Beta1-selective blockade for prevention of postmenopausal bone loss: A randomized controlled trial

选择性阻断 Beta1 预防绝经后骨质流失：一项随机对照试验

• 批准号: 10321957
• 负责人: Dennis M Black
• 金额: $ 240.56万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10321957
• 关键词: Address; Affect; Aging; American; Atenolol; Biopsy; Bone Density; Bone Resorption; Bone necrosis; Cardiovascular Agents; Catecholamines; Clinical; Clinical Trials; Data; Development; Disease; Distal; Dose; Double-Blind Method; Drug usage; Dual-Energy X-Ray Absorptiometry; FDA approved; Femoral Fractures; Femur; Fracture; Health Care Costs; Heart Rate; Human; Individual; Intervention; Intervention Studies; Jaw; Knock-out; Label; Left; Measures; Messenger RNA; Metoprolol; Molecular; Mus; Neck; Osteoblasts; Osteogenesis; Osteopenia; Osteoporosis; Osteoporosis prevention; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physicians; Placebo Control; Placebos; Plasma; Play; Population; Population Study; Postmenopausal Osteoporosis; Postmenopause; Premenopause; Prevention; Propranolol; Radial; Randomized; Randomized Controlled Trials; Resolution; Rest; Risk; Rodent; Rodent Model; Role; Safety; Serum; Sympathetic Nervous System; Syndrome; Testing; Tissues; Translating; Vertebral column; Woman; X-Ray Computed Tomography; antagonist; base; beta-2 Adrenergic Receptors; bone; bone loss; bone metabolism; bone turnover; clinically significant; cortical bone; cost; cost effective; fracture risk; high risk; human old age (65+); novel; novel strategies; osteoporosis with pathological fracture; patient subsets; prevent; radius bone structure; receptor; response; side effect; skeletal; substantia spongiosa; tibia; transcriptome sequencing; treatment group; trend; virtual

Osteoporosis is a disease of aging that leads to ~2 million fractures and ~$17 billion in healthcare costs annually. Although several drugs are FDA-approved for the treatment of osteoporosis, the potential for serious side effects (e.g., osteonecrosis of the jaw, atypical femur fractures) has led most physicians to use these drugs only for the treatment, but not the prevention, of osteoporosis. This has led to the current situation where most postmenopausal women must wait until they develop frank osteoporosis (i.e., fractures, or sufficiently high fracture risk) to begin drug therapy. As such, there is a compelling need for novel, relatively low-risk and low-cost pharmacological approaches to prevent osteoporosis. The current proposal aims to translate evidence from rodent studies showing that the sympathetic nervous system (SNS) is an important regulator of bone metabolism to a simple, cost-effective, and safe approach for osteoporosis prevention. In key Preliminary Data, we obtained multiple lines of evidence to establish clearly the role of the SNS in regulating human bone metabolism. A critical component of these data was a “proof-of- concept” interventional study demonstrating that β1-selective blockers (atenolol, nebivolol), but not a non- selective β-AR blocker (propranolol), have favorable effects on bone turnover and bone mineral density (BMD) in postmenopausal women. Based on these data, we will perform a randomized, double-blind, placebo- controlled 2 year clinical trial addressing the following Specific Aims: (1) Test the hypothesis that treatment with a widely used, inexpensive, and relatively β1-selective blocker (atenolol) will prevent bone loss at the lumbar spine and femur neck as assessed by dual-energy X-ray absorptiometry in 420 postmenopausal women without pre-existing osteoporosis (Aim 1a); and evaluate the tolerability and safety of atenolol when used for the prevention of bone loss (Aim 1b). (2) Evaluate the effects of atenolol on trabecular and cortical bone microarchitecture using high resolution-peripheral quantitative computed tomography (Aim 2a), on bone turnover markers (Aim 2b), and test whether baseline measures of bone turnover or of sympathetic activity (resting heart rate, plasma catecholamine levels) are predictive of the BMD response to atenolol over 2 years (Aim 2c). (3) In a subset of patients, explore the underlying molecular and cellular mechanisms for the effects of β1-selective blockade on bone in humans using analyses of osteoblast populations isolated from bone biopsies as well as tissue-level bone formation rates on quadruple-labelled bone biopsies (Aim 3). The proposed studies will rigorously test whether atenolol is efficacious and safe for the prevention of osteoporosis in postmenopausal women and also further define the mechanisms of SNS effects on bone in humans. If our proposed clinical trial demonstrates protection from bone loss in postmenopausal women by atenolol, this would fill a crucial clinical need, as these women currently have virtually no pharmacological options for osteoporosis prevention.

骨质疏松症是一种衰老性疾病，导致约200万例骨折和约170亿美元的医疗费用 每年。虽然有几种药物是FDA批准用于治疗骨质疏松症，但严重的潜在风险是， 副作用（例如，颌骨骨坏死，非典型股骨骨折）导致大多数医生使用这些 仅用于治疗而非预防骨质疏松症的药物。这导致了目前的局面， 大多数绝经后妇女必须等到她们发展出明显的骨质疏松症（即，骨折，或充分 高骨折风险）来开始药物治疗。因此，迫切需要新颖的、相对低风险的且 低成本的药理学方法来预防骨质疏松症。 目前的建议旨在翻译啮齿动物研究的证据，表明交感神经 系统（SNS）是一种重要的骨代谢调节剂，是一种简单、经济、安全的方法， 骨质疏松症的预防在关键的初步数据中，我们获得了多条证据，以明确地建立 SNS在调节人体骨代谢中的作用。这些数据的一个关键组成部分是“证明- 概念”干预性研究表明，β1-选择性阻滞剂（阿替洛尔，奈必洛尔），而不是非 选择性β-AR阻滞剂（普萘洛尔），对骨转换和骨密度（BMD）有良好的影响 在绝经后妇女中。基于这些数据，我们将进行一项随机、双盲、安慰剂- 对照的2年临床试验，解决以下具体目的：（1）测试假设，治疗 与广泛使用的，廉价的，相对β1-选择性阻滞剂（阿替洛尔）将防止骨丢失在 420例绝经后妇女腰椎和股骨颈双能X线骨密度测定 既往无骨质疏松症的女性（目标1a）;并评估阿替洛尔的耐受性和安全性， 用于预防骨质流失（目的1b）。(2)评价阿替洛尔对小梁和皮质的影响 使用高分辨率外周定量计算机断层扫描（Aim 2a）对骨进行骨微结构分析 转换标志物（目标2b），并测试是否基线测量骨转换或交感神经活动 （静息心率、血浆儿茶酚胺水平）可预测阿替洛尔治疗2年后的BMD反应 (Aim 2c）。(3)在一个患者子集中，探索影响的潜在分子和细胞机制 β1-选择性阻滞剂对人体骨的作用，使用从骨中分离的成骨细胞群的分析 活组织检查以及四重标记骨活组织检查的组织水平骨形成率（目的3）。 拟议的研究将严格测试阿替洛尔是否有效和安全地预防 绝经后妇女的骨质疏松症，并进一步确定SNS对骨的作用机制， 人类如果我们提出的临床试验证明， 阿替洛尔，这将填补一个关键的临床需求，因为这些妇女目前几乎没有药理学 预防骨质疏松症的选择。