Novel Combination Therapy for Osteoporosis in Men

在美国，每年发生的150万例骨折中，三分之一发生在男性身上。骨质疏松症和 与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。 髋部骨折的男性的死亡率是相同髋部骨折女性的两倍。几个 被批准用于治疗男性骨质疏松症的药物[双膦酸类、地诺舒单抗和替帕拉特(TPTD)或 PTH(1-34)]，但我们对如何最有效地使用它们知之甚少。TPTD对 治疗男性骨质疏松症，因为它显著改善了骨量，重建了微结构， 提高骨骼强度，减少骨折。人们对如何在 治疗男性骨质疏松症。它应该只作为单一疗法使用，还是同时使用或连续使用 与其他代理商带来的最大好处是什么？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的男性骨质疏松症的联合治疗。众所周知， TPTD通过刺激成骨细胞中的甲状旁腺素受体(PTH-Rs)实现其合成代谢作用。 血统。仿钙剂通过激活钙离子来模拟高细胞外钙浓度([Ca]e)的影响 感知受体表达于多种细胞类型，包括成骨细胞和破骨细胞。工作由我们完成 其他研究小组发现，OBS中的CaSR在控制骨形成方面发挥着重要作用 分异和成矿作用。在实验室的临床前模型中，我们发现每天注射TPTD 与一种研究用的拟钙剂(NPS-R568)同时服用，仅6周内显著增加 骨量和骨小梁和皮质微结构的改善 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 甲状旁腺激素受体和CASRs(TPTD+拟钙剂Cinacalcet)在男性高血压患者中同时激活的假设 低骨密度(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，我们提出了一个随机、双盲、{{安慰剂对照 对48名低骨量男性的临床试验。我们计划有两个治疗武器。目标1将确定影响 TPTD+Cinacalcet与TPTD+安慰剂治疗11个月后骨密度和骨代谢的比较 骨量低的男性。我们将评估以下方面的反应：(A)腰椎(LS)骨密度(主要终点)和 股骨颈(FN)骨密度；和(B)骨形成标志物血清1型N末端前肽的水平 胶原(P1NP)。假设1a提出，TPTD+Cinacalcet对LS和FN的BMD反应更大 与TPTD+安慰剂相比。假设1b提出，血清P1NP的增加随着 TPTD+桂皮钙与TPTD+安慰剂的比较。目标2将确定药效学反应 TPTD+桂皮钙和TPTD+安慰剂治疗低骨量男性。我们将评估：(A)急性和 药效学研究中血清[Ca]和血浆完整甲状旁腺素的慢性变化 对24名男性(12名/治疗组)进行的研究；以及(B)两种治疗方法对尿钙排泄的影响 治疗方案(在所有48名随机分组的男性中)。假设2a提出血清[Ca]不会降低到5% 低于正常范围的下限，对联合应用TPTD+Cinacalcet的反应。 假设2b提出，接受治疗的男性每24小时尿钙排泄量不超过350毫克 长期使用TPTD+Cinacalcet。这项研究的完成将提供关键证据来支持 一种针对CASRs和CASRs同时激活的新型联合疗法的疗效 甲状旁腺素受体在骨骼中实现更大的骨骼合成代谢作用，最终目标是改善骨骼健康 降低男性退伍军人骨质疏松性骨折的伤残、发病率和死亡率。

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.