Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate

AsthmaNet Investigators

doi:10.1016/j.jaci.2019.01.049

Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate

AsthmaNet Investigators

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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 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.

Original language	English (US)
Pages (from-to)	416-425.e7
Journal	Journal of Allergy and Clinical Immunology
Volume	144
Issue number	2
DOIs	https://doi.org/10.1016/j.jaci.2019.01.049
State	Published - Aug 2019

Funding

Supported by grants HL098102, U10HL098096, UL1TR000150, UL1TR000430, UL1TR000050, HL098075, UL1TR001082, HL098090, HL098177, UL1TR000439, HL098098, UL1TR000448, HL098107, HL098112, HL098103, UL1TR000454, and HL098115 awarded by the National Heart, Lung, and Blood Institute.Disclosure of potential conflict of interest: J. C. Cardet reports grants from the National Institute of Allergy and Infectious Diseases (NIAID) during the conduct of the study and Castro reports grants from the National Institutes of Health (NIH) and American Lung Association (ALA) during the conduct of the study; personal fees from Aviragen, Boehringer Ingelheim, Boston Scientific, Elsevier, Genentech, GlaxoSmithKline, Holaira, and Teva; and grants from Amgen, Boehringer Ingelheim, Genentech, Gilead, GlaxoSmithKline, Invion, MedImmune, sanofi-aventis, and Vectura all outside the submitted work. V. M. Chinchilli, S. Lazarus, and S. P. report grants from NIH/National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study. A.-M. Dyer reports grants from the NHLBI during the conduct of the study. M. Kraft reports grants from the NIH, Roche, Sanofi, and Chiesi and other support from TEVA, AstraZeneca, and Elsevier outside the submitted work. R. F. Lemanske reports grants from the NHLBI during the conduct of the study; nonfinancial support from the American Academy of Allergy, Asthma & Immunology AAAAI; grants from a Clinical and Translational Science Award from the NIH; personal fees from LSU, Elsevier, and UpToDate; and grants from the Childhood Origins of Asthma (COAST) study and AsthmaNet outside the submitted work. N. Lugogo reports personal fees from AstraZeneca and consulting fees from TEVA outside the submitted work. D. Mauger reports grants from the NIH during the conduct of the study and nonfinancial support from GlaxoSmithKline, Merck, and TEVA outside the submitted work. W. C. Moore reports grants from the NIH/NHLBI during the conduct of the study; grants and personal fees from AstraZeneca and Sanofi Regeneron; and grants from Boehringer Ingelheim, GlaxoSmithKline, and Pearl Therapeutics, Novartis outside the submitted work. J. Solway reports consulting fees from Sanofi, Genzyme, and Regeneron and gifts from the Rafael Rivera III Memorial Foundation for Asthma Research to the University of Chicago that were designated for asthma research in his laboratory. M. E. Wechsler reports personal fees from AstraZeneca, BSCI, Novartis, Vectura, Regeneron, Genentech, Sentien, and Boehringer Ingelheim and grants and personal fees from Teva, GlaxoSmithKline, and Sanofi all outside the submitted work. S. Wenzel reports grants and personal fees from AstraZeneca and Sanofi; grants from Boehringer Ingelheim, GlaxoSmithKline, and Novartis; and personal fees from Pieris and UpToDate outside the submitted work. E. Israel reports personal fees from AstraZeneca, Novartis, Philips Respironics, Regeneron Pharmaceuticals, TEVA Specialty Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Sanofi, Merck, Entrinsic Health Solutions, and GlaxoSmithKline and other support from Vorso Corp, Pneuma Respiratory, and 4D Pharma; grants from Genentech, Sanofi, and Boehringer Ingelheim; and nonfinancial support from Boehringer Ingelheim, GlaxoSmithKline, Merck, Sunovion, TEVA, TEVA Specialty Pharmaceuticals outside the submitted work. The rest of the articles declare that they have no relevant conflicts of interest. Supported by grants HL098102, U10HL098096, UL1TR000150, UL1TR000430, UL1TR000050, HL098075, UL1TR001082, HL098090, HL098177, UL1TR000439, HL098098, UL1TR000448, HL098107, HL098112, HL098103, UL1TR000454, and HL098115 awarded by the National Heart, Lung, and Blood Institute. Disclosure of potential conflict of interest: J. C. Cardet reports grants from the National Institute of Allergy and Infectious Diseases (NIAID) during the conduct of the study and Castro reports grants from the National Institutes of Health (NIH) and American Lung Association (ALA) during the conduct of the study; personal fees from Aviragen, Boehringer Ingelheim, Boston Scientific, Elsevier, Genentech, GlaxoSmithKline, Holaira, and Teva; and grants from Amgen, Boehringer Ingelheim, Genentech, Gilead, GlaxoSmithKline, Invion, MedImmune, sanofi-aventis, and Vectura all outside the submitted work. V. M. Chinchilli, S. Lazarus, and S. P. report grants from NIH/ National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study. A.