Abstract
BackgroundVitamin-D2 (D2) treatment has been associated with a decrease in 25-hydroxy (25(OH)) vitamin-D3 (D3) level, suggesting that D3 treatment would be preferred to raise total 25(OH) vitamin-D (D) level. We postulated that D2 treatment-associated decrease in 25(OH)D3 level is related to the increase in 25(OH)D level rather than being D2-specific, and thus there would be a similar D3 treatment-associated decrease in 25(OH)D2 level.MethodsFifty volunteers were block-randomized to 50,000 IU D2 or placebo orally once (study-1) and fifty volunteers received 50,000 IU D2 orally once and 4 days later block-randomized to 50,000 IU D3 or placebo orally once (study-2). Interventions were concealed from volunteers and research coordinators and blindly-administered. Serum 25(OH)D2 and 25(OH)D3 levels were blindly-determined at baseline and days 14, 28, 42, and 56, post-randomization by high performance liquid chromatography assay. Results of 97 participants were analyzed. Primary outcome measure was day-28 D2-associated change in 25(OH)D3 level in study-1 and D3-associated change in 25(OH)D2 level in study-2, adjusted for baseline levels.ResultsMean (95% confidence interval) difference between the active and placebo arms in the decrease in day-28 25(OH)D3 (study-1) and 25(OH)D2 (study-2) levels was 13.2 (9.7 to 16.6) and 9.8 (5.2 to 14.4) nmol/L, respectively. Corresponding differences at day-56 were 10.8 (6.8 to 14.8) and 1.7 (− 7.6 to 11.1) nmol/L, respectively. The difference between the placebo and active arms in area-under-the-curve at day-28 (AUC28) and day-56 (AUC56) were 262.3 (197.8 to 326.7) and 605.1 (446.3 to 784.0) for 25(OH)D3 (study-1) and 282.2 (111.2 to 453.3) and 431.2 (179.3 to 683.2) nmol.d/L for 25(OH)D2 (study-2), respectively. There were significant correlations between day-28 changes in 25(OH)D2 and 25(OH)D3 levels in study-1 (rho = − 0.79, p < 0.001) and study-2 (rho = − 0.36, p = 0.01), and between day-28 changes in 25(OH)D2 level and baseline 25(OH)D level in study-2 (rho = − 0.42, p = 0.003).ConclusionsCompared to placebo, D3 treatment is associated with a decrease in 25(OH)D2 level similar in magnitude to D2-treatment associated decrease in 25(OH)D3 level; however, the D3-placebo difference in 25(OH)D2 level is shorter-lasting. Changes in 25(OH)D2 and 25(OH)D3 levels are correlated with each other and with baseline 25 (OH) D levels, suggesting a common regulatory mechanism.Trial registrationClinicalTrial.gov identifier: NCT03035084 (registered January 27, 2017).
Highlights
Vitamin-D2 (D2) treatment has been associated with a decrease in 25-hydroxy (25(OH)) vitamin-D3 (D3) level, suggesting that D3 treatment would be preferred to raise total 25(OH) vitamin-D (D) level
One participant in study-1 (D2 arm) was excluded because blood sample analysis showed no increase in 25(OH)D2 level or D2 level, indicating formulation failure or that the dose was not ingested
In study-2 (D3 arm), one participant withdrew for personal reasons and another was excluded because of high 25(OH)D2 level (83 nmol/L) before receiving the 50,000 IU D2 loading dose, indicating that a large dose of vitamin D was ingested between screening for eligibility and actual enrollment in the study
Summary
Vitamin-D2 (D2) treatment has been associated with a decrease in 25-hydroxy (25(OH)) vitamin-D3 (D3) level, suggesting that D3 treatment would be preferred to raise total 25(OH) vitamin-D (D) level. We postulated that D2 treatment-associated decrease in 25(OH)D3 level is related to the increase in 25(OH)D level rather than being D2-specific, and there would be a similar D3 treatment-associated decrease in 25(OH)D2 level Both ergocalciferol (vitamin-D2, D2) and cholecalciferol (vitamin-D3, D3) are commonly and effectively used to prevent and treat vitamin-D deficiency. Their active dihydroxy metabolites, 1,25-dihydroxyvitamin D2 (1,25(OH)2D2) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), are comparable in binding to vitamin-D receptor [1], and their 25-hydroxy (25(OH)) metabolites, 25(OH)D2 and 25(OH)D3, are comparable substrates for kidney 1-alpha hydroxylase [2, 3]. This interpretation is consistent with the results of numerous studies [8,9,10, 18, 21, 22], showing significant negative correlation between baseline 25(OH)D level and response to treatment and non-linear response of 25(OH)D level to increasing doses of vitamin-D [23,24,25]
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