Bone demineralization is improved by ivacaftor in patients with cystic fibrosis carrying the p.Gly551Asp mutation

Abstract

Low bone mineral density (BMD) is a common problem in adults with cystic fibrosis (CF), the etiology of which is multifactorial. In this study, we provide the first evidence that ivacaftor improves BMD in CF patients carrying the p.Gly551Asp mutation. Consistently, in vitro experiments with TNF-α-stimulated primary F508del-CFTR osteoblasts demonstrated that correction of p.Phe508del-CFTR markedly decreased RANKL protein production, a major factor of bone resorption. These clinical and fundamental observations suggest that rescue of mutated CFTR protein improves bone remodeling and support the link between CFTR and bone cell physiology. These findings represent a step forward in the development of potential new therapies for CF-related bone disease.

Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2 years of treatment with ivacaftor in a real-world setting

“…A case-report of CFRD resolution with ivacaftor therapy in a 25-year-old male with CF has been published [19]. Although improvements in bone mass density have been reported in 7 adult patients carrying a Gly551Asp-CFTR mutation and taking ivacaftor [20], our results were not conclusive. This might partly be explained by the fact that our population was younger and had better bone mass density at baseline.…”

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

“…Ivacaftor treatment was demonstrated to improve exocrine pancreatic function as well as insulin secretion profile, which may alleviate or even reverse CFrelated diabetes (Hayes et al, 2014;Davies et al, 2016;Tsabari et al, 2016;Kelly et al, 2019). Ivacaftor treatment was also demonstrated to improve bone health (Sermet-Gaudelus et al, 2016) and vascular tone abnormalities (Adam et al, 2016). A recent review nicely summarizes the current understanding of CFTR modulators on extra-pulmonary complications in CF (Sergeev et al, 2019).…”

Bone mineral density is related to lung function outcomes in young people with cystic fibrosis—A retrospective study

“…All patients who were eligible for government funding for Ivacaftor ® were on Ivacaftor ® (at the time of data collection, this was those aged six and above but is approval is now for children two and above). Given the short‐time period these children were exposed to Ivacaftor ® at the time of data collection, it is unlikely that there would be a big difference even though a recent study has shown the drug to improve bone physiology …”

“…Given the short-time period these children were exposed to Ivacaftor ® at the time of data collection, it is unlikely that there would be a big difference even though a recent study has shown the drug to improve bone physiology. 17…”