-M. Dyer reports grants from the NHLBI during the conduct of the study. M. Kraft reports grants from the NIH, Roche, Sanofi, and Chiesi and other support from TEVA, AstraZeneca, and Elsevier outside the submitted work. R. F. Lemanske reports grants from the NHLBI during the conduct of the study; nonfinancial support from the American Academy of Allergy, Asthma & Immunology AAAAI; grants from a Clinical and Translational Science Award from the NIH; personal fees from LSU, Elsevier, and UpToDate; and grants from the Childhood Origins of Asthma (COAST) study and AsthmaNet outside the submitted work. N. Lugogo reports personal fees from AstraZeneca and consulting fees from TEVA outside the submitted work. D. Mauger reports grants from the NIH during the conduct of the study and nonfinancial support from GlaxoSmithKline, Merck, and TEVA outside the submitted work. W. C. Moore reports grants from the NIH/ NHLBI during the conduct of the study; grants and personal fees from AstraZeneca and Sanofi Regeneron; and grants from Boehringer Ingelheim, GlaxoSmithKline, and Pearl Therapeutics, Novartis outside the submitted work. J. Solway reports consulting fees from Sanofi, Genzyme, and Regeneron and gifts from the Rafael Rivera III Memorial Foundation for Asthma Research to the University of Chicago that were designated for asthma research in his laboratory. M. E. Wechsler reports personal fees from AstraZeneca, BSCI, Novartis, Vectura, Regeneron, Genentech, Sentien, and Boehringer Ingelheim and grants and personal fees from Teva, GlaxoSmithKline, and Sanofi all outside the submitted work. S. Wenzel reports grants and personal fees from AstraZeneca and Sanofi; grants from Boehringer Ingelheim, GlaxoSmithKline, and Novartis; and personal fees from Pieris and UpToDate outside the submitted work. E. Israel reports personal fees from AstraZeneca, Novartis, Philips Respironics, Regeneron Pharmaceuticals, TEVA Specialty Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Sanofi, Merck, Entrinsic Health Solutions, and GlaxoSmithKline and other support from Vorso Corp, Pneuma Respiratory, and 4D Pharma; grants from Genentech, Sanofi, and Boehringer Ingelheim; and nonfinancial support from Boehringer Ingelheim, GlaxoSmithKline, Merck, Sunovion, TEVA, TEVA Specialty Pharmaceuticals outside the submitted work. The rest of the articles declare that they have no relevant conflicts of interest. We thank the following coordinators and staff for their enthusiasm and determination to completing this project and manuscript: Nicole Grossman, Wanda Phipatanakul, Brittney Dioneda, Nicolas Fandino, William Gallop, Waheed Khan, Carrie Nettles, Mobolaji Odewole, Gabriela Sauza, Thomas Voigt, Camille Yongue, Jessica Yu, Pedro Avila, Ravi Kalhan, Sharon Rosenberg, Jenny Hixon, Lucius Robinson, Edward Naureckas, Jerrica Hill, Niloofar Shirkhodaei, Leidy Gutierrez, Byung Yu, AnnaMaria Kayaloglou, Grace Li, Samantha Zitzer, Ryan Dunn, James Good, Richard Martin, Mary Gill, Allen Stevens, Loren Denlinger, Nizar Jarjour, Julia Bach, Jennifer Bagley, Barbara Miller, Ann Sexton, Cindi Baffi, Merritt Fajt, Marc Gauthier, Russel Traister, Melissa Ilnicki, Jenelle Mock, Chase Hall, Junfang Jiao, Abhaya Trivedi, Vanessa Curtis, Brenda Patterson, Cheryl Shelton, Kelly True, Shanti Chodagiri, Kelly Norsworthy, Julian Silva, Cristine Berry, Christian Bime, Tara Carr, Mark Goforth, Jamie Goodwin, Ashish Mathur, Argelia Benavides, Valerie Bloss, Samantha Castro, Czarina Cooper, Sarah David, Silvia Lopez, Marisol Posada, Natalie Provencio, Elizabeth Ryan, Ronald Schunk, Faryal Shareef, Jesus Wences, Eugene Bleecker, and Cheryl Wilmoth. We also thank and acknowledge Shamsah Kazani for her ideas that contributed to this trial's inception (while being an AsthmaNet investigator from