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.

Trial registration: ClinicalTrials.gov NCT02230332.

Keywords: bisphosphonate; bronchoprotection; controller therapy; downregulation; loss of bronchoprotection; salmeterol; β(2)-Adrenergic receptor; β(2)-agonists.

Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Figures

FIG 1.

ALfA trial study schema: ex vivo B2AR assays were conducted on PBMCs. These included radioligand binding assays to quantify B2AR cell-surface density and cAMP ELISAs to measure B2AR intracellular signaling. MCh, Methacholine challenge; SPMCh, modified methacholine challenge in which participants receive 2 puffs of open-label fluticasone/salmeterol (115/21 μg) 1 hour before the start of the challenge.

FIG 2.

Participant flow diagram.

FIG 3.

Effect of alendronate and placebo on SPMCh PC20 values: change in SPMCh PC20 values from visit 2 to visit 3 for placebo and alendronate groups. Geometric means, 95% CIs, and P values from blocked ANOVAs are presented. MCh, Methacholine challenge.

FIG 4.

Effect of alendronate on change in PBMC B2AR cell-surface density. A, Change in PBMC B2AR cell-surface density (determined by radioligand binding assay) from visit 2 to visit 3 for the placebo and alendronate groups. Geometric means, 95% CIs, and P values from blocked ANOVAs are presented. B, Correlation between change in PBMC B2AR cell-surface density and SPMCh PC20 doubling dose dilutions from visit 2 to visit 3. Pearson correlation coefficients and P values are presented for the alendronate and placebo groups, respectively.

FIG 5.

Effect of alendronate on change in PBMC B2AR cell signaling (change in intracellular cAMP levels). A, Change in PBMC B2AR signaling (determined by using a cAMP ELISA) from visit 2 to visit 3 for the placebo and alendronate groups, as determined by using agonist-stimulated intracellular cAMP levels. Geometric means, 95% CIs, and P values from blocked ANOVA are presented. B, Correlation between change in PBMC B2AR signaling and SPMCh PC20 doubling dose dilutions from visit 2 to visit 3. Pearson correlation coefficients and P values are presented for the alendronate and placebo groups, respectively. ISO, Isoproterenol.