Research Summaries

We are pleased to present summaries of various research studies into Paget's Disease below.  

You will also find further research information and articles of interest in our Member's Area. Please log-in or register free to access articles such as: Epidemiology of Paget’s Disease by Professor Terence O’Neill. If you have research you would like to share with us please get in touch.

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.

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.

 

COMMENT

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.
In newly diagnosed patients who had not received any previous treatments, the results could be different. It is known that a single infusion of zoledronate will suppress Paget’s disease for at least 6.5 years. Recent studies of zoledronate have also shown better health outcomes in those receiving the medication compared with those who did not. My own conclusions are that in long established patients with a lot of past treatments there would be no advantage in pursuing an intensive regime, but as Professor Ralston has said we must treat individuals. In those newly diagnosed, however, I have hope that modern treatment with zoledronate may prove to be advantageous. I look forward to further research to inform us.

Relevant papers
1. Reid IR, Miller P Lyles K et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease, New Eng J Med 2005:353;898-908.
2. Hosking D, Lyles K, Brown JP et al. Long term control of bone turnover in Paget’s disease with zoledronic acid and risedronate. J Bone Miner res 2007;22:142-8.
3. Reid IR, Lyles K, Su G et al. A single infusion of zoledronic acid produces sustained remissions in Paget disease: data to 6.5 years. J Bone Miner Res 2011;26:2261-70.

Molecular Testing Could Provide Earlier Diagnosis of Rare Paget’s Associated Bone Cancer

In 2016, a research student from Norwich, Darrell Green, was the recipient of the Allan Reid Student Research Bursary to pursue exciting research into a rare bone cancer (osteosarcoma) associated with Paget’s Disease of Bone.

Allan Reid, from Glasgow, was unlucky enough to develop osteosarcoma arising from Paget’s disease. Whilst this is a very rare complication, it is a devastating illness, with a poor prognosis. Allan died in 2014, aged 57, just 7 years after he was first diagnosed with Paget’s. To enable some good to come out of his death, his distraught family, friends and colleagues, set about raising thousands of pounds for the Paget’s Association. It was fitting that a bursary be named in Allan’s memory.

Allan Reid, from Glasgow, was unlucky enough to develop osteosarcoma arising from Paget’s disease. Whilst this is a very rare complication, it is a devastating illness, with a poor prognosis. Allan died in 2014, aged 57, just 7 years after he was first diagnosed with Paget’s. To enable some good to come out of his death, his distraught family, friends and colleagues, set about raising thousands of pounds for the Paget’s Association. It was fitting that a bursary be named in Allan’s memory.

The bursary helped support a study at the University of East Anglia (UEA). There researchers have discovered a way to identify the type of bone cancer seen to arise in some sufferers of Paget’s disease of bone, which is often missed until it is too advanced to treat.

Paget’s disease of bone affects the cycle of bone renewal, weakening and deforming bones and is quite common in people over the age of 50. Usually, this condition is not life-threatening by itself but in just under 1 per cent of patients a type of bone cancer known as osteosarcoma can develop.

Paget’s disease of bone affects the cycle of bone renewal, weakening and deforming bones and is quite common in people over the age of 50. Usually this condition is not life-threatening by itself but in just under 1 per cent of patients a type of bone cancer known as osteosarcoma can develop.
According to a letter published in the journal Endocrine Related Cancer today, the team from the University of East Anglia have identified a molecule, which regulates a gene known to cause Paget’s disease and thought to cause its subsequent transformation into bone cancer.

Researchers used next generation sequencing to investigate the expression of microRNAs – molecules essential in many biological functions – and compared results from patients with Paget’s disease, patients with Paget’s disease and established osteosarcoma, and patients with neither.
They identified a particular microRNA called miR-16, which appeared to be expressed at a low level in cases of Paget’s disease, but switches to a high expression in cases of Paget’s disease with osteosarcoma. Although the study used a small sample number, the results are a promising step forward in diagnosing the cancer.

Dr Darrell Green from UEA’s Norwich Medical School said, “Study of Paget’s associated osteosarcoma is particularly difficult because it is a very rare cancer and availability at tissue banks is scarce. This small study however, shows that molecular testing could provide a robust diagnosis, which is especially useful in rare cancers. The results are also promising for potentially identifying a mechanism for how Paget's disease arises in the first place”

Professor Bill Fraser from UEA’s Norwich Medical School said, “Day-to-day symptoms of Paget’s disease and Paget’s associated osteosarcoma can be very similar, meaning that in many cases the progression to cancer isn’t spotted until it may be too advanced to treat. This type of testing, detecting the switch of miR-16 expression, could provide the crucial distinction, at an earlier stage of cancer development.”
Professor Roger Francis, Chair of the Paget's Association which part-funded the study said, "This is an exciting paper, demonstrating a possible mechanism for the development of osteosarcoma, a rare complication of Paget's Disease of Bone. Nevertheless, this is a small study and the findings require investigation in future studies”.

