Serum Vitamin D: Correlates of Baseline Concentration and Response to Supplementation in VITAL-DKD

Cora M. Best; Leila R. Zelnick; Kenneth E. Thummel; Simon Hsu; Christine Limonte; Ravi Thadhani; Howard D. Sesso; JoAnn E. Manson; Julie E. Buring; Samia Mora; I-Min Lee; Nancy R. Cook; Georgina Friedenberg; Heike Luttmann-Gibson; Ian H. de Boer; Andrew N. Hoofnagle


J Clin Endocrinol Metab. 2022;107(2):525-537. 

In This Article

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).

Setting: Community-based.

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.[1] 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.[2] 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.[3]

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.[4] 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[7] 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.[8] More recent evidence highlights the contribution of genetic variation.[9] 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.