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, 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

Abstract

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. This trial was registered at clinicaltrials.gov as NCT02925195.

Keywords: HbA1c harmonization program; cholecalciferol; randomized clinical trial; standardization; vitamin D; vitamin D deficiency; vitamin D insufficiency; vitamin D standardization program.

© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Change in PTH by baseline 25(OH)D. The horizontal line in each white box indicates the median; top and bottom box borders indicate the first and third quartiles, respectively. The vertical whiskers extending from the boxes depict the most extreme observation within 1.5 times the IQR of the nearest quartile. On each side of the white boxes are kernel density estimations that show the distribution shape of the data. Wider sections represent a higher probability that participants of the population (n = 453) will take on the given value; the thinner sections represent a lower probability. PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D.
FIGURE 2
FIGURE 2
Loess curve showing change in PTH by baseline 25(OH)D among participants assigned to vitamin D3 (n = 453). The shaded area represents the pointwise 95% CI around the values on the fitted Loess curve. The red circle at 21 ng/mL represents the 25(OH)D concentration where a segmented threshold effect was seen using a threshold linear regression model with robust SEs (37). The test for statistical significance is based on a maximum likelihood ratio statistic. PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D.

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