Bone Organoids Across the Development-to-Remodeling Continuum: From Tissue Formation to Functional Competence and Translation

Bone organoids are emerging as three-dimensional skeletal models that reproduce selected aspects of bone development, organization, and function under controlled conditions. Physiologically relevant models require more than cellular aggregation and mineral deposition; they must progressively acquire organized matrices, multicellular interactions, vascular and metabolic support, and mechanical responsiveness. In this review, we examine developmental principles guiding bone-organoid construction, including skeletal hierarchy, cellular niches, ossification pathways, and spatiotemporal signaling. We then discuss current strategies based on skeletal, mesenchymal stromal, and pluripotent stem cells, together with advances in biomaterials, three-dimensional bioprinting, perfusion, and microfluidic culture. To organize these developments, we introduce the development-to-remodeling continuum (DRC), which distinguishes tissue formation from multicellular integration, adaptive responsiveness, and remodeling competence. We assess collagen-mineral organization, osteocyte-network formation, vascular and metabolic maturation, osteoblast-osteoclast coupling, marrow and immune integration, and mechanical adaptation. We further evaluate applications in developmental and disease modeling, drug assessment, personalized modeling, and bone regeneration. Current limitations include variability, incomplete maturation, transport constraints, and insufficient functional benchmarking. By linking construction strategies to specific bone-related functions and the evidence supporting them, the DRC provides a framework for evaluating functional claims in relation to intended application and translational readiness.