Current treatments for osteolytic cancers include a combination of radiation, chemotherapy and cytotoxic products, but toxic side effects are still of major concern. Studies have shown that osteoclast activity is increased in patients with osteolytic cancers such as Multiple Myeloma (MM), through increased expression of Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) leading to RANKL/RANK signaling, resulting in osteoclast activation and ultimately bone resorption. Moreover, Osteoprotegerin (OPG) is drastically decreased in these patients who presents with bone lesion. Thus, the use of OPG as a therapeutic molecule would greatly decrease osteolytic damage and reduce morbidity. However, despite the of OPG potential in inhibiting the activation of bone resorbing osteoclast, OPG also binds to tumor related apoptosis-inducing ligand (TRAIL) making tumor cells resistant to apoptosis. TRAIL binds to the Death Receptor 4 and 5 (DR4, DR5) and initiate cell death of Transformed cells such as MM. The present study was designed to develop a novel therapeutic approach to the treatment of osteolytic bone damage by use of genetically altered OPG retaining RANKL binding but abolished of TRAIL binding. In order to eliminate TRAIL binding while maintaining RANKL binding, we created mutant OPG-Fc constructs by site directed mutagenesis based on interactive domain identification and by superimposing structural models of TRAIL, OPG and DR5. The mutant OPGs were produced in HEK 293 cells for characterization of potential mutants and their TRAIL binding ability. We conclude that using site-directed mutagenesis at the N-terminal of OPG effectively retains RANKL binding property but abolishes TRAIL binding property as determined by osteoclast and TRAIL assays respectively. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4943. doi:1538-7445.AM2012-4943