Evaluation of an association between RANKL and OPG with bone disease in people with cystic fibrosis

• Published in: Journal of cystic fibrosis 2023-01, Vol.22 (1), p.140-145
• Main Authors: Abid, Shadaan, Lee, MinJae, Rodich, Bailey, Hook, Jessica S., Moreland, Jessica G., Towler, Dwight, Maalouf, Naim M., Keller, Ashley, Ratti, Gregory, Jain, Raksha
• Format: Article
• Language: English
• Subjects: Biomarkers; Bone Density; Bone Diseases; Bone Remodeling; Cystic fibrosis; Cystic Fibrosis - complications; Dual-energy x-ray absorptiometry; Humans; Osteoporosis; Osteoprotegerin; Osteoprotegerin - metabolism; Receptor activator of NF-κB
• ISSN: 1569-1993; 1873-5010
• DOI: 10.1016/j.jcf.2022.08.011

•Limited treatment options have been explored for CF related bone disease.•We demonstrated elevated RANKL, decreased OPG and elevated RANKL/OPG in people with CF relative to healthy controls.•We also show elevated RANKL/OPG in people with CF bone disease versus those without bone disease.•The RANKL/OPG difference persisted after adjusting for a number of variables known to impact bone health and may be a useful marker for low bone density in CF.•Further evaluation of the safety and efficacy of antiresorptive agents that target RANKL such as denosumab is warranted. As people with Cystic Fibrosis (CF) live longer, extra-pulmonary complications such as CF-related bone disease (CFBD) are becoming increasingly important. The etiology of CFBD is poorly understood but is likely multifactorial. Bones undergo continuous remodeling via pathways including RANK (receptor activator of NF-κB)/sRANKL (soluble ligand)/OPG (osteoprotegerin). We sought to examine the association between sRANKL (stimulant of osteoclastogenesis) and OPG levels (inhibitor of osteoclast formation) and CFBD to investigate their potential utility as biomarkers of bone turnover in people with CF. We evaluated sRANKL and OPG in plasma from people with CF and healthy controls (HC) and compared levels in those with CF to bone mineral density results. We used univariable and multivariable analysis to account for factors that may impact sRANKL and OPG. We found a higher median [IQR] sRANKL 10,896pg/mL [5,781–24,243] CF; 2,406pg.mL [659.50–5,042] HC; p= 0.0009), lower OPG 56.68pg/mL [36.28–124.70] CF; 583.20pg/mL [421.30–675.10] HC; p < 0.0001), and higher RANKL/OPG in people with CF no BD than in HC (p < 0.0001). Furthermore, we found a higher RANKL/OPG ratio 407.50pg/mL [214.40–602.60] CFBD; 177.70pg/mL [131.50–239.70] CF no BD; p = 0.007) in people with CFBD versus CF without bone disease. This difference persisted after adjusting for variables thought to impact bone health. The current screening recommendations of imaging for CFBD may miss important markers of bone turnover such as the RANKL/OPG ratio. These findings support the investigation of therapies that modulate the RANK/RANKL/OPG pathway as potential therapeutic targets for bone disease in CF.