title: Manipulation of the anabolic and catabolic responses with BMP-2 and zoledronic acid in a rat femoral fracture model.
abstract: Bone repair involves a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone matrix at the fracture site. It has been reported that the optimal time point for single-dose zoledronic acid (ZA) administration systemically increased the strength of bone morphogenetic protein (BMP)-7-mediated callus. However, its repair mechanism during bone fracture healing remains unknown. We aimed to investigate the synergic effect of recombinant human (rh) BMP-2 and ZA in a rat femoral fracture model. Fifty-eight rats were divided into 4 groups. Group I (n=14) animals were implanted with a carrier alone. Group II (n=15) animals were implanted with a carrier containing 1-μg rhBMP-2. Group III (n=14) animals were implanted with a carrier and a subcutaneous systemic ZA injection 2 weeks after surgery. Group IV (n=15) animals were implanted with a carrier containing 1-μg rhBMP-2 and ZA subcutaneous injection 2 weeks after surgery. The rats were euthanized after 6 weeks and their fractured femurs were explanted and assessed by manual palpation, radiographs, and high-resolution micro-computerized tomography (micro-CT) and were subjected to biomechanical and histological analysis. The fusion rates in Group IV (93.3%) were considerably higher than those in Groups I (28.6%), II (53.3%), and III (57.1%). Additionally, the radiographic scores of Group IV were higher than those in Groups I, II, and III. In micro-CT analysis, the tissue volume (TV) of the callus was higher in Group IV than in Groups I and II (p<0.05). New bone volume (BV) and trabecular spacing (Tb.Sp) also showed essentially the same trend as that of TV. The ratio of BV to TV (BV/TV), the trabecular number (Tb.N), and the trabecular thickness (Tb.Th) was higher in Groups III and IV than in Groups I and II (p<0.05). In biomechanical analysis, the ultimate loads at failure and stiffness in Groups III and IV were on average higher than those in Groups I and II (p<0.05), while the energy absorption of Group IV was higher than those of Groups I and II (p<0.05). The synergic effect of rhBMP-2 and ZA given systemically as a single dose at the optimal time was efficacious for fracture repair and significantly enhanced bone fusion. Our results suggest that this combination facilitates bone healing and has potential clinical application.
authors.affiliation: Department of Orthopaedic Surgery, Oita University, Oita, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Doi
authors.forename: Masashi
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Toyomi
authors.initials: T
authors.lastname: Yoshiiwa
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Hara
authors.forename: Masashi
authors.initials: M
authors.lastname: Kataoka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsumura
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology / Q000627:therapeutic use*; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D010173:Palpation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000627:therapeutic use*; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D045930:Anabolic Agents; D055396:Bone Morphogenetic Protein 2; D004164:Diphosphonates; D007093:Imidazoles; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D000077211:Zoledronic Acid