VITAMIN D3
& VITAMIN D2

Not Slightly Different

What Happens Inside?

Metabolic Fate of D3 and D2 are not the same

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Vitamin D3 and Vitamin D2 undergo a two-step enzymatic process to become biologically active.

First, in the liver these inert prohormones are converted to circulating inactive forms- 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3, calcifediol], respectively.

Next, in the kidneys, it is converted to active forms 1,25-dihydroxy Vitamin D2 [1,25(OH)2D2] and 1,25-dihydroxy Vitamin D3 [1,25(OH)2D3, calcitriol].

There are stark differences in the metabolic fates of Cholecalciferol and Ergocalciferol in the body that should not be ignored.

The different structure of Ergocalciferol (additional methyl group) directly affects the rate of ergocalciferol conversion to serum 25(OH)D and also its affinity for Vitamin D binding protein and Vitamin D receptors, which are all critical steps involved in the activation of Vitamin D.

Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–281

Adapted from: An Acad Bras Cienc. 2022 Aug 19;94(2):e20201545.

Better Bioefficacy

Vitamin D3 is significantly better at raising the total 25(OH)D levels (the biomarker for Vitamin D status).

 

(Equivalent doses of 50,000 IU single dose 28-day
evaluation; 20 healthy adults) J Clin Endocrinol Metab, November 2004,
89(11):5387–5391

Equivalent doses of 50,000 IU/week for 12 weeks; 33 healthy adults)
J Clin Endocrinol Metab, March 2011, 96(3): E447–E452

Better Potency

Vitamin D3 is approximately 87% more potent in raising and maintaining serum 25(OH)D concentrations and produces 2-3 fold greater storage of Vitamin D than does equimolar D2.

Vitamin D2 metabolites have weaker binding to the Vitamin D Binding Protein (DBP), which binds the nutrient and carries it throughout the body to exert its action. Less affinity results in a shorter circulating half-life for 25(OH)D2 vs. 25(OH)D3. The relative binding of Vitamin D and its metabolites to DBP determines the circulating half-lives of these substances.

Vitamin D2 is shown not only to have reduced hydroxylation of Vitamin D3 (a necessary activation step in normal Vitamin D metabolism) but also to increase the catabolism (breakdown) of 25(OH)D3 for excretion.

Better Stability

Vitamin D3 has been shown to have a significantly longer half-life (and thus extended opportunity for its biological effects in the body) than Vitamin D2.

Vitamin D3 is more stable on the shelf compared to D2 and is more likely to remain active for a longer period of time and when exposed to different conditions (temperature, humidity, and storage). This is perhaps why the amount of Vitamin D2 in certain fortified food products have been significantly lower than that advertised on the label in numerous instances.

(Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin
supplement. Am J Clin Nutr. 2006;84(4):694–697.) (Jones G. Pharmacokinetics of
vitamin D toxicity. Am J Clin Nutr. 2008;88(2):582S–586S.)

Holick MF. Vitamin D deficiency. N Engl J Med.
2007;357(3):266–281.

More Natural Form

Vitamin D3 is the natural form of Vitamin D and the form synthesized in human skin during exposure to sunlight as compared to D2 which cannot be synthesized by humans.

Extensive Evidence

Vitamin D3 has been the most utilized form of Vitamin D in clinical trials, and there have only been a few clinical trials of Vitamin D2 to prevent bone fractures in adults.

Equivalent doses of 50,000 IU/week for 12 weeks; 33 healthy adults J Clin Endocrinol Metab, March 2011, 96(3): E447–E452

Eager to Know?

Notable Findings

Vitamin D3 is More Potent than Vitamin D2

Vitamin D3 is More Potent than Vitamin D2

D3 is approximately 87% more potent in raising and maintaining serum 25(OH)D concentrations and produces 2- to 3-fold greater storage of Vitamin D than does equimolar D2.

Głabska D, Kołota A, Lachowicz K, Skolmowska
D, Stachoń M, Guzek D. The influence of vitamin D intake and status on mental
health in children: a systematic review. Nutrients. 2021;13(3):952.)

With Vitamin D3, the increase in 25(OH)D was 70% greater (1.70 times) than the increase obtained with Vitamin D2.

(Equivalent doses of 4000 IU daily/14 days; 72 healthy adults) Am J Clin Nutr 1998;68:854–8.

 

Vitamin D3 Having Better Efficacy Than Vitamin D2

Vitamin D3 raises and maintains 25(OH)D levels to a substantially greater degree than does Vitamin D2, with a differential potency of at least 3-fold, and more likely closer to 10-fold.Vitamin D3 is significantly better at raising the total 25(OH)D levels (the biomarker for Vitamin D status).
(Equivalent doses of 50,000 IU single dose 28-day evaluation; 20 healthy adults) J Clin Endocrinol Metab, November 2004, 89(11):5387–5391.
Vitamin D3 is more efficacious and faster in increasing the level of total Vitamin D than Vitamin D2.
(Equivalent doses of 50,000 IU/wk for 12 weeks; 250 healthy adults) Ibnosina Journal of Medicine and Biomedical Sciences, April-June 2019, 11(2),58-61.

 

Equivalent doses of 50,000 IU/week for 12 weeks; 33 healthy adults J Clin Endocrinol Metab, March 2011, 96(3): E447–E452

Equivalent doses of 50,000 IU/week for 12 weeks; 33 healthy adults J Clin Endocrinol Metab, March 2011, 96(3): E447–E452

Vitamin D3 is More Bioavailable than
Vitamin D2

Vitamin D3 increases the total 25(OH)D concentration more than Vitamin D2. Vitamin D2 supplementation was associated with a decrease in 25(OH)D3, in bioavailability evaluation in healthy adults.
(Equivalent doses of 2000 IU/day for 8 weeks; 119 healthy adults) J Clin Endocrinol Metab, November 2013, 98(11):4339–4345.

Vitamin D3 Seems More Appropriate than D2 to Sustain Adequate Levels of 25(OH)D in a Pharmacokinetic Approach

In long term, D2-supplemented group 25(OH)D levels declined faster than in the D3 group, Vitamin D3 seems more appropriate to sustain adequate levels of 25(OH)D, which could be relevant for classic and non-classic effects of Vitamin D.

(Equivalent loading dose 1000,000 IU/D1; maintenance dose 4800 IU/day D7-D20, follow up D77; 33 adults) European Journal of Clinical Nutrition (2015), 1–6.

Equivalent doses of 50,000 IU/week for 12 weeks; 33 healthy adults J Clin Endocrinol Metab, March 2011, 96(3): E447–E452

D3 is More Efficacious than D2
Meta Analysis Review

D3 is More Efficacious than D2
Meta Analysis Review

Vitamin D3 was found to be more efficacious at raising serum 25(OH)D concentrations than is Vitamin D2, and thus Vitamin D3 could potentially become the preferred choice for supplementation in two separate meta-analysis.

Meta analysis of 24 studies; 1277 subjects; 2. Meta analysis of 7 studies) Nutrients 2021, 13,
3328 2) Am J Clin Nutr. 2012; 95:1357–64.

In Vehicles Relevant to Food Fortification Strategies,Vitamin D3 was More Effective than Vitamin D2

In Vehicles Relevant to Food Fortification Strategies,Vitamin D3 was More Effective than Vitamin D2

In daily supplementation, Vitamin D2 or Vitamin D3 added to juice or food, at a relatively low dose of 600 IU/d, Vitamin D3 was more efficacious than Vitamin D2 at increasing total 25(OH)D.

Over the years, Vitamin D3 has been extensively studied from skeletal to non-skeletal benefits.

Clin Nutr 2017;106:481–90.