title: Alendronate treatment for infants with osteogenesis imperfecta: demonstration of efficacy in a mouse model.
abstract: Recent non-placebo-controlled studies of the bisphosphonate pamidronate have shown it to be effective in reducing fractures and improving bone density in infants and children with osteogenesis imperfecta (OI). To evaluate the effects of bisphosphonate treatment in a controlled study, the oim/oim mouse model of OI was studied. Nursing infant mouse pups (approximately 2 wk old) with moderate to severe OI (oim/oim mouse) and age- and background-matched control mice (+/+) were treated either with the third-generation bisphosphonate alendronate (ALN), or with saline. Fracture risk, bone quality, and growth were evaluated over a 12-wk treatment period. ALN at a dose of 0.03 mg/kg/d or saline was administered via s.c. injection to infant oim/oim and wild-type (+/+) mice from 2 to 14 wk of age (n = 20 per subgroup). The average number of fractures sustained by the ALN-treated oim/oim mice was reduced significantly compared with the untreated oim/oim mice (0.7 +/- 0.7 fractures/mouse versus 2.0 +/- 0.2 fractures/mouse). Bone density increased significantly in the femur and the spine with treatment (2.0 +/- 0.5 versus 1.2 +/- 0.5 in femur and 2.1 +/- 0.5 versus1.6 +/- 0.5 in spine). Histologic evaluation revealed the percentage of metaphyseal tibial bone increased significantly with treatment in both +/+ and oim/oim mice. Mechanical testing revealed an increase in structural stiffness for both treated +/+ and oim/oim mice compared with untreated animals. None of the material properties examined were significantly altered with treatment, nor was spinal curvature affected. Weight gain and long bone growth were comparable in the treated and untreated oim/oim mice. In wild-type mice, femur lengths were significantly shorter in the treated mice compared with untreated counterparts. This animal study demonstrates that treatment of OI in mice as early as 2 wk of age with ALN appears to be effective in reducing fractures and increasing bone properties. Based on the data from this study, ALN therapy in infants with OI should prove to be effective.
authors.affiliation: Perinatology Division, The New York Presbyterian Hospital-Cornell University, New York, USA. EM9119@aol.com
authors.forename: Edith A
authors.initials: EA
authors.lastname: McCarthy
authors.forename: Cathleen L
authors.initials: CL
authors.lastname: Raggio
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hossack
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Miller
authors.forename: Sargam
authors.initials: S
authors.lastname: Jain
authors.forename: Adele L
authors.initials: AL
authors.lastname: Boskey
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Camacho
mesh_terms: D019386:Alendronate / Q000627:therapeutic use*; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D024042:Collagen Type I / Q000172:deficiency; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004548:Elasticity; D005260:Female; D005598:Fractures, Spontaneous / Q000517:prevention & control; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010013:Osteogenesis Imperfecta / Q000188:drug therapy* / Q000473:pathology
chemical_list: D024042:Collagen Type I; D019386:Alendronate