether it is vitamin D₂ or vitamin D₃. The scientific community is aware that these molecules are not equivalent. Therefore, vitamin D₂ should no longer be regarded as a nutrient appropriate for supplementation or fortification of foods.