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


ABSTRACT: BACKGROUND:Loss of bronchoprotection (LOBP) with a regularly used long-acting ?2-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to ?2-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 ?g 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.

SUBMITTER: Cardet JC 

PROVIDER: S-EPMC6950766 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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<h4>Background</h4>Loss of bronchoprotection (LOBP) with a regularly used long-acting β<sub>2</sub>-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β<sub>2</sub>-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate.<h4>Objective</h4>We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients.<h4>Methods</h4>We conducted a randomized, double  ...[more]

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