Effect of EHDP on fracture healing in dogs.

Ethane-1-hydroxy-1,1-diphosphonate (EHDP) was administered subcutaneously to mature beagle dogs at dose levels of 0.1, 0.5, and 5.0 mg/kg/day for a 20 week period to determine the drug's effects on fracture healing. Uniform, transverse fractures of the midshaft radius were created in one limb and treated by external splintage. Drug-induced effects on fracture healing were monitored radiographically, histologically, and histomorphometrically; mechanical properties of the healing bones were determined in 4-point bending tests. At a dose of 0.1 mg/kg/day, ultimate load at failure and flexural rigidity of the fractured limbs equaled or exceeded that of saline control animals, and radiographic healing was normal. At a dose of 0.5 mg/kg/day ultimate load at failure and flexural rigidity of the fractured limbs proved inferior to saline control values, and radiographic healing appeared delayed. At a dosage of 5.0 mg/kg/day, there was obvious radiographic nonunion, and the callus of fractured radii had little inherent flexural rigidity or strength. Histomorphometrically, no differences were noted between control animals and the 0.1 or 0.5 mg/kg/day groups; however, mineralization activity appeared totally disrupted at the higher dosage level (5.0 mg/kg/day). In the 5.0 mg/kg/day group, EHDP-induced effects proved reversible with mineralization evident as early as 3 weeks following drug withdrawal. In mature beagle dogs EHDP proved to have dose-dependent and reversible inhibitory effects on secondary fracture healing.