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Abstract: Large bone defects in load-bearing bone can result from tumor resection, osteomyelitis, trauma and other factors. Although bone has the intrinsic potential to self-repair and regenerate, the repair of large bone defects which exceed a certain critical size remains a substantial clinical challenge. Traditionally, repair methods involve using autologous or allogeneic bone tissue to replace the lost bone tissue at defect sites, and autogenous bone grafting remains the “gold standard” treatment. However, the application of traditional bone grafts is limited by such drawbacks as the quantity of extractable bone, donor-site morbidities, and the risk of rejection. In recent years, clinical demand for alternatives to traditional bone grafts has promoted the development of novel bone grafting substitutes. In addition to osteoconductivity and osteoinductivity, optimal mechanical properties have recently been the focus of efforts to improve the treatment success of novel bone-grafting alternatives in load-bearing bone defects, but most biomaterial synthetic scaffolds cannot provide sufficient mechanical strength. A fundamental challenge is to find an appropriate balance between mechanical and tissue-regeneration requirements. In this review, the use of traditional bone grafts in load-bearing bone defects as well as their advantages and disadvantages are summarized and reviewed. Furthermore, we highlight recent development strategies for novel bone grafts appropriate for load-bearing bone defects based on substance, structural, and functional bionics to provide ideas and directions for future research.