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Alendronate treatment for infants with osteogenesis imperfecta: demonstration of efficacy in a mouse model
Edith A McCarthy1, Cathleen L Raggio, Michael D Hossack
1Perinatology Division, The New York Presbyterian Hospital-Cornell University, New York, USA. EM9119@aol.com
Insights
Alendronate (ALN) treatment in young osteogenesis imperfecta (OI) mice significantly reduced fractures and improved bone density and quality. Early ALN therapy in OI mice shows promise for treating infants with this bone disorder.
Area of Science:
- Biochemistry
- Orthopedics
- Pediatrics
Background:
- Osteogenesis imperfecta (OI) is a genetic disorder characterized by fragile bones.
- Previous studies suggest bisphosphonates may be effective in treating OI.
- A controlled study is needed to confirm the efficacy of bisphosphonate treatment in OI.
Purpose of the Study:
- To evaluate the effects of alendronate (ALN) on fracture risk, bone quality, and growth in a mouse model of OI.
- To determine if early-onset ALN treatment is effective in improving bone properties in OI.
Main Methods:
- The oim/oim mouse model of OI was used, along with wild-type controls.
- Infant mice (2 weeks old) were treated with ALN (0.03 mg/kg/d) or saline for 12 weeks.
- Evaluations included fracture assessment, bone mineral density, histology, mechanical testing, and growth measurements.
Main Results:
- ALN treatment significantly reduced fractures in oim/oim mice compared to controls.
- Bone density and metaphyseal tibial bone percentage increased significantly with ALN treatment.
- Mechanical testing showed increased structural stiffness in ALN-treated mice; growth and spinal curvature were unaffected.
Conclusions:
- Early-onset ALN treatment in mice with OI effectively reduces fractures and improves bone quality.
- ALN therapy shows potential for treating infants diagnosed with osteogenesis imperfecta.
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.
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