Abstract Metastatic bone disease is a common feature of many types of cancer and has a severe impact on the quality of life of patients. Hence, specific therapeutic strategies inhibiting tumor induced osteolysis are urgently needed. In this study, we aimed to interfere with integrin adhesion receptors, which are central players of the bone resorption process, including osteoclastogenesis as well as osteoclast/bone matrix interaction. For this purpose, we used a cyclic RGD peptide which blocks integrin áVâ3 and áVâ5-ligand binding. Our results revealed that the RGD peptide blocked osteoclast maturation in a dose-dependent manner. In detail, pre-osteoclasts treated with the RGD peptide exhibited reduced cell spreading, migration and adhesion on RGD-containing matrix proteins, such as osteopontin and fibrinogen, which are ligands of integrin áVâ3. The activation of the most upstream signal transduction molecules of the integrin receptor-initiated pathway, such as FAK and c-Src, were consistently blocked by the RGD peptide. First evidence has suggested that the RGD peptide might interfere with metastatic bone disease in vivo and the evidence presented herein describes the underlying mechanisms of the inhibitory effect of the RGD peptide on áV-integrin expressing pre-osteoclasts by blocking integrin ligand binding and interfering with osteoclast maturation and cell behavior. In conclusion, our findings suggest that using an RGD peptide to interfere with áV-integrins on osteoclasts may represent a novel therapeutic strategy in the treatment of malignant bone disease. Citation Format: Gerald Prager, Daniela Bianconi, Anastasia Chillà, Alexandra Dorda, Nisha Geetha, Matthias Unseld, Despoina Sykoutri, Marina Poettler, Kurt Redlich, Christoph Zielinski. Effects of an RGD peptide in osteoclast maturation and behavior as a therapeutic option for metastatic bone disease. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 406. doi:10.1158/1538-7445.AM2015-406