Pathogenesis and precision management of osteogenesis imperfecta: from genetic mechanisms to novel therapies.

BACKGROUND

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous skeletal dysplasia characterized by systemic bone fragility. Beyond skeletal manifestations, OI is a multisystem condition involving dentinogenesis imperfecta, hearing loss, joint hyperlaxity, and cardiopulmonary complications. The diagnostic paradigm for OI has undergone a revolutionary shift from traditional clinical phenotyping to a molecular etiology-based framework. Driven by advancements in high-throughput sequencing, mutations in over 20 implicated genes have expanded the current OI nosology to at least 23 distinct types.

DATA SOURCES: This narrative review was conducted by searching for papers using PubMed/MEDLINE. Relevant publications were identified using single and/or combined keywords including: osteogenesis imperfecta, genes (such as COL1A1 and COL1A2), animal models, phenotypes (such as osteopenia and femoral bowing), and drug therapies (such as bisphosphonate and denosumab), mesenchymal stem cells, gene therapy, and pluripotent stem cells.

RESULTS

This review systematically delineates the molecular pathogenesis of OI, categorizing defects into disrupted collagen biosynthesis, impaired post-translational modification, aberrant procollagen trafficking, and dysfunctional osteoblast differentiation or mineralization pathways. Of note, we highlight the unique genetic landscape and clinical characterization of OI within Asian populations. Furthermore, we evaluate the transition towards precision management. Surgical management of OI has been optimized by telescopic rodding and a multidisplinary approach. Bisphosphonates remain a cornerstone of medical therapy, though responses vary with OI genotypes. Emerging targeted biologics include denosumab, romosozumab, setrusumab, and fresolimumab. Finally, we discuss the transformative potential of cell-based therapies, particularly mesenchymal stem cells. Precision gene editing technologies, such as CRISPR-Cas9, offer a strategy in addressing the root genetic causes of OI.

CONCLUSIONS

Integrating molecular diagnostics with robust genotype-phenotype correlations is essential for advancing personalized care. Future breakthroughs will rely on the translation of gene and cell therapies to ultimately improve the long-term clinical outcomes for patients with OI.