Relative Efficacy of Vitamin D2 and Vitamin D3 in Improving Vitamin D Status: Systematic Review and Meta-Analysis

Background: Widespread prevalence of vitamin D deficiency has been documented globally. Commonly used interventions to address this deficiency include supplementation and/or fortification with either ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3), but the relative efficacy of these two vitamers is unclear. The current study aimed to evaluate the relative efficacy of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) for raising the serum levels of vitamin D metabolites and functional indicators including serum parathyroid (PTH) levels, isometric muscle strength, hand grip strength and bone mineral density. Methods: Randomized and non-randomized controlled studies evaluating relative efficacy of ergocalciferol and cholecalciferol were systematically reviewed to synthesize quantitative and qualitative evidence as per the recommendations of according to “Preferred Reporting Items for Systematic reviews and Meta-analysis” guidelines. Search terms were constructed on the basis of the “participants”, “intervention”, “control”, “outcome” and “study type” (PICOS) strategy to systematically search the popular electronic databases. Relevant data from studies meeting inclusion and exclusion criteria were extracted and analyzed. Meta-regression, subgroup and sensitivity analyses were performed to investigate the influence of study-level characteristics including intervention dosage, frequency of dosing, interval between the last dose and test for outcome assessment, participant characteristics and analytical methods. Results: Apparently healthy human participants (n = 1277) from 24 studies were included for meta-analysis. The quantitative analysis suggested higher efficacy of cholecalciferol than ergocalciferol in improving total 25(OH)D (mean difference: 15.69, 95%CI: 9.46 to 21.93 nmol/L) and reducing PTH levels, consistently across variable participant demographics, dosage and vehicle of supplementation. Meta-regression suggested smaller differences in the efficacy of cholecalciferol and ergocalciferol at lower doses. Average daily dose was the single significant predictor of effect size, as revealed by multivariate meta-regression analysis. Conclusions: Compared to ergocalciferol, cholecalciferol intervention was more efficacious in improving vitamin D status (serum levels of total 25(OH)D and 25(OH)D3) and regulating PTH levels, irrespective of the participant demographics, dosage and vehicle of supplementation.

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Vitamin D2 and D3 Supplementation Effect on Serum 25(OH)D Levels: A Meta-Analysis

Current Developments in Nutrition ◽

10.1093/cdn/nzaa067_009 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1782-1782

Author(s):

Meline Chakalian ◽

Joyce Cao ◽

Jiang Hu ◽

Casey Vanous ◽

Simon Sum

Keyword(s):

Vitamin D ◽

Meta Analysis ◽

Small Sample ◽

Relative Potency ◽

Health Concern ◽

Outcome Variable ◽

Vitamin D2 ◽

Baseline Serum ◽

Meta Regression ◽

The Impact

Abstract Objectives Vitamin D insufficiency is a global health concern that affects nearly 50% of the population worldwide. Growing demand for vegan/vegetarian products has aroused interest in the plant-sourced D2 form for use in dietary supplements. However, vitamin D2’s ability to raise serum 25(OH)D levels in relation to D3 among existing scientific literature is inconclusive. This study sought to compare vitamin D2 to D3 in increasing serum 25(OH)D levels in order to better understand the relative potency and dosage required to address vitamin D insufficiencies. Methods PubMed and Embase databases were searched through July of 2018. Randomized controlled trials comparing D2 and D3 supplementation of equivalent dosages and the resulting increase in serum 25(OH)D levels in adults were eligible for this meta-analysis. A meta regression was conducted to compare the impact of both vitamin D forms on serum 25(OH)D levels. The outcome variable evaluated was the serum 25(OH)D levels. Results Nine RCTs (n = 628) with vitamin D dose ranging from 10 mcg per day to 1250 mcg per week, and an intervention duration from 2 to 16 weeks were eligible. Subjects included healthy adults as well as those with chronic kidney disease. There was substantial heterogeneity among the studies (I2 = 78.07%). The meta-regression showed vitamin D supplementation regardless of form was effective in raising serum 25(OH)D levels (P < 0.0001). The mean effect size expressed as the standardized mean difference (SMD) from baseline serum 25(OH)D levels was 1.16 [95% CI: 0.83, 1.49] for D2 and 1.52 [95% CI: 0.99, 2.04] for D3. While there was a trend of greater increase caused by D3 numerically, the difference between D2 and D3 was not statistically significant. When duration and frequency of supplementation were examined, similar trends of non-significant greater increases for D3 relative to D2 were observed. Conclusions This research shows both vitamin D2 and D3 supplementation can significantly increase serum 25(OH)D levels. Though the results did not reach statistical significance, there is a consistent trend of vitamin D3 offering additional effectiveness relative to D2. The high heterogeneity across studies and small sample size likely contributed to the non-significant results and limited the ability to identify a quantitative relative potency that can be used for a D2 dosage recommendation. Funding Sources None.

