Advances in the genetics of Paget's disease of bone: from pathophysiology, diagnosis to clinical implications

Paget's Disease of Bone (PDB) is a chronic, late-onset skeletal disorder characterized by highly localized regions of increased bone resorption, accompanied by excessive and abnormal new bone formation. Consequently, PDB serves as a crucial model for elucidating the genetic and molecular mechanisms governing both abnormal osteoclast formation and osteoclast-induced osteoblast/osteocyte activities.

This narrative review based on the available indexed literature examines the genetics of PDB and its connections with the pathophysiology of the disease, focusing on interactions with bone cells, environmental factors, clinical presentation, and complications.

PDB research highlights the importance of genetic studies, and the need for further research especially in families not linked to SQSTM1 pathogenic variants. Enhancing education for health care professionals is critical, given PDB's rarity and its exclusion from medical curricula, which leads to diagnostic delays and mismanagement. Further exploration of gene-environmental interactions and the role of bone cells in lesion formation remains a priority. Advances in precision medicine may soon allow genetic testing to predict the risk of PDB using polygenic risk scores, leading to targeted prevention strategies. Future treatments may involve SQSTM1 gene inhibitors, such as siRNA, offering a personalized approach to early prevention and management of PDB.