Delayed Short Course Treatment with Teriparatide (PTH1–34) 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 pre-clinical work demonstrating teriparatide (PTH1–34) 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 μg/kg/day) and various treatment regimens on radiographic, histologic and biomechanical healing at 2, 4, and 9 weeks. Only the high dose (40 μg/kg) of PTH1–34 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, PTH1–34 treatment from 1 to 5 weeks post-op demonstrated similar osteogenic effects as immediate-daily treatment for 9 weeks, but failed to achieve a significant increase in biomechanics at 9 weeks. Micro-CT 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 PTH1–34 were enhanced intramembranous bone formation and remodeling at the graft-host junction. These findings support the potential use of PTH1–34 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 following the endochondral phase to promote osteoblastic bone formation and remodeling to achieve superior union with modest callus formation.