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Vitamin D: Colecalciferol (Vitamin D3) vs Ergocalciferol (Vitamin D2)?

Vitamin D is a fat-soluble nutrient that is essential for maintaining optimal health and wellbeing. Its primary function is to aid in the absorption of calcium, essential for strong bones and teeth, and it also plays a vital role in maintaining a strong immune system and promoting cell growth. There are two main forms of Vitamin D, cholecalciferol (Vitamin D3) and ergocalciferol (Vitamin D2), which differ in their source and biochemical structure. Despite the misinformation being spread in the health and wellness industry, it is important to note that these two forms are not interchangeable. Studies on binding of the Vitamin D receptor in rats have shown equipotency between ergocalciferol and cholecalciferol, leading many resources to cite them as interchangeable. However, it is important to note that Vitamin D3 has superior stability, bioactivity, and bioavailability compared to Vitamin D2. The body's preferred form of vitamin D is also cholecalciferol (vitamin D3) as it is produced naturally and more efficient at increasing blood levels. There is now a significant body of evidence to support the superiority of cholecalciferol (vitamin D3) over ergocalciferol (vitamin D2).

Cholecalciferol (Vitamin D3)

Vitamin D3, also referred to as cholecalciferol, is a form of vitamin D that is synthesised in the skin upon exposure to UVB radiation from the sun. It is also present in certain animal-derived foods, including fatty fish, egg yolks, and liver. This dietary source of vitamin D may be limited for individuals following a vegan diet, increasing the likelihood of deficiency. However, it is important to note that many individuals do not achieve adequate vitamin D intake through diet alone and may require additional sources, such as sunlight or supplements, to meet their nutritional needs. In recent years, advancements in technology have led to the development of plant-based sources of vitamin D3, specifically from lichen and algae.

Ergocalciferol (Vitamin D2)

Ergocalciferol, also known as Vitamin D2, is a form of vitamin D that is found in a limited number of plant-based foods such as mushrooms and fortified foods. Unlike Vitamin D3, which is synthesised in the skin when exposed to UVB radiation from the sun, Vitamin D2 is not produced by the body and must be obtained through dietary sources or primarily synthetically produced supplements. While Vitamin D2 is considered to be biologically inactive, it can be converted to the active form, calcitriol, in the body, but the efficiency of this conversion is lower in comparison to that of Vitamin D3. Therefore, many experts consider Vitamin D3 as the more preferred form of Vitamin D supplement.

Vitamin D deficiency

Vitamin D deficiency is a widespread issue, commonly referred to as an "invisible epidemic." The two primary ways to measure serum levels and determine deficiency are through the measurement of both free and total 25-hydroxyvitamin D (25(OH)D), which is the primary form of vitamin D found in the blood. Free 25(OH)D refers to the portion of 25(OH)D that is not bound to proteins in the blood, while total 25(OH)D refers to the sum of both free and protein-bound 25(OH)D. It is important to measure both free and total 25(OH)D because the amount of free 25(OH)D can vary depending on the level of proteins in the blood, and this can affect how much vitamin D is available for the body to use.

Cholecalciferol (Vitamin D3) vs Ergocalciferol (Vitamin D2)

Vitamin D3 (cholecalciferol) has been consistently shown to be more effective at raising and maintaining vitamin D levels in the body compared to ergocalciferol. In scientific studies, vitamin D3 increased total and free 25D levels by almost twice as much as vitamin D2. The structural differences between vitamin D2 and D3 account for this difference, as vitamin D3 has a higher affinity for binding to the vitamin D receptor (VDR) in the body, which is the main mechanism through which vitamin D exerts its effects. Vitamin D2, on the other hand, has increased catabolism (i.e., it's broken down more quickly) and its metabolites have weaker binding affinity. This means that vitamin D3 is more effective at activating the VDR and regulating the various processes in the body that are controlled by vitamin D.

Additional Benefits of Vitamin D3

In addition to being more effective at raising and maintaining vitamin D levels, vitamin D3 has also been shown to have other benefits. A study by the Universities of Surrey and Brighton found that vitamin D3 is more effective than D2 in fortifying the body against viral and bacterial diseases. Researchers discovered that D3 stimulates the type I interferon signaling system in the body, a key part of the immune system that provides a first line of defense against bacteria and viruses. The study suggests that it is important for people to take a vitamin D3 supplement, or suitably fortified foods, especially in the winter months. The researchers also highlighted that vitamin D3 should be the preferred form for fortified foods and supplements.

