Leveraging modeling-based bone formation for osteoporosis treatment

利用基于模型的骨形成治疗骨质疏松症

• 批准号: 10366040
• 负责人: Xiaowei Sherry Liu
• 金额: $ 42.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366040
• 关键词: Adult; Anabolic Agents; Antibodies; Bone Resorption; Bone Surface; Bone Tissue; Bone remodeling; Bone structure; Chronic; Clinical; Collagen; Coupled; Data; Deposition; Development; Hardness; Heterogeneity; Image; Image Analysis; Knowledge; Length; Life; Longevity; Mechanics; Minerals; Modeling; Modulus; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; PTH gene; Periodicity; Predisposition; Rattus; Regimen; Research Project Grants; Resistance; Sequential Treatment; Site; Skeleton; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Treatment Protocols; Withdrawal; base; bone; bone loss; bone mass; bone strength; design; imaging platform; improved; innovation; insight; mechanical properties; mineralization; novel; novel therapeutics; parathyroid hormone-related protein; recruit; regenerative; response; standard care; treatment duration; treatment effect; treatment optimization; treatment strategy

Project Summary The healthy skeleton continuously renews itself throughout the lifespan via closely coupled bone resorption and remodeling-based bone formation. In contrast, modeling-based bone formation, i.e., de novo bone formation without prior activation of bone resorption, is less commonly found in the adult skeleton, but has been identified as an important mechanism by which anabolic agents for osteoporosis, e.g., intermittent parathyroid hormone (PTH) and PTH related peptide (PTHrP), and sclerostin antibody (Scl-Ab), rapidly elicit new bone formation. By developing a novel imaging platform that enables reliable identification of MBF and RBF and subsequent tissue-level mechanical testing in adult rat bone, we discovered that MBF responds faster than RBF to anabolic treatments. Moreover, bone tissue resulting from MBF has a greater resistance to anabolic treatment withdrawal-induced bone loss and increased heterogeneity of elastic modulus compared to pre-existing bone and bone tissue resulting from RBF. These exciting preliminary data provide a strong scientific premise to support our central hypothesis that MBF is a highly efficient regenerative mechanism that leads to sustainable therapeutic benefits on bone tissue quantity and quality, and whole bone strength. Furthermore, our data suggest that, upon early withdrawal from anabolic treatment, ongoing bone formation continues at MBF sites, forming an “anabolic window” that retains the treatment effect; In contrast, the majority of bone tissue formed at RBF sites were resorbed following treatment withdrawal. Therefore, we propose that a cyclic and sequential treatment regimen with alternating anabolic and anti-resorptive treatments will lead to increased mineral deposition and number of MBF, improved retention of bone tissue at RBF and quiescent bone surface, and improved tissue heterogeneity and whole bone strength. The overall objective of this study is to elucidate the cellular mechanisms (Aim 1a) and mechanical consequences (Aim 2a) of MBF and RBF, and to evaluate the new treatment regimen which leverages MBF to improve and extend treatment efficacy (Aim 2a and 2b) using a rat model. By combining our innovative imaging and image analyses with tissue-level mechanical testing approaches, this proposed research project will fill the critical knowledge gap of long-term mechanical consequences of bone tissue formed through MBF and RBF, and provide important insight for the clinical design and optimization of treatment strategies that modulate MBF, a highly efficient but often overlooked regenerative mechanism.

项目总结