Correction of the Gene Defect in Cystic Fibrosis: Is It Too Late for Bone?

Cystic fibrosis (CF) is the most common autosomal recessive disease among Whites in the United States (1). CF results from a single mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (1). More than 1000 mutations of the CFTR gene have been described with varying degrees of impact on the production and function of the CFTR protein. The CFTR protein is an important chloride channel responsible for the transport of chloride and water on epithelial surfaces. A mutated CFTR results in viscous secretions on epithelial surfaces that affect the respiratory, digestive, endocrine, and reproductive systems (1). Patients with CF have increased morbidity and mortality from recurrent lung infections that result in a progressive decline in lung function and eventually respiratory failure. Improvements in CF care over the past decade have led to increased prevalence of other comorbidities, including CF-related diabetes and CF-related bone disease.

The first drug to address the underlying genetic defect of CF was ivacaftor, approved by the US Food and Drug Administration (FDA) in 2012 for patients with CF and the G551D mutation (2). The G551D mutation results in production of a CFTR protein that has a chloride channel that does not open properly. G551D accounts for approximately 5% of the mutations in people with CF as opposed to approximately 85% of the mutations that arise from the F508del mutation. Ivacaftor belongs to the class of CFTR modulator drugs called “CFTR potentiators,” which increase the time that the mutated gate remains open. The phase 3 trial leading to FDA approval of ivacaftor found improvements in lung function that were sustained up to 2 years (3). Subsequently, ivacaftor has been studied in clinical trials in combination with other CFTR potentiators and correctors, drugs that restore misfolded CFTR protein, including the most recently FDA approved combination of 2 correctors and 1 potentiator, elexacaftor/tezacaftor/ivacaftor.

What happens to CF bone disease after receipt of a CFTR modulator drug? In this issue of The Journal of Clinical Endocrinology & Metabolism (4), Putman and colleagues examined 3 cohorts of individuals with CF who were matched on age, race, and sex. One cohort of CF patients had the G551D CFTR mutation, one cohort had primarily other mutations of CFTR (2 individuals had G551D) and did not receive any CFTR modulator therapy, and one cohort consisted of participants without CF. The cohort with the G551DCFTR mutation was studied at the time of initiation of ivacaftor and followed for 2 years. The other 2 cohorts were followed over the same time period. The authors report that adults with the G551DCFTR mutation had significant increases in cortical area, thickness, and porosity at the tibia and radius after 2 years following treatment with ivacaftor, whereas there were no changes seen in these bone measures in the untreated CF and healthy control groups. There were no differences in bone mineral density change between any of the 3 cohorts over the 2-year observation period.

These study findings are the first to report prospective bone outcomes in response to receipt of a CFTR modulator drug. While the results are very encouraging, there are many points for discussion. We know that ivacaftor improves lung function and improves weight and quality of life in patients with CF with G551D mutations (3). The beneficial changes in cortical bone in this study could be due to the impact of ivacaftor on nutrition and physical activity, which indirectly improved the bone measures. The CFTR protein has been described in osteoblasts and osteoclasts and may have a direct action on bone mass, turnover, architecture, and strength (5). However, baseline measures of osteoblast and osteoclast biology including osteocalcin, P1NP (procollagen type I N-terminal propeptide), and C-telopeptide were no different in the CF and non-CF cohorts. Change in estimates of bone strength did not differ over the 2-year period between the 3 cohorts. The CF control group by design was enriched with more deleterious CFTR mutations including homozygous F508del in 38.5% and heterozygous F508del in 42% of the cohort. Despite being enriched in F508del mutations and thus not eligible for ivacaftor therapy, the CF control group experienced no significant change in bone mineral density, cortical porosity, or trabecular and cortical bone area compared to the healthy controls. These findings may suggest that the CF cohorts were well managed in terms of vitamin D nutrition (mean intake of the CF control group was 3700 IU daily), calcium, nutrition, and physical activity. It is also important to note that the individuals with CF who received ivacaftor experienced increased cortical porosity, which is typically associated with increased bone fragility in non-CF populations. However, these participants did not have detrimental changes in bone strength estimates. It is unclear at this point whether the increase in cortical porosity would lead to long-term bone architectural changes leading to increased risk for fracture or simply reflect increased bone remodeling.

Several CFTR modulators and their combinations are under investigation for treatment of CF. There is hope that these new CFTR modulators and combinations of drugs, especially when given at earlier ages, will prevent and/or improve CF bone health and other endocrine-associated diseases such as CF-related diabetes and CF-associated hypogonadism (6, 7). One study, the PROMISE study, will examine longitudinally the impact of triple combination therapy with elexacaftor/tezacaftor/ivacaftor in adults and children with CF on not only lung outcomes but also endocrine outcomes, including CF diabetes and CF bone disease (8). Until long-term data are available with CFTR modulator therapies, CF bone disease should be prevented with adequate nutrition, vitamin D, calcium, physical activity, addressing gonadal status, and avoidance of glucocorticoids when possible. Although fracture data are limited for the use of pharmacologic therapies in CF, clinicians should consider pharmacologic therapy in patients with CF at the highest risk of fracture.

CF is a remarkable story of bedside to bench back to the bedside. Early restoration of the production and/or function of the CFTR protein for patients with CF will lead to a cure of CF and its complications. Restoration of the CFTR may improve bone health either directly at the bone or indirectly via improved lung and nutritional health. Further study of the role of CFTR in bone biology may lead to novel approaches to the treatment of CF bone disease.

Glossary

Abbreviations

CF

cystic fibrosis

CFTR

cystic fibrosis transmembrane conductance regulator

FDA

Food and Drug Administration

Additional Information

Disclosures: The author has nothing to disclose. Dr. Tangpricha receives research funding from the Cystic Fibrosis Foundation.

Data Availability

Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study.