Abstract
BACKGROUND: Cystic fibrosis-related bone disease contributes substantially to fragility fractures and morbidity in patients with cystic fibrosis (CF). Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators have been shown to improve pulmonary and nutritional outcomes, but their impact on skeletal health remains incompletely defined. METHODS: We conducted a retrospective cohort study using the TriNetX Research Network, which aggregates deidentified electronic medical records from 168 health care organizations. Patients with CF who initiated CFTR modulators between 2012 and 2023 were compared with matched CF patients without modulator exposure. Sub-analyses examined outcomes in patients receiving elexacaftor/tezacaftor/ivacaftor (ETI) versus non-ETI modulators. A 1:1 propensity score matching algorithm balanced demographic and clinical covariates. The primary outcome was 2-year fracture risk. Relative risks (RR) with 95 % confidence intervals (CI) were calculated. RESULTS: After matching, 5639 patients receiving CFTR modulators were compared with controls. Modulator therapy was associated with significantly reduced risk of overall fracture (RR 0.48, p < .0001), with protective effects observed for hand or wrist, forearm, upper limb, femur, lower leg, and vertebral fractures. Both ETI and non-ETI modulators were associated with significantly lower fracture risk compared with no therapy. There were no significant differences in fracture outcomes between ETI and non-ETI users. CONCLUSION: In this large, population-based analysis, CFTR modulator therapy was associated with lower 2-year fracture risk. These findings extend the benefits of modulator therapy beyond pulmonary and nutritional domains, highlighting its potential role in skeletal protection.