To examine the effect of alendronate (4-amino-1-hydroxybutylidene bisphosphonate) on fracture repair, the drug was given to mature beagle dogs orogastrically at 2 mg/kg/day for 9 weeks preceding fracture. 16 weeks after fracture, or both before and after fracture (25 weeks). A transverse mid-diaphyseal fracture of the right radius was surgically induced and was stabilized by external coaptation splinting. Fracture healing and bone remodeling were evaluated by radiography, gross and histological examination, and bone histomorphometry. The mechanical properties of the fracture callus were determined by a four-point bending test. Radiographs and gross and microscopic examination demonstrated normal bone healing at the fracture site in all dogs. In dogs that received alendronate during the fracture healing period, at 16 weeks the calluses were approximately 2-3 times larger than those in dogs that received a placebo during the healing period. This is consistent with slower callus bone remodeling, an expected pharmacological effect of the compound. Bone histomorphometry demonstrated that treatment with alendronate did not inhibit bone formation or mineralization. Mechanical testing showed that the ultimate load at failure and the flexural rigidity of both the fractured and contralateral intact bone were unaffected by treatment with alendronate. Therefore, in this study, treatment with alendronate before or during fracture healing, or both, resulted in no adverse effects on the union, strength, or mineralization of bone in mature beagle dogs.

Spontaneously occurring diseases of the kidneys are very common in laboratory rats. These diseases include chronic progressive nephrosis, nephrocalcinosis, renal tubular epithelial hyaline droplets, renal tubular hypertrophy, and renal tubular basophilia. As increasing numbers of rats are used in long-term toxicity and carcinogenicity studies, recognizing spontaneously occurring renal lesions and understanding their etiology and pathogenesis are important in making an assessment of the safety of drugs and chemicals that are being tested. The purpose of this paper is to review the incidence, morphology, and pathogenesis of these spontaneous diseases. Some of the factors that alter the incidence and/or severity of these spontaneous diseases will also be discussed.

Alendronate (4-amino-1-hydroxybutylidene bisphosphonate) is a novel amino bisphosphonate that is being developed for the treatment of osteolytic bone disorders such as osteoporosis. As part of a 2-year carcinogenicity study, we investigated the morphologic and biomechanical effects of long-term alendronate (ALN) therapy, given throughout skeletal growth, maturation, and aging, on rat vertebrae and femora. Three treatment groups, receiving either deionized water, low- (1.00 mg/kg), or high-dose (3.75 mg/kg) ALN, were given daily oral treatment for 105 weeks. Results from mechanical tests indicate that ALN therapy (in males) increased the vertebral ultimate compressive load by 96% in the high- and 51% in the low-dose groups when compared with controls. ALN similarly increased the male ultimate femoral bending load by 59% in the high- and 31% in the low-dose groups. Vertebrae and femora from female rats treated with both high- and low-dose ALN also failed at significantly higher loads than controls, but no differences were seen between low- and high-dose groups. Morphologic analysis of both male and female vertebrae revealed a dose-dependent increase in area fraction of bone. Rats receiving high-dose ALN had a greater area fraction of bone than those receiving low doses. Both groups were greater than controls. Thus, the administration of ALN resulted in increased femoral cortical bending load when compared with control animals, as well as increased vertebral ultimate compressive load commensurate with a dose-related preservation of vertebral bone.(ABSTRACT TRUNCATED AT 250 WORDS)

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