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.

在美国每年发生的150万个骨折中，其中三分之一发生在男性中。骨质疏松和 与骨折有关的残疾是老年男性退伍军人的关键健康问题。骨折也会增加死亡率。 骨折的男性的死亡率是女性的死亡率的两倍。一些 药物被批准用于治疗男性[双膦酸盐，地诺单抗和teriparatide（TPTD）或 pth（1-34）]，但是我们对如何最有效使用它们几乎没有洞察力。 TPTD对 治疗男性的骨质疏松症是因为它基本上改善了骨骼质量，重建了微体系结构， 改善骨骼强度并减少骨折。关于使用TPTD的最佳方法知之甚少 治疗雄性骨质疏松症。它是否仅作为单一疗法或同时或顺序使用 与其他代理商一起带来了最大的好处？拟议的临床试验是为了测试新颖的努力 基于小鼠激动人心的临床前发现，男性骨质疏松症的联合疗法。众所周知 TPTD通过在成骨细胞（OB）中刺激PTH受体（PTH-RS）来实现其合成作用 血统。通过激活CA-来模仿高细胞外钙浓度（[CA] E）的影响 在许多细胞类型中表达的传感受体（CASR），包括骨骼中的OBS和破骨细胞。我们的工作 其他群体发现，CASR中的CASR在控制骨形成中起着重要作用 分化和矿化。在实验室的临床前模型中，我们发现每天注射TPTD 在短短6周内同时与研究性钙化剂（NPS-R568）同时显着增加 骨骼质量并改善了骨骼的小梁和皮质微体系结构，这两种微型 成年雄性小鼠的计算机断层扫描和组织形态法。基于这些结果，我们建议测试 男性中PTH-RS和CASR（TPTD+钙化cinacalcet）的同时激活的假设 低骨矿物质密度（BMD）比单独的PTH-R激活产生更大的合成代谢反应 （TPTD+安慰剂）。为了检验这一假设，我们提出了一个随机，双盲的，{{安慰剂对照 48名骨质质量低的男性的临床试验}}。我们计划两个治疗臂。 AIM 1将决定效果 与TPTD+Cinacalcet的11个月治疗与BMD和骨代谢的TPTD+安慰剂相比 骨质低的男性。我们将评估：（a）腰椎（LS）BMD（主要终点）和 股骨颈（FN）BMD; （b）1型骨形成标记血清N末端肽的水平 胶原蛋白（P1NP）。假设1a提出，TPTD+Cinacalcet具有LS和FN BMD响应更大 与TPTD+安慰剂相比。假设1b提出血清P1NP的增加，随着 与TPTD+安慰剂相比，TPTD+Cinacalcet。 AIM 2将确定对药效的反应 TPTD+cinacalcet和低骨质男性的TPTD+安慰剂治疗。我们将评估：（a）急性和 药物动力学药物给药后血清[CA]和血浆完整PTH的慢性变化 在24名男性（12/治疗臂）的子集中进行研究； （b）两种处理 方案{在所有48个随机男性中}。假设2a提出血清[CA]不降至5％ 在响应组合TPTD+cinacalcet的给药的响应时，正常范围的下限低于正常范围的下限。 假设2b提出，在接受治疗的男性中，尿液CA排泄不超过每24小时的350毫克 长期与TPTD+Cinacalcet。这项研究的完成将提供关键证据，以支持 一种新型组合疗法的功效，旨在针对CASR的同时激活和 骨骼中的PTH-RS以实现更大的骨骼合成代谢作用，其最终目标是改善骨骼健康 并降低了男性退伍军人骨质疏松性骨折的残疾，发病率和死亡率。