This research was funded by cancer charity The Big C and The Paget’s Association. The letter ‘miR-16 is highly expressed in Paget’s associated osteosarcoma’ is published in Endocrine Related Cancer (2017)
The study is available in full by following this link until 11 April 2017.

This type of complication is rare. Anyone who has any concerns about this can call our Nurse Helpline on 0161 7994646 or contact us by following this link.

Clinical Presentation of Paget's Disease

A summary of Dr Tan and Professor Ralston’s paper: Clinical Presentation of Paget's Disease: Evaluation of a Contemporary Cohort and Systematic Review

A Summary by Diana Wilkinson, Specialist Paget’s Nurse, of The Paget’s Association.

In a paper published in August of this year in the journal “Calcified Tissue International”, Dr Adrian Tan and Professor Stuart Ralston evaluated the presenting features of Paget’s disease in eighty eight UK patients referred to a specialist clinic between 2005 and 2013. In 22% of patients there were no symptoms demonstrating that in some people Paget’s disease does not cause health problems. The majority of patients however, did have symptoms. Bone pain was found to be the most common, occurring in 74% of patients. In three quarters of these patients the pain was considered to be due to the Paget’s disease and in one-quarter co-existing osteoarthritis. Bisphosphonate treatment was given for pain in thirty four cases and about two-thirds of patients responded positively with an improvement in pain. Patients who had had Paget’s for a shorter length of time were more likely to respond. Unfortunately a number of patients already had complications by the time the diagnosis was made. Bone deformity was found in 18%, deafness in 8%, and fracture caused by Paget’s disease in 6%. The authors commented that this finding emphasised the importance of making the diagnosis early in Paget’s disease, before complications had occurred.

The authors also conducted a systematic review of studies in which the presenting features had been reported. Bone pain was again the most common presenting feature (52% of cases) followed by deformity (21%), deafness (9%) and fracture (8%).
The authors concluded that although current treatments are effective, some patients don’t respond well because the disease is too advanced. They commented that further research is required to determine if earlier detection and treatment might benefit people at risk of developing Paget’s disease, especially people with a family history of the disease.

Research is already in progress to find out more about this issue. The ZiPP study (Zoledronate in the Prevention of Paget’s) trial aims to determine if genetic testing can be combined with bisphosphonate therapy to prevent or delay the onset of Paget’s disease in people with abnormalities of the SQSTM1 gene. This research is being carried out by Professor Ralston and his team in Edinburgh with the support of the Medical Research Council and Arthritis Research UK. The Paget’s Association has been highlighting the research at its information days and in Paget’s News, and we are aware that many of you have been involved. When asked about the results of the recent paper Professor Ralston commented: “The recent study which was led by Dr Adrian Tan shows that we cannot be complacent about Paget’s disease. Although we now have very good treatments for Paget’s it is important that they are given early enough to prevent complications developing, since when they are present they are impossible to reverse. The ZIPP study is important since it will provide a proof of concept that complications can be prevented. If successful the same approach could be used for other people with a family history of Paget’s who do not have SQSTM1 abnormalities”

Reference: Tan, A., Ralston, S.H., (2014), Clinical Presentation of Paget's Disease: Evaluation of a Contemporary Cohort and Systematic Review, Calcified Tissue International, Aug 27.

The above summary was published in Paget's News, Nov. 2014.

The ZiPP Study

The ZiPP Study

The Paget’s Association is pleased to be supporting the ZiPP study – Zoledronate in the Prevention of Paget’s. The ZiPP study is a clinical research study being run by the Edinburgh Clinical Trials Unit. We know that in some families, Paget’s disease can be passed down. The study aims to determine if early treatment can prevent Paget’s disease occurring in people who are genetically predisposed to the condition. Those with Paget’s disease who are taking part in the study were given a simple blood test to screen for the presence of a genetic change that predisposes to Paget’s disease. The children or siblings of those who tested positive were also invited to take the test. Those children or siblings who tested positive were invited to take part in the trial which involved receiving an infusion of either Zoledronic acid (a drug that is currently used to treat Paget’s) or a placebo (a dummy drug).
The ZiPP study is taking place not only in the UK, but also in other countries such as Italy, Spain, Belgium, New Zealand and Australia. Recruitment for the study has now closed. Once this major research study has been completed, it will depend on the outcome as to whether or not the test could be made available in the future.

2014

What goes wrong inside bone cells?

What goes wrong inside bone cells in Paget’s disease?

Dr Rob LayfDr R. Layfieldield is a biochemist based at the University of Nottingham, who has researched Paget’s disease since 2002. Here he gives an overview of his work and an insight in to the valuable role that organisations such as the Paget’s Association play in supporting research.

