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

Abstract

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. We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients. We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250μg of fluticasone twice daily for 2weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC20 value. 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. 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.