Long-Term Administration of Clodronate Does Not Prevent Fracture Healing in Rats

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Abstract
Clinicians have been concerned that fractures do not heal properly in individuals exposed to bisphosphonate treatment, a treatment that strongly affects bone metabolism. The current study attempted to clarify the long-term effects of clodronate (dichloromethylene bisphosphonate) treatment on fracture healing in growing rats. Clodronate was administered subcutaneously twice a week in a dose of 2 mg/kg or 10 mg/kg. Physiologic saline served as a control. After 24 weeks of treatment, the tibiae were fractured, and the treatment was continued for another 4 weeks and 8 weeks. At both end points the cross-sectional areas of the callus, measured by peripheral quantitative computed tomography, were greater in the clodronate-treated rats than in controls, but there were no significant differences in bone mineral density. There were no significant differences between treatments in radiologic healing, histomorphometry, or in mechanical failure load of the callus with the exception of increased tensile stiffness at a dose of 2 mg/kg at 4 weeks. Clodronate treatment does not seem to prolong the fracture healing process, even when administered on a long-term basis before the fracture. Clodronate increases the size of the callus, but has only a minor effect on its biomechanical properties. The current results suggest that long-term clodronate treatment does not inhibit fracture healing.