Longitudinal changes in bone mineral density after initiation of elexacaftor-tezacaftor-ivacaftor in youth and adults with cystic fibrosis: PROMISE-ENDO

Background Low bone mineral density (BMD) and increased fracture risk are common in individuals with cystic fibrosis (CF). The extent to which the CF transmembrane conductance regulator (CFTR) modulator elexacaftor-tezacaftor-ivacaftor (ETI) benefits BMD was a focus of the endocrine sub-study of PROMISE , a multicenter observational study of clinically prescribed ETI. We examined changes in whole-body (WB), lumbar spine (LS), total hip (TH), and femoral neck (FN) areal BMD (aBMD, g/cm²) in the 24–30 months (mos) following ETI initiation. Methods Participants had CF, ≥1 F508del mutation, and were aged ≥12 years (y). Dual-energy X-ray absorptiometry (DXA) scans of the WB, LS, TH, and FN were collected before and following 12–18 mos and 24–30 mos of ETI therapy. Changes in aBMD Z-scores (aBMDZ) were examined with longitudinal mixed effects models. Results Baseline aBMDZ was below-average at all skeletal sites in youth and adults (aBMDZ <0). Mixed model results for youth [ n = 60 at baseline; average age 15y (range: 12–19.8); 48 % female] revealed decreases in WB (less head) (β-coefficient=–0.27; 95 %CI: –0.46, -0.09), LS (β=–0.26; 95 %CI: –0.42, –0.10), TH (β=–0.29; 95 %CI: –0.45, –0.13), and FN (β=–0.37; 95 %CI: –0.57, –0.17) aBMDZ between baseline and 12–18 mos. These changes persisted but did not worsen at 24–30 mos. Changes in adult [ n = 73 at baseline; average age 28y (range: 20–58.8); 51 % female] aBMDZ were negative but modest compared to youth (no β-coefficient >–0.11). Conclusions Youth aBMDZ was lower at multiple skeletal sites 12–18 mos after ETI initiation, and these changes persisted at 24–30 mos. Adult aBMDZ generally remained unchanged.