In the United States, vitamin D supplementation is primarily available as vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Although these two have historically been considered interchangeable and equipotent, the current body of literature strongly supports the preference of Vitamin D3 (cholecalciferol) over D2 (ergocalciferol).
Vitamin D2 versus Vitamin D3
Vitamin D3 (cholecalciferol) is produced by the human body in response to sunlight and is also available through dietary sources, such as fish. In contrast, vitamin D2 (ergocalciferol) is not produced in the human body, but is created by exposing certain plant-derived materials to ultraviolet light.
When the manufacturing method for ergocalciferol was created, binding studies of the vitamin D receptor in rats showed equipotency between ergocalciferol and cholecalciferol. On the basis of this animal data, most resources cite the two being equipotent and interchangeable.
Given that both ergocalciferol and cholecalciferol undergo metabolic changes in the human body, which differ from other animals, it should make sense that a binding study in rats may not be sufficient to show equivalence. In fact, recent literature (Trang 1998, Armas 2004, Houghton 2006) convincingly demonstrates that cholecalciferol is 1.7 to 3 times more potent and has a longer-lasting effect than ergocalciferol in increasing serum 25-hydroxyvitamin D levels, the active form of vitamin D in humans. The difference in duration of effect and potency are well demonstrated in a study by Armas et al:
Healthy volunteers were given a single 50,000 unit dose of either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol)
Why is ergocalciferol prescribed?
If ergocalciferol is less potent and has a shorter duration of effect, why is it used? The most likely reason is due to dosage formulations. Unlike cholecalciferol, which is typically only available as a maximum dose of 5,000 units per capsule or tablet, ergocalciferol is available as a monster 50,000 unit dose. This larger dose may be seen as more convenient for patients or healthcare providers who want to provide supplementation on a weekly or monthly basis.
Surrogate versus Clinical Outcomes
Although 25-hydroxyvitamin D levels are a better surrogate than a rat binding study, clinical outcomes are the most relevant. Low levels of 25-hydroxyvitamin D (less than 20 ng/mL; Bjelakovic 2014) are very common in North America and have been associated with a wide variety of diseases including osteoporosis, bone fractures, malignancy, cardiovascular disease, infections, and more. The majority of the data supports association, not causation, of low vitamin D levels. In other words, much of the data does not clearly support the idea that vitamin D supplementation in a patient with low vitamin D levels reduces the risk of these diseases.
With that said, a recent Cochrane review (Bjelakovic 2014) analyzed the all-cause mortality benefit of vitamin D supplementation (both D2 and D3) by pooling 95,286 participants from 56 randomized clinical trials. In this meta-analysis, about 80% of participants received cholecalciferol (median dose 800 units/day) and about 20% received ergocalciferol (median 1000 units/day). The vast majority were women (77%), and most were older than 70 years of age.
The Cochrane review calculated an all-cause mortality relative risk (RR) of 0.97 (95% CI 0.94-0.99, p=0.02), which represented a raw difference in mortality of 12.5% (control) vs. 12.7% (vitamin D). The authors calculated a number needed to treat (NNT) of 150 over five years; however, the NNT calculates to 500 over a weighted mean of 4.4 years using the raw difference in mortality rates. Importantly, the difference in mortality was only demonstrated for trials examining cholecalciferol. Although ergocalciferol did make up a minority of the meta-analysis, it was adequately powered to detect a 5% difference in relative risk reduction.
- Cholecalciferol (vitamin D3) is more potent and longer acting than ergocalciferol (vitamin D2) as measured by the active form of vitamin D in the blood (25-hydroxyvitamin D).
- Low vitamin D levels are common in North America; most data supports an association between low vitamin D levels and disease. Much less data supports a cause-and-effect relationship between vitamin D supplementation and prevention of specific diseases.
- Vitamin D supplementation with cholecalciferol (D3) appears to have a small but statistically significant benefit in improving all-cause mortality among elderly women. The mortality benefit in younger patients or male patients is not clear.
- Ergocalciferol (D2) is less studied than cholecalciferol and was not shown to confer a mortality benefit in a recent Cochrane meta-analysis despite adequate statistical power.
- For patients who meet criteria for vitamin D supplementation (which is an entire argument in itself), vitamin D3 (cholecalciferol) should be selected over vitamin D2 (ergocalciferol).
- Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab. 2004 Nov;89(11):5387-91. PMID 15531486.
- Trang HM, Cole DE, Rubin LA, et al. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr. 1998 Oct;68(4):854-8. PMID 9771862
- Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr. 2006 Oct;84(4):694-7. PMID 17023693.
- Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470. PMID 24414552.