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The PRISM study (Paget’s disease, Randomised trial of Intensive versus Symptomatic Management) was carried out by an Edinburgh research team, supported by a research grant from the Association. This looked at newly identified genes to see if it would be possible to predict the severity, complications or response to treatment in people with Paget’s disease.

Novel genetic determinants of clinical outcome and quality of life in the PRISM study

Dr Nerea Alonso PhD, Dr Omar Albagha, PhD, Prof Stuart H Ralston MD
Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Edinburgh EH4 2XU

The symptoms and signs of Paget’s disease of bone (PDB) differ a lot in different people. Some people who have Paget's disease don't have any symptoms at all and are quite untroubled by the condition whereas many patients develop bone pain. In a few patients complications can develop such as bending of the bones (bone deformity), fractures (broken bones) and hearing difficulty (deafness) if the skull is involved. There have been many theories over the years as to what causes Paget's disease and what influences severity. Various triggers have been suggested such as virus infections, poor nutrition, toxins and injuries. There is increasing evidence however that inherited factors play a key role in Paget’s disease. It has been known for over half a century that Paget’s disease often runs in families and this suggests that genetic factors may play a role in disease causation and in determining the severity of Paget’s disease.

Many advances have been made in the past 10 years in identifying the genes that predispose to Paget's disease. The most important is a gene called sequestosome 1 (SQSTM1). This is abnormal in about 10% of Paget's patients overall but about 40% of people who have a family history of Paget’s disease have an abnormal SQSTM1 gene. People with Paget’s who have an abnormal SQSTM1 gene are liable to pass the gene onto their children who have a high risk (up to 90%) of developing Paget's disease in later life. It is possible nowadays to test for the presence of the abnormal SQSTM1 gene in people with Paget's on a simple blood test and researchers based in Edinburgh are conducting a study at present (called the ZiPP study) in which grown-up children of patients with Paget's are being offered the SQSTM1 test to see if they are at risk of developing Paget's disease. If you have Paget’s disease, have children above the age of 30 and are interested in finding out more about this study, please contact the ZiPP study office at the University of Edinburgh on 0131-537-3847, or by emailing Laura Forsyth, the ZiPP study manager on: laura.forsyth@ed.ac.uk .

Apart from the SQSTM1 gene, seven other genes have been linked to the development of Paget's disease. In this research project we analyzed the relationship between all of these genes and the severity of Paget's in patients who took part in PRISM study (Paget’s Disease, Randomised Trial of Intensive versus Symptomatic Management) which was also supported by a research grant the Paget's Association.

We were able to check for the presence of each of the seven new genes and SQSTM1 from blood tests that were collected during the study. We related the gene abnormalities to information about severity of the disease, such as bone deformity and bone pain, complications, quality of life and previous bisphosphonate treatment.

We found that the greater number of abnormal gene variants were carried, the more extensive was Paget's disease. In addition, when we combined information from the new genes with SQSTM1 testing we were able to identify groups of people with a differing risk of severe disease as shown in the graph below. People with the fewest number of risk genes who tested negative for SQSTM1 had less severe disease (lowest to medium groups) whereas those with the greatest number of risk genes who also tested positive for SQSTM1 (high to highest groups) had the most severe disease. The same was true for the number of affected bones.

Although we found that the genes predicted severity it was a relief to find out that there was no difference in response of alkaline phosphatase activity or quality of life to treatment during the trial according to genetic risk category. This is importanPRISM chartt since it means that people who are at increased genetic risk of Paget's can still respond well to treatment.

We are carrying out further research to define how this information should be used in clinical practice. One possibility is that we could offer the children of patients with Paget's disease genetic tests for SQSTM1 and the other genes. If the tests were positive we could keep a close eye on these people to screen for early signs of Paget's, for example by performing blood tests or bone scans periodically. The other possibility would be to actually give these people treatment to prevent the development of Paget's as we are doing in the ZIPP study. Before we do this we would ideally like to refine the genetic markers so that we can gain more accurate prediction and that is exactly what we are doing at present.

Published in Paget's News Aug. 2013

Reference: Langston AL, Campbell MK, Fraser WD, MacLennan GS, Selby PL, Ralston SH, PRISM Trial Group, (2010), Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget's disease of bone.  Journal Of Bone And Mineral Research, Jan; Vol. 25 (1), pp. 20-31


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