Which oral formulation of vitamin D is preferred: vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol)?
Response from Darrell Hulisz, PharmD
Associate Professor, Case Western Reserve University School of Medicine, Cleveland, Ohio; Clinical Specialist in Family Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio
Vitamin D is essential for adequate gastrointestinal absorption of calcium. Insufficient amounts of vitamin D over time reduces serum calcium and can trigger a compensatory release of parathyroid hormone.[1,2] This may produce secondary hyperparathyroidism, resulting in mobilization of calcium from bone and a reduction in bone mineral density.[2,3] Long-term vitamin D insufficiency can lead to muscle weakness and increase the risk for osteoporotic fractures, falls, rickets, and osteomalacia.[2,4,5] Some experts suggest that, based on epidemiologic evidence, vitamin D deficiency may increase the risk for certain chronic illnesses, including various cancers, autoimmune diseases, and cardiovascular disease.
Although some foods, such as milk and orange juice, are fortified with vitamin D, studies have shown that many individuals still consume low amounts of this nutrient or have insufficient vitamin D serum levels.[2,6,7] This may in part be related to changing dietary patterns in this United States, such as low consumption of milk and foods rich in vitamin D (eg, salmon, eel, tuna, and mackerel). Since most biologically active vitamin D comes from skin exposure to sunlight, the increased widespread use of broad-spectrum, high sun-protection-factor sunscreens in recent years may also contribute to the rise in vitamin D deficiency.
Several guidelines have been issued by national organizations that recommend varying amounts of vitamin D intake. Perhaps the most current, authoritative consensus report has been issued by the Institute of Medicine.This guideline recommends a daily dietary allowance of vitamin D of 600-800 IU/day for most patients. However, increased amounts are necessary for treating insufficiency and deficiency. Although much attention has been given to vitamin D intake, most consensus statements do not delineate the differences between the 2 major oral formulations: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol).
Vitamin D is produced cutaneously and converted to active metabolites in the liver and kidney. On exposure to ultraviolet irradiation, provitamin D3 (7-dehydrocholesterol) in the skin is converted to previtamin D3, which is then isomerized to more stable vitamin D3 via a thermally induced transformation. Vitamin D3, whether cutaneously formed or obtained in the diet as cholecalciferol, is subsequently hydroxylated in the liver to 25-hydroxyvitamin D. This is the major circulating form of vitamin D that is assayed to detect deficiency. 25-hydroxyvitamin D is hydroxylated again in the kidney to form 1,25-dihydroxyvitamin D3, the major biologically active form of vitamin D, also known as calcitriol. Thus, in the setting of severe renal impairment, formulations of calcitriol are preferred over ergocalciferol and cholecalciferol because the terminal hydroxylation occurs in the kidney.
Regarding the manufacturing of oral vitamin D formulations, ergocalciferol is made from ultraviolet irradiation of ergosterol in yeast. Cholecalciferol is made from irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol. Traditionally, oral formulations of vitamin D2 and D3 have long been regarded as equivalent in their clinical activity. However, studies indicate that ergocalciferol (vitamin D2) is much less potent and has a shorter duration of action than cholecalciferol.[9-11]
Historically, ergocalciferol has been used instead of cholecalciferol for severe vitamin D deficiency. This is out of convention, or perhaps because high-dose ergocalciferol is more widely available in doses of up to 50,000 IU per softgel capsule from multiple manufacturers. Although this dose of cholecalciferol is available from at least 1 manufacturer, it is often challenging to find in retail outlets. Based on this author’s experience, and verified by others, it is often difficult to raise 25-hydroxyvitamin D levels with ergocalciferol in patients with severe vitamin D deficiency.
Armas and colleagues administered single oral doses of 50,000 IU of the respective vitamin D preparations to 20 healthy male volunteers, and followed the time course of 25-hydroxyvitamin D levels over a period of 28 days. A pharmacokinetic analysis was also done. Both ergocalciferol and cholecalciferol produced similar initial increases in serum levels of 25-hydroxyvitamin D over the first 3 days, indicating equivalent absorption. However, levels continued to increase with cholecalciferol and peaked at day 14, whereas levels decreased rapidly with ergocalciferol and were no different from baseline at day 14. The investigators concluded that ergocalciferol potency is less than 30% of that of cholecalciferol and that it has a markedly shorter duration of action.
This study is consistent with other single, high-dose studies[9,10,12] that indicate the mean time to peak concentration of ergocalciferol to be about 3 days compared with 14 days for cholecalciferol. A review by Houghton and Vieth estimated that cholecalciferol is more than 3 times as effective as ergocalciferol in elevating 25-hydroxyvitamin D and maintaining those levels for a longer time. These authors also note that cholecalciferol metabolites have superior affinity for vitamin D-binding proteins in plasma, relative to ergocalciferol.
In conclusion, ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) are not bioequivalent and should not be considered interchangeable. Although few head-to-head trials exist, based on pharmacokinetic studies and limited clinical evidence, cholecalciferol is preferred over ergocalciferol. Because of its shorter half-life and decreased potency, this is especially relevant in the setting of severe deficiency, where high-dose ergocalciferol is often only given once weekly. Health professionals should encourage use of cholecalciferol over ergocalciferol in all patients without severe renal failure, either as a general supplement or as a treatment for vitamin D deficiency.
- Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
- Allain TJ, Dhesi J. Hypovitaminosis D in older adults. Gerontology. 2003;49:273-278.
- Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001;22:477-501.
- Gallacher SJ, McQuillian C, Harkness M, Finlay F, Gallagher AP, Dixon T. Prevalence of vitamin D inadequacy in Scottish adults with non-vertebral fragility fractures. Curr Med Res Opin. 2005;21:1355-1361.
- Bischoff HA, Stähelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res. 2003;18:343-351.
- Calvo MS, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr. 2004;80(suppl 6):1710S-1716S.
- Holick MF, Siris ES, Binkley N, et al. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab. 2005; 90:3215-3224.
- Institute of Medicine of the National Academy of Sciences. Dietary reference intakes for calcium and vitamin D. November 2010. Available at: www.iom.edu/vitaminD Accessed June 17, 2011.
- Tjellesen L, Hummer L, Christiansen C, Rødbro P. Serum concentration of vitamin D metabolites during treatment with vitamin D2 and D3 in normal premenopausal women. Bone Miner. 1986:1:407-413.
- Trang HM, Cole DE, Rubin LA, Pierratos A, Siu S, Vieth R. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr. 1998;68:854-858.
- Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab. 2004;89:5387-5391.
- Ilahi M, Armas LA, Heaney RP. Pharmacokinetics of a single, large dose of cholecalciferol. Am J Clin Nutr. 2008; 87:688-691.
- Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr. 2006;84:694-697.