Food-Fortified Vitamin D3 More Effective than D2 at Raising Serum 25(OH)D Levels

by Ashley Jordan Ferira, PhD, RDN

A food fortification trial demonstrated that 600 IU of daily vitamin D₃ had a significantly greater impact than 600 IU of daily vitamin D₂ in elevating serum blood levels of 25-hydroxyvitamin D [25(OH)D].^1-2

Vitamin D is essential for skeletal health and many emerging extraskeletal physiological processes, but remains one of the most common micronutrient dietary gaps, resulting in widespread hypovitaminosis D globally. Understanding how much vitamin D the body needs daily, in what form, and from what sources is still being discovered.

There are two forms of vitamin D: plant-based ergocalciferol (vitamin D₂) and animal-based cholecalciferol (vitamin D₃). D₂ can be found in UV-irradiated mushrooms, certain fortified foods (breakfast cereals, margarine, and milk), dietary supplements, and vitamin D prescription medications. D₃ is found in oily fish, egg yolks, fortified milk, and dietary supplements.⁴ Chemically, D₂ and D₃ are almost identical except for key side chain differences, with D₂ having an additional double bond. D₃ has been shown to have a higher affinity to the vitamin D binding protein, hepatic 25-hydroxylase (enzyme that converts vitamin D to the circulating 25(OH)D form) and vitamin D receptor.  Whether these chemical and cellular differences translate into differential abilities in raising serum 25(OH)D, the clinical measure of vitamin D status, has been a hotly debated topic since the early 20^th century.⁵

Research literature to date demonstrates a robust case gaining momentum for vitamin D₃ and against vitamin D₂ for supplementation.^4-5 In particular, a 2012 systematic review and meta-analysis by of randomized controlled vitamin D supplementation trials in humans explored a head-to-head comparison of vitamin D₂ vs. D₃ in raising serum 25(OH)D; vitamin D₃ was clearly shown to be more efficacious at raising and maintaining serum 25(OH)D levels than vitamin D₂.⁴ Authors concluded that vitamin D₃ may be considered the preferred choice for supplementation.⁴

Since natural sources of vitamin D (dietary input and UVB exposure from the sun) are limited, and a daily vitamin D supplementation regimen is a personal health decision, vitamin D fortification of the food supply is an important, strategic public health measure to help increase dietary vitamin D intake and improve status in the general population.⁶ Clarity is needed to elucidate whether D₂ and D₃ are equally effective sources for food fortification, since both forms are currently utilized in the food supply.⁶ A study by Tripkovic et al. helps to shed light on key differences.¹

Results were published in The American Journal of Clinical Nutrition by Dr. Laura Tripkovic and colleagues from a randomized, double-blind, placebo-controlled food fortification trial that included 335 healthy South Asian and white European women aged 20–64 years.¹ Participants were randomized to one of five groups:

1) Placebo: Placebo juice with placebo biscuit

2) D2J: Juice supplemented with 15 mcg vitamin D₂ with placebo biscuit

3) D2B: Placebo juice with biscuit supplemented with 15 mcg vitamin D₂

4) D3J: Juice supplemented with 15 mcg vitamin D₃ with placebo biscuit

5) D3B: Placebo juice with biscuit supplemented with 15 mcg vitamin D₃

Fifteen mcg of vitamin D is equivalent to 600 IU of vitamin D, which is the US Recommended Daily Allowance (RDA) for ages 1-70 years.⁷ The daily food-fortified intervention was 12 weeks long during the winter, and serum total 25(OH)D levels were collected at baseline, week 6 and week 12. Data analysis combined ethnic groups.

D₃-fortified consumption was shown to be twice as effective as D₂ in raising 25(OH)D serum levels in the body.¹ While the placebo group experienced a 25% reduction in serum 25(OH)D levels over the course of the study, the D2J and D2B groups saw 25(OH)D increases of 33% and 34%, respectively. Most effective, however, were the D₃ groups, with 25(OH)D increases in the D3J and D3B groups of 75% and 74%, respectively. The D3J group induced higher incremental increases in 25(OH)D levels: 16.9 nmol/L higher than the D2J group, 16.0 nmol/L higher than the D2B group, and 42.9 nmol/L higher than the placebo group.¹ Both juice- and biscuit-supplemented vitamin D₃ groups demonstrated similar results, with no statistical differences seen between D3J and D3B groups.¹ Compared to white European women, the South Asian women demonstrated a greater increase in 25(OH)D levels in response to both D2 and D3, which was likely caused by their lower baseline vitamin D status.¹

This study shows that modest supplementation levels (600 IU daily) of D₃ in food and beverage sources twice as effective at raising serum levels of 25(OH)D than vitamin D₂.¹This study and previous supplementation studies may impact future policy and practice for vitamin D supplementation source. Additional research addressing dose response, bioactivity of D₃ versus D₂ and the impact of foods with high levels of vitamin D₃ is needed.²

Why is this Clinically Relevant?

• Vitamin D insufficiency and deficiency are common clinical observations; repletion via vitamin D supplementation is effective
• Vitamin D supplementation studies have previously shown vitamin D₃ to be more efficacious than D₂ at raising and maintaining serum 25(OH)D levels⁴
• Food- and beverage-fortified D₃ is twice as effective as D₂ in raising vitamin D serum 25(OH)D levels¹ ; a relatively low dose of vitamin D (15 mcg, or 600 IU) daily over 12 weeks during the wintertime can increase serum 25(OH)D levels by clinically relevant amounts
• Government, industry and healthcare officials and practitioners should incorporate the totality of research demonstrating the superiority of vitamin D₃ over vitamin D₂ into their public health, product, and patient recommendations, respectively.
• For vegans preferring the plant-sourced vitamin D₂ form, clinicians should consider recommending higher D₂ dosing (relative to vitamin D₃), likely at least 2x higher, via dietary and/or supplemental D₂ sources

Link to abstract

Citations

1. Tripkovic L, Wilson LR, Hart K, et al. 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;106(2):481-490.
2. Medscape. Vitamin D₃, Not D₂, Is Key to Tackling Vitamin D Deficiency. http://www.medscape.com/viewarticle/882482#vp_1. Accessed August 18, 2017.
3. Ross AC, Taylor CL, Yaktine AL, Valle HBD. Dietary reference intakes for calcium and Vitamin D. National Academy Press. Washington, D.C. 2011.
4. Tripkovic L, Lambert H, Hart K, et al. 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;95:1357-1364.
5. Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr. 2006;84(4):694-697.
6. Wilson LR, Tripkovic L. Vitamin D deficiency as a public health issue: using vitamin D2 or vitamin D3 in future fortification strategies. Proc Nutr Soc. 2017;76(3):392-399.
7. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. National Academy Press. Washington, D.C. 2010.