A Controlled Study of the Effects of Alendronate in a Growing Mouse Model of Osteogenesis Imperfecta

Abstract

Recent studies have reported that bisphosphonates reduce fracture incidence and improve bone density in children with osteogenesis imperfecta (OI). However, questions still persist concerning the effect of these drugs on bone properties such as ultrastructure and quality, particularly in the growing patient. To address these issues, the third-generation bisphosphonate alendronate was evaluated in the growing oim/oim mouse, an animal model of moderate- to-severe OI. Alendronate was administered to 6-weekold mice during a period of active growth at a dosage of 73 mg alendronate/kg/day for the first 4 weeks and 26 μg alendronate/ kg/day for the next 4 weeks. Positive treatment effects included a reduction in the number of fractures sustained by the alendronate-treated oim/oim mice compared with untreated oim/oim mice (2.1 ± 2.0 vs 3.2 ± 1.6 fractures per mouse), increased femoral metaphyseal density (0.111 ± 0.02 vs 0.034 ± 0.04 g/cm₂), a tendency towards reduced tibial bowing (4.0 ± 3.7 vs 6.1 ± 5.8°), and towards increased femoral diameter (1.22 ± 0.12 vs 1.15 ± 0.11 mm). Potential negative effects included a persistence of calcified cartilage in the treated oim/oim metaphyses compared with treated wildtype (+/+) (33.8 ± 11.1 vs 22.1 ± 10.2%), and significantly shorter femora compared with nontreated oim/oim mice (14.8 ± 0.67 vs 15.3 ± 0.37 mm). This preclinical study demonstrates that alendronate is effective in reducing fractures in a growing mouse model of OI, and is also an important indicator of potential positive and negative outcomes of third-generation bisphosphonate therapy in children with OI.