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: 9088351
• 负责人: TIMOTHY A DAMRON
• 金额: $ 33.22万
• 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/9088351
• 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; Soft tissue sarcoma; Specimen; Structure; Surface; Techniques; Testing; Time; Urologic Cancer; Work; bisphosphonate; bone; bone loss; bone strength; bone turnover; cancer therapy; clinically relevant; crosslink; crystallinity; follow-up; glycation; in vivo; irradiation; mouse model; nanoindentation; novel; pentosidine; prevent; response; 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在特定的解剖部位很常见，例如泌尿科或妇科癌症治疗后的骨盆，并可能导致毁灭性的并发症，包括软性骨折治疗后股骨等四肢部位的截肢。 -组织肉瘤。由于对潜在的病理生理学了解不足，在制定预防或治疗策略方面缺乏进展。虽然已描述了受辐射骨的组织学（早期增加，后来减少破骨细胞骨转换）和结构（骨小梁丢失）特性的改变，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，受辐射的骨骼表现出脆化行为，实际上是成分参数导致了这种脆性行为。该提案重点 研究了两种骨骼成分的变化、它们与生物力学变化的关系，以及有利地改变这些成分变化的转化潜力，从而改善了辐照骨骼的生物力学特性。该提案建立在我们实验室使用小动物后肢辐射模型研究辐射后生长板病理生理学的记录基础上，并结合支持每个当前假设的初步数据。所使用的动物模型在组织学、血管和结构变化方面已得到很好的表征，这些变化概括了人类检索辐照标本中的发现。目标 1 通过拉曼光谱研究与未辐照骨骼相比，使用局部辐照模型对骨骼进行辐照对胶原交联、结晶度改变以及矿物质：基质比例改变的影响。在目标 2 中，我们探索受辐照的骨是否会随着时间的推移以比拉曼终点中观察到的化学交联变化更慢的速度积累高级糖基化终末产物 (AGE)，以剂量依赖的方式，并且在干骺端骨内膜表面也最为突出。在目标 3 中，评估骨材料和骨结构的生物力学特性，以确定材料和功能特性的损失是否与胶原蛋白/矿物质和 AGE 的变化相对应。在目标 4 中，我们测试辐射防护剂（氨磷汀）、合成代谢剂 (PTH) 或抗再吸收剂（双膦酸盐）是否能够减少辐射后胶原蛋白和 AGE 的变化以及维持骨生物力学。鉴于目前对放射后骨折缺乏了解以及潜在可转化疗法的可用性，临床影响的潜力很大。此外，非侵入性拉曼技术正在开发作为骨折风险预测的一种手段，可能在追踪受辐射的骨骼方面被证明是有用的。