There are still some uncertainties about the causes of Paget’s disease, but it is generally believed to be due to a combination of genetic and environmental influences.
Genetic factors play a key role in predisposing to Paget's disease. It is thought that people who develop Paget’s disease inherit variations in one or more genes that regulate osteoclast activity, causing bone resorption to be increased. This is thought to be responsible for the increased bone remodelling that is typical of the disease. The most important predisposing gene for Paget’s is called Sequestosome 1 (SQSTM1). Abnormalities of SQSTM1 have been identified in 40% to 50% of people with a family history of Paget's disease and also in 5% to 10% of people who have no family history. The children of people with Paget’s disease are about seven times more likely to develop Paget’s disease than people who don’t have a family history.
Environmental factors also play a role in Paget’s disease, as evidenced by the fact, that over the last few decades, the frequency and severity of the disease have declined in many countries, and is most marked in regions that previously had a high prevalence, such as the UK. Various environmental triggers have been suggested, including dietary calcium or vitamin D deficiency, exposure to environmental toxins, repetitive mechanical stress on the bone, skeletal trauma and slow viral infections. Despite this, researchers have yet to discover which environmental factors influence the development of Paget’s disease.