Delayed short‐course treatment with teriparatide (PTH1–34) improves femoral allograft healing by enhancing intramembranous bone formation at the graft–host junction

Clinical management of critical bone defects remains a major challenge. Despite preclinical 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 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 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 after the endochondral phase to promote osteoblastic bone formation and remodeling to achieve superior union with modest callus formation. © 2012 American Society for Bone and Mineral Research