Abstract and Introduction
Context: The effect of daily vitamin D supplementation on the serum concentration of vitamin D (the parent compound) may offer insight into vitamin D disposition.
Objective: To assess the total serum vitamin D response to vitamin D3 supplementation and whether it varies according to participant characteristics. To compare results with corresponding results for total serum 25-hydroxyvitamin D [25(OH)D], which is used clinically and measured in supplementation trials.
Design: Exploratory study within a randomized trial.
Intervention: 2000 International Units of vitamin D3 per day (or matching placebo).
Participants: 161 adults (mean ± SD age 70 ± 6 years; 66% males) with type 2 diabetes.
Main Outcome Measures: Changes in total serum vitamin D and total serum 25(OH)D concentrations from baseline to year 2.
Results: At baseline, there was a positive, nonlinear relation between total serum vitamin D and total serum 25(OH)D concentrations. Adjusted effects of supplementation were a 29.2 (95% CI: 24.3, 34.1) nmol/L increase in serum vitamin D and a 33.4 (95% CI: 27.7, 39.2) nmol/L increase in serum 25(OH)D. Among those with baseline 25(OH)D < 50 compared with ≥ 50 nmol/L, the serum vitamin D response to supplementation was attenuated (15.7 vs 31.2 nmol/L; interaction P-value = 0.02), whereas the serum 25(OH)D response was augmented (47.9 vs 30.7 nmol/L; interaction P-value = 0.05).
Conclusions: Vitamin D3 supplementation increases total serum vitamin D and 25(OH)D concentrations with variation according to baseline 25(OH)D, which suggests that 25-hydroxylation of vitamin D3 is more efficient when serum 25(OH)D concentration is low.
Vitamin D is a nutrient and prohormone that is metabolized through two sequential hydroxylation reactions to form 1,25-dihydroxyvitamin D [1,25(OH)2D], a hormone important for mineral homeostasis and bone health. The first hydroxylation takes place primarily in the liver where 25-hydroxylase enzymes convert vitamin D to 25-hydroxyvitamin D [25(OH)D]. Cytochrome P450 family 2 subfamily R member 1 (CYP2R1) is the principal 25-hydroxylase in humans. Additional enzymes that catalyze 25-hydroxylation of vitamin D include cytochrome P450 family 27 subfamily A member 1, which is thought to play a role in 25(OH)D3 formation in the presence of pharmacologic doses of vitamin D3.
Because of its long half-life, circulating 25(OH)D concentration is used to assess vitamin D status. Most clinical strategies to correct 25(OH)D deficiency involve supplementation with vitamin D2 or vitamin D3 to achieve a target total 25(OH)D concentration. For this reason, studies of vitamin D pharmacokinetics have focused almost exclusively on the dose-response of serum 25(OH)D concentration to vitamin D supplementation. Some[5,6] but not all meta-analyses determined that the dose-response of serum 25(OH)D to total vitamin D intake is nonlinear. In addition, the 25(OH)D response to a given dose of vitamin D is highly varied between individuals. A systematic review explained approximately 50% of the interindividual variation in response with body weight, age, type of supplement (vitamin D2 or D3), concomitant intake of calcium supplements, and baseline serum 25(OH)D concentration. More recent evidence highlights the contribution of genetic variation. For example, variants of the GC gene encoding the vitamin D binding protein (DBP) are strongly associated with the 25(OH)D response.[10,11] Although unconfirmed, this may relate to genetically determined differences in serum DBP concentration, which also varies according to clinical condition, sex, and life stage.
Pharmacokinetic models can comprehensively describe vitamin D disposition and predict the serum 25(OH)D response to vitamin D dose, taking into account individual characteristics. However, such models are built from primary data on how circulating levels of not only 25(OH) D but also parent vitamin D change with supplementation.[12–14] As far as we know, few studies have described how the circulating parent vitamin D concentration responds to long-term supplementation, and no studies have identified participant characteristics that modify this response. Doing so could shed light on vitamin D pharmacokinetics and interindividual variation in response to vitamin D treatment.
We quantified total serum vitamin D concentration (the sum of vitamin D2 and vitamin D3 concentrations) at baseline and year 2 in a subset of participants from the VITamin D and OmegA 3 TriaL to Prevent and Treat Diabetic Kidney Disease (VITAL-DKD), which was ancillary to the nationwide VITamin D and OmegA 3 TriaL (VITAL). Our objectives were to determine the effect of 2000 International Units (IU) of vitamin D3 per day on the total serum vitamin D concentration and whether this varied according to participant characteristics. Results were compared with those for total serum 25(OH)D concentration.
J Clin Endocrinol Metab. 2022;107(2):525-537. © 2022 Endocrine Society