Novel Combination Therapy for Osteoporosis in Men

男性骨质疏松症的新型联合疗法

• 批准号: 10409693
• 负责人: DOLORES M. SHOBACK
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409693
• 关键词: Acute; Adult; Affect; Alendronate; American; Anabolic Agents; Biochemical; Bone Density; Bone structure; Calcium; Calcium-Sensing Receptors; Cell Lineage; Cells; Chronic; Clinical Trials; Collagen Type I; Combined Modality Therapy; Controlled Clinical Trials; Data; Death Rate; Diagnosis; Double-Blind Method; Drug usage; Estrogens; Excretory function; Forteo; Fracture; Goals; Health; Hip Fractures; Hip region structure; Hormonal; Hormone Receptor; Hour; Hyperparathyroidism; Injections; Investigation; Lead; Mesenchymal Stem Cells; Minerals; Morbidity - disease rate; Mus; N-terminal; Neck; Normal Range; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporotic; PTH gene; Parathyroid gland; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Placebo Control; Placebos; Plasma; Play; Postmenopause; Pre-Clinical Model; Randomized; Rattus; Recombinants; Regimen; Risedronate; Role; Safety; Serum; Serum Markers; Testing; Toxicology; Treatment Protocols; Vertebral column; Veterans; Woman; Work; base; bisphosphonate; bone; bone cell; bone mass; bone metabolism; bone strength; bone turnover; cell type; cinacalcet; design; disability; double-blind placebo controlled trial; extracellular; follow-up; fracture risk; high risk; improved; insight; male; man; men; microCT; mineralization; mortality; novel; optimal treatments; osteoblast differentiation; osteoporosis with pathological fracture; parathyroid hormone (1-34); parathyroid hormone-related protein; peptide hormone; pre-clinical; primary endpoint; receptor; recruit; response; screening; skeletal; stem cell differentiation; targeted treatment; treatment arm; treatment comparison; treatment strategy; urinary

In the US of the 1.5 million fractures that occur annually, one-third of them occur in men. Osteoporosis and fracture-related disability are key health problems in older male veterans. Fractures also increase mortality. Men who fracture their hips have twice the mortality of women sustaining those same hip fractures. Several drugs are approved to treat osteoporosis in men [bisphosphonates, denosumab, and teriparatide (TPTD) or PTH(1-34)], but we have little insight as to how to use them most effectively. TPTD has great appeal for treating osteoporosis in men because it substantially improves bone mass, rebuilds the microarchitecture, improves bone strength, and reduces fractures. Little is known about the best ways to employ TPTD in the treatment of male osteoporosis. Should it be used only as monotherapy or does concurrent or sequential use with other agents lead to the greatest benefit? The proposed clinical trial is an effort to test a novel combination therapy for osteoporosis in men based on exciting preclinical findings in mice. It is known that TPTD achieves its anabolic effects by stimulating PTH receptors (PTH-Rs) in cells of the osteoblast (OB) lineage. Calcimimetics mimic the effects of high extracellular calcium concentrations ([Ca]e) by activating Ca- sensing receptors (CaSRs) expressed in many cell types including OBs and osteoclasts in bone. Work by us and other groups have found that CaSRs in OBs play an important role in controlling bone formation, OB differentiation, and mineralization. In preclinical models in the lab, we found that daily injections of TPTD given concurrently with an investigational calcimimetic agent (NPS-R568) in just 6 weeks markedly increased bone mass and improved both trabecular and cortical microarchitecture of bone as assessed by both micro- computed tomography and histomorphometry in adult male mice. Based on these results, we propose to test the hypothesis that concurrent activation of PTH-Rs and CaSRs (TPTD+calcimimetic cinacalcet) in men with low bone mineral density (BMD) produces greater anabolic responses than PTH-R activation alone (TPTD+placebo). To test this hypothesis, we propose a randomized, double-blinded, {{placebo-controlled clinical trial in 48 men with low bone mass}}. We plan two treatment arms. Aim 1 will determine the effects of 11 months treatment with TPTD+cinacalcet compared to TPTD+placebo on BMD and bone metabolism in men with low bone mass. We will assess responses in: (a) lumbar spine (LS) BMD (primary endpoint) and femoral neck (FN) BMD; and (b) levels of the bone formation marker serum N-terminal pro-peptide of type 1 collagen (P1NP). Hypothesis 1a proposes that LS and FN BMD responses are greater with TPTD+cinacalcet compared to TPTD+placebo. Hypothesis 1b proposes that serum P1NP increases are greater with TPTD+cinacalcet compared to TPTD+placebo. Aim 2 will determine the pharmacodynamic responses to TPTD+cinacalcet and to TPTD+placebo treatment in men with low bone mass. We will assess: (a) acute and chronic changes in the serum [Ca] and plasma intact PTH after drug administration in a pharmacodynamic study in a subset of 24 men (12/treatment arm); and (b) changes in urinary Ca excretion with both treatment regimens {in all 48 randomized men}. Hypothesis 2a proposes that serum [Ca] does not decrease to > 5% below the lower limits of the normal range in response to the administration of combined TPTD+cinacalcet. Hypothesis 2b proposes that urinary Ca excretion does not exceed 350 mg per 24 hours in men treated chronically with TPTD+cinacalcet. Completion of this study will provide critical evidence to support the efficacy of a novel combination therapy that is designed to target the concurrent activation of CaSRs and PTH-Rs in bone to achieve greater skeletal anabolic effects with the ultimate goal of improving skeletal health and reducing the disability, morbidity, and mortality of osteoporotic fractures in male veterans.

