PRECLINICAL STUDIES OF ALENDRONATE

Abstract

Alendronate has been developed for the treatment of diseases characterized by increased bone resorption, such as osteoporosis. It increases metaphyseal bone density, bone volume, femoral bending strength and vertebral compressive strength, in a dose-dependent manner, in growing, intact rats. In ovariectomized (OVX) rats, alendronate increases femoral bone mass and tibial trabecular bone volume in a dose-dependent manner, and increases femoral midshaft bending strength. In rats immobilized by unilateral sciatic neurectomy, it inhibits bone loss and is dose-dependent. In rats, alendronate prevents high-turnover osteopenia induced by hyperthyroidism or by administration of immunosuppressant agent cyclosporin-A. Also in rats, treatment with prostaglandin E 2 and alendronate does not inhibit prostaglandin E 2-induced stimulation of bone formation on endocortical and periosteal surfaces. It does, however, prevent prostaglandin E 2-induced cortical bone porosity as a result of increased bone resorption, leading to an increase in cortical thickness and an increase in three-point bending strength of the femoral midshaft. At up to five times the dose used for treatment of osteoporosis in clinical trials, alendronate causes no abnormalities in bone remodeling, bone structure, or structural mechanical properties of the femur or vertebrae in intact beagles. Treatment with alendronate before or during fracture healing, or both, has no adverse effects on the union, strength, bone formation or mineralization of bone in mature beagle dogs. In intact minipigs, sodium fluoride increases and alendronate decreases bone turnover, while sodium fluoride, but not alendronate, decreases L4 strength and femoral stiffness. Small-angle X-ray scattering and backscattered electron imaging show that the trabecular bone matrix is more uniformly mineralized after alendronate treatment. In OVX baboons, which show bone changes similar to those seen in postmenopausal women, alendronate prevents an increase in bone turnover, and increases both bone volume and strength in vertebrae, in a dose-dependent manner. Alendronate also reduces the bone loss of alveolar support associated with periodontitis in monkeys. Thus, alendronate inhibits bone resorption and bone turnover, increases bone quantity accompanied by improved bone quality in some of the intact animals and in the animal models.