Bisphosphonates vs Denosumab After Low-Trauma Fractures

Importance Patients are at high risk of refracture and death in the immediate period following low-trauma fracture, but comparative evidence for antiresorptive therapies is limited. Objective To compare refracture and all-cause mortality between patients who initiated nitrogen-containing bisphosphonates (N-BPs) and denosumab therapy after fractures. Design, Setting, and Participants This cohort study used sequential target trial emulation of monthly trials among treatment-naive adults 50 years or older through the 12 months after incident low-trauma fracture with a new-user, active-comparator design. Linked administrative health data from the population of New South Wales, Australia, was used. Women entered from January 1, 2011, to June 30, 2018, and men from January 1, 2014, to June 30, 2018, both with 3 years of follow-up. Data were analyzed from December 1, 2025, to May 31, 2026. Exposures N-BP (alendronate, risedronate or zoledronic acid) vs denosumab. Main Outcomes and Measures Three-year all-cause mortality and refracture. Primary analyses estimated intention-to-treat (ITT) associations with inverse probability weighting. Secondary analyses included per-protocol and Fine-Gray competing-risk analyses. Hazard ratios (HRs) greater than 1.00 indicated higher risk with N-BP. Results The cohort included 15 099 participants (overall mean [SD] age, 77.2 [9.2] years), of whom 12 529 (83.0%) were women and 2570 (17.0%) were men (79.9 [8.4] years). All-cause mortality rates with N-BP vs denosumab were 48.1 vs 48.9 per 1000 person-years in women and 123.0 vs 116.4 per 1000 person-years in men, with no clear association in women (ITT HR, 0.98 [95% CI, 0.87-1.10]) or men (ITT HR, 1.09 [95% CI, 0.93-1.25]). Refracture rates were 52.7 vs 46.5 per 1000 person-years in women and 70.5 vs 58.8 per 1000 person-years in men. Initiation of N-BP therapy was associated with higher refracture risk in women (ITT HR, 1.14 [95% CI, 1.05-1.26]) and men (ITT HR, 1.21 [95% CI, 1.03-1.42]). Competing-risk estimates were similar; per-protocol estimates were higher in women (HR, 1.30 [95% CI, 1.09-1.55]) and men (HR, 1.48 [95% CI, 1.10-1.98]). Risks were strongest following nonhip-nonvertebral (NHNV) fractures in women (HR, 1.21 [95% CI, 1.06-1.38]) and men (HR, 1.54 [95% CI, 1.10-2.15]). Conclusions and Relevance In this cohort study emulating a target trial, initiation of N-BP and denosumab therapy was associated with similar mortality, whereas initiation of N-BP was associated with higher refracture risk, particularly after NHNV fractures.