Translating PTH Therapy as an Adjuvant for Structural Allografting

将 PTH 疗法转化为结构性同种异体移植的佐剂

• 批准号: 8344380
• 负责人: Edward M. Schwarz
• 金额: $ 34.96万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-16 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8344380
• 关键词: Adjuvant; Adjuvant Therapy; Allografting; Amputation; Animal Model; Animals; Autologous Transplantation; Biomechanics; Canis familiaris; Clinical; Clinical Management; Clinical Trials; Control Groups; Data; Defect; Distal; Dose; Enrollment; Evaluation; Failure; Femur; Fracture; Fracture Healing; Funding; Healed; Human; Injury; Label; Limb Salvage; Literature; Metals; Minerals; Modeling; Molecular; Morphologic artifacts; Mus; Natural History; Operative Surgical Procedures; Orthopedics; Osteogenesis; Outcome; Outcome Measure; Patient Self-Report; Patients; Pharmaceutical Preparations; Placebos; Probability; Radiology Specialty; Randomized; Regimen; Regression Analysis; Retinal Cone; Rodent Model; Scanning; Signal Pathway; Technology; Teriparatide; Testing; Therapeutic Intervention; Time; Torque; Translating; Validation; Work; X-Ray Computed Tomography; base; bone; bone healing; calcein green; clinically relevant; cohort; cost; disability; efficacy trial; healing; improved; in vivo; long bone; longitudinal analysis; minimally invasive; pre-clinical; primary outcome; programs; prospective; secondary outcome; success; trauma care

The clinical management of critical (>3cm) defects in bone from traumatic injuries remains a major challenge for both amputation and limb salvage cases. Thus, the quest for a practical adjuvant therapy, such as teriparatide (PTH{1-34}), remains a high priority. Despite extensive work concluding that PTH{1-34} is effective in small animal models of fracture healing, success in translating this technology into a human therapy remains elusive. To this end we have made remarkable progress during the initial funding period of this CORT by developing a computerized tomography (CT) outcome measure (Union Ratio) that correlates with torsional biomechanics; and clinical cone beam (CB) CT with metal artifact suppression to quantify massive allograft healing in dogs and humans. Now we propose to perform a definitive large animal study (canine femoral defect), with translational outcome measures to formally establish PTH{1-34} efficacy in a clinically relevant model of challenging bone healing. Two cohorts of skeletally mature dogs will be studied to evaluate PTH{1-34} effects on femoral allograft healing. In Aim 1 the dogs will be randomized to placebo or PTH{1-34} treatments, followed by longitudinal CB-CT, and sacrificed at 8-weeks or 6-months to assess eariy and mature allograft healing. The primary outcome will establish PTH{1-34} effects on ex vivo torsional biomechanics (stiffness and torque to failure), and the secondary outcomes, including histomorphometry. will establish PTH{1-34} effects on in vivo radiology (Union Ratio and bone volume). In Aim 2 we will use these data to demonstrate that the Union Ratio correlates significantly with fracture healing (torsional biomechanics) compared to the current clinical standard of subjective x-ray scoring. Finally, in Aim 3 we will complete the ongoing clinical pilot of the natural history of human massive allograft healing determined by CB-CT at 0.5, 8 and 18-months. Union Ratios will be quantified from these data to derive a power calculation for a PTH{1-34} efficacy clinical trial in limb salvage patients.

创伤性骨缺损（>3cm）的临床处理仍然是一个主要的问题， 截肢和保肢手术都面临挑战。因此，寻求一种实用的辅助治疗， 例如特立帕妥（PTH{1-34}），仍然是高度优先事项。尽管广泛的工作得出结论，PTH{1-34} 在骨折愈合的小动物模型中有效，成功地将这项技术转化为人类 治疗仍然难以捉摸。在这方面，我们在最初的供资期间取得了显著进展 通过开发一种计算机断层扫描（CT）结果测量（联合比率）， 与扭转生物力学相关;以及具有金属伪影抑制的临床锥形束（CB）CT， 量化狗和人的大量同种异体移植愈合。现在我们建议进行一次大规模的 动物研究（犬股骨缺损），采用转化结局指标正式确定PTH{1-34} 在挑战骨愈合的临床相关模型中的有效性。两组成年犬 将进行研究，以评价PTH{1-34}对股骨同种异体移植物愈合的影响。在目标1中，狗将 随机接受安慰剂或PTH{1-34}治疗，随后进行纵向CB-CT，并在8周时处死 或6个月以评估早期和成熟的同种异体移植物愈合。主要结局将确定PTH{1-34} 对体外扭转生物力学（刚度和失效扭矩）的影响，以及次要结局， 包括组织形态测量学。将确定PTH{1-34}对体内放射学的影响（愈合率和骨 卷）。在目标2中，我们将使用这些数据来证明工会比率与以下因素显著相关： 骨折愈合（扭转生物力学）与当前主观X线临床标准的比较 得分。最后，在目标3中，我们将完成正在进行的人类自然史的临床试验。 在0.5、8和18个月时通过CB-CT确定的大块同种异体移植物愈合。工会比率将被量化 从这些数据中推导出在保肢患者中进行的PTH{1-34}疗效临床试验的把握度计算。