Association between ramelteon use and risk of fragility fractures: A retrospective cohort study

The effect of melatonin receptor agonists on bone remains unclear. This retrospective cohort study provides the first evidence that the short- to mid-term use of ramelteon is not associated with the risk of fracture. Further research with longer follow-up is needed to clarify the effects of ramelteon on bone health.

Recent studies have suggested that melatonin may have the potential to treat osteoporosis. However, few studies have examined the effects of melatonin receptor agonists on bone health. This study aimed to evaluate the association between ramelteon use and the risk of fragility fractures.

We conducted a retrospective cohort study from April 2014 to November 2022 using the DeSC database, a large healthcare claims database in Japan, employing an active comparator and new-user design. Female participants aged ≥ 50 years were included in the study. Exposure was defined as the first dispensation of ramelteon or orexin receptor antagonists. The outcome was a composite of major fragility fractures, including hip, vertebral, wrist, proximal humeral, and ankle fractures. To adjust for potential confounders, we used overlap weighting analysis with propensity scores. Cox regression analyses were performed both before and after applying overlap weighting.

A total of 106,511 individuals were identified, including 23,312 new ramelteon users and 83,199 new orexin receptor antagonist users. The overall fracture incidence was 9,429 per 100,000 person-years in the ramelteon group and 7,330 per 100,000 person-years in the orexin receptor antagonist group. The adjusted hazard ratio for overall fractures associated with ramelteon use was 1.07 (95% confidence interval: 0.99-1.17). The results were consistent across fracture types, age groups, and landmark analyses.

In a real-world setting, short- to mid-term ramelteon use was not associated with an increased risk of fractures. Future studies should consider longer follow-up periods to further investigate the effects of ramelteon on bone health.