Background & Aim Gene therapy in the context of the bone remains an underdeveloped field, and most approaches have focused on local delivery of therapeutic transgenes. Generating delivery systems capable of affecting the entire skeleton is particularly challenging compared to discrete organs. Viral vectors have great potential as delivery systems for gene editing technology. In particular, adeno-associated viruses (AAVs) have been identified as ideal candidates for gene therapy due to their high efficiency, low immunogenicity, and selective tropism towards different tissues. In this study we aimed to assess a panel of natural and engineered AAV variants for their tropism towards murine bone cells. Methods, Results & Conclusion We screened 18 natural and engineered recombinant AAV (rAAV) variants. AAVs constitutively expressed Cre-recombinase (under a CAG promoter) and transduction efficiency was assessed using a local injection into a murine tibial fracture model using the Ai9 tdTomato Cre reporter mouse line. Fluorescent alkaline phosphatase (AP) staining was used to identify whether transduced cells were osteoblastic. A single injection of rAAV was administered into midshaft tibial fractures at surgery and yielded robust tdTomato expression within the callus at 2 weeks for AAV8, AAV9, and AAV-DJ (Fig. 1a). Next, a model of systemic delivery by intravenous injection into the tail vein of Ai9 mice was performed, with Cre-expression restricted using bone cell-specific promoters Sp7 and Col2.3. At moderate doses (5 × 1011/mouse or ∼2.5 × 1013/kg) tdTomato+ osteoblasts and osteocytes were observed throughout the long bones (Fig. 1b). Minimal tdTomato expression was observed in other tissues including brain, heart, lung, liver, and spleen, indicating both Sp7 and Col2.3 were able to largely restrict Cre expression to bone cells. To summarize, we have identified AAV variants with a high tropism for murine bone cells, and vectors for high efficiency in vivo gene delivery to bone. The AAV8-Sp7-Cre vector has significant practical applications for inducing gene deletion in floxed mouse models in post-natal bone. Future work will validate AAV vectors that enable targeted CRISPR gene editing that have relevance to the treatment of genetic bone disease.