Results of PRISM-EZ Trial
Some of you may be familiar with the Paget’s Randomised trial of Intensive versus Symptomatic Management (PRISM) study. The trial which started back in 2001 recruited 1324 patients with Paget’s Disease of Bone (PDB) and was supported by grants from Arthritis Research UK and the Paget’s Association. The PRISM study examined the advantages of purely treating symptoms, or giving sufficient bisphosphonate to achieve a normal alkaline phosphatase (ALP) level. (The ALP blood test is the commonest test used to assess the activity of the disease). 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.
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.
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.
Our Vice-Chairman, Dr Stephen Tuck comments on the PRISM-EZ results.
This is a very important study and its results are particularly relevant to those people who have established disease and who may have been receiving treatment for a long time. Initially, the results seem very disappointing as it would be hoped that intensive therapy to suppress the excessive bone cell activity that underlies Paget’s disease would be beneficial. The suggestion of increased fractures is particularly worrying. There are, however, a number of things that need to be considered.
Firstly, the absolute number of fractures was very small and was not statistically different between the two groups. The result could be a chance finding and much further work would need to be done before any conclusions could be drawn. Furthermore, the patients were recruited many years ago now, and long before modern therapy with zoledronate was introduced. The majority of patients recruited, had established disease, with 70% having had previous bisphosphonate treatment, and 50% having normal alkaline phosphatase levels at entry. So it is possible that better results could be obtained with patients who are newly diagnosed and who had untreated active disease at baseline. As established patients, some of their health problems could be due to complications of the illness such as secondary osteoarthritis, which will not respond to bisphosphonates.