SAT-732 Longitudinal Changes in Bone Mineral Density After Initiation of Elexacaftor-Tezacaftor-Ivacaftor in Youth and Adults with Cystic Fibrosis

Abstract Disclosure: M. Shirley Bezerra: None. B. Zemel: None. R.J. Gallop: None. R. Walega: None. S. Schwarzenberg: None. S.D. Freedman: None. G.M. Solomon: None. C.L. Chan: None. A. Kelly: None. Context: Low bone mineral density (BMD) and increased fracture risk are common in individuals with cystic fibrosis (CF). Recent advances in CF care include development of elexacaftor-tezacaftor-ivacaftor (ETI), a therapy that in a large majority of patients restores function of the aberrant CF transmembrane conductance regulator protein. The extent to which ETI may benefit BMD alongside its observed positive effects on lung function, body mass index (BMI), and inflammation was a focus of the endocrine sub-study of PROMISE, a multicenter, prospective observational study of clinically prescribed ETI (NCT04038047). Objective: To examine changes in whole-body (WB), lumbar spine (LS), and hip areal BMD (aBMD, g/cm2) in the 24-30 months (mos) following initiation of ETI therapy. Methods: Participants were aged >12 years at enrollment, had at least one F508del mutation, and were recruited from one of 16 CF Foundation Therapeutics Development Network centers designated for the PROMISE endocrine sub-study. Dual-energy X-ray absorptiometry (DXA) scans of the WB, LS, and hip, and measures of height, weight, and pulmonary function (ppFEV1) were collected before and following 12-18 mos and 24-30 mos of ETI therapy. Changes in aBMD standard deviation scores (aBMDz), calculated using pediatric and Hologic reference ranges for youth and adults, respectively, were examined using longitudinal mixed-effects models accounting for within-individual correlated measures. BMIz and ppFEV1 were included as covariates. Results: BMD of the WB, LS, and hip was low at baseline for youth (WB less head aBMDz [mean; 95%CI]: -0.94; -1.22 to -0.66; LS aBMDz: -0.34; -0.60 to -0.08; hip aBMDz: -0.48; -0.80 to -0.15) and adults (WB aBMDz: -0.36; -0.69 to -0.03; LS aBMDz: -0.60; -0.86 to -0.35; hip aBMDz: -0.44; -0.61 to -0.27) compared to age and sex-matched peers without CF. Mixed-model results for youth (n=60 at baseline; average age 15 years [range: 12-19.8]; 48% female) revealed a decrease in WB less head (β-coefficient=-0.27; 95%CI: -0.46 to -0.09, p=0.004), spine (β=-0.26; 95%CI: -0.42 to -0.10, p=0.002), and hip (β=-0.29; 95%CI: -0.45 to -0.13, p=0.001) aBMDz between baseline and 12-18 mos. These changes persisted but did not worsen at 24-30 mos. BMIz and ppFEV1 were positively associated with aBMDz in all models. Changes in adult (n=74 at baseline; average age 28 years [range: 20-58.8]; 51% female) aBMDz were also negative, but modest compared to youth (no β-coefficient > -0.11). Conclusion: Youth aBMDz was lower at multiple skeletal sites 12-18 mos after ETI initiation, and these changes persisted out to 24-30 mos. Adult aBMDz generally remained unchanged across visits. These results do not support improved BMD in people with CF on ETI therapy over 2 years. Future analyses will seek to use a historical control group to assess the extent to which ETI may slow negative trends in aBMDz and affect long-term bone fragility. Presentation: Saturday, July 12, 2025