Rest-activity circadian rhythms and osteoporosis: A prospective cohort and Mendelian randomization study

Abstract

Background

Disruptions in rest-activity circadian rhythms (RAR) have been shown to be associated with an increased risk of osteoporosis. However, there remains a scarcity of prospective studies examining this association.

Methods

This longitudinal cohort study utilized data from the UK Biobank, including 90,029 participants who were initially free of OP and had reliable accelerometer data at baseline, with a median follow-up time of 8.1 years. Participants newly lost to follow-up within the first two years were excluded. We assessed the associations of eleven RAR variables including nonparametric variables relative amplitude (RA), most active 10-h period counts (M10), least active 5-h period counts (L5), interdaily stability (IS), and intradaily variability (IV), and parametric variables amplitude, mesor, pseudo-F statistic, acrophase, alpha, and beta with the risk of OP using Cox models adjusted for multiple confounders. Mediation analyses were conducted to determine whether inflammatory markers mediated the associations between RAR variables and OP incidence. Additionally, two-sample MR analyses were conducted to infer causality.

Results

In this study, 1702 new-onset OP cases were documented. Higher RA(adjusted hazard ratio 0.87 [95 % CI 0.83–0.92]) and M10 (0.73 [0.60–0.89]) were associated with a lower risk of osteoporosis, while higher L5 (1.09 [1.04–1.15]) was associated with an increased risk. The associations between these three RAR variables and osteoporosis risk were possibly mediated by leukocyte count and platelet-to-lymphocyte ratio, with mediation proportions ranging from 6.06 % to 13.84 %. Higher alpha of parametric variables (0.92 [0.88–0.97]) were associated with a lower risk of osteoporosis. Two-sample MR analyses suggested potential significant associations between RA, L5, pseudo-F and femoral neck bone mineral density, consistent with observational results.

Conclusions

Our findings suggest that circadian rhythm disruption, as indicated by impaired RAR variables, was associated with higher osteoporosis risk. Circadian rhythm disruption may be a modifiable risk factor that could be targeted for osteoporosis prevention.