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

骨质疏松症是一种衰老疾病，可导致约 200 万例骨折和约 170 亿美元的医疗费用 每年。尽管 FDA 批准了多种药物用于治疗骨质疏松症，但潜在的严重后果 副作用（例如颌骨坏死、非典型股骨骨折）导致大多数医生使用这些药物 药物只能治疗骨质疏松症，不能预防骨质疏松症。这就导致了现在的局面 大多数绝经后妇女必须等到她们出现明显的骨质疏松症（即骨折，或充分 高骨折风险）开始药物治疗。因此，迫切需要新颖的、相对低风险的和 预防骨质疏松症的低成本药理学方法。 目前的提案旨在转化啮齿动物研究的证据，表明交感神经 系统（SNS）是骨代谢的重要调节剂，是一种简单、经济且安全的方法 预防骨质疏松症。在关键的初步数据中，我们获得了多方面的证据来明确确定 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”介入研究证明β1选择性阻滞剂（阿替洛尔、奈必洛尔），但不是非 选择性 β-AR 阻滞剂（普萘洛尔），对骨转换和骨矿物质密度 (BMD) 有良好影响 在绝经后妇女中。根据这些数据，我们将进行一项随机、双盲、安慰剂试验 为期 2 年的对照临床试验，旨在解决以下具体目标：(1) 检验治疗的假设 与广泛使用、廉价且相对 β1 选择性阻滞剂（阿替洛尔）一起使用可防止骨质流失 双能 X 线骨密度仪对 420 名绝经后妇女的腰椎和股骨颈进行评估 先前没有骨质疏松症的女性（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（目标 1b）。 (2)评价阿替洛尔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（目标 2a）在骨上构建骨微结构 转换标记（目标 2b），并测试骨转换或交感神经活动的基线测量 （静息心率、血浆儿茶酚胺水平）可预测 2 年内对阿替洛尔的 BMD 反应 （目标 2c）。 (3) 在一部分患者中，探索影响的潜在分子和细胞机制 通过对从骨中分离的成骨细胞群进行分析，研究β1对人类骨的选择性阻断 活检以及四重标记骨活检的组织水平骨形成率（目标 3）。 拟议的研究将严格测试阿替洛尔是否有效且安全地预防 绝经后妇女骨质疏松症的研究，并进一步明确了 SNS 对骨质疏松症的影响机制 人类。如果我们提出的临床试验证明可以通过以下方式保护绝经后妇女免受骨质流失 阿替洛尔，这将满足关键的临床需求，因为这些女性目前几乎没有药物 预防骨质疏松症的选择。

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.