Brigham and Women's Hospital). Finally, we thank all the trial participants and their families for their time, patience, and commitment. Supported by grants HL098102, U10HL098096, UL1TR000150, UL1TR000430, UL1TR000050, HL098075, UL1TR001082, HL098090, HL098177, UL1TR000439, HL098098, UL1TR000448, HL098107, HL098112, HL098103, UL1TR000454, and HL098115 awarded by the National Heart, Lung, and Blood Institute. Disclosure of potential conflict of interest: J. C. Cardet reports grants from the National Institute of Allergy and Infectious Diseases (NIAID) during the conduct of the study and Castro reports grants from the National Institutes of Health (NIH) and American Lung Association (ALA) during the conduct of the study; personal fees from Aviragen, Boehringer Ingelheim, Boston Scientific, Elsevier, Genentech, GlaxoSmithKline, Holaira, and Teva; and grants from Amgen, Boehringer Ingelheim, Genentech, Gilead, GlaxoSmithKline, Invion, MedImmune, sanofi-aventis, and Vectura all outside the submitted work. V. M. Chinchilli, S. Lazarus, and S. P. report grants from NIH/ National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study. A.-M. Dyer reports grants from the NHLBI during the conduct of the study. M. Kraft reports grants from the NIH, Roche, Sanofi, and Chiesi and other support from TEVA, AstraZeneca, and Elsevier outside the submitted work. R. F. Lemanske reports grants from the NHLBI during the conduct of the study; nonfinancial support from the American Academy of Allergy, Asthma & Immunology AAAAI; grants from a Clinical and Translational Science Award from the NIH; personal fees from LSU, Elsevier, and UpToDate; and grants from the Childhood Origins of Asthma (COAST) study and AsthmaNet outside the submitted work. N. Lugogo reports personal fees from AstraZeneca and consulting fees from TEVA outside the submitted work. D. Mauger reports grants from the NIH during the conduct of the study and nonfinancial support from GlaxoSmithKline, Merck, and TEVA outside the submitted work. W. C. Moore reports grants from the NIH/ NHLBI during the conduct of the study; grants and personal fees from AstraZeneca and Sanofi Regeneron; and grants from Boehringer Ingelheim, GlaxoSmithKline, and Pearl Therapeutics, Novartis outside the submitted work. J. Solway reports consulting fees from Sanofi, Genzyme, and Regeneron and gifts from the Rafael Rivera III Memorial Foundation for Asthma Research to the University of Chicago that were designated for asthma research in his laboratory. M. E. Wechsler reports personal fees from AstraZeneca, BSCI, Novartis, Vectura, Regeneron, Genentech, Sentien, and Boehringer Ingelheim and grants and personal fees from Teva, GlaxoSmithKline, and Sanofi all outside the submitted work. S. Wenzel reports grants and personal fees from AstraZeneca and Sanofi; grants from Boehringer Ingelheim, GlaxoSmithKline, and Novartis; and personal fees from Pieris and UpToDate outside the submitted work. E. Israel reports personal fees from AstraZeneca, Novartis, Philips Respironics, Regeneron Pharmaceuticals, TEVA Specialty Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Sanofi, Merck, Entrinsic Health Solutions, and GlaxoSmithKline and other support from Vorso Corp, Pneuma Respiratory, and 4D Pharma; grants from Genentech, Sanofi, and Boehringer Ingelheim; and nonfinancial support from Boehringer Ingelheim, GlaxoSmithKline, Merck, Sunovion, TEVA, TEVA Specialty Pharmaceuticals outside the submitted work. The rest of the articles declare that they have no relevant conflicts of interest. Supported by grants HL098102, U10HL098096, UL1TR000150, UL1TR000430, UL1TR000050, HL098075, UL1TR001082, HL098090, HL098177, UL1TR000439, HL098098, UL1TR000448, HL098107, HL098112, HL098103, UL1TR000454, and HL098115 awarded by the National Heart, Lung, and Blood Institute.Disclosure of potential conflict of interest: J. C. Cardet reports grants from the National Institute of Allergy and Infectious Diseases (NIAID)during the conduct of the study and Castro reports grants from the National Institutes of Health (NIH)and American Lung Association (ALA)during the conduct of the study; personal fees from Aviragen, Boehringer Ingelheim, Boston Scientific, Elsevier, Genentech, GlaxoSmithKline, Holaira, and Teva; and grants from Amgen, Boehringer Ingelheim, Genentech, Gilead, GlaxoSmithKline, Invion, MedImmune, sanofi-aventis, and Vectura all outside the submitted work. V. M. Chinchilli, S. Lazarus, and S. P. report grants from NIH/National Heart, Lung, and Blood Institute (NHLBI)during the conduct of the study. A.