Paget's disease of bone is a chronic focal skeletal disorder that affects up to 
2-3% of the population over the age of 60 years. Paget's disease is primarily a 
disease of the osteoclast. The pathologic abnormality in patients with Paget's 
disease involves increased bone resorption by the osteoclasts, followed by 
abundant new bone formation that is of poor quality. Genetic linkage analysis 
indicated that 40% of patients with Paget's disease have an affected first 
degree relative and 1% of patients develop osteosarcoma. Paget's disease is an 
autosomal dominant trait with genetic heterogeneity. Recurrent mutations in the 
ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1/p62) are identified 
in patients with Paget's disease. Osteoclasts and osteoclast precursors from 
patients with Paget's disease contain paramyxoviral transcripts and appear 
hyperresponsive to 1,25-(OH)2D3 and RANK ligand (RANKL). It has been suggested 
that the enhanced sensitivity of osteoclast precursors for 1,25-(OH)2D3 in 
Paget's disease results from increased expression of coactivators of vitamin D 
receptor (VDR). However, a cause and effect relationship for the paramyxoviral 
infection and SQSTM1/p62 gene mutations associated with this disease and 
osteoclast abnormalities are unclear. Therefore, the etiology of Paget's disease 
remains uncertain.