Paget's disease of bone (PDB) is a chronic, invalidating disease affecting up to 1% of subjects after 50 years of age. It is characterized by enlargement and deformation in one or more bones, leading to pain, osteoarthritis, deformity and fractures. In some cases pagetic tissue may undergo neoplastic transformation in osteosarcoma and less frequently giant cell tumor (GCT). Despite the recent advances (with the identification of mutations in SQSTM1 gene in up to 45% of familial PDB), the mechanisms causing PDB remain in large part unknown. This project had 2 main objectives: 1) the identification of a new gene causing PDB and GCT in patients without SQSTM1 mutation (through the analysis of a large pedigree with 14 affected members) and 2) the analysis of the response to bisphosphonate treatment in relation to the presence of SQSTM1 gene mutations (Pharmacogenetic analysis). The use of modern techniques of molecular biology led us to the identification of a new gene causing PDB (ZNF687) in the large pedigree. Mutations in the same gene were observed in 2 additional families, in all the 7 analyzed cases of PDB associated with GCT, and in 4 patients with severe PDB without neoplastic degeneration. Even though the exact mechanism linking ZNF687 to PDB remains to be investigated in detail, our experimental analyses demonstrated that this gene is important for osteoclast and osteoblast cells (the cells involved in bone resorption and bone formation, respectively). Pharmacogenetic analysis demonstrated that patients with SQSTM1 may require a more aggressive treatment regimen (i.e. with potent bisphosphonates such as Zoledronic Acid) for long-term disease remission. Taken together these data have improved our understanding of PDB pathogenesis, increasing the options for an early diagnosis (with the addition of another gene associated with increased disease severity as well as with an enhanced prevalence of neoplastic degeneration). These efforts, together with the pharmacogenetic implications are thus expected to impact on the diagnosis, prevention and treatment of this invalidating disease over the next years.