Observational and genetic evidence highlight the association of human sleep behaviors with the incidence of fracture

Abstract

We combined conventional evidence from longitudinal data in UK Biobank and genetic evidence from Mendelian randomization (MR) approach to infer the causality between sleep behaviors and fracture risk. We found that participants with insomnia showed 6.4% higher risk of fracture (hazard ratio [HR] = 1.064, 95% CI = 1.038-1.090, P = 7.84 × 10^-7), falls and bone mineral density (BMD) mediated 24.6% and 10.6% of the intermediary effect; the MR analyses provided the consistent evidence. A U-shape relationship was observed between sleep duration and fracture risk (P < 0.001) with the lowest risk at sleeping 7-8 h per day. The excessive daytime sleepiness and "evening" chronotype were associated with fracture risk in observational study, but the association between chronotype and fracture did not show in MR analyses. We further generated a sleep risk score (SRS) with potential risk factors (i.e., insomnia, sleep duration, chronotype, and daytime sleepiness). We found that the risk of fracture increased with an increasing SRS (HR = 1.087, 95% CI = 1.065-1.111, P = 1.27 × 10^-14). Moreover, 17.4% of the fracture cases would be removed if all participants exhibited a healthy sleep pattern. In conclusion, insomnia had a causal effect on fracture, falls had a larger intermediary effect than BMD in this association. Individuals with fracture risk could benefit from the intervention on unhealthy sleep pattern.

Fig. 1. Forest plot of observational and Mendelian randomization analyses for the relationships of insomnia with fracture risk.

The 95% confidence interval was presented in the error bar. Model 0 was adjusted for confounders, including age, sex, body mass index, education, smoking, alcohol consumption, physical activity, cognitive impairment, depression, and the use of glucocorticoid medication, benzodiazepines, and antidepressants; Model 1 = Model 0 + BMD; Model 2 = Model 0 + falls; Model 3 = Model 0 + BMD + falls. * the P-value of the intercept term. BMD bone mineral density, CI confidence interval, HR hazard ratio, IVW inverse-variance weighted, MR Mendelian randomization, MR-PRESSO MR pleiotropy residual sum and outlier, OR odds ratio.

Fig. 2. Observational association of sleep duration with fracture risk using a restricted cubic spline based on model 0 based on different cut points.

a Sleeping 7 h per day and b sleeping 8 h per day. Hazard ratios are indicated by blue solid lines and the 95% confidence intervals by blue shaded areas. The red line denotes the harzard ratio of one. In all these analyses, models were adjusted for risk factors for fracture, including age, sex, body mass index, education, smoking, alcohol consumption, physical activity, cognitive impairment, depression, and the use of glucocorticoid medication, benzodiazepines, and antidepressants.

Fig. 3. Forest plot of observational analyses for the relationships of sleep risk score with fracture risk.

The 95% confidence interval was presented in the error bar. Model 0 was adjusted for confounders, including age, education, sex, smoking, alcohol consumption, physical activity, body mass index, and the use of glucocorticoid, benzodiazepines, and antidepressants; Model 1 = Model 0 + BMD; Model 2 = Model 0 + falls; Model 3 = Model 0 + BMD + falls. BMD bone mineral density, CI confidence interval, IVW inverse-variance weighted, MR Mendelian randomization, MR-PRESSO MR pleiotropy residual sum and outlier, OR odds ratio.

Fig. 4. An overview of the study design.

IVW inverse-variance weighted, MR Mendelian randomization, MR-PRESSO MR pleiotropy residual sum and outlier, wGRS weighted genetic risk score.