Is the Decline of Paget's Continuing in the UK?

Mr Michael Cook and Professor Terence O’Neill, from the University of Manchester, discuss below research published in April 2021, which looks at the occurrence of Paget’s disease in the UK. Professor O’Neill is the director of the Paget’s Association’s Centre of Excellence in Salford.

Research conducted in the 1970s and 1980s indicated that Paget’s disease was more frequent in the UK than elsewhere in the world, and within the UK was most frequent in the North West of England.  Research suggested also that the disease appeared to be declining in frequency.  The reason for the geographic variation in occurrence and also the decline in frequency was unexplained.  There have been no recent data on trends in the disease in the UK and so it remained unknown whether the disease has continued to decrease in frequency and whether it remains more common in the North West region.     

Using grant funding from the Paget’s Association and the Michael Davie Research Foundation, we conducted a research study to look at this.   We analysed data from a large primary care register, which included records of over 11 million people in the UK.  We looked at people who were newly recorded as having been diagnosed with Paget’s disease, and using this information we were able to work out how the disease varied in frequency in different parts of the country, and also whether it had changed in frequency during the years between 1999 to 2015.    

The results of the research have now been published in a peer-reviewed scientific journal.  Using the primary care database we found over 3,500 new cases of Paget’s disease in patients aged 18 years and over, who had been diagnosed in the past 20 years.   We found, as has been shown previously, that the frequency of the disease increased with age, in both men and women, but was more common in men at all ages.   One of the key findings though, was that the frequency of the disease appeared to be continuing to decrease.  Compared to 1999, by 2015 the frequency of diagnosed Paget’s disease had declined by over 60% to just over one in 50,000 people per year.   This decrease in frequency was seen across all parts of the country, though interestingly it remained more common in the North West of England than other parts of the UK.

The reason for the decrease in frequency is unknown.  Paget’s disease is known to be uncommon in people of African, Middle Eastern and Asian descent and it is unclear to what extent the demographic changes in the UK population may have influenced these changes in disease frequency. Unfortunately, this is not something that we were able to look at in the present study.  

About one in eight affected individuals have a family history of the disease, and research studies have identified a number of genetic variants which predispose to the disease.  Although genetic factors are important, the decrease in disease frequency that we have observed, suggests that there have been changes in environmental triggers for the disease over recent decades.  Little is known about the influence that environmental factors have in Paget’s disease but several potential factors have been suggested such as vitamin D deficiency, poor dietary calcium intake, and exposure to environmental toxins.  The only factors that have been studied experimentally in detail are viral infections. There have been some suggestions that chronic infection with measles virus, canine distemper virus and respiratory syncytial virus may be involved in Paget’s and it has also been found that people with Paget’s have higher levels of antibodies to the mumps virus than unaffected individuals. However, studies on the role of viruses have so far yielded inconclusive results.

We wondered whether poverty or levels of socio-economic deprivation might be important and looked in the primary care database at whether the frequency of disease varied by socioeconomic status.  Using a widely used marker of socioeconomic status (known as the index of multiple deprivation) our results showed that the disease did vary by poverty levels, with the frequency of disease 30% higher in the most, compared to least deprived areas.   How social class may influence the disease is unclear, though this is probably due to either increased exposure or susceptibility to one or more other environmental triggers, including possible viral infection. 

We wondered whether the excess of Paget’s disease in the North West of England might be explained by differences in levels of socioeconomic deprivation, however, when we analysed the data we found that the higher frequency in the North West persisted, even after taking into account levels of deprivation, and so the reason for the North West excess remains unknown and for which further research is needed. 

Our research focused on people who had been diagnosed with Paget’s disease.  The majority of people with the disease are asymptomatic and have not been diagnosed.  Our findings though, in relation to the decrease in frequency of diagnosed disease, are consistent with results of a couple of recent small x-ray surveys, which suggest there has been a decline in the overall frequency of disease.  

We thank the Paget’s Association and also the Michael Davie Research Foundation for supporting the research.

