Preclinical safety profile of alendronate.

Acute toxicity studies showed that the LD50 values of oral alendronate in female animals corresponded to human oral doses of 27,800 mg in rats and 48,300 mg in mice; LD50 values in male animals were even higher. Chronic toxicity studies showed clinically nonrelevant retention of primary spongiosa of bone in areas of endochondral bone formation, serum biochemical changes (reductions in serum concentrations of calcium, phosphate and alkaline phosphatase) and nephrotoxicity. Of the 5 genotoxicity studies performed, 4 showed no evidence of mutagenicity, including those most relevant to human carcinogenic potential. Carcinogenicity studies in rats and mice at maximum tolerated doses showed no increased tumour incidence associated with alendronate treatment. Alendronate had no effect on fertility or reproductive performance in male or female rats receiving oral doses up to 5 mg/kg/day. No adverse developmental effects were noted at doses up to 25 mg/kg/day in rats and 35 mg/kg/day in rabbits. Alendronate had no deleterious effect on bone strength or morphology. The evidence presented in these studies supports the conclusion that alendronate administered to humans at therapeutic doses is a safe drug for the treatment of postmenopausal osteoporosis.