Delayed Short-Course Treatment With Teriparatide (PTH_(1-34)) Improves Femoral Allograft Healing by Enhancing Intramembranous Bone Formation at the Graft-Host Junction

摘要

Clinical management of critical bone defects remains a major challenge. Despite preclinical work demonstrating teriparatide (PTH_(1-34)) effectiveness in small animals, inconclusive data from clinical trials have raised questions of dose and regimen. To address this, we completed a comprehensive study in the murine femoral allograft model, to assess the effects of dose (0.4, 4, and 40 mug/kg/day) and various treatment regimens on radiographic, histologic, and biomechanical healing at 2,4, and 9 weeks. Only the high dose (40 mug/kg) of PTH_(1-34) demonstrated significant effects when given daily over 9 weeks. Remarkably, equivalent biomechanical results were obtained with delayed, short treatment from 2 to 6 weeks that did not induce a significant increase in endochondral bone formation and callus volume. In contrast, PTH_(1-34) treatment from 1 to 5 weeks postop demonstrated similar osteogenic effects as immediate daily treatment for 9 weeks, but failed to achieve a significant increase in biomechanics at 9 weeks. MicroCT and histologic analyses demonstrated that the 2-week delay in treatment allowed for timely completion of the endochondral phase, such that the prominent effects of PTPTH_(1-34) were enhanced intramembranous bone formation and remodeling at the graft-host junction. These findings support the potential use of PTH_(1-34) as an adjuvant therapy for massive allograft healing, and suggest that there may be an ideal treatment window in which a short course is administered after the endochondral phase to promote osteoblastic bone formation and remodeling to achieve superior union with modest callus formation.