Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

Abstract

Mutations within the gene encoding for the chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR) results in cystic fibrosis (CF), the most common lethal autosomal recessive genetic disease that causes a number of long-term health problems, as the bone disease. Osteoporosis and increased vertebral fracture risk associated with CF disease are becoming more important as the life expectancy of patients continues to improve. The etiology of low bone density is multifactorial, most probably a combination of inadequate peak bone mass during puberty and increased bone losses in adults. Body mass index, male sex, advanced pulmonary disease, malnutrition and chronic therapies are established additional risk factors for CF-related bone disease (CFBD). Consistently, recent evidence has confirmed that CFTR plays a major role in the osteoprotegerin (OPG) and COX-2 metabolite prostaglandin E2 (PGE2) production, two key regulators in the bone formation and regeneration. Several others mechanisms were also recognized from animal and cell models contributing to malfunctions of osteoblast (cell that form bone) and indirectly of bone-resorpting osteoclasts. Understanding such mechanisms is crucial for the development of therapies in CFBD. Innovative therapeutic approaches using CFTR modulators such as C18 have recently shown in vitro capacity to enhance PGE2 production and normalized the RANKL-to-OPG ratio in human osteoblasts bearing the mutation F508del-CFTR and therefore potential clinical utility in CFBD. This review focuses on the recently identified pathogenic mechanisms leading to CFBD and potential future therapies for treating CFBD.

Adult Care in Cystic Fibrosis

“…91,92 Other complications related to CF include combination of CFTR dysfunction and inflammation and CF-related arthropathy, which is poorly understood, and CF-associated osteopenia, which is a common occurrence in chronic systemic inflammatory diseases and, in part, related to CFTR dysfunction. 10,[93][94][95] In addition to conditions related to CF with increasing age, degenerative conditions and cancers are also emerging problems in care delivery. 1,96 There is some evidence to suggest that chronic inflammation accelerates aging, and there are some anecdotal reports of cardiovascular events and some biomarkers that are indicators of increased cardiovascular risk factors.…”

Long‐term extrapulmonary comorbidities after lung transplantation in cystic fibrosis: Update of specificities

“…Nevertheless, despite the improvement of care over recent years, a significant number of patients with CF had low BMD Z scores and reported fractures . The pathophysiology is thought to be multifactorial, and recent data suggest a direct role for CFTR protein dysfunction . Many risk factors have been identified to explain bone loss: chronic lung infection with elevated levels of pro‐inflammatory cytokines, malabsorption leading to vitamin D and K deficiency, hypogonadism and delayed puberty, glucocorticoid therapy, physical inactivity, and low body mass index .…”

“…47 Many risk factors have been identified to explain bone loss: chronic lung infection with elevated levels of pro-inflammatory cytokines, malabsorption leading to vitamin D and K deficiency, hypogonadism and delayed puberty, glucocorticoid therapy, physical inactivity, and low body mass index. 42,47 A recent study has confirmed that the severity of pulmonary disease is related to low BMD even in young patients. 48 Furthermore, among all patients awaiting LT, the lowest BMD values are reported for patients with CF, 49,50 yet osteoporosis is common to all patients with end-stage lung diseases.…”

Endocrine Disorders in Cystic Fibrosis

“…Recent studies in rodent models suggest that correction of the CFTR function may prevent deterioration of bone microarchitecture associated with CF bone disease 50 . CTFR correctors hold promise to improve the bone disease associated with CF; however, no data on humans have been reported 51 .…”