Translating PTH Therapy as an Adjuvant for Structural Allografting

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。

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.