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的疾病，可导致约200万个骨折和约170亿美元的医疗费用 尽管几种药物是FDA批准用于治疗骨质疏松症的，但可能会严重 副作用（例如，下颌的骨坏死，非典型股骨骨折）已导致大多数医生使用这些 仅用于治疗的药物，但不用于预防骨质疏松症。这导致了当前的情况 大多数绝经后妇女必须等到他们发展坦率的骨质疏松症（即骨折或足够的骨折 高骨折风险）开始药物治疗。因此，对新颖，相对较低的风险和 低成本药物预防骨质疏松症。 当前的提案旨在翻译啮齿动物研究的证据，表明交感神经 系统（SNS）是对简单，成本效益且安全的方法的骨骼代谢的重要调节剂 预防骨质疏松症。在关键的初步数据中，我们获得了多种证据，以清楚地确定 SN在控制人骨代谢中的作用。这些数据的关键组成部分是“证明 概念”的介入研究表明，β1选择性阻滞剂（阿替洛尔，奈比洛尔），但不是非 - 选择性β-AR阻滞剂（普萘洛尔），对骨骼更新和骨矿物质密度（BMD）具有有利的影响 在绝经后妇女中。基于这些数据，我们将执行随机，双盲的安慰剂 - 控制的2年临床试验解决以下特定目的：（1）检验以下假设： 具有广泛使用，廉价且相对于β1选择性阻滞剂（atenolol）的使用，将防止在 腰椎腰椎和股骨颈部通过双能X射线绝对肽段评估420绝经后的绝经 妇女没有预先存在的骨质疏松症（AIM 1A）；并评估Atelol的耐受性和安全性 用于预防骨质流失（AIM 1B）。 （2）评估Atelol对小梁和皮质的影响 使用高分辨率 - 外围定量计算机断层扫描（AIM 2A）的骨微体系结构 营业额标记（AIM 2B），并测试骨骼周转或交感性活动的基线测量 （静息心率，血浆儿茶酚胺水平）可预测2年内对乙洛尔的BMD反应 （AIM 2C）。 （3）在一部分患者中，探索潜在的分子和细胞机制以产生影响 使用从骨头分离的成骨细胞种群的分析，在人类骨骼上的β1选择性阻滞 在四倍标记的骨骼活检的活检以及组织水平的骨形成率（AIM 3）。 拟议的研究将严格测试Atelol是否有效且安全可预防 绝经后妇女的骨质疏松症，还进一步定义了社交媒体对骨骼影响的机制 人类。如果我们提出的临床试验证明了通过 atelol，这将满足至关重要的临床需求，因为这些女性目前几乎没有药理 预防骨质疏松症的选择。