Abstract Accelerated bone loss is associated with a number of metabolic and neoplastic conditions. Estrogen-receptor modulation, bisphosphonates (BP), and RANKL-inhibitors (RLI) are useful for metabolic bone disease. Parenteral BPs and RLIs are also associated with skeletal morbidity, including osteonecrosis. No oral agent has yet proved suitable for treatment or prevention of adverse skeletal-related events (SREs) in cancer patients (pts) with bone metastases. Our prior work showed that low-dose gallium (G) nitrate administered by subcutaneous injection (SC) reduced markers of accelerated bone resorption in pts with bone metastases from various tumor types, as well as advanced Paget's disease. Moreover, extended therapy for 6-12 mos (0.5 mg/kg SC 2 wks on/2 wks off) produced substantial increases in total body calcium (measured by neutron activation analysis) in pts with myeloma receiving chemotherapy. However, inorganic G-compounds also exhibit low oral availability. Therefore, we synthesized a series of organic G-containing compounds to test their suitability as facilitators of long-term G administration. This work isolated several lead compounds that were then evaluated in animal studies. Methods: Isolated compounds were administered by oral gavage to dogs (Calvert Laboratories, Inc.), which then underwent serial blood sampling over 24 hrs. The objective was to achieve target plasma concentrations at specific times that had proved effective in acutely normalizing elevated blood calcium in human subjects with cancer-related hypercalcemia. Results: Various amino acid-like complexes yielded unpredictable results. Proline and carnosine showed only modest oral availability, compared with mandalate and histidine complexes that were superior. Among other organic bidentate G compounds, G4544(a) achieved a peak target, but time-to-peak (TTP) concentrations was delayed. G-4544(b), the same complex but with reduced nitrate content, improved TTP concentrations, but a follow-on study in human subjects failed to reproduce observations in dog (Proc. AACR 2010). To date, the complexes G4546 and G4547 yielded the best results, promptly achieving peak stable concentrations consistent with target objectives. Conclusion: The organic G compound, G4546, will be advanced into human clinical trials to determine its suitability for extended treatment of oncology patients who may develop accelerated bone loss. 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 3779. doi:1538-7445.AM2012-3779