A single injection of a bone-strengthening drug could prevent Paget’s disease in people who carry a high-risk genetic mutation. Paget’s disease causes bones to remodel too quickly, leading to deformity, pain, fractures, and hearing loss. Current treatments help manage symptoms but are of limited benefit once complications have set in. The problem is that doctors have no way to stop the disease before it starts—even in people known to be genetically susceptible. This trial tests whether genetic testing can identify at-risk individuals before they develop any bone lesions, and whether giving them a potent bisphosphonate can prevent those lesions from forming. Participants receive either the drug or a placebo, with repeat doses if needed, and are followed for several years to track new bone lesions, pain, and quality of life. If the approach works, it could underpin a routine clinical programme of genetic screening and targeted prevention for familial Paget’s disease. That would shift the paradigm from treating established bone damage to preventing it entirely in those who carry the mutation.
View original technical description
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.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know