-M. Dyer reports grants from the NHLBI during the conduct of the study. M. Kraft reports grants from the NIH, Roche, Sanofi, and Chiesi and other support from TEVA, AstraZeneca, and Elsevier outside the submitted work. R. F. Lemanske reports grants from the NHLBI during the conduct of the study; nonfinancial support from the American Academy of Allergy, Asthma & Immunology AAAAI; grants from a Clinical and Translational Science Award from the NIH; personal fees from LSU, Elsevier, and UpToDate; and grants from the Childhood Origins of Asthma (COAST)study and AsthmaNet outside the submitted work. N. Lugogo reports personal fees from AstraZeneca and consulting fees from TEVA outside the submitted work. D. Mauger reports grants from the NIH during the conduct of the study and nonfinancial support from GlaxoSmithKline, Merck, and TEVA outside the submitted work. W. C. Moore reports grants from the NIH/NHLBI during the conduct of the study; grants and personal fees from AstraZeneca and Sanofi Regeneron; and grants from Boehringer Ingelheim, GlaxoSmithKline, and Pearl Therapeutics, Novartis outside the submitted work. J. Solway reports consulting fees from Sanofi, Genzyme, and Regeneron and gifts from the Rafael Rivera III Memorial Foundation for Asthma Research to the University of Chicago that were designated for asthma research in his laboratory. M. E. Wechsler reports personal fees from AstraZeneca, BSCI, Novartis, Vectura, Regeneron, Genentech, Sentien, and Boehringer Ingelheim and grants and personal fees from Teva, GlaxoSmithKline, and Sanofi all outside the submitted work. S. Wenzel reports grants and personal fees from AstraZeneca and Sanofi; grants from Boehringer Ingelheim, GlaxoSmithKline, and Novartis; and personal fees from Pieris and UpToDate outside the submitted work. E. Israel reports personal fees from AstraZeneca, Novartis, Philips Respironics, Regeneron Pharmaceuticals, TEVA Specialty Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Sanofi, Merck, Entrinsic Health Solutions, and GlaxoSmithKline and other support from Vorso Corp, Pneuma Respiratory, and 4D Pharma; grants from Genentech, Sanofi, and Boehringer Ingelheim; and nonfinancial support from Boehringer Ingelheim, GlaxoSmithKline, Merck, Sunovion, TEVA, TEVA Specialty Pharmaceuticals outside the submitted work. The rest of the articles declare that they have no relevant conflicts of interest. We thank the following coordinators and staff for their enthusiasm and determination to completing this project and manuscript: Nicole Grossman, Wanda Phipatanakul, Brittney Dioneda, Nicolas Fandino, William Gallop, Waheed Khan, Carrie Nettles, Mobolaji Odewole, Gabriela Sauza, Thomas Voigt, Camille Yongue, Jessica Yu, Pedro Avila, Ravi Kalhan, Sharon Rosenberg, Jenny Hixon, Lucius Robinson, Edward Naureckas, Jerrica Hill, Niloofar Shirkhodaei, Leidy Gutierrez, Byung Yu, AnnaMaria Kayaloglou, Grace Li, Samantha Zitzer, Ryan Dunn, James Good, Richard Martin, Mary Gill, Allen Stevens, Loren Denlinger, Nizar Jarjour, Julia Bach, Jennifer Bagley, Barbara Miller, Ann Sexton, Cindi Baffi, Merritt Fajt, Marc Gauthier, Russel Traister, Melissa Ilnicki, Jenelle Mock, Chase Hall, Junfang Jiao, Abhaya Trivedi, Vanessa Curtis, Brenda Patterson, Cheryl Shelton, Kelly True, Shanti Chodagiri, Kelly Norsworthy, Julian Silva, Cristine Berry, Christian Bime, Tara Carr, Mark Goforth, Jamie Goodwin, Ashish Mathur, Argelia Benavides, Valerie Bloss, Samantha Castro, Czarina Cooper, Sarah David, Silvia Lopez, Marisol Posada, Natalie Provencio, Elizabeth Ryan, Ronald Schunk, Faryal Shareef, Jesus Wences, Eugene Bleecker, and Cheryl Wilmoth. We also thank and acknowledge Shamsah Kazani for her ideas that contributed to this trial's inception (while being an AsthmaNet investigator from Brigham and Women's Hospital). Finally, we thank all the trial participants and their families for their time, patience, and commitment. Supported by grants HL098102 , U10HL098096 , UL1TR000150 , UL1TR000430 , UL1TR000050 , HL098075 , UL1TR001082 , HL098090 , HL098177 , UL1TR000439 , HL098098 , UL1TR000448 , HL098107 , HL098112 , HL098103 , UL1TR000454 , and HL098115 awarded by the National Heart, Lung, and Blood Institute .

