Juan Carlos Cardet1, Xiaofeng Jiang2, Quan Lu2, Norma Gerard3, Kristen McIntire1, Homer A Boushey4, Mario Castro5, Vernon M Chinchilli6, Christopher D Codispoti7, Anne-Marie Dyer6, Fernando Holguin8, Monica Kraft9, Stephen Lazarus4, Robert F Lemanske10, Njira Lugogo11, Dave Mauger6, Wendy C Moore12, James Moy7, Victor E Ortega12, Stephen P Peters12, Lewis J Smith13, Julian Solway14, Christine A Sorkness10, Kaharu Sumino5, Michael E Wechsler15, Sally Wenzel8, Elliot Israel16. 1. Department of Medicine, Brigham and Women's Hospital, Boston, Mass. 2. Departments of Environmental Health, Genetics & Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Mass. 3. Department of Pediatrics, Boston Children's Hospital, Boston, Mass. 4. Department of Medicine, University of California San Francisco, San Francisco, Calif. 5. Department of Medicine, Washington University, St Louis, Mo. 6. Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pa. 7. Department of Medicine, Rush University Medical Center and Department of Pediatrics, Stroger Hospital of Cook County, Chicago, Ill. 8. Department of Medicine, Pittsburgh University, Pittsburgh, Pa. 9. Department of Medicine, University of Arizona, Tucson, Ariz. 10. Departments of Medicine and Pharmacy Practice, University of Wisconsin, Madison, Wis. 11. Department of Medicine, Duke University, Durham, NC. 12. Department of Internal Medicine, Wake Forest University, Winston-Salem, NC. 13. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill. 14. Department of Medicine, University of Chicago, Chicago, Ill. 15. Department of Medicine, National Jewish University, Denver, Colo. 16. Department of Medicine, Brigham and Women's Hospital, Boston, Mass. Electronic address: eisrael@bwh.harvard.edu.
Abstract
BACKGROUND:Loss of bronchoprotection (LOBP) with a regularly used long-acting β2-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β2-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate. OBJECTIVE: We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 μg offluticasonetwice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC20 value. RESULTS: The mean doubling dose reduction in SPMCh PC20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P = .62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P = .81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P = .86) and 0.8 for placebo (P = .15; P = .31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P = .43) and 1.02 for placebo (P = .84; P = .44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP. CONCLUSION: This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP.
RCT Entities:
BACKGROUND: Loss of bronchoprotection (LOBP) with a regularly used long-acting β2-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β2-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate. OBJECTIVE: We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 μg of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC20 value. RESULTS: The mean doubling dose reduction in SPMCh PC20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P = .62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P = .81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P = .86) and 0.8 for placebo (P = .15; P = .31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P = .43) and 1.02 for placebo (P = .84; P = .44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP. CONCLUSION: This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP.
Authors: M Profita; R Gagliardo; R Di Giorgi; F Pompeo; M Gjomarkaj; G Nicolini; J Bousquet; A M Vignola Journal: Allergy Date: 2005-03 Impact factor: 13.146