Objectives

To determine whether alendronate can reduce long-acting β2-adrenergic receptor agonist-associated loss of bronchoprotection in inhaled corticosteroid–treated patients.

Background

Long-acting β2-adrenergic receptor agonists (LABAs) can be used to supplement inhaled corticosteroids (ICSs) in asthma patients with inadequately controlled symptoms. However a significant portion of patients still do not obtain adequate control using this treatment strategy. This may be due to the loss of bronchoprotection (LOBP) that can occur with regular LABA use, meaning the treatment has diminished capacity to protect against airway narrowing in response to bronchoconstrictors. At the time of the ALFA study, the mechanism causing LOBP was unknown, but thought to be related to β2-adrenergic receptor (B2AR) downregulation through internalization, B2AR phosphorylation by G protein–coupled receptor (GPCR) kinases, and/or uncoupling from the adenylyl cyclase-mediated signaling pathway, among other mechanisms. Previous in vitro research has found that alendronate prevents both BA-induced internalization and loss of functional activation, and may preserve bronchoprotection against acetylcholine after long-term BA exposure. Therefore, the ALFA study hypothesized that alendronate would reduce LOBP occurrence in asthma patients treated with ICSs and regularly administered LABAs. The study also aimed to identify the mechanism responsible for LOBP, explore the role of exhaled nitric oxide in predicting LOBP, and investigate salivary α-amylase as a potential biomarker for B2AR dynamics.

Participants

Adults with physician-diagnosed asthma were eligible to participate if they also met the following criteria: evidence of either bronchodilator reversibility (post-bronchodilator FEV1 ≥ 12%) or airway hyperresponsiveness (PC20 ≤ 8 mg/mL); FEV1 ≥ 50% of predicted and ≥ 1L; salmeterol-protected methacholine challenge (SPMCh) value < 16 mg/mL; and treated with stable ICS controller monotherapy for 4 or more weeks. 38 participants were enrolled in the alendronate treatment arm and 40 participants were enrolled in the placebo treatment arm.

Design

ALFA was a 10-week, randomized, double-blind, placebo-controlled, parallel-arm trial. Eligible participants were treated with 250 μg of fluticasone propionate twice daily during a 2-week run-in period and then randomized to receive either 10 mg/d oral alendronate or placebo with 250 μg of fluticasone propionate and 50 μg of salmeterol in a combination Diskus device twice daily for 8 weeks during the treatment phase. Prior asthma treatments (including short-acting β2-adrenergic receptor agonists) were discontinued to prevent potential confounding on B2AR dynamics. Participants used 17 μg per puff of ipratropium as a primary rescue inhaler during the study. SPMCh was used to assess LOBP at randomization and after 8 weeks of treatment. The primary outcome was change in SPMCh PC20 value after 8 weeks of treatment expressed as logarithm base 2.

Conclusions

This study did not find evidence that alendronate reduces LABA-associated LOBP. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients.

Cardet JC, Jiang X, Lu Q, et al. Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate. J Allergy Clin Immunol. 2019 Aug;144(2):416-425.e7. doi: 10.1016/j.jaci.2019.01.049. Epub 2019 Mar 11.

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