 - Michael J Cook, Terence W O’Neill; Centre for Epidemiology Versus Arthritis, Stopford Building, University of Manchester, Manchester, UK

Reference: Cook, M., Pye, S., Lunt, M., Dixon, W., Ashcroft, D., O'Neill, T., Incidence of Paget’s Disease of Bone in the UK: Evidence of a Continuing Decline. Rheumatology, 2021. 

The ZiPP Study

The ZiPP study is a clinical research study being run by the Edinburgh Clinical Trials Unit.

First Results of the ZiPP Study Revealed 

Genetic factors are known to be important in the development of Paget’s disease. Apart from age, having a family history of the disease is one of the most important risk factors for the development of Paget’s. The Zoledronate in the Prevention of Paget’s disease (ZiPP) study was designed to investigate the feasibility of conducting a large-scale program of genetic testing, coupled with targeted intervention with zoledronic acid or a dummy treatment (placebo), in people with a family history of Paget’s disease. Although we now know that there are more than 13 gene variants that predispose to Paget’s disease, the ZiPP study focused only on people who tested positive for variants in the SQSTM1 gene, which are the single most common cause of Paget’s disease.

The ZiPP investigators published the results of the baseline characteristics of people who took part in the study earlier this year in the Journal of Bone and Mineral Research. Of the 222 people who took part in the study 20 (9%) had early signs of Paget’s disease, which was seen on bone scans carried out at the baseline study visits. While biochemical markers of bone turnover, such as alkaline phosphatase and other markers, were, on average, higher in people who had evidence of Paget’s on their bone scan, in most cases, they were still in the normal range. The authors also commented that none of the participants, with evidence of early Paget’s disease on their scan, had any symptoms or signs of the condition. 

The researchers concluded that, in its early stages, Paget’s is a clinically silent condition and may remain so for many years until complications develop. This is in keeping with the findings of a previous study by researchers at the Paget’s Association’s Centre of Excellence in Edinburgh, which revealed that in about 40% of individuals, Paget’s first presents with a complication of the disease, such as deformity, fracture, or deafness. Lead author Dr Owen Cronin said “The ZiPP study has shown that a programme of genetic testing, coupled with therapeutic intervention, is acceptable to people with a family history of Paget’s disease. We are now waiting eagerly for the remaining participants to complete their end of study visits so that we can determine if the bisphosphonate, zoledronic acid, can halt the disease”.

Reference
Cronin et al. (2020). Characteristics of Early Paget’s Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort. J Bone Miner Res, 35: 1246-1252. doi:10.1002/jbmr.4007

This summary was published in Paget's News, the magazine of the Paget's Association, in 2020.

Vitamin D and Side Effects

When bisphosphonates, like zoledronic acid, are given for the first time, patients commonly experience a flu-like reaction, known as acute-phase reaction (APR), for 2-3 days after the infusion. Typical symptoms include fever, aches and pains, and feeling a bit off colour. The symptoms are usually mild but can be severe in some cases. Previous research in people with osteoporosis had suggested that vitamin D deficiency might be associated with worsening of the APR. Based on this, a group of researchers in Italy, led by Dr Daniella Merlotti, conducted a study to investigate possible associations between vitamin D and the APR in people with Paget’s disease.

The study was in two parts. Firstly, the researchers carried out blood tests to look at the serum levels of vitamin D in 330 patients with Paget’s disease, who had been treated with infusions of zoledronic acid or neridronate (a bisphosphonate that is used in Italy for the treatment of Paget’s). This showed that the APR occurred in a very high proportion of patients with vitamin D deficiency. Based on this, they conducted a second study in which they gave patients vitamin D at a dose of 50 000 IU/weekly, for 8 weeks before the infusion, to determine if this might reduce the risk of the frequency of the APR. The study showed that the overall frequency of the APR was about 10%, in the people who had been given vitamin D, compared with an overall frequency of  30% in the 330 patients who were studied in the first phase of the research, suggesting that low levels of vitamin D might increase the risk of an APR following intravenous bisphosphonates. 

Vitamin D supplements are usually prescribed prior to administration of intravenous bisphosphonates to reduce the risk of blood calcium levels falling. This study re-emphasises the importance of taking vitamin D supplements prior to receiving a bisphosphonate infusion, and suggests that they might help reduce the risk of developing flu-like symptoms, as well as reducing the risk of low calcium levels.

