However, about 10-15 percent of people that develop the disease without any family history also have a mutation in the SQSTM1 gene.Pagets disease of bone is associated with mutations in RANK. Receptor Activator of Nuclear Factor κ B (RANK), which is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding. Additional genetic associations include:

Pathogenesis
The pathogenesis of Pagets disease is described in four stages:
Osteoclastic activity
Mixed osteoclastic – osteoblastic activity
Osteoblastic activity
Malignant degenerationInitially, there is a marked increase in the rate of bone resorption in localized areas, caused by large and numerous osteoclasts. These localized areas of pathological destruction of bone tissue (osteolysis) are seen radiologically as an advancing lytic wedge in long bones or the skull. When this occurs in the skull, it is called osteoporosis circumscripta. The osteolysis is followed by a compensatory increase in bone formation induced by the bone-forming cells, called osteoblasts, that are recruited to the area. This is associated with accelerated deposition of lamellar bone in a disorganized fashion. This intense cellular activity produces a chaotic picture of trabecular bone ("mosaic" pattern), rather than the normal linear lamellar pattern. The resorbed bone is replaced and the marrow spaces are filled by an excess of fibrous connective tissue with a marked increase in blood vessels, causing the bone to become hypervascular. The bone hypercellularity may then diminish, leaving a dense "pagetic bone," also known as burned-out Pagets disease.
Any bone or bones can be affected, but Pagets disease occurs most frequently in the spine, skull, pelvis, femur, and lower legs. Osteogenic sarcoma, a form of bone cancer, is a rare complication of Pagets disease occurring in less than one percent of those affected. The development of osteosarcoma may be suggested by the sudden onset or worsening pain. Epidemiology
Pagets disease of bone is the second most common metabolic bone disorder, after osteoporosis. The overall prevalence and severity of Pagets disease are decreasing; the cause for these changes is unclear. Pagets disease is rare in people less than 55 years of age, and the prevalence increases with age. Evidence from studies of autopsy results have demonstrated Pagets disease in about 3 percent of people older than 40 years of age. Pagets disease is more common in males than females. Rates of Pagets disease are about 50 percent higher in men than in women. About 15 percent of people with Pagets disease also have a family member with the disease. In cases where the disease is familial, it is inherited in an autosomal dominant fashion, although not all people that inherit the affected version of the genes will express the disease (incomplete penetrance).The incidence of Pagets disease varies considerably with geographic location. Pagets predominantly affects people of European descent, whereas people of African, Asian, or Indian descent are less commonly affected. Pagets disease is less common in Switzerland and Scandinavia than in the rest of Western Europe.