Enhancement of experimental fracture healing with parathyroid hormone (1-34)

PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact open-help@bu.edu.Thesis (D.Sc.D)--Boston University, Henry M. Goldman School of Dental Medicine, 2004 (Prothodontics).Includes bibliographic references (leaves 76-87).Substantial progress has been made in the use of surgically implanted recombinant proteins to enhance fracture healing where there is nonunion or substantial loss of bone. However, a systemically administered therapy that could promote fracture healing would be desirable. We therefore tested the hypothesis that a once-daily subcutaneous injection of Parathyroid hormone (1-34) (PTH (1-34)) could enhance fracture healing. Two hundred seventy male Sprague Dawley rats underwent standard, closed mid diaphyseal femoral fractures. Immediately post fractures, animals were divided into three groups and administered daily injections of 5[Mu]g PTH (1-34)Kg, 30[Mu]g PTH (1-34)/Kg, or aqueous vehicle alone (control) for a maximum of 35 days treatment. Each group was further divided into three subgroups, which were euthanized on day 21 , 35, or 84 post fractures respectively. At necropsy, bones were harvested and the calluses subjected to quantitative micro computerized tomography (QCT) scan and mechanical torsion testing to failure. Additionally, calluses from three animals in each group were analyzed by histomorphometry. The 30[Mu]gPTH (1 -34)[Mu]g/day dose produced significant increases on day 21 post fracture for bone mineral content (BMC; P=.008), bone mineral density (BMD; P=.001), and percent cartilage in the callus approaching the significant level (P=.061) relative to controls. On day 35, the 30[Mu]g PTH (1-34)/Kg/day group (p[less than].000) showed increases in BMC and BMD. At this time, the 30[Mu]g PTH (1-34)Kg/day group also showed a significant increase in torque strength (p=.006). While dosing was discontinued after day 35, analyses performed after 84 days in rats previously treated with 30[Mu]g PTH (1-34)/Kg/day showed sustained increases over control for BMC (p=.017) and BMD (P=.041). Histological analysis and geometric measurements of the calluses further showed that there was no change in osteoclast number, while overall cortical diameters in the PTH (1-34) treated animals were greatest at 84 days. These data show that daily subcutaneous administration of low-dose PTH (1 -34), enhances fracture healing by increasing BMD, BMC, and strength, and produces a sustained anabolic effect throughout the remodeling phase of fracture repair