A single faulty gene, SQSTM1, condemns up to 40% of inherited Paget’s disease patients to crippling bone deformities and deafness by middle age—and this trial aims to stop the disease before it starts. The problem is that bisphosphonate drugs can treat Paget’s disease, but by the time symptoms appear, the bones have already suffered irreversible damage. This research asks whether genetic testing can identify at-risk individuals early enough for preventive treatment to work. The team will screen people with a family history of Paget’s disease for the SQSTM1 mutation, then randomly assign carriers to receive either an active bisphosphonate or a placebo for five years. Neither patients nor doctors will know who gets what. If the trial shows that early, targeted treatment prevents bone abnormalities from developing, the approach could become routine NHS care. That would shift Paget’s disease from a condition managed after damage occurs to one prevented entirely in high-risk families—sparing thousands from chronic pain, fractures, and hearing loss. The research is a direct test of a practical intervention, not fundamental science; its success would mean a clear, deployable change in clinical practice.
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Paget disease of bone (PDB) is a serious bone disease which causes pain, arthritis and deafness and which can cause softening of the bones causing then to enlarge and become bent. Up to 40% of patients with the PDB have inherited it from family members and a mutation in the gene SQSTM1 is an important cause of the disease. Patients who have the SQSTM1 gene usually develop severe Paget disease starting from the age of about 40 and can end up crippled. Paget disease can be treated with drugs called bisphosphonates but often the disease has caused irreversible damage to the bones before these drugs are prescribed. The aim of this research is to find out if better results can be obtained by giving early treatment to people who are genetically at risk of getting the disease because of the SQSTM1 gene, but who have not yet developed it. We will do this by carrying out genetic tests on people with a family history of Paget disease to see if they carry the SQSTM1 gene. People who are found to carry the gene will be invited to take part in a research study in which 50% will be given an active treatment which we think might prevent the disease. The other 50% will be given a dummy treatment. We will then follow both groups of people up for 5 years and compare the results at the end of this time. We will carry out special bone scans to see if people in the trial have developed bone abnormalities characteristic of the disease and to see if the active treatment has prevented this to any extent. We will also study the effects of treatment on symptoms and look for any side effects of the treatment. Neither the patients nor their doctors will know what treatment they have received so that we can make an objective assessment of the possible risks and benefits of the treatment. If the research shows that genetic testing combined with active treatment can prevent the development of the disease this is important since it could probably be introduced as part of routine care in the NHS. This could help prevent the development of the serious complications that can occur in Paget disease and improve the outlook for people who have a family history of the disease.
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