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.
- 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.
- What goes wrong inside bone cells?
What goes wrong inside bone cells in Paget’s disease?
Dr Rob Layfield 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 important 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