Clinical and Biomarker Modifiers of Vitamin D Treatment Response: The Multi-Ethnic Study of Atherosclerosis

Background: Different 25-hydroxyvitamin D (25(OH)D) thresholds for treatment with vitamin D supplementation have been suggested, and are derived almost exclusively from observational studies. Whether other characteristics including race/ethnicity, body mass index (BMI), and estimated glomerular filtration rate (eGFR) should also influence the threshold for treatment is unknown.

Objective: Identify clinical and biomarker characteristics that modify the response to vitamin D supplementation.

Methods: 666 older adults in the Multi-Ethnic Study of Atherosclerosis (MESA) were randomized to 16 weeks of oral vitamin D3 (2000 IU/d; n=499) or placebo (n=167). Primary outcomes were changes in serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations from baseline to 16 weeks

Results: Among 666 participants randomized (mean age 72 years, 53% female, 66% racial/ethnic minority), 611 (92%) completed the study. Mean (SD) change in PTH was -3 (16) pg/mL with vitamin D3 vs 2 (18) pg/mL with placebo (estimated mean difference, -5 (95% CI: – 8, -2) pg/mL). Within the vitamin D3 group, lower baseline 25(OH)D was associated with a larger decline in PTH in a non-linear fashion. With baseline 25(OH)D >30 ng/mL as the reference, 25(OH)D <20 ng/mL was associated with a larger decline in PTH with vitamin D3 supplementation (-10 (95% CI: -15, -6) pg/mL) whereas 25(OH)D 20-30 ng/mL was not (-2 (95% CI: -6, 1) pg/mL). A segmented threshold model identified a baseline 25(OH)D concentration of 21 (95% CI: 13, 31) ng/mL as an inflection point for difference in change in PTH. Race/ethnicity, BMI and eGFR did not modify vitamin D treatment response. There was no significant change in 1,25(OH)2D in either treatment group.

Conclusions: Of characteristics most commonly associated with vitamin D metabolism, only baseline 25(OH)D <20 ng/mL modified the PTH response to vitamin D supplementation, providing support from a clinical trial to use this threshold to define insufficiency.