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Purpose: Autografts, the gold standard treatment for large bone defects, present complications, especially in conditions with reduced bone-repair capacity, such as osteoporosis. Escherichia coli -derived recombinant human bone morphogenesis protein-2 (ErhBMP-2), was used in this study to improve the osteoinductivity of β-tricalcium phosphate (β-TCP). This study evaluated the bone-repair capacity of ErhBMP-2-loaded β-TCP on osteoporosis rabbit model, relative to the sole use of autograft and β-TCP treatments., Methods: The osteoporosis rabbit model was induced through ovariectomy and glucocorticoid dosing; 2-cm segmental ulnar defects were created, which were treated with either autograft, β-TCP alone, or ErhBMP-2-loaded β-TCP or left untreated. The quality of newly formed ulnae was evaluated 8 weeks after ulnar surgery through micro-CT, biomechanical, histological, and histomorphometric assessments., Results: The osteoporosis rabbit model was developed and maintained till the end of the study. The maximal load and stiffness in the ErhBMP-2-loaded TCP group were significantly higher than those in the autograft group, whereas the TCP-alone group performed similarly as did the untreated group in the force loading and stiffness tests. According to the micro-CT evaluation, the ErhBMP-2-loaded TCP group had significantly higher bone volume relative to the autograft and TCP-alone groups. Histological assessments revealed better defect bridging and marrow formation in the ErhBMP-2-loaded TCP group relative to the TCP-alone group. Mineral apposition rates were significantly higher in the ErhBMP-2-loaded TCP and autograft groups than in the TCP-alone and untreated groups., Conclusion: Relative to autografts, ErhBMP-2-loaded TCP, as an alternative grafting material, provides better or comparable healing on critical-sized long bone defects in the osteoporosis rabbit model., Competing Interests: The authors have declared no conflict of interest., (© 2020 The Authors.)