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

骨质疏松症是一种老年性疾病，导致约200万人骨折，医疗费用约为170亿美元 每年一次。尽管有几种药物被FDA批准用于治疗骨质疏松症，但严重的 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 只用于治疗而不是预防骨质疏松症的药物。这导致了目前的情况， 大多数绝经后妇女必须等到她们出现明显的骨质疏松症(即骨折或足够 高骨折风险)开始药物治疗。因此，迫切需要新颖、相对低风险和 预防骨质疏松症的低成本药理方法。 目前的提案旨在翻译来自啮齿动物研究的证据，该证据表明，交感神经 系统(SNS)是骨代谢的重要调节器，是一种简单、经济、安全的治疗方法 预防骨质疏松症。在关键的初步数据中，我们获得了多条证据，以明确确立 SNS在调节人体骨代谢中的作用。这些数据的一个重要组成部分就是“证据-- 概念性干预研究显示β-1选择性阻滞剂(阿替洛尔、奈比洛尔)，而不是非 选择性β-AR阻滞剂心得安对骨转换和骨密度有良好作用 在绝经后妇女中。基于这些数据，我们将进行随机、双盲、安慰剂- 针对以下特定目标的对照2年临床试验：(1)检验治疗的假设 使用一种广泛使用的、廉价的、相对β1选择性的阻滞剂(阿替洛尔)将防止 420例绝经后腰椎和股骨颈双能X线骨密度仪测量结果分析 无骨质疏松症的妇女(目标1a)；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 使用高分辨率外周定量计算机断层扫描(AIM 2a)的骨骼微结构 转换标志物(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年内阿替洛尔对骨密度的反应 (目标2c)。(3)在一组患者中，探索这些影响的潜在分子和细胞机制 应用骨分离成骨细胞群分析β-1对人骨骼的选择性阻断 四重标记骨活检的活检以及组织水平骨形成率(目标3)。 拟议的研究将严格测试阿替洛尔是否对预防高血压有效且安全。 并进一步明确SNS对绝经后妇女骨质疏松的作用机制。 人类。如果我们提议的临床试验证明通过以下方式保护绝经后妇女不会发生骨丢失 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.