Biochemical and Biomechanical Changes to Bone Following Radiotherapy

放射治疗后骨的生化和生物力学变化

• 批准号: 8612817
• 负责人: TIMOTHY A DAMRON
• 金额: $ 34.61万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8612817
• 关键词: Advanced Glycosylation End Products; Aftercare; Amifostine; Amputation; Anabolic Agents; Anatomy; Animal Model; Animals; Anisotropy; Behavior; Biochemical; Biomechanics; Blood Vessels; Bone Resorption; Bone Surface; Chemicals; Chemistry; Clinical; Collagen; Data; Dose; Dual-Energy X-Ray Absorptiometry; Epiphysial cartilage; Evaluation; Femur; Fluorescence; Fracture; Free Radicals; Functional disorder; Health; Hindlimb; Histologic; Human; Intervention; Lead; Limb structure; Location; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Mechanics; Minerals; Modeling; Osteogenesis; Pelvis; Prevention strategy; Property; Radiation; Radiation therapy; Raman Spectrum Analysis; Retrieval; Risk; Scanning; Site; Skeleton; Specimen; Structure; Surface; Techniques; Testing; Time; Urologic Cancer; Work; bisphosphonate; bone; bone loss; bone strength; bone turnover; cancer therapy; clinically relevant; crosslink; follow-up; glycation; in vivo; irradiation; mouse model; nanoindentation; novel; pentosidine; prevent; public health relevance; response; sarcoma; soft tissue; substantia spongiosa; tibia

DESCRIPTION (provided by applicant): Post-radiation fractures after radiotherapy are prevalent in specific anatomic locations, such as the pelvis following urologic or gynecologic cancer treatment, and may lead to devastating complications including amputation in extremity sites such as the femur after treatment for soft-tissue sarcoma. Lack of progress in developing strategies for prevention or treatment is limited by poor understanding of underlying pathophysiology. While altered histologic (early increased, later decreased osteoclastic bone turnover) and structural (trabecular bone loss) properties of irradiated bone have been described, CT and DXA clinical scans are often normal and fail to predict fracture risk. Preliminary animal model work suggests irradiated bone behaves in an embrittled fashion and that it is in fact compositional parameters that cause this brittle behavior. This proposal focuses on two bone compositional changes, their relationship to biomechanical changes, and the translational potential to favorably alter those compositional changes with consequent improvement in biomechanical properties of irradiated bone. This proposal builds upon our lab's track record of using small animal hind limb irradiation models to study post-radiation growth plate pathophysiology combined with preliminary data supportive of each current hypothesis. The animal model to be used has been well characterized with respect to the histologic, vascular, and structural changes, which recapitulate findings in human retrieval irradiated specimens. Aim 1 investigates the effects of irradiation of bone using a focal irradiation model on collagen cross-linking, altered crystallinity, and altered mineral:matrix ratio compared to non-irradiated bone via Raman spectroscopy. In Aim 2, we explore whether irradiated bone accumulates advanced glycation end products (AGEs) over time at a slower rate than chemical cross-link changes observed in Raman endpoints, in a dose dependent fashion, and also most prominently at the metaphyseal endosteal surface. In Aim 3, the biomechanical properties of the bone material and bone structure are assessed to determine if loss in material and functional properties correspond to changes in collagen/mineral and AGEs. In Aim 4, we test whether a radioprotectant (amifostine), anabolic agent (PTH), or anti-resorptive agent (bisphosphonate) are capable of decreasing post-radiation collagen and AGE alterations as well as maintain bone biomechanics. Given the current lack of understanding of post-radiation fractures and the availability of potentially translatable therapies, the potential for clinical impact is high. Furter, non-invasive Raman techniques are being developed as a means of fracture risk prediction that may prove useful in following irradiated bones.

描述（由申请人提供）：放射治疗后的放射后骨折常见于特定的解剖部位，如泌尿外科或妇科癌症治疗后的骨盆，并可能导致毁灭性的并发症，包括在软组织肉瘤治疗后的四肢部位截肢，如股骨。由于缺乏对潜在病理生理学的理解，在制定预防或治疗策略方面缺乏进展。虽然已经描述了受照射骨的组织学改变（早期增加，后来减少破骨细胞骨转换）和结构特性（小梁骨丢失），但CT和DXA临床扫描通常是正常的，无法预测骨折风险。初步的动物模型工作表明，受辐照的骨头表现出脆化的行为，实际上是成分参数导致了这种脆性行为。该提案的重点是