Randomised trial of genetic testing and targeted bisphosphonate therapy to prevent SQSTM1 mediated Paget s disease

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.

Paget disease of bone (PDB) is characterised by increased bone turnover affecting one or multiple bones throughout the skeleton. Although some patients are asymptomatic, others develop complications such as bone deformity, pain, deafness, fracture and an increased risk of osteoarthritis. Genetic factors play an important role in PDB and mutations of the SQSTM1 gene have recently been found to be an important cause of PDB occurring in between 20% - 50% of patients with a positive family history. Carriers of SQSTM1 mutations develop severe disease with an early age at onset and the penetrance is approximately 90% by the age of 70. Mutations of SQSTM1 are highly specific for PDB and have not so far been reported to occur in unaffected controls. Bisphosphonates are highly effective at suppressing the elevated bone turnover which is characteristic of PDB and can help bone pain, but they are of limited benefit in patients with established disease who have already developed complications. In this study, we will test the hypothesis that genetic testing coupled with prophylactic treatment with the potent bisphosphonate Zoledronic acid can prevent the development of focal bone lesions characteristic of PDB in carriers of SQSTM1 mutations. Subjects between the age of 40-65 who have a positive family history of PDB but who have not yet developed clinical signs of PDB will be screened for the presence of SQSTM1 mutations. Those who are found to carry SQSTM1 mutations will be invited to take part in an intervention study comparing the effects of a single injection of Zoledronic acid with placebo. Repeat infusions of Zoledronic acid will be given after 30 months in patients with evidence of high bone turnover and participants reviewed after 5 years when the development of new bone lesions will be assessed by radionuclide bone scan. The effects of the intervention on bone pain and quality of life will also be studied. This programme of research will allow us to determine if the development and progression of PDB bone lesions and symptoms can be prevented by prophylactic therapy in genetically susceptible individuals. If positive effects on these outcomes were to be demonstrated, this would underpin the introduction of a programme of genetic testing and targeted intervention for familial PDB in routine clinical practice.