Sex-specific 25-hydroxyvitamin D threshold concentrations for functional outcomes in older adults: PRoject on Optimal Vitamin D in Older adults (PROVIDO)

Background: Threshold serum 25-hydroxyvitamin D [25(OH)D] concentrations for extraskeletal outcomes are uncertain and could differ from recommendations (20-30 ng/mL) for skeletal health. Objectives: We aimed to identify and validate sex-specific threshold 25(OH)D concentrations for older adults' physical function. Methods: Using 5 large prospective, population-based studies-Age, Gene/Environment Susceptibility-Reykjavik (n = 4858, Iceland): Health. Aging, and Body Composition (n = 2494, United States); Invecchiare in Chianti (n = 873, Italy): Osteoporotic Fractures in Men (n = 2301, United States); and Study of Osteoporotic Fractures (n = 5862, United States)-we assessed 16,388 community-dwelling adults (10,376 women, 6012 men) aged >= 65 y. We analyzed 25(OH)D concentrations with the primary outcome (incident slow gait: women <0.8 m/s: men <0.825 m/s) and secondary outcomes (gait speed, incident self-reported mobility, and stair climb impairment) at median 3.0-y follow-up. We identified sex-specific 25(OH)D thresholds that best discriminated incident slow gait using machine learning in training data (2/3 cohort-stratified random sample) and validated using the remaining (validation) data and secondary outcomes. Results: Mean age in the cohorts ranged from 74.4 to 76.5 y in women and from 73.3 to 76.6 y in men. Overall, 1112/6123 women (18.2%) and 494/3937 men (12.5%) experienced incident slow gait, 1098/7011 women (15.7%) and 474/3962 men (12.0%) experienced incident mobility impairment, and 1044/6941 women (15.0%) and 432/3993 men (10.8%) experienced incident stair climb impairment. Slow gait was best discriminated by 25(OH)D <24.0 ng/mL compared with 25(OH)D >= 24.0 ng/mL in women (RR: 1.29; 95% CI: 1.10, 1.50) and 25(OH)D <21.0 ng/mL compared with 25(OH)D >= 21.0 ng/mL in men (RR: 1.43; 95% CI: 1.01, 2.02). Most associations between 25(OH)D and secondary outcomes were modest; estimates were similar between validation and training datasets. Conclusions: Empirically identified and validated sex-specific threshold 25(OH)D concentrations for physical function for older adults, 24.0 ng/mL for women and 21.0 ng/mL for men, may inform candidate reference concentrations or the design of vitamin D intervention trials.