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.

Craniofacial disorders and dysplasias: Molecular, clinical, and management perspectives

“…In addition, germline mutations of zinc finger protein 687 ( ZNF687) and profilin 1 ( PFN1) genes are known to be associated with severe, early-onset polyostotic Paget disease of bone ( Gennari et al, 2022 ). Familial association has been demonstrated as well as an association with paramyxovirus based on occurrence of cytoplasmic and nuclear inclusions of virus in osteoclasts ( Banaganapalli et al, 2023 ). Histologically, the severity of the disease correlates with frequency of intranuclear inclusions.…”

Paget's disease of bone in the patient presented with a bowed leg

“…Paget's disease of the bone (PDB) is the second most prevalent metabolic bone disorder worldwide, with a prevalence rate of 1.5%-8.3% characterized by disorganized bone remodeling as a result of fast bone resorption and bone formation by osteoclast and osteoblasts activity, respectively. [1][2][3] Along with long bone deformities, protruded foreheads, fractures, and hearing loss may occur. 4 In case of doubt, the diagnosis must be confirmed by radiographic modalities.…”

Paget’s Disease of the Bone and Lynch Syndrome: An Exceptional Finding

“…Recent Genome Wide Association Studies (GWAS) identified susceptibility genes, loci and single nucleotide variants, including rs1561570 within the OPTN gene, rs484959 near the CSF1 gene, rs3018362 near the TNFRSF11A gene, rs5742915 within the PML gene, and others [ 1 ]. Another role in disease development may be played by epigenetic modifications of genes involved in bone metabolism such as RANKL (receptor activator of nuclear factor-kB ligand), OPG (osteoprotegerin), HDAC2, DNMT1, and SQSTM1 [ 10 ]. Among the environmental factors, we mention exposure to zoonoses (canine distemper) and viral infections (measles and respiratory syncytial virus), environmental toxins, vitamin D deficiency in childhood and skeletal injury, and repetitive mechanical loading [ 11 , 12 , 13 , 14 , 15 ].…”

“…Mostly, they include: bone pain in the affected region; possible warmth and redness accompanying pain due to an increased vascularisation; bone enlargement and deformities such as bowing of the legs, skull enlargement, and kyphosis may be present; and the axial skeleton, which is most commonly affected. Other clinical elements are: constipation, abdominal pain, and hearing loss, as well as headache, especially related to skull involvement [ 10 , 24 , 25 ].…”