Another study found that vitamin D3 decreased mortality in elderly people living independently or in institutional care. Vitamin D3 is about 87% more potent than vitamin D2 in terms of its ability to bind to the VDR and activate the vitamin D pathway and produces two to three times greater storage of vitamin D in the body compared to D2.

Conclusion

In conclusion, the evidence clearly supports cholecalciferol (Vitamin D3) as the superior form of vitamin D compared to ergocalciferol (Vitamin D2). Vitamin D3 is more efficient at increasing blood levels, more effective at activating the VDR and regulating various processes in the body, and has a host of additional benefits including fortifying the body against viral and bacterial diseases, and decreasing mortality in elderly people. While the optimal daily amount of vitamin D and its potential to cure diseases remains a subject of debate, there is a strong link between vitamin D deficiency and poor health outcomes. Therefore, it is recommended that vitamin D3 should be the preferred form for fortified foods and supplements.

References and further reading

  • “Office of Dietary Supplements, National Institutes of Health - Vitamin D,” n.d. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/.

  • The Nutrition Source, Harvard School of Public Health. “Vitamin D,” November 14, 2022. https://www.hsph.harvard.edu/nutritionsource/vitamin-d/.

  • Golden, Katie E, MD “GoodRx - Vitamin D2: What You Should Know,” October 12, 2021. http://www.goodrx.com/well-being/supplements-herbs/vitamin-d2-vs-vitamin-d3-whats-the-difference.

  • Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, Hyppönen E, Berry J, Vieth R, Lanham-New S. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 2012 Jun;95(6):1357-64. doi: 10.3945/ajcn.111.031070. Epub 2012 May 2. PMID: 22552031; PMCID: PMC3349454.

  • Lisa A Houghton, Reinhold Vieth, The case against ergocalciferol (vitamin D2) as a vitamin supplement, The American Journal of Clinical Nutrition, Volume 84, Issue 4, October 2006, Pages 694–697, https://doi.org/10.1093/ajcn/84.4.694. PMID: 17023693.

  • Shieh A, Chun RF, Ma C, Witzel S, Meyer B, Rafison B, Swinkels L, Huijs T, Pepkowitz S, Holmquist B, Hewison M, Adams JS. Effects of High-Dose Vitamin D2 Versus D3 on Total and Free 25-Hydroxyvitamin D and Markers of Calcium Balance. J Clin Endocrinol Metab. 2016 Aug;101(8):3070-8. doi: 10.1210/jc.2016-1871. Epub 2016 May 18. PMID: 27192696; PMCID: PMC4971338.

  • Durrant LR, Bucca G, Hesketh A, Möller-Levet C, Tripkovic L, Wu H, Hart KH, Mathers JC, Elliott RM, Lanham-New SA, Smith CP. Vitamins D2 and D3 Have Overlapping But Different Effects on the Human Immune System Revealed Through Analysis of the Blood Transcriptome. Front Immunol. 2022 Feb 24;13:790444. doi: 10.3389/fimmu.2022.790444. PMID: 35281034; PMCID: PMC8908317.

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  • 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 Oct;68(4):854-8. doi: 10.1093/ajcn/68.4.854. PMID: 9771862.

  • 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. PMID: 2849489.

  • Romagnoli E, Mascia ML, Cipriani C, Fassino V, Mazzei F, D'Erasmo E, Carnevale V, Scillitani A, Minisola S. Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J Clin Endocrinol Metab. 2008 Aug;93(8):3015-20. doi: 10.1210/jc.2008-0350. Epub 2008 May 20. PMID: 18492750.

  • Tripkovic L, Wilson LR, Hart K, Johnsen S, de Lusignan S, Smith CP, Bucca G, Penson S, Chope G, Elliott R, Hyppönen E, Berry JL, Lanham-New SA. Daily supplementation with 15 μg vitamin D2 compared with vitamin D3 to increase wintertime 25-hydroxyvitamin D status in healthy South Asian and white European women: a 12-wk randomized, placebo-controlled food-fortification trial. Am J Clin Nutr. 2017 Aug;106(2):481-490. doi: 10.3945/ajcn.116.138693. Epub 2017 Jul 5. PMID: 28679555.

