DEVELOPMENT OF A TREATMENT FOR OSTEOGENESIS IMPERFECTA

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The goal of this study is to use an animal model to test a method for treating a class of bone diseases known as osteogenesis imperfecta (OI). In these disorders, the patient has one of numerous possible mutations in the genes that code for Type l collagen. This results in the production of abnormal Type l collagen molecules, or insufficient amounts of this structural protein, or both. In any case, there can be substantial weakening of the patient's bone tissue. This leads to fractures caused by (1) the weakened bone material, and (2) excessive porosity produced by the bone's attempt to repair itself by remodeling. OI patients can only be cured through correction of their genome, a prospect on the horizon but unlikely to affect many patients soon. In the meantime, we propose that substantial amelioration of this disease can be achieved in children by controlling the bone modeling and remodeling processes so as to compensate for, and restrain negative responses to, the collagen defect. The agent we propose to use for this purpose is alendronate, a bisphosphonate that blocks bone resorption. This drug could benefit the juvenile OI patients by blocking the normal resorptive process on the metaphyseal surfaces of the patient's long bones, resulting in larger bones that compensate for the weak material within the cortex. Unfortunately, however, it is also possible that alendronate could interfere with the growth of the patient and produce negative as well as positive effects in terms of skeletal development. The specific aims are to 1) use the oim transgenic mouse model to test this method of treatment and elucidate its mechanisms in detail, and 2) determine whether the use of alendronate in children will have negative effects of their growth.