The skeleton is frequently affected in patients with Neurofibromatosis type I (NF1). Manifestations include mild shortness of stature and reduced bone mineral density, but also focal bony lesions such as pseudarthrosis (bone non-union following fracture) that are associated with significant morbidity. The natural history and pathogenesis of the NF1 skeletal abnormalities are poorly understood and therapeutic options for these manifestations are limited. The overall goal of this work is to address whether bone quality and mechanical properties of dysplastic NF1 bones can be improved by the elimination of pyrophosphate, a potent physiological inhibitor of bone mineralization whose production was found increased in Nf1-deficient osteoprogenitors. If so, fracture and pseudarthrosis could be prevented in these patients, avoiding significant clinical problems and healthcare costs. A second main goal is to understand the nature of the cellular interactions at the origin of NF1 pseudarthrosis, as a way to identify novel strategies to prevent it. Finally and based on the beneficial effect of rALP on bone structure, composition and strength in our mouse models of NF1 pseudarthrosis, we propose to transition to the next logical step, which is to develop tools to predict the bone alterations seen in this population of children, before skeletal dysplasia develops. For that purpose, we will compare novel approaches to predict strength and fracture risk of the NF1 dysplastic bones, using methods that are free of radiation and non-invasive, as children with NF1 are prone to tumor formation.