title: A single systemic dose of pamidronate improves bone mineral content and accelerates restoration of strength in a rat model of fracture repair.
abstract: Complications in fracture repair that lead to a delay in union remain clinically problematic. We believe that unwanted pre-mature catabolism of the healing callus, for example, in stress shielded situations, diminishes the rate at which strength is restored in bone repair and possibly leads to delayed union. We hypothesized that a single systemic dose of a nitrogen-containing bisphosphonate (N-BP) would increase bone mineral content (BMC), volume, and mechanical strength of union in fracture repair. We also set out to investigate local delivery to assess whether systemic exposure could be eliminated, due to concerns of bisphosphonate dosing of non-target organs. After an open osteotomy fixed with a K wire, 40 12-week old Wistar male rats were divided into four groups of 10: saline control, bolus systemic subcutaneous injection of pamidronate (3 mg/kg), local low dose of pamidronate (0.1 mg), and a local high dose of pamidronate (1.0 mg). Rats were sacrificed 6 weeks post-operatively. Operated and non-operated femora underwent radiographic evaluation, quantitative computer tomography, and biomechanical testing in torsion. The growth plates and metaphyses of the tibia of the non-operated side were assessed for evidence of systemic exposure in the local groups. Significant increases in callus BMC and volume of the bolus systemic dose group were found compared to the saline control (p< or =0.05). Further, the strength of the systemic dose callus was increased by 60% from 0.35 Nm (+/-0.11) for the saline control callus to 0.56 Nm (+/-0.25) for the systemic group (p=0.05). Local treatment did not result in increased strength. The contralateral tibial growth plates of the local groups showed evidence of systemic exposure by the presence of retained primary spongiosa. This study confirms that a single perioperative systemic dose of pamidronate leads to significant increases in the BMC, volume, and strength of healing fractures in rats, making single dose N-BP therapy an appealing candidate for further examination in fracture repair.
authors.affiliation: School of Aerospace, Mechanical and Mechatronic Engineering, University of Sydney, NSW 2006, Australia.
authors.forename: Negin
authors.initials: N
authors.lastname: Amanat
authors.forename: Richard
authors.initials: R
authors.lastname: Brown
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Bilston
authors.forename: David G
authors.initials: DG
authors.lastname: Little
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010027:Osteotomy; D000077268:Pamidronate; D051381:Rats; D017208:Rats, Wistar; D013978:Tibial Fractures / Q000503:physiopathology
chemical_list: D004164:Diphosphonates; D000077268:Pamidronate