在美国，每年发生 150 万例骨折，其中三分之一发生在男性。骨质疏松症和 骨折相关的残疾是老年男性退伍军人的主要健康问题。骨折也会增加死亡率。 髋部骨折的男性死亡率是同样髋部骨折女性的两倍。一些 批准用于治疗男性骨质疏松症的药物 [双磷酸盐、狄诺塞麦和特立帕肽 (TPTD) 或 PTH(1-34)]，但我们对如何最有效地使用它们知之甚少。 TPTD 具有巨大的吸引力 治疗男性骨质疏松症，因为它可以显着改善骨量，重建微结构， 提高骨骼强度，减少骨折。对于在环境中使用 TPTD 的最佳方法知之甚少。 治疗男性骨质疏松症。应该仅用作单一疗法还是同时或序贯使用 与其他代理商一起带来最大的效益？拟议的临床试验是为了测试一种新的 基于小鼠令人兴奋的临床前发现，针对男性骨质疏松症的联合疗法。据了解 TPTD 通过刺激成骨细胞 (OB) 中的 PTH 受体 (PTH-R) 实现合成代谢作用 血统。拟钙剂通过激活 Ca- 来模拟高细胞外钙浓度 ([Ca]e) 的影响 传感受体 (CaSR) 在许多细胞类型中表达，包括骨中的 OB 和破骨细胞。由我们工作 等小组发现OB中的CaSR在控制骨形成中发挥重要作用，OB 分异作用、矿化作用。在实验室的临床前模型中，我们发现每天注射 TPTD 与研究中的拟钙剂 (NPS-R568) 同时服用，在短短 6 周内显着增加 骨量并改善了骨的小梁和皮质微结构（通过微结构评估） 成年雄性小鼠的计算机断层扫描和组织形态计量学。基于这些结果，我们建议测试 男性中 PTH-R 和 CaSR（TPTD+拟钙剂西那卡塞）同时激活的假设 低骨矿物质密度 (BMD) 比单独激活 PTH-R 产生更大的合成代谢反应 （TPTD+安慰剂）。为了检验这一假设，我们提出了一项随机、双盲、{{安慰剂对照 对 48 名低骨量男性进行的临床试验}}。我们计划两个治疗组。目标1将决定效果 与 TPTD+安慰剂相比，TPTD+西那卡塞治疗 11 个月对 BMD 和骨代谢的影响 骨量低的男性。我们将评估以下方面的反应：(a) 腰椎 (LS) BMD（主要终点）和 股骨颈（FN）BMD； (b)骨形成标志物血清N末端1型前肽的水平 胶原蛋白（P1NP）。假设 1a 提出 TPTD+西那卡塞的 LS 和 FN BMD 反应更大 与 TPTD+安慰剂相比。假设 1b 提出，血清 P1NP 增加幅度更大 TPTD+西那卡塞与 TPTD+安慰剂相比。目标 2 将确定药效学反应 低骨量男性的 TPTD+西那卡塞和 TPTD+安慰剂治疗。我们将评估： (a) 急性和 药效学给药后血清 [Ca] 和血浆完整 PTH 的慢性变化 研究对象为 24 名男性（治疗组 12 名）； (b) 两种治疗后尿钙排泄的变化 治疗方案{在所有 48 名随机男性中}。假设 2a 提出血清 [Ca] 不会降低至 > 5% 低于对联合 TPTD+西那卡塞给药的正常范围下限。 假设 2b 表明接受治疗的男性尿钙排泄量每 24 小时不超过 350 毫克 长期使用 TPTD+西那卡塞。这项研究的完成将为支持 一种新型联合疗法的功效，该疗法旨在同时激活 CaSR 和 骨骼中的 PTH-R 可实现更大的骨骼合成代谢作用，最终目标是改善骨骼健康 减少男性退伍军人骨质疏松性骨折的残疾、发病率和死亡率。