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Ivacaftor Improves Skeletal Outcomes in Patients with Cystic Fibrosis

Key findings

  • In a two-year prospective study, changes in bone health were investigated in 26 patients with cystic fibrosis (CF) who had the G551D-CFTR mutation and received ivacaftor, 26 patients with CF not treated with ivacaftor and 26 healthy volunteers
  • In adults, ivacaftor therapy was associated with significantly increased cortical microarchitecture at both the radius and the tibia; there were no differences in bone changes between cohorts in pediatric subjects
  • Cortical porosity in ivacaftor-treated adults increased at both the radius and the tibia, suggesting a possible increase in bone remodeling, and these changes were not associated with an effect on bone strength
  • Changes in other skeletal outcomes, including areal bone mineral density and trabecular microarchitecture, did not differ significantly in ivacaftor-treated patients compared with the two control groups
  • For now, it is unclear whether ivacaftor-related changes in bone microarchitecture have clinical effects

As life expectancy improves for patients with cystic fibrosis (CF), comorbid bone disease has become more prevalent. Recent studies suggest dysfunction of the Cftr gene, the cause of CF, also plays a role in CF-related bone disease. For example, the CFTR protein has been found in human osteoclasts and osteoblasts, and patients with CF show increased markers of bone resorption and decreased markers of bone formation.

Researchers at Massachusetts General Hospital wondered whether ivacaftor, which enhances the activity of the CFTR protein, might improve bone health in patients with CF. They determined in a two-year prospective study that ivacaftor does improve cortical bone in patients with the G551D-CFTR mutation.

Melissa S. Putman, MD, MS, endocrinologist, and Joel S. Finkelstein, MD, associate director of the Bone Density Center, both in the Endocrine Unit at Mass General, and colleagues published the details of their findings in The Journal of Clinical Endocrinology and Metabolism.

Study Methods

The team recruited three cohorts of children (ages 6–17 years) and adults (ages 18–75 years):

  • Patients with CF and at least one copy of the G551D mutation who were treated with ivacaftor (initially, ivacaftor was approved only for patients with this mutation, which is present in only about 5% of the CF population)
  • Patients with CF not treated with ivacaftor, usually because they did not have the G551D mutation
  • Healthy volunteers

The two control cohorts were matched by age, race and gender to the ivacaftor cohort.

At baseline, 12 months and 24 months, areal bone mineral density (aBMD) of the lumbar spine, total hip, femoral neck and whole body were measured using dual-energy X-ray absorptiometry (DXA). Volumetric BMD (vBMD) and bone microarchitecture of the distal radius and tibia were assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT). 15 adults and 11 children in each cohort completed baseline evaluations.

Primary Outcomes: HR-pQCT Results

  • The ivacaftor cohort showed significantly increased cortical area and volume at both the radius and the tibia; there was no significant increase in the control groups
  • Among adults, cortical porosity in the ivacaftor cohort increased at both the radius and the tibia significantly more than in the control groups, but the absolute values were small and were not associated with decrements in bone strength
  • There were no significant differences among cohorts with respect to change in vBMD or change in trabecular microarchitecture at the radius or tibia

Secondary Outcomes

There were no significant differences between the three cohorts in:

  • Change in aBMD
  • Change in BMD Z-scores
  • Change in bone turnover markers
  • Fracture incidence

Clinical Relevance

Ivacaftor improves multiple aspects of health in patients with CF, including pulmonary function, nutritional status and frequency of exacerbations. Thus, it may improve bone health apart from a direct effect of CFTR potentiation. This study provided supportive evidence: the increase in cortical microarchitecture was independent of pulmonary function and body mass index.

For now, it's unclear whether the ivacaftor-related changes in bone microarchitecture will have a clinical impact. It will be interesting to see the effects on bone of the recently approved triple combination therapy, ivacaftor/tezacaftor/elexacaftor. It targets the most common Cftr mutation, F508del, present in about 90% of CF patients.

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