Keywords

bisphosphonate
bronchoprotection
controller therapy
downregulation
loss of bronchoprotection
salmeterol
β-Adrenergic receptor
β-agonists

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.jaci.2019.01.049

Cite this

@article{15f65541be3b4a839148477af9169710,

title = "Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate",

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 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.",

keywords = "bisphosphonate, bronchoprotection, controller therapy, downregulation, loss of bronchoprotection, salmeterol, β-Adrenergic receptor, β-agonists",

author = "{AsthmaNet Investigators} and Cardet, {Juan Carlos} and Xiaofeng Jiang and Quan Lu and N. Gerard and Kristen McIntire and Boushey, {Homer A.} and M. Castro and Chinchilli, {Vernon M.} and Codispoti, {Christopher D.} and Dyer, {Anne Marie} and Fernando Holguin and Monica Kraft and Stephen Lazarus and Lemanske, {Robert F.} and N. Lugogo and Dave Mauger and Moore, {Wendy C.} and J. Moy and Ortega, {Victor E.} and Peters, {Stephen P.} and Smith, {Lewis J.} and Julian Solway and Sorkness, {Christine A.} and Kaharu Sumino and Wechsler, {Michael E.} and S. Wenzel and Elliot Israel",

note = "Publisher Copyright: {\textcopyright} 2019 American Academy of Allergy, Asthma & Immunology",

year = "2019",

month = aug,

doi = "10.1016/j.jaci.2019.01.049",

language = "English (US)",

volume = "144",

pages = "416--425.e7",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "2",

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TY - JOUR

T1 - Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate

AU - AsthmaNet Investigators

AU - Cardet, Juan Carlos

AU - Jiang, Xiaofeng

AU - Lu, Quan

AU - Gerard, N.

AU - McIntire, Kristen

AU - Boushey, Homer A.

AU - Castro, M.

AU - Chinchilli, Vernon M.

AU - Codispoti, Christopher D.

AU - Dyer, Anne Marie

AU - Holguin, Fernando

AU - Kraft, Monica

AU - Lazarus, Stephen

AU - Lemanske, Robert F.

AU - Lugogo, N.

AU - Mauger, Dave

AU - Moore, Wendy C.

AU - Moy, J.

AU - Ortega, Victor E.

AU - Peters, Stephen P.

AU - Smith, Lewis J.

AU - Solway, Julian

AU - Sorkness, Christine A.

AU - Sumino, Kaharu

AU - Wechsler, Michael E.

AU - Wenzel, S.

AU - Israel, Elliot

PY - 2019/8

Y1 - 2019/8

N2 - 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.

AB - 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.

KW - bisphosphonate

KW - bronchoprotection

KW - controller therapy

KW - downregulation

KW - loss of bronchoprotection

KW - salmeterol

KW - β-Adrenergic receptor

KW - β-agonists

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U2 - 10.1016/j.jaci.2019.01.049

DO - 10.1016/j.jaci.2019.01.049

M3 - Article

C2 - 30872116

AN - SCOPUS:85065788317

SN - 0091-6749

VL - 144

SP - 416-425.e7

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 2

ER -

Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate

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