Lary Christine W, Atkinson Elizabeth J, Spillane Jennifer, Nayema Zannatun, Roy Tyler A, Peters Rebecca, Scott Griffin T, Chen Hongyu, Nagarajan Archana, Brown Aaron, Motyl Katherine J, Monroe David G, Khosla Sundeep
Roux Institute at Northeastern University, Department of Public Health and Health Sciences, Portland, ME 04101, United States.
MaineHealth Institute for Research, Center for Molecular Medicine, Scarborough, ME 04074, United States.
J Bone Miner Res. 2025 Feb 2;40(2):231-240. doi: 10.1093/jbmr/zjae200.
Motivated by studies showing an association between beta blocker (BB) use and positive bone outcomes, a pilot randomized control trial was performed at the Mayo Clinic which randomized postmenopausal women to placebo, propranolol (40 or 80 mg twice daily), atenolol (50 mg/d), or nebivolol (5 mg/d) to determine changes in bone turnover markers (BTMs) and in BMD over 20 wk. Pharmacogenetic effects and microRNA-mediated mechanisms involving beta adrenergic receptor and related genes have previously been found. We sought to validate these effects and discover new candidates in an ancillary study to the pilot clinical trial. We genotyped all participants and performed microRNA (miRNA) sequencing at baseline and at 20 wk for 24 participants from the atenolol or placebo groups. We discovered several variants in ADRB1, ADRB2, and HDAC4 which showed significant pharmacogenetic effects with BMD at multiple sites and with BTMs. Our miRNA results showed a significant treatment effect for miR-19a-3p over time with atenolol use in the low-responder group compared to placebo. Overall, the longitudinal miRNA analysis showed a large number of miRNAs which were up-regulated over the trial in the low responders but not the high responders compared to placebo, of which miR-19a-3p was one example. Finally, we compared the response to atenolol treatment for cardiovascular traits (pulse and blood pressure) with the response for the bone resorption marker, C-terminal telopeptide, and found a largely independent effect. Our results have implications for personalized therapy and for understanding mechanisms of BB treatment effect on bone.
鉴于有研究表明β受体阻滞剂（BB）的使用与积极的骨骼结果之间存在关联，梅奥诊所开展了一项先导性随机对照试验，将绝经后女性随机分为安慰剂组、普萘洛尔组（40或80毫克，每日两次）、阿替洛尔组（50毫克/天）或奈必洛尔组（5毫克/天），以确定20周内骨转换标志物（BTM）和骨密度（BMD）的变化。此前已发现涉及β肾上腺素能受体及相关基因的药物遗传学效应和微小RNA介导的机制。我们试图在该先导性临床试验的一项辅助研究中验证这些效应并发现新的候选因素。我们对所有参与者进行了基因分型，并在基线和20周时对来自阿替洛尔或安慰剂组的24名参与者进行了微小RNA（miRNA）测序。我们在ADRB1、ADRB2和HDAC4中发现了几个变体，这些变体在多个部位的骨密度和骨转换标志物方面显示出显著的药物遗传学效应。我们的miRNA结果显示，与安慰剂相比，低反应组使用阿替洛尔后，miR-19a-3p随时间有显著的治疗效果。总体而言，纵向miRNA分析显示，与安慰剂相比，在试验过程中，低反应者中有大量miRNA上调，而高反应者中则没有，miR-19a-3p就是其中一个例子。最后，我们比较了阿替洛尔治疗对心血管特征（脉搏和血压）的反应与对骨吸收标志物C端肽的反应，发现两者在很大程度上是独立的效应。我们的结果对个性化治疗以及理解BB治疗对骨骼的作用机制具有启示意义。
