Osteogenesis imperfecta (OI) is a heterogenous type 1 collagenopathy that results in bone fragility and fractures. There is no standard-of-care treatment to reduce fracture risk for adults with OI. The sialic acid-binding immunoglobulin-like lectin 15 (Siglec 15) immunoreceptor modulates osteoclast development and bone resorption. Prior studies in growing rats demonstrated that Siglec 15 antibodies increased bone mass and improved bone mechanical properties. This study evaluated the safety and efficacy of a Siglec 15 monoclonal antibody, NP159 (NextCure Inc.), in female oim/oim and wildtype (WT) mice. Mice (n = 20/group) were treated from 14 to 26 weeks with either NP159 (10 mg/kg/dose weekly for 4 weeks, then biweekly for 8 weeks), weekly alendronate (ALN, 0.21 mg/kg), or weekly saline (equivalent to NP159). Faxitron images (anterior-posterior and medial-lateral) were taken at enrollment and sacrifice to evaluate fracture incidence and healing. Left femurs were analyzed for length, micro-CT parameters, and biomechanical testing. Right tibias were analyzed by Fourier transform infrared spectroscopy. NP159 reduced fracture incidence in oim/oim, 85% of whom were fracture-free at sacrifice compared to 65% in the ALN group and 55% in the saline group. NP159 treatment enhanced bone strength and structure in oim/oim, with mineral:​matrix and carbonate:​phosphate content that normalized towards the WT saline group. Unlike ALN, NP159 had a larger increase in bone stiffness(p < 0.05) and enhanced both bone microarchitecture and mineralization without altering Bone Mineral Density. Overall, these findings demonstrate the therapeutic value of NP159 in addressing the presently unmet clinical need for safe and efficacious long-term treatments for adults with OI.