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  • Jones KS, Assar S, Harnpanich D, Bouillon R, Lambrechts D, Prentice A, Schoenmakers I. 25(OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype. J Clin Endocrinol Metab. 2014 Sep;99(9):3373-81. doi: 10.1210/jc.2014-1714. Epub 2014 Jun 2. PMID: 24885631; PMCID: PMC4207933.

  • Paul Glendenning, Gerard T. Chew, Hannah M. Seymour, Melissa J. Gillett, Peter R. Goldswain, Charles A. Inderjeeth, Samuel D. Vasikaran, Mario Taranto, Alexander A. Musk, William D. Fraser, Serum 25-hydroxyvitamin D levels in vitamin D-insufficient hip fracture patients after supplementation with ergocalciferol and cholecalciferol, Bone, Volume 45, Issue 5, 2009, Pages 870-875, ISSN 8756-3282, https://doi.org/10.1016/j.bone.2009.07.015. Epub 2009 Jul 23. PMID: 19631774.

  • Seijo M, Mastaglia S, Brito G, Somoza J, Oliveri B. Es equivalente la suplementación diaria con vitamina D2 o vitamina D3 en adultos mayores? [Is daily supplementation with vitamin D2 equivalent to daily supplementation with vitamin D3 in the elderly?]. Medicina (B Aires). 2012;72(3):195-200. Spanish. PMID: 22763155.

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  • Glendenning P, Chew GT, Seymour HM, Gillett MJ, Goldswain PR, Inderjeeth CA, Vasikaran SD, Taranto M, Musk AA, Fraser WD. Serum 25-hydroxyvitamin D levels in vitamin D-insufficient hip fracture patients after supplementation with ergocalciferol and cholecalciferol. Bone. 2009 Nov;45(5):870-5. doi: 10.1016/j.bone.2009.07.015. Epub 2009 Jul 23. PMID: 19631774.

  • Tripkovic L, Wilson LR, Hart K, Johnsen S, de Lusignan S, Smith CP, Bucca G, Penson S, Chope G, Elliott R, Hyppönen E, Berry JL, Lanham-New SA. Daily supplementation with 15 μg vitamin D2 compared with vitamin D3 to increase wintertime 25-hydroxyvitamin D status in healthy South Asian and white European women: a 12-wk randomized, placebo-controlled food-fortification trial. Am J Clin Nutr. 2017 Aug;106(2):481-490. doi: 10.3945/ajcn.116.138693. Epub 2017 Jul 5. PMID: 28679555.

  • Mastaglia, S., Mautalen, C., Parisi, M. et al. Vitamin D2 dose required to rapidly increase 25OHD levels in osteoporotic women. Eur J Clin Nutr 60, 681–687 (2006). https://doi.org/10.1038/sj.ejcn.1602369. PMID: 16391587.

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  • Oliveri, B., Mastaglia, S., Brito, G. et al. Vitamin D3 seems more appropriate than D2 to sustain adequate levels of 25OHD: a pharmacokinetic approach. Eur J Clin Nutr 69, 697–702 (2015). https://doi.org/10.1038/ejcn.2015.16. Epub 2015 Mar 18. PMID: 25782422.

  • Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005 May 11;293(18):2257-64. doi: 10.1001/jama.293.18.2257. PMID: 15886381.

  • Zarei A, Hulley PA, Sabokbar A, Javaid MK, Morovat A. 25-Hydroxy- and 1α,25-Dihydroxycholecalciferol Have Greater Potencies than 25-Hydroxy- and 1α,25-Dihydroxyergocalciferol in Modulating Cultured Human and Mouse Osteoblast Activities. PLoS One. 2016 Nov 28;11(11):e0165462. doi: 10.1371/journal.pone.0165462. PMID: 27893751; PMCID: PMC5125576.

  • Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004;79(3):362-371. doi: 10.1093/ajcn/79.3.362. Erratum in: Am J Clin Nutr. 2004 May;79(5):890. PMID: 14985208.

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  • Brown, James. “Vitamin D2 and D3: What’s the Difference and Which Should You Take?” The Conversation, March 7, 2022. https://theconversation.com/vitamin-d2-and-d3-whats-the-difference-and-which-should-you-take-178210.

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