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）：放疗后的放射后骨折在特定的解剖学位置（例如泌尿外科或妇科癌症治疗后的骨盆）中普遍存在，并可能导致遭受损害的并发症，包括肢体部位的肢体截肢，例如股骨治疗后的软性肉瘤肉瘤后的股骨。在制定预防或治疗策略方面缺乏进展受到对潜在病理生理学的理解不足。虽然已经描述了组织学的改变（早期增加，后来减少的破骨骨骨转换），并且已经描述了辐照骨的结构（小梁骨质损失）特性，但CT和DXA临床扫描通常正常并且无法预测断裂风险。初步动物模型的工作表明，受辐照的骨骼行为以一种拥抱的方式，实际上是组成参数会导致这种脆弱的行为。该提案重点是 在两个骨成分变化上，它们与生物力学变化的关系以及有利改变这些组成变化的转化潜力，从而改善了受辐射骨的生物力学特性。该提案建立在我们实验室使用小动物后肢辐照模型来研究放射后生长板病理生理学的往绩上，并结合了每个当前假设的初步数据支持。相对于组织学，血管和结构变化，要使用的动物模型已得到很好的特征，这些变化概括了人类检索辐照样本中的发现。 AIM 1使用局灶性辐照模型研究骨辐照的影响，与通过拉曼光谱法相比，与未辐射的骨相比，与未辐照的骨相比，矿物质比改变了矿物质：基质比。在AIM 2中，我们探讨了辐照骨是否以较慢的速度累积了高级糖基化最终产物（年龄）是否比在拉曼终点，剂量依赖性的方式中观察到的化学交联变化，并且在形态上的底层表面最为突出。在AIM 3中，评估了骨骼物质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对应于胶原蛋白/矿物质和年龄的变化。在AIM 4中，我们测试了放射治疗剂（氨基氨酸酯），合成代谢剂（PTH）或抗敏化剂（双膦酸盐）是否能够减少放射后胶原蛋白和年龄改变以及维持骨生物力学。鉴于目前缺乏对辐射后骨折的了解以及潜在的可翻译疗法的可用性，因此临床影响的潜力很高。开发，正在开发非侵入性拉曼技术作为骨折风险预测的一种手段，这可能在遵循辐照骨骼中很有用。