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Effect of smoking on the serum levels of 25-hydroxyvitamin D depends on the assay employed

Acta Endocrinologica ◽

10.1530/eje-10-0150e ◽

2010 ◽

Vol 163 (6) ◽

pp. 965 ◽

Cited By ~ 2

Author(s):

Guri Grimnes ◽

Bjørg Almaas ◽

Anne Elise Eggen ◽

Nina Emaus ◽

Yngve Figenschau ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D3 ◽

Serum Levels ◽

Ultraviolet B ◽

Vitamin D2 ◽

Super-doses of dietary vitamin D3 intake in aged laying hens illustrates limitation of 24,25-dihydroxycholecalciferol conversion

10.1101/2021.10.14.464328 ◽

2021 ◽

Author(s):

Matthew F. Warren ◽

Pete M. Pitman ◽

Dellila D. Hodgson ◽

Kimberly A. Livingston

Keyword(s):

Vitamin D ◽

Vitamin D3 ◽

Laying Hens ◽

Dietary Vitamin ◽

Plasma Vitamin ◽

Vitamin D Metabolites ◽

Vitamin D Status ◽

Blood Calcium ◽

Reduce Risk ◽

Dietary Vitamin D

Background: Humans take vitamin D supplements to reduce risk of vitamin D deficiency and reduce the risk of osteoporosis. However, it is unclear how dietary super-dose (10,000x greater than requirement) can affect vitamin D status in aged animals. Aged laying hens could potentially be a model to compare with women in peri- or postmenopausal stages of life because their bone health is physiologically taxed from egg production and they are highly susceptible to osteoporosis. Objective: We investigated dietary super-dose impacts of cholecalciferol (vitamin D3) on vitamin D status in aged laying hens in production. Methods: Forty-eight 68-wk old Hy-Line Brown laying hens were individually housed in cages with eight hens per dietary treatment for eleven weeks. Hens were randomly assigned to one of six groups of dietary vitamin D3 supplementation and fed ad libitum. Supplementation levels were 400 (recommended dosage for hens), 800, 7,400, 14,000, 20,000, and 36,000 IU D3/kg of feed. At termination of the study, all hens were euthanized and we collected blood, feces, and tibia and humerus bones. Ionized (free) blood calcium, fecal calcium, bone calcium, and plasma vitamin D metabolites were measured. Results: We did not discern any dietary effects in tissue and fecal calcium. We observed that increasing dietary vitamin D3 increased plasma vitamin D3, 25-hydroxycholecalciferol, and 24,25-dihydroxycholecalciferol concentrations (p < 0.0001 for all 3 metabolites). We also observed super-dose fed hens had decreased kidney 24-hydroxylase expression (p = 0.0006). Conclusions: Although dietary vitamin D3 super-doses did not affect calcium status in our aged laying hens, it is possible there is an age-related effect of not being as sensitive to vitamin D efficacy. We suggest future research should explore how 24-hydroxylation mechanisms are affected by vitamin D supplementation. Further understanding of 24-hydroxylation can help ascertain ways to reduce risk of vitamin D toxicity.

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Vitamin D3 is more effective than vitamin D2 in maintaining vitamin D status in healthy adults during the winter months

The FASEB Journal ◽

10.1096/fasebj.25.1_supplement.218.3 ◽

2011 ◽

Vol 25 (S1) ◽

Author(s):

Lisa A Houghton ◽

Victoria Logan ◽

Andrew R Gray ◽

Michelle Harper ◽

Meredith C Rose

Keyword(s):

Vitamin D ◽

Vitamin D3 ◽

Healthy Adults ◽

Vitamin D2 ◽

Vitamin D Status

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Vitamin D metabolites in serum from hypoparathyroid patients treated with vitamin D2 and lα-hydroxy vitamin D3

Pediatric Research ◽

10.1203/00006450-198101000-00044 ◽

1981 ◽

Vol 15 (1) ◽

pp. 78-78 ◽

Cited By ~ 1

Author(s):

L Aksnes ◽

D Aarskog

Keyword(s):

Vitamin D ◽

Vitamin D3 ◽

Vitamin D2 ◽

Vitamin D Metabolites

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An LC-MS/MS Method for Analysis of Vitamin D Metabolites and C3 Epimers in Mice Serum: Oral Supplementation Compared to UV Irradiation

Molecules ◽

10.3390/molecules26175182 ◽

2021 ◽

Vol 26 (17) ◽

pp. 5182

Author(s):

Amir Sohail ◽

Asma Al Menhali ◽

Soleiman Hisaindee ◽

Iltaf Shah

Keyword(s):