Reference
Merlotti et al. (2020). Preventive Role of Vitamin D Supplementation for Acute Phase Reaction after Bisphosphonate Infusion in Paget’s Disease. The Journal of clinical endocrinology and metabolism, 105(3), dgz138. https://doi.org/10.1210/clinem/dgz138

This summary was published in Paget's News, the magazine of the Paget's Association, in 2020.

Scientists Solve an 800-year-old Mystery Related to Paget’s Disease

Funding from the Paget’s Association has helped scientists solve an 800-year-old mystery related to Paget’s Disease of Bone. Scientific research at the molecular level, on a collection of medieval skeletons from Norton Priory in Cheshire, could help rewrite history after revealing they were affected by an unusual ancient form of the disorder.

(Scroll down to watch a video about this research)

The study was made possible with funding from the Wellcome Trust, the Paget’s Association and the Michael Davie Research Foundation. Coordinated by researchers at the University of Nottingham, the research involved analysing proteins and genetic material preserved in the bones and teeth that are more than 800 years old.

The work suggests that ancient remains can hold a chemical memory of disease and that similar molecular analysis could be used to explore the evolution of other human disorders.

The study, published in a highly respected journal*, is significant because it indicates that ancient Paget’s disease may have been far more common than the modern disease and developed much earlier in life. 
Paget’s disease is nowadays the second most common metabolic bone disorder and affects around 1% of the UK population over the age of 55, with an especially high prevalence in the North West of England. Both genetic and environmental factors are important in the disease, a likely explanation for the regional variations in its incidence. Paget’s disease can result in the weakening of the affected bone, causing deformity, pain, and sometimes fracture. In very rare cases, a bone affected by Paget’s disease can develop osteosarcoma, a malignant bone cancer. 
Dr Carla Burrell, who received the Doreen Beck Research Bursary Award from the Paget’s Association, together with Professor Silvia Gonzalez from Liverpool John Moores University, found that more than 15% of the skeletons at Norton Priory had extensive disease throughout up to 75% of their skeletons, compared to the modern-day population with Paget’s disease, who typically have just one or a few bones affected. The research also revealed that the medieval disease started in young adulthood, whereas nowadays Paget’s tends to develop after the age of 55.

Surprisingly though, the medieval cases showed almost no evidence of the complications that are common in modern-day Paget’s disease.

One of the skeletons analysed was thought to be that of William Dutton, a medieval Canon at the Priory who died in the late 14th century. He was aged between 45 and 49 when he died and had bone disease affecting more than 75% of his skeleton, including pelvic osteosarcoma. Further analyses indicated he had a marine-based diet typical of a high-status individual, and was local to the North West of England, pointing to some local environmental factor that may have triggered his disease.

Coordinating the project, Professor Robert Layfield from the Nottingham Paget’s Association Centre of Excellence (PACE), said: “X-ray analyses of medieval skeletons from the collection at Norton Priory first directed us to unusually extensive pathological changes resembling, but also very different, to modern-day Paget’s disease. 
We carried out a much closer inspection of the remains using a technique called paleoproteomics – protein sequencing using mass spectrometry. This technique allows analysis of bone samples at the molecular level by extracting proteins from the ancient bone cells. Remarkably these proteins are well-preserved, whereas DNA degrades over extensive periods of time. Effectively the proteins offer an insight into the biology of the cell when it was alive many hundreds of years ago.

We were able to identify one ancient protein that is diagnostic of Paget’s disease. This indicates the people who died at Norton were affected by a very different form of Paget’s disease to what we see today. Our research shows how proteomics can be used to examine and diagnose disease in ancient bones, and importantly also in ancient teeth. It backs up the theory that Norton Priory and perhaps the North West, in general, was a hotspot for this early form of Paget’s and opens up new questions about its natural history and risk factors.”
A major finding in parallel to protein sequencing was the successful analysis of ancient microRNAs in the 600 year old skeleton that was affected by pelvic osteