Menopausal hormone therapy and frailty risk: a nationwide Korean target trial emulation study

Abstract Background Menopause is associated with functional decline, but evidence linking menopausal hormone therapy (MHT) to frailty risk remains limited. Aims To evaluate whether achievement of a prespecified MHT exposure threshold was associated with lower frailty risk among MHT initiators. Methods Using the NHIS-HEALS database (2002–2019), we conducted a nationwide new-user cohort study of 31,294 women aged ≥ 45 years who initiated systemic MHT and were non-frail at baseline, with up to 10 years of follow-up. The outcome was transition to high frailty risk status (Hospital Frailty Risk Score [HFRS] > 15). The target strategy was ≥ 28 cumulative days of MHT within 60 days of initiation. Strategies were compared by clone–censor–weighting within a target trial emulation framework, with doubly robust estimation. Results Overall, 25,907 participants (82.8%) achieved the target strategy, which was associated with a lower risk of transition (aHR, 0.88; 95% CI, 0.85–0.92; adjusted 10-year risk difference, − 3.7%; 95% CI, − 4.7 to − 2.8). The association was more pronounced among women aged ≥ 50 years and those with intermediate baseline frailty risk (HFRS 5–15; aHR, 0.77), and differed by formulation (tibolone, aHR 0.63; estrogen-only therapy, aHR 0.94). Discussion The outcome was based on a claims-derived frailty risk score, and because both groups comprised MHT initiators, the findings reflect early adherence rather than MHT use versus non-use. Conclusions Achievement of the specific early MHT exposure threshold was associated with lower transition to high frailty risk status.