Clinical and biomarker modifiers of vitamin D treatment response: The Multi-Ethnic Study of Atherosclerosis

Simon Hsu, David K. Prince, Kayleen Williams, Norrina B. Allen, Gregory L. Burke, Andrew N. Hoofnagle, Xiaohui Li, Kiang J. Liu, Robyn L. McClelland, Erin D. Michos, Bruce M. Psaty, Steven J. Shea, Kenneth M. Rice, Jerome I. Rotter, David Siscovick, Russell P. Tracy, Karol E. Watson, Bryan R. Kestenbaum, Ian H. De Boer

Research output: Contribution to journalArticlepeer-review


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, BMI, and estimated glomerular filtration rate (eGFR), should also influence the threshold for treatment is unknown. Objectives: The aim was to identify clinical and biomarker characteristics that modify the response to vitamin D supplementation. Methods: A total of 666 older adults in the Multi-Ethnic Study of Atherosclerosis (MESA) were randomly assigned to 16 wk 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 wk. Results: Among 666 participants randomly assigned (mean age: 72 y; 53% female; 66% racial/ethnic minority), 611 (92%) completed the study. The mean (SD) change in PTH was -3 (16) pg/mL with vitamin D3 compared with 2 (18) pg/mL with placebo (estimated mean difference: -5; 95% CI: -8, -2 pg/mL). Within the vitamin D3 group, lower baseline 25-hydroxyvitamin D [25(OH)D] was associated with a larger decline in PTH in a nonlinear 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 of 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.

Original languageEnglish (US)
Pages (from-to)914-924
Number of pages11
JournalAmerican Journal of Clinical Nutrition
Issue number3
StatePublished - Mar 1 2022


  • HbA1c harmonization program
  • cholecalciferol
  • randomized clinical trial
  • standardization
  • vitamin D
  • vitamin D deficiency
  • vitamin D insufficiency
  • vitamin D standardization program

ASJC Scopus subject areas

  • Nutrition and Dietetics
  • Medicine (miscellaneous)


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