Vitamin D ◽

Vitamin D3 ◽

Uv Light ◽

Mouse Serum ◽

Vitamin D2 ◽

Vitamin D Metabolites ◽

Serum Samples ◽

Deficient Diet ◽

Ms Analysis ◽

Significant Difference

Introduction: The most common forms of vitamin D in human and mouse serum are vitamin D3 and vitamin D2 and their metabolites. The aim of this study is to determine whether diet and sunlight directly affect the circulating concentrations of vitamin D metabolites in a mouse model. We investigated the serum concentrations of eight vitamin D metabolites—vitamin D (vitamin D3 + vitamin D2), 25OHD (25OHD3 + 25OHD2), 1α25(OH)2D (1α25(OH)2D2, and 1α25(OH)2D3)—including their epimer, 3-epi-25OHD (3-epi-25OHD3 and 3-epi-25OHD2), and a bile acid precursor 7alpha-hydroxy-4-cholesten-3-one (7αC4), which is known to cause interference in liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Method: The LC-MS/MS method was validated according to FDA-US guidelines. The validated method was used for the analysis of mouse serum samples. Forty blood samples from mice were collected and divided into three groups. The first group, the DDD mice, were fed a vitamin D-deficient diet (25 IU VD3/kg of diet) and kept in the dark; the second group, the SDD mice, were maintained on a standard-vitamin D diet (1000 IU VD3) and kept in the dark; and the third group, SDL, were fed a standard-vitamin D diet (1000 IU VD3) but kept on a normal light/dark cycle. LC-MS/MS was used for the efficient separation and quantitation of all the analytes. Results: The validated method showed good linearity and specificity. The intraday and interday precision were both <16%, and the accuracy across the assay range was within 100 ± 15%. The recoveries ranged between 75 and 95%. The stability results showed that vitamin D metabolites are not very stable when exposed to continuous freeze–thaw cycles; the variations in concentrations of vitamin D metabolites ranged between 15 and 60%. The overlapping peaks of vitamin D, its epimers, and its isobar (7αC4) were resolved using chromatographic separation. There were significant differences in the concentrations of all metabolites of vitamin D between the DDD and SDL mice. Between the groups SDD (control) and SDL, a significant difference in the concentrations of 3-epi-25OHD was noted, where C3 epimer was about 30% higher in SDL group while no significant differences were noted in the concentrations of vitamin D, 25OHD, 1α25(OH)2D, and 7αC4 between SDD and SDL group. Conclusions: A validated method, combined with a simple extraction technique, for the sensitive LC-MS/MS determination of vitamin D metabolites is described here. The method can eliminate the interferences in LC-MS/MS analysis caused by the overlapping epimer and isobar due to them having the same molecular weights as 25OHD. The validated method was applied to mouse serum samples. It was concluded that a standard-vitamin D diet causes an increase in the proportion of all the vitamin D metabolites and C3 epimers and isobar, while UV light has no pronounced effect on the concentrations of the majority of the vitamin D metabolites except 3-epi-25OHD. Further studies are required to confirm this observation in humans and to investigate the biochemical pathways related to vitamin D’s metabolites and their epimers.

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Mechanisms for differences in the efficacy of vitamin D2 and vitamin D3: assessment of post-supplementation decline in vitamin D status in the D2-D3 Study

Proceedings of The Nutrition Society ◽

10.1017/s0029665116001312 ◽

2016 ◽

Vol 75 (OCE3) ◽

Author(s):

L.R. Wilson ◽

L. Tripkovic ◽

K. Hart ◽

C.P. Smith ◽

G. Bucca ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D3 ◽

Vitamin D2 ◽

Vitamin D Status

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The Effects of Vitamin D-Enriched Mushrooms and Vitamin D3 on Cognitive Performance and Mood in Healthy Elderly Adults: A Randomised, Double-Blinded, Placebo-Controlled Trial

Nutrients ◽

10.3390/nu12123847 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3847

Author(s):

Ian T. Zajac ◽

Mary Barnes ◽

Paul Cavuoto ◽

Gary Wittert ◽

Manny Noakes

Keyword(s):

Vitamin D ◽

Cognitive Performance ◽

Vitamin D3 ◽

Serum Vitamin ◽

Vitamin D Supplementation ◽

Vitamin D Metabolites ◽

Vitamin D Status ◽

Cross Sectional ◽

Healthy Elderly ◽

Double Blinded

Despite abundant cross-sectional evidence that low vitamin D status is associated with risk of cognitive decline in ageing, interventional evidence for benefits of vitamin D supplementation is lacking. This study was a 6 month randomised, double-blinded placebo-controlled clinical trial of the effects of vitamin D3 (D3), enhanced vitamin D2 in a mushroom matrix (D2M), standard mushroom (SM) and placebo (PL) on cognition and mood in n = 436 healthy older male (49%) and female volunteers aged ≥ 60 years. Primary end points were change in serum vitamin D metabolites (25-OH-D, 25-OH-D2 and 25-OH-D3), cognitive performance, and mood over 24 weeks. Levels of total 25-OH-D and 25-OH-D3 were maintained in the D3 arm but decreased significantly (p < 0.05) in the remaining arms (D2M, SM and PL). Analysis also revealed differential changes in these metabolites depending on total vitamin D status at baseline. There were no significant effects of treatment on any of the measures of cognitive function or mood. Overall, the results show that daily supplementation of ~600 IU of vitamin D3 was sufficient to maintain 25-OH-D throughout winter months, but in contrast to existing cross-sectional studies there was no support for benefit of vitamin D supplementation for mood or cognition in healthy elderly people.

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