Observational studies have suggested that sleep and circadian disturbances are potentially modifiable risk factors for low bone mineral density (BMD), but the causal relationship is unclear. This study aimed to 1) replicate the findings by examining observational association of sleep traits with low eBMD; 2) examine whether these associations were causal by using mendelian randomization (MR) analyses, and 3) investigate potential modulation effects of sex and menopause. 398,137 White British subjects (aged 39-73y) with valid BMD estimated by quantitative ultrasound of the heel (eBMD) at baseline were included. Linear regression analyses and inverse-variance weighted method were used as main methods for observational and one-sample MR analyses respectively, to investigate the associations between self-reported sleep traits (sleep duration, chronotype, daytime sleepiness and insomnia) and low eBMD. Furthermore, sensitivity analyses were performed in subgroups based on sex and menopause in both observational and MR analyses. In observational analyses, short/long sleep, insomnia and definite eveningness were associated with low eBMD (short sleep: β = -0.045, effect in standard deviation change of rank-based inverse normally transformed eBMD; long sleep: β = -0.028; sometimes insomnia: β = -0.012; usually insomnia: β = -0.021; definite eveningness: β = -0.047), while definite morningness was associated with decreased risk of low eBMD (β = 0.011). Subgroup analyses suggested associations of short/long sleep and definite eveningness with low eBMD among men, short sleep with low eBMD among premenopausal women, and short sleep, eveningness and daytime sleepiness among postmenopausal women. In bidirectional MR analyses, there was no causal relationship between sleep traits and eBMD in either overall sample or subgroup analyses. In summary, although observational analysis showed a robust association of low eBMD with sleep duration, chronotype and insomnia, there was no evidence of causal relationship as suggested by MR analysis.This article is protected by copyright. All rights reserved.
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