The interaction of anabolic and antiresorptive agents in osteoporosis therapy

骨质疏松症治疗中合成代谢药物和抗骨吸收药物的相互作用

• 批准号: 8721705
• 负责人: Joy Tsai
• 金额: $ 6.58万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-05 至 2015-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721705
• 关键词: Acute; Affect; Age; Alendronate; Anabolic Agents; Binding; Biochemical Markers; Bone Density; Bone Resorption; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Data; Disease; Distal; Dose; Enrollment; Failure; Finite Element Analysis; Fracture; Functional disorder; Future; Goals; Healthcare Systems; Hip region structure; Hour; Incidence; Individual; Injection of therapeutic agent; Ligands; Measures; Monoclonal Antibodies; Morbidity - disease rate; Nuclear; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Patients; Peripheral; Pharmaceutical Preparations; Population; Porosity; Postmenopause; Prevalence; Property; Public Health; Radial; Randomized; Randomized Controlled Trials; Relative (related person); Reporting; Research; Resolution; Risk; Serum Markers; Structure; TRANCE protein; Teriparatide; Testing; Therapeutic; Thick; United States; Vertebral column; Woman; X-Ray Computed Tomography; aged; aging population; base; bisphosphonate; bone; bone quality; bone strength; bone turnover; cohort; cost; design; effective therapy; evidence base; high risk men; improved; innovation; mortality; novel; novel strategies; open label; osteoporosis with pathological fracture; prevent; public health relevance; receptor; response; skeletal; subcutaneous; tibia; treatment strategy

DESCRIPTION (provided by applicant): Osteoporosis is a common disease that causes significant morbidity and mortality. The widespread prevalence of osteoporosis results in >2 million fractures yearly with an estimated cost of $17 billion in the US alone. Current agents are unable to completely restore skeletal integrity in patients with established osteoporosis and are inadequate to match the anticipated rise in fracture incidence in our aging population. Thus, continued efforts to develop innovative, evidence-based osteoporosis treatment strategies are crucial. The scientific focus of this proposal is the optimization of combination antiresorptive an anabolic osteoporosis therapies. In contrast to disappointing results from combining bisphosphonates with teriparatide (hPTH1-34 or TPTD), the combination of denosumab (DMAB), a monoclonal antibody that binds to receptor activator of nuclear factor-kB ligand (RANKL), and TPTD was recently reported to increase bone mineral density more than either drug alone. One specific aim of this proposal is to further understand the mechanisms underlying the additive properties of this therapeutic combination by assessing the changes in bone structure, microarchitecture, and strength in this same cohort. Specifically, high-resolution peripheral quantitative computed tomography of the distal tibia and radius will be used to compare the effects of combination TPTD and DMAB therapy versus each individual agent on cortical and trabecular volumetric bone density, cortical thickness and porosity, trabecular microarchitecture, and estimated bone strength (via micro finite element analysis). A further aim of this proposal is to expand on the recent novel finding from the above study that bone resorption is potently and equally suppressed when DMAB and TPTD are combined than when DMAB is given alone. Specifically, this proposed study will test the hypothesis that DMAB, but not alendronate, will fully inhibit the acute pro-resorptive effect of an increased dose of TPTD in postmenopausal osteoporotic women. If confirmed, this will suggest that higher doses of TPTD (40-mcg), when combined with DMAB, may improve skeletal integrity significantly more than DMAB and standard dose TPTD (20-mcg). Forty postmenopausal osteoporotic women aged 60+ will be enrolled in a short-term, open label randomized controlled trial. Subjects will be randomized to receive DMAB or alendronate therapy for 8 weeks. Subjects will also receive a single injection of TPTD 40-mcg both before and after the 8 weeks of antiresorptive therapy. The relative ability of each antiresorptive agent to inhibit TPTD-induced bone resorption will be evaluated by measuring biochemical markers of bone resorption prior to and 4 hours after the TPTD injection both at baseline and after 8-weeks of antiresorptive therapy. This study will provide a better mechanistic understanding of effects of combined osteoclast inhibition and osteoblast stimulation and aid in the design of innovative clinical trials designed to improve skeletal integrity in women and men at high risk for fracture.

描述（由申请人提供）：骨质疏松症是一种常见疾病，会引起明显的发病率和死亡率。骨质疏松症的普遍流行率每年导致200万个骨折，仅在美国，估计成本为170亿美元。目前的药物无法完全恢复已建立骨质疏松症的患者的骨骼完整性，并且不足以与我们老龄化人群的骨折发生率预期升高相匹配。因此，继续努力开发创新的，循证的骨质疏松治疗策略至关重要。该提案的科学重点是优化抗吸收性的合成代谢骨质疏松疗法。与将双膦酸酯与Teriparatide（HPTH1-34或TPTD）相结合的令人失望的结果，Denosumab（DMAB）的组合，一种与核因子-KB配体（RANKL）的受体激活剂结合的单克隆抗体，最近据报道TPTD的近期与单独的骨头骨矿物质矿物质矿物质的单独使用相比。该提案的一个具体目的是进一步了解该治疗组合的添加特性的基础机制，通过评估同一队列中的骨结构，微体系结构和强度的变化。具体而言，将使用胫骨和半径的高分辨率外周量化计算机断层扫描来比较TPTD和DMAB治疗组合的影响与每个单独的药物对皮质和小to骨体积骨密度，皮质厚度和毛孔厚度，皮层厚度，皮层厚度，Trabecular Miprorage骨强度（通过MICTARTAINE BONETER ENTERTER）的影响（通过MIPTAINTIAL分析）。该提案的另一个目的是从上述研究中扩展到最近的新发现，即当DMAB和TPTD合并时，骨吸收受到有效和同样抑制，而不是单独给出DMAB时。具体而言，这项拟议的研究将检验以下假设：DMAB（而不是alendronate）将完全抑制TPTD剂量增加在 绝经后骨质疏松妇女。如果得到证实，这将表明，与DMAB结合使用，较高剂量的TPTD（40-MCG）可能会明显高于DMAB和标准剂量TPTD（20-MCG）。绝经后的40岁以上的绝经后骨质疏松妇女将在短期开放标签随机对照试验中招募。受试者将被随机接受DMAB或Alendronate治疗8周。受试者在8周的抗吸收治疗之前和之后还将单次注射TPTD 40-MCG。每种抗吸收剂抑制TPTD诱导的骨吸收的相对能力将通过测量在基线和基线后4个星期和8周的抗吸收性治疗后测量骨吸收的生化标记。这项研究将对整骨细胞抑制和成骨细胞刺激的影响的影响有更好的理解，并有助于设计创新的临床试验，旨在改善男性和男性的骨骼完整性，处于裂缝高风险。