PRISM and PRISM-EZ studies

The Paget’s Randomised trial of Intensive versus Symptomatic Management (PRISM) research study was carried out by an Edinburgh research team and was supported by grants from Arthritis Research UK and the Paget’s Association. [2017]

The PRISM study examined the advantages of purely treating symptoms, or giving sufficient bisphosphonate to achieve a normal alkaline phosphatase (ALP) level (ALP is a blood test used to assess the activity of the disease). The PRISM study started in 2001, recruited 1324 patients with Paget’s Disease of Bone (PDB).

The PRISM study showed that the two groups had similar effects with respect to the occurrence of fractures, orthopaedic procedures, hearing loss, bone pain, quality of life and adverse events. The conclusion of the authors of the PRISM study was that intensive bisphosphonate treatment did not produce better clinical outcomes compared to symptomatic treatment. Although this study lasted 3 years, it was thought that differences in response to treatment may emerge from even longer disease control and so the PRISM study was extended to investigate this possibility. The extension of the trial was called the PRISM-EZ study, standing for PRISM, Extension with Zoledronic acid.

Results of the PRISM-EZ study

The PRISM-EZ trial started in 2007 and involved 502 people who had already taken part in PRISM. Intensive bisphosphonate therapy was continued in 270 of these, with the aim of maintaining normal bone turnover using the highly potent bisphosphonate, zoledronic acid, as the treatment of first choice. In 232 people, symptomatic treatment continued where bisphosphonates were only given to treat bone pain.

Blood tests were carried out for alkaline phosphatase (ALP) and the levels were significantly lower in the intensive group when the study commenced. The differences in the levels of ALP between the two groups increased as the study progressed. The study found no evidence to suggest that greater suppression of bone turnover with “intensive” therapy was associated with better symptom control. Similarly, quality of life was measured using various tools and there were no clinically important differences in quality of life or bone pain between the two groups.

Fractured bones were nearly twice as common in patients who had been treated with intensive therapy and orthopaedic procedures were also required more frequently. However, the number of patients who had fractures and required surgery was quite small and no definite conclusions could be drawn. In both groups, those who had fractures were more likely to have received bisphosphonates than those who had not had a fracture. The authors concluded that long-term intensive bisphosphonate therapy aimed at maintaining ALP levels within the normal range does not offer any clinical benefit over giving treatment only when symptoms are present.

The results of the PRISM-EZ study suggest that in patients with established Paget’s disease, intensive bisphosphonate therapy to suppress bone turnover does not provide any benefit. The study shows that in patients with well-established disease, the focus should be on using bisphosphonate treatment to control bone pain that is thought to be due to disease activity. One of the researchers and co-author of the paper, Professor Stuart Ralston, from the University of Edinburgh, who led the study commented, “The take-home message from PRISM-EZ is that doctors should be treating the patient with Paget’s disease and not simply treating the level of ALP!” He also added that the results of PRISM-EZ applied to people who had established Paget’s disease and that it wasn’t known if bisphosphonate treatment in early asymptomatic disease is beneficial. You may be aware of, and even be part of research known as the ZiPP study (Zoledronic acid in the Prevention of Paget's), which is addressing this issue. We look forward to the results in due course.

Reference: Tan, A., Goodman, K., Walker, A., Hudson, J., MacLennan, G. S., Selby, P. L., Fraser, W. D., Ralston, S. H. and for the PRISM-EZ Trial Group (2017), Long-Term Randomized Trial of Intensive Versus Symptomatic Management in Paget's Disease of Bone: The PRISM-EZ Study. Journal of Bone Mineral Research.

More detail on the PRISM study

Dr Nerea Alonso, Dr Omar Albagha, Prof Stuart H Ralston, Institute of Genetics and Molecular Medicine from the University of Edinburgh explain the PRISM study below. (2010)

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

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.

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