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

AsthmaNet Investigators

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 languageEnglish (US)
Pages (from-to)416-425.e7
JournalJournal of Allergy and Clinical Immunology
Volume144
Issue number2
DOIs
StatePublished - Aug 1 2019

Fingerprint

Alendronate
Adrenal Cortex Hormones
Adrenergic Receptors
Placebos
Methacholine Chloride
Therapeutics
Down-Regulation
Prenylation
Adrenergic Agonists
Radioligand Assay
Random Allocation
Cyclic AMP
Asthma
Enzyme-Linked Immunosorbent Assay
Lung
Salmeterol Xinafoate

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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",
year = "2019",
month = "8",
day = "1",
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",

}

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

In: Journal of Allergy and Clinical Immunology, Vol. 144, No. 2, 01.08.2019, p. 416-425.e7.

Research output: Contribution to journalArticle

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 - 2019/8/1

Y1 - 2019/8/1

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

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SP - 416-425.e7

JO - Journal of Allergy and Clinical Immunology

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