Modeling rare genetic skeletal disorders with bone organoids: a narrative review

Rare genetic skeletal disorders (RGSDs) encompass a heterogeneous group of hundreds rare conditions affecting the skeletal system. The rarity of these disorders, phenotypic and genetic diversity, combined with the limitations of conventional cellular and animal RGSD models, have hindered progress in understanding their pathophysiology and developing effective therapies. However, the latest advances in stem cell and bone tissue engineering techniques offer transformative opportunities in investigation of RGSD, particularly through bone organoids that enable disease modeling within a precision medicine framework. This review outlines the progress in RGSD organoid research, starting with the pivotal concepts of RGSDs bone biology, and extending to the disease-specific molecular signatures essential for selecting cell sources, biomaterials, and biofabrication strategies to improve the translational relevance of the models. We critically evaluate existing bone organoid models for osteogenesis imperfecta, hypophosphatasia, fibrous dysplasia, Gaucher disease, and other representative RGSDs. Finally, we consider ethical implications of animal-free and patient-centric organoid research. By integrating the latest advancements in RGSD biology and organoid research, this review outlines how molecular pathophysiology can guide organoid design and highlights key methodological advances that could accelerate therapeutic discovery and progress in precision skeletal medicine.