title: Delayed short-course treatment with teriparatide (PTH(1-34)) improves femoral allograft healing by enhancing intramembranous bone formation at the graft-host junction.
abstract: 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 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 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 PTH(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.
authors.affiliation: University of Rochester, Department of Biomedical Engineering, Rochester, NY 14642, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takahata
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: Tony
authors.initials: T
authors.lastname: Chen
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
authors.forename: Hani A
authors.initials: HA
authors.lastname: Awad
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D016025:Bone Transplantation; D020219:Chondrogenesis / Q000187:drug effects; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000601:surgery / Q000637:transplantation*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D016348:Osseointegration / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011859:Radiography; D019379:Teriparatide / Q000494:pharmacology*; D014184:Transplantation, Homologous; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D012333:RNA, Messenger; D019379:Teriparatide