Labor ipse voluptas - “work itself is a pleasure” - was the family motto of Sir James Paget, the physician who first described the condition that we now know as Paget’s disease of bone. Indeed it was a genuine pleasure to receive an invitation to attend the Paget’s Association Information Day in Manchester on 13th September 2013, and to give a presentation about some of the work that goes on in my research laboratory at the University of Nottingham. For those members who were not able to attend (and those that were, and maybe, were baffled by the biochemistry!), I will try to summarise some of the main points that I covered on the day.

I will start by saying that I feel very fortunate to have received funding from the Paget’s Association for my group’s research and am of the firm belief that this has directly improved our understanding of the condition, specifically the molecular basis of Paget’s disease. In other words, the support has really helped towards answering the question that my research addresses - “what goes wrong inside bone cells in Paget’s disease?” At the outset it is probably also worth setting the context of which funding from the Association sits. In my role at the University I spend about half of my time teaching biochemistry to undergraduate (medical and science) students. The other half of my time is spent on research, and most of this researching Paget’s disease, a condition that has fascinated me for over 10 years. Whilst the teaching side is well supported, the total amount of funding that is allocated to research in this setting is very low (in fact nil!). So to do any research (not just in to Paget’s disease) requires that financial support is secured from outside agencies, be they government-funded or charities, and a large part of the job is in trying to raise such funds. That is why support for research from organisations such as the Paget’s Association is so important.

So to return to the question above, “what does go wrong inside bone cells in Paget’s disease?” Before we deal with this, we first need to think about the different types of cells that are found in bone, and a process they control that we know as ‘bone remodelling’. There are two types of bone cells that are important in Paget’s disease - so-called ‘osteoclasts’, whose normal job is to resorb or break down bone, on a microscopic scale, throughout the skeleton. Once they have done this a second type of bone cell, the ‘osteoblast’, replaces the bone that has been removed with new bone. This concerted action of osteoclasts and osteoblasts is known as ‘bone remodelling’. It might seem counter-intuitive to do this, but bone remodelling is vital to ensure that the skeleton is healthy. The analogy I give is DIY around the house. You might re-decorate your utility room just to spruce it up a bit. Then a few months later buy some new curtains in the living room and a new hall carpet. This might at the time seem futile and a waste of money. If you don’t do this however, in a few years your house will start falling into disrepair.

In Paget’s disease, this bone remodelling cycle goes wrong, at specific sites throughout the skeleton. The principal problem is with the osteoclasts - too many are produced and they are too active, resorbing bone too efficiently. So more osteoblasts are produced to counteract the problem, and we end up in a situation where bone remodelling is dramatically increased and the new bone formed is of the wrong structure. Buy why does this happen? Well in some, but not all cases, there are mutations (changes in the DNA) in one particular gene called the SQSTM1 gene that we think cause the disease. It is this genetic or familial ‘form’ of Paget’s disease that we research, as experimentally it is easier to study, but importantly what we learn is relevant for all cases of Paget’s disease. The mutant SQSTM1 gene produces what we will for simplicity call a ‘Paget’s protein’. My group investigate how this Paget’s protein is different from the normal (non-mutant) form and how the processes that the protein controls in osteoclasts are altered in the disease. With support from the Paget’s Association, we have already found that the Paget’s protein has a different shape to its normal counterpart, and that three different biological pathways in osteoclasts are affected when it is produced. In the longer term, information of this type could be used to devise new treatments. Your support has also helped us lever additional funding from other bodies to continue important aspects of this research.

You might ask why we need to know this sort of information, given that (as we heard at the Information Day) existing treatments for Paget’s disease (e.g. zoledronate) can be very effective, and in fact, epidemiological studies show that the incidence of Paget’s disease is falling in the UK? Well firstly, zoledronate is not appropriate for everybody, and as we move to a point where clinical trials will reveal whether pre-symptomatic treatment for those at higher risk of Paget’s disease may be considered, new forms of treatment might be needed. And secondly yes, the incidence is falling, but several hundred thousand people in the UK alone are still currently affected, and the fall in the incidence of Paget’s disease we see at present may not necessarily continue in the future.

I hope that in the same way that I was reminded of the human side of Paget’s disease at the Information Day, this piece gives you a small insight in to the human side of basic medical research. One thing I was left with after the meeting was a strong feeling of community - whether we are doctors, scientists, staff at the Association or individuals directly and indirectly affected by Paget’s disease, we are all the same and we are linked by a common goal - a desire to improve the quality of life of those affected by Paget’s disease.

Published in Paget's News, 2013

The PRISM Study

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. This summary was published in "Paget's News" in 2013.

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: [email protected] .

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

An article regarding the PRISM study by Dr D. Hosking is available under Research in the Member's Area. 

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