Objectives: The bone loss after a spinal cord injury (SCI) is particularly rapid, progressive, and severe, which predisposes to an increased risk for fractures that results in hospitalization, increased cost, and decreased quality of life. The rate of bone loss after SCI is at least an order of magnitude greater than that of postmeno- pausal osteoporosis. About 25-46% of persons with SCI may have a fracture over their lifetime. Importantly, risk of fracture may preclude upright activity-based rehabilitation and/or use of the promising exoskeleton techno- logies (e.g., ReWalk or eLegs) and, possibly in the future, transcutaneous spinal cord stimulation for ambulation and advances in neurorepair. Despite the pressing nature of this problem, to date, there is no practical approach to safely and efficaciously treat bone loss and fracture in Veterans with chronic SCI. This application will address the critical need for an effective and safe therapeutic approach for paralyzed Veterans with bone fragility. Anti- Siglec-15 antibody (Ab) can inhibit osteoclast fusion and maturation, but does not inhibit the formation of mono- nuclear pre-osteoclasts, thus maintaining the beneficial communication between bone resorption and formation. These unique features make Siglec-15 Ab distinct from the current anti-resorptive agents that inhibit the activity of both osteoclasts and osteoblasts, which is believed to be a major factor associated with their questionable efficacy in reversing bone loss in those with chronic SCI and the rare, but devasting, side effects of atypical femoral fracture and osteonecrosis of the jaw. The potentially safer therapeutic profile of Siglec-15 Ab also makes it feasible to be used for longer periods of time to treat bone loss in Veterans with chronic SCI compared to the anti-resorptive or bone anabolic agents currently on the market. The latter agents are approved by the FDA to be prescribed only for 1-2 years due to the safety concerns, which would limit their utility in those with chronic SCI. We have recently demonstrated that Siglec-15 Ab (NP159) almost fully prevents the SCI-induced loss of bone mass and preserves trabecular micro-architecture in a rat model of acute SCI. NP159 decreases osteoclast maturation and bone resorption while increasing osteoblastogenesis to maintain bone formation, a process that involves the regulation of microRNA (miR)-183. We also found that the targeted deletion of Siglec-15 allele inhibits bone loss after SCI. A recent report has shown that NP159 promotes bone formation and fracture healing in animal models. The overall goal of this project is to extend our earlier findings and further develop Siglec-15 Ab as a novel treatment option with unique anti-resorptive activity and bone anabolic properties to reverse the marked sublesional bone loss to a clinically relevant degree and to improve skeletal integrity and fracture healing in Veterans with chronic SCI. To achieve our goal, the following preclin...