Department of Medicine, Brigham and Women's Hospital, Boston, Mass.
Departments of Environmental Health, Genetics & Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Mass.
J Allergy Clin Immunol. 2019 Aug;144(2):416-425.e7. doi: 10.1016/j.jaci.2019.01.049. Epub 2019 Mar 11.
Loss of bronchoprotection (LOBP) with a regularly used long-acting β-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β-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 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 PC value.
The mean doubling dose reduction in SPMCh PC 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.
长效β-肾上腺素能受体激动剂（LABA）的支气管保护作用丧失（LOBP）已有充分记录。LOBP 归因于 β-肾上腺素能受体（B2AR）下调，这一过程需要法尼酰化，而阿仑膦酸钠可抑制法尼酰化。
我们旨在确定阿仑膦酸钠是否可以减少吸入皮质类固醇（ICS）治疗患者中与 LABA 相关的 LOBP。
我们进行了一项随机、双盲、安慰剂对照、平行设计的概念验证试验。78 名持续性哮喘患者接受 250μg 氟替卡松每天两次治疗 2 周后，随机接受阿仑膦酸钠或安慰剂，同时接受沙美特罗治疗 8 周。在随机分组前和 ICS 加 LABA 治疗 8 周后评估沙丁胺醇保护的乙酰甲胆碱挑战（SPMCh）和 PBMC B2AR 数量（放射性配体结合测定）和信号（环 AMP ELISA）。LOBP 的定义为 SPMCh PC 值减少超过 1 倍。
阿仑膦酸钠组 SPMCh PC 值的平均倍增剂量减少为 0.50，安慰剂组为 0.27（P=.62）。阿仑膦酸钠组有 38%的参与者和安慰剂组有 33%的参与者出现 LOBP（P=.81）。ICS 加 LABA 治疗后/前 B2AR 数量的比值为阿仑膦酸钠组 1.0（P=.86），安慰剂组 0.8（P=.15；治疗组间差异 P=.31）。阿仑膦酸钠组的 B2AR 信号比值为 0.89（P=.43），安慰剂组为 1.02（P=.84；治疗组间差异 P=.44）。出现和未出现 LOBP 的患者的肺功能和 B2AR 数量及信号变化相似。
本研究未发现阿仑膦酸钠可降低与 LABA 相关的 LOBP 的证据，这与仅三分之一的参与者发生 LOBP 有关。LOBP 在同时接受 ICS 和 LABA 治疗的哮喘患者中似乎比预期的要少见。PBMC 中测量的 B2AR 下调似乎与 LOBP 无关。
