Paget's disease: a review of the epidemiology, etiology, genetics, and treatment

Abstract

Paget's disease of bone (PDB) is the second most prevalent metabolic bone disorder worldwide, with a prevalence rate of 1.5%-8.3%. It is characterized by localized areas of accelerated, disorganized, and excessive bone production and turnover. Typically, PDB develops in the later stages of life, particularly in the late 50s, and affects men more frequently than women. PDB is a complex disease influenced by both genetic and environmental factors. PDB has a complex genetic basis involving multiple genes, with SQSTM1 being the gene most frequently associated with its development. Mutations affecting the UBA domain of SQSTM1 have been detected in both familial and sporadic PDB cases, and these mutations are often associated with severe clinical expression. Germline mutations in other genes such as TNFRSF11A, ZNF687 and PFN1, have also been associated with the development of the disease. Genetic association studies have also uncovered several PDB predisposing risk genes contributing to the disease pathology and severity. Epigenetic modifications of genes involved in bone remodelling and regulation, including RANKL, OPG, HDAC2, DNMT1, and SQSTM1, have been implicated in the development and progression of Paget's disease of bone, providing insight into the molecular basis of the disease and potential targets for therapeutic intervention. Although PDB has a tendency to cluster within families, the variable severity of the disease across family members, coupled with decreasing incidence rates, indicates that environmental factors may also play a role in the pathophysiology of PDB. The precise nature of these environmental triggers and how they interact with genetic determinants remain poorly understood. Fortunately, majority of PDB patients can achieve long-term remission with an intravenous infusion of aminobisphosphonates, such as zoledronic acid. In this review, we discuss aspects like clinical characteristics, genetic foundation, and latest updates in PDB research.

Keywords: Paget’s disease of bone; SQSTM1; environmental factors; genetics factors; osteoclast (OCs).