Paget’s Disease of Bone

Abstract

Paget’s disease of bone (PDB) is the second most common metabolic bone disease in elderly people, after osteoporosis. PDB is characterized by focal abnormal bone remodeling, preferentially affecting the axial skeleton, which gradually leads to bone deformity and pathological fracture.

The exact etiology of PDB has not been fully elucidated yet. A combination of environmental and genetic factors is suspected to contribute to the development of the disease, with genetic causes being responsible for up to 40% of individuals with PDB having at least one first-degree affected relative. Currently, only the sequestosome 1 (SQSTM1) gene, encoding the homonym SQSTM1/p62 protein, has been clearly identified as responsible for the development of the late-onset classical PDB, with germline mutations occurring in about 40–50% of familial and 2.5–10% of sporadic PDB cases. However, the disease shows an incomplete penetrance even among mutation carriers, and a high inter- and intrafamilial genetic heterogeneity has been demonstrated in linkage studies of PDB pedigrees, suggesting that the PDB phenotype could be the result of mutations or polymorphisms in multiple genes.