- •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.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of Cystic Fibrosis
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- The prevalence of osteoporosis, osteopenia, and fractures among adults with cystic fibrosis: a systematic literature review with meta-analysis.Calcif Tissue Int. 2010; 86: 1-7
- Guide to bone health and disease in cystic fibrosis.J Clin Endocrinol Metab. 2005; 90: 1888-1896
- Osteoporosis and osteopenia in adults and adolescents with cystic fibrosis: prevalence and associated factors.Thorax. 2000; 55: 798-804
- Bone density, body composition, and inflammatory status in cystic fibrosis.Am J Respir Crit Care Med. 2000; 162: 789-794
- Osteoporosis in patients with cystic fibrosis.Clin Chest Med. 1998; 19: 555-567
- Cystic fibrosis bone disease treatment: current knowledge and future directions.J Cyst Fibros. 2019; 18: S56-S65
- Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.Cell. 1997; 89: 309-319
- Functions of RANKL/RANK/OPG in bone modeling and remodeling.Arch Biochem Biophys. 2008; 473: 139-146
- CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications.J Clin Endocrinol Metab. 2007; 92: 4514-4521
- Serum RANKL, osteoprotegerin (OPG) and RANKL/OPG ratio in children with systemic lupus erythematosus.Lupus. 2019; 28: 1233-1242
- Denosumab in postmenopausal women with low bone mineral density.N Engl J Med. 2006; 354: 821-831
- Baseline RANKL:OPG ratio and markers of bone and cartilage degradation predict annual radiological progression over 11 years in rheumatoid arthritis.Ann Rheum Dis. 2010; 69: 1623-1628
- The RANKL/OPG system is activated in inflammatory bowel disease and relates to the state of bone loss.Gut. 2005; 54: 479-487
- Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases.JAMA. 2004; 292: 490-495
- Osteoblast CFTR inactivation reduces differentiation and osteoprotegerin expression in a mouse model of cystic fibrosis-related bone disease.PLoS ONE. 2013; 8: e80098
- Overexpression of RANKL in osteoblasts: a possible mechanism of susceptibility to bone disease in cystic fibrosis.J Pathol. 2016; 240: 50-60
- Cystic fibrosis and bone disease: defective osteoblast maturation with the F508del mutation in cystic fibrosis transmembrane conductance regulator.Am J Respir Crit Care Med. 2014; 189: 746-748
- Cystic fibrosis bone disease: is the CFTR corrector C18 an option for therapy?.Eur Respir J. 2015; 45: 845-848
- Osteoclast function, bone turnover and inflammatory cytokines during infective exacerbations of cystic fibrosis.J Cyst Fibros. 2010; 9: 93-98
- The TNF and TNF receptor superfamilies: integrating mammalian biology.Cell. 2001; 104: 487-501
- RANK-L and RANK: t cells, bone loss, and mammalian evolution.Annu Rev Immunol. 2002; 20: 795-823
- Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin.Immunity. 2003; 19: 849-861
- Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils.Arthritis Res Ther. 2007; 9: R25
- IL-8 correlates with reduced baseline femoral neck bone mineral density in adults with cystic fibrosis: a single center retrospective study.Sci Rep. 2021; 11: 15405
- Bone turnover markers, osteoprotegerin and RANKL cytokines in children with cystic fibrosis.Adv Med Sci. 2013; 58: 338-343
- Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human bone.Thorax. 2007; 62: 650-651
- Cystic fibrosis transmembrane conductance regulator (CFTR) regulates the production of osteoprotegerin (OPG) and prostaglandin (PG) E2 in human bone.J Cyst Fibros. 2010; 9: 69-72
Denosumab prescribing information. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Prolia/prolia_pi.pdf. 2022.
- Antiresorptive therapies for osteoporosis: a clinical overview.Nat Rev Endocrinol. 2011; 8: 81-91
Published online: August 27, 2022
Accepted: August 16, 2022
Received in revised form: August 15, 2022
Received: February 14, 2022
© 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.