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.