Risedronate activity in the fetal and neonatal mouse

Otosclerosis, chronic otitis media with and without cholesteatoma, and Paget's disease of bone are just a few of the many diseases of the ear that exhibit abnormalities of bone modeling and remodeling. These diseases result in chronic infection, vestibular dysfunction, and hearing loss. Bisphosphonates are a promising new class of drugs potentially useful in the treatment of these disorders. Currently used in diseases with high rates of bone turnover (Paget's disease of bone, hypercalcemia of malignancy, and osteoporosis), they have been found to be strong inhibitors of bone resorption. A third generation bisphosphonate, 2-(3-pyrindyl)-hydroxyethylidene bisphosphonate (risedronate) is being investigated for toxicity, increased efficacy, and oral administration. In this study the in vitro and in vivo anti-resorptive activity of risedronate was quantified by measuring calcium release in a neonatal mouse calvarial culture system. This model was used to test direct in vitro effects, in vivo exposure in neonatal mice, and the possible effects of in utero and lacteal exposure. Calcium release activated by parathyroid hormone (PTH) was significantly inhibited when risedronate was only present in the pre-incubation media. When risedronate was administered subcutaneously to neonatal mice it resulted in a significant decrease in PTH-activated calcium release in explanted calvaria in vitro. Transplacental and lactational transfer of biologically effective risedronate was not demonstrated in this study; however, a paradoxic increase in PTH-stimulated calcium release in vitro from calvaria theoretically exposed transplacentally and lacteally was noted. This effect was unexplained by the data.