lay of OS development. Thus, prophylactic treatment with bisphosphonates, which have safely and effectively been used to treat Paget’s disease of the bone, could benefit patients at elevated risk of developing OS or could be used as an adjuvant therapy after removal of a primary OS lesion. In addition to the increased risk of developing OS secondary to radiation therapy, several genetic cancer syndromes exist that place affected people at high risk for OS development. Alterations and mutations in the p53, retinoblastoma or neurofibromatosis1 pathways predispose patients to OS and components are these pathways are commonly mutated in spontaneous human OS. Notably, the incidence of OS is markedly increased in patients with hereditary retinoblastoma and in patients with the autosomal dominant Li Fraumini p53 mutations. The diminished cost of genomic sequencing has enabled more testing for cancer predisposition syndromes. For example NF1 mutations occur in 1 in 1000 people and NF1 patients are at increased risk for OS. Our data would 552-41-0 suggest that clinical trials to evaluate agents like zoledronic acid in the prevention of OS in high-risk populations and to prevent recurrence and metastasis after resection/treatment of primary OS tumors should be considered. Preclinical studies demonstrate that ZA can decrease prostate cancer osteoblastic bone metastasis and tumor growth. Bisphosphonate administration to patients with localized breast cancer has been associated with improved disease-free survival, decreased metastasis, lower occurrence of new breast cancers and decreased numbers of bone marrow micrometastases. Here we report a role for bisphosphonates in the prevention of OS development in a high risk model, which would be difficult to evaluate using xenograft models of established OS and osteoblastic metastases. In summary, our data suggest a role for ARF as a regulator of normal bone remodeling and malignant bone tumor formation. The sensitivity of OS development to repression of bone resorption broadens the range of potential therapeutic prevention targets for patients at high risk for OS development. Tax+Arf-/- osteosarcoma tumors arise primarily in jaw and skull bones. The locations of n = 50 OS tumors arising in Tax+Arf-/- mice. The majority of tumors arose in the mandible, often presenting with malocclusion prior to palpable tumor. Other bones of the skull include the frontal, parietal and premaxillary lobes. Maxillary bones contain the upper incisors and upper molars. Tumors occasionally arise in the long bones of the legs, however, these arise much later than the 
tumors of the skull and jaw. significant increase in Tax+Arf-/- osteoblast differentiation relative to Arf deficiency alone. In vitro differentiation of Arf+/+, Tax+, Arf-/- and Tax+Arf-/- OB from primary bone marrow stromal cells under osteogenic conditions. Cells were co-stained for alkaline phosphatase expression and mineralization at indicated days. Representative of.3 independent experiments. Note that the experiment presented here is the same presented in Fig 1e. Acknowledgments We are grateful to N. Campbell, D. Huey, S. Gross, V. Salazar, L. Lanigan, M. Tomasson, S. Teitelbaum, F.P. Ross and D. Novak for excellent advice and/or technical assistance. MicroCT services provided by Washington University Center for Musculoskeletal Research. Author Contributions Conceived and designed the experiments: DAR MAH JCH HD LKS MCE SN MDL DP-W TJR JDW LR KNW. Performed the experi