Paget's Disease of Bone in Italy

Abstract

Epidemiological studies of Paget's disease of bone (PDB) suggest a pronounced geographical variation in the prevalence of the disease and a decrease in prevalence and clinical severity over time. To analyze epidemiological and clinical features of PDB in Italy, we recently established a registry of Italian PDB cases and performed radiological, biochemical, and bone scan surveys in the towns of Siena and Turin. The overall prevalence of PDB in Italy varied between 0.7% and 2.4%. Prevalence rates increased with age and were higher in men than in women. We observed clinically confirmed familial aggregation in 15-26% of cases. Pedigree analysis indicated an autosomal dominant pattern of inheritance with variable penetrance. SQSTM1 gene analysis in two Italian studies revealed the presence of at least three different mutations accounting for both familial and sporadic cases. Interestingly, no decrease in the prevalence of PDB over time was observed, the opposite of what is described in populations of British descent. However, clinical severity of PDB cases included in the Registry in 2002-2004 seemed reduced with respect to that of PDB patients from the previous epidemiological studies, including a 1950-1956 Italian study. Of interest, a consistent association between PDB and animal-related factors and a significantly higher prevalence of the disease in rural than in urban districts were observed. These findings are in keeping with an important role of the environment in the pathogenesis of PDB, perhaps facilitating the expression of the disease in genetically susceptible subjects. Finally, there was also preliminary evidence indicating regional clustering of PDB in Italy, with a concentration of cases in rural districts of Campania and Tuscany. These districts may represent high prevalence areas of PDB in Italy, similar to what has been observed in other countries. Extrapolation estimates suggest that ∼150,000-300,000 subjects may be affected with PDB in our country. These results confirm PDB to be the most common bone remodeling disorder in elderly people in Italy, excluding osteoporosis.

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

“…In keeping with our previous observations, (27,28) PDB subjects from Campania showed an earlier age at diagnosis (56.6 AE 11.3 versus 61.4 AE 12.1, p < .0001) and an increased clinical severity with respect to PDB patients from other Italian regions. In particular, an increased proportion of polyostotic cases (72.5% versus 50.4%, p < .0001) and an increased number of affected skeletal sites (3.1 AE 2.2 versus 2.2 AE 1.9, p < .0001) were observed in PDB patients from Campania than in patients from other regions.…”

“…(35)(36)(37) In fact, more than 50% of the patients described originated in or descended from ancestors who lived in this Italian region. (27) Thus it can be speculated that a different gene is responsible for this particular variant of familial PDB, alone or in combination with an environmental trigger. (38) Phenotype-genotype associations in PDB have not been investigated extensively, and the results from available reports are conflicting.…”

“…Patients from this region also showed increased severity of disease often associated with peculiar phenotypic characteristics (ie, giant cell tumor) and an increased number of familial cases. (26)(27)(28) In this study we compared the clinical characteristics and prevalence and type of SQSTM1 mutations in a large sample of unrelated PDB patients from several Italian regions, including patients from the high-prevalence area of Campania. This sample also included three families with PDB associated with giant cell tumor.…”

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

“…Even though patients with SQSTM1 mutations generally show an increased disease severity than SQSTM1-negative patients, (9,10) we recently identified SQSTM1-negative patients with a severe phenotype and the presence of peculiar phenotypic characteristics, including the occurrence of giant cell tumors (GCT) originating from affected skeletal sites. (9,11,12) This complication represents a very uncommon clinical feature of PDB (described in less than 100 cases worldwide), and mainly occurs in patients with severe polyostotic PDB. (11)(12)(13)(14)(15) GCTs may be multifocal and aggressive, leading to increased morbidity and mortality of patients.…”

“…(9,11,12) This complication represents a very uncommon clinical feature of PDB (described in less than 100 cases worldwide), and mainly occurs in patients with severe polyostotic PDB. (11)(12)(13)(14)(15) GCTs may be multifocal and aggressive, leading to increased morbidity and mortality of patients. Patients with extensive, recurrent, and/or biologically more aggressive tumors may require wide excision, and often do not respond to antiresorptive compounds commonly in use to treat PDB such as calcitonin or bisphosphonates.…”