Mechanisms Underlying the Bone Modeling Effects of Combined Anabolic/Antiresorptive Administration

合成代谢/抗骨吸收联合给药的骨建模效果背后的机制

• 批准号: 10091668
• 负责人: Marie Demay
• 金额: $ 6.87万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091668
• 关键词: Address; Adipocytes; Affect; Age; American; Anabolic Agents; Aspirate substance; Biology; Biopsy; Biopsy Specimen; Bone Density; Bone Formation Stimulation; Bone Marrow; Bone Resorption; Bone Resorption Stimulation; CD34 gene; Cells; Chronic; Clinical Trials; Core Biopsy; Coupling; Disease; Drug Combinations; Evaluation; Forteo; Health; Hormones; Human; Intervention; Label; Ligands; Marrow; Modeling; Molecular; Molecular Analysis; Nuclear; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Osteoporotic; PECAM1 gene; PTH gene; Patients; Pharmaceutical Preparations; Pharmacology; Postmenopause; Process; Property; Public Health; RNA analysis; Randomized; Receptor Activation; Reporting; Resistance; Sampling; Serum Markers; Signal Pathway; Skeleton; Stromal Cells; T-Lymphocyte; TRANCE protein; Techniques; Testing; Therapeutic; Time; Treatment Efficacy; Treatment Protocols; Woman; base; bisphosphonate; bone; bone cell; bone mass; bone metabolism; bone strength; design; drug efficacy; enhancing factor; experience; fracture risk; fragility fracture; high risk; hormone analog; human study; improved; indexing; inhibitor/antagonist; innovation; men; novel; osteogenic; osteoporosis with pathological fracture; receptor; response; skeletal; success

One in three women and one in five men will experience an osteoporotic fracture during their lifetime. Currently available medications reduce fracture risk but are unable to fully restore skeletal integrity. Thus, there remains an urgent need for osteoporosis treatments that rapidly and effectively restore bone strength. Unlike most chronic conditions, osteoporosis has historically been treated with only one drug at a time. Attempts to combine anabolic agents with the most commonly used antiresorptive agents (bisphosphonates) did not prove efficacious. In contrast, we recently reported that the combination of teriparatide and the receptor activator of nuclear factor-κB ligand (RANKL) inhibitor, denosumab, increases bone density and improves bone microarchitecture and estimated strength more than either drug alone and more than any available therapy. We have hypothesized that the efficacy of this combination is dependent on denosumab’s capacity to fully block teriparatide’s stimulation of bone resorption while allowing for teriparatide-induced stimulation of bone formation (modeling-based bone formation). In this proposal, we will directly assess the ability of teriparatide to stimulate modeling-based bone formation when bone resorption is blocked by denosumab. Furthermore, we will define the cellular and molecular mechanisms by which this combination achieves its efficacy. To accomplish these aims, we will perform a short-term clinical trial in which postmenopausal osteoporotic women are randomized to receive three-months of teriparatide, denosumab or both medications. Iliac crest bone biopsy specimens will then be sampled from all subjects after quadruple-labeling, an innovative technique that is able to assess the effects of short-term interventions on bone resorption and formation without requiring “paired” biopsies in a single subject. With this technique, we are also able to evaluate treatment-induced changes in both static and dynamic indices of bone metabolism in each bone envelope separately (cancellous, endocortical, intra-cortical, and periosteal) and thus calculate the proportion of remodeling versus modeling- based bone formation in each skeletal compartment. Biopsy specimens will also be used for immunohistochemical evaluation of osteoblasts, osteoclasts, marrow adipocytes and signaling pathways that regulate osteogenesis. An additional 3.5-mm core will be obtained for RNA analyses of bone and the marrow microenvironment. Furthermore, cells will be isolated from marrow aspirates to evaluate for osteogenic potential (CFU-OB), lineage markers and signaling pathway activation. The successful completion of this study will allow us to better define the mechanisms that underlie the unparalleled efficacy of the specific combination of RANKL inhibition and PTH-receptor stimulation. This new understanding, in turn, will provide the framework for the design of studies with the potential to fundamentally advance osteoporosis treatment.

目前，三分之一的女性和五分之一的男性在一生中都会经历骨质疏松性骨折。 现有的药物可以降低骨折风险，但无法完全恢复骨骼完整性，因此，仍然存在这种情况。 迫切需要能够快速有效地恢复骨质强度的骨质疏松症治疗方法。 对于慢性疾病，骨质疏松症历来一次仅使用一种药物进行治疗。 将合成代谢药物与最常用的抗再吸收药物（双磷酸盐）结合使用并没有证明 相反，我们最近报道了特立帕肽和受体激活剂的组合是有效的。 核因子-κB 配体 (RANKL) 抑制剂狄诺塞麦可增加骨密度并改善骨质 微结构和估计强度比单独使用任何一种药物和任何可用的疗法都要好。 我们发现，这种组合的疗效取决于地诺塞麦完全发挥作用的能力。 阻断特立帕肽对骨吸收的刺激，同时允许特立帕肽诱导的骨刺激 在本提案中，我们将直接评估特立帕肽的能力。 当骨吸收被狄诺塞麦阻断时，刺激基于模型的骨形成。 将定义该组合实现其功效的细胞和分子机制。 为了实现这些目标，我们将进行一项短期临床试验，其中绝经后骨质疏松妇女 随机接受三个月的特立帕肽、狄诺塞麦或两种药物治疗。 经过四重标记后，将从所有受试者中采集活检标本，这是一种创新技术， 能够评估短期干预对骨吸收和形成的影响，而不需要 通过这种技术，我们还能够对单个受试者进行“配对”活检来评估治疗引起的。 每个骨膜（松质骨、松质骨、 皮质内、皮质内和骨膜），从而计算重塑与建模的比例- 基于每个骨骼室中的骨形成的活检标本也将用于 成骨细胞、破骨细胞、骨髓脂肪细胞和信号通路的免疫组织化学评估 将获得额外的 3.5 毫米核心用于骨和骨髓的 RNA 分析。 此外，将从骨髓抽吸物中分离细胞以评估成骨作用。 潜在（CFU-OB）、谱系标记和信号通路激活的研究顺利完成。 将使我们能够更好地定义特定组合无与伦比的功效背后的机制 RANKL 抑制和 PTH 受体刺激的新认识反过来将提供框架。 设计有可能从根本上推进骨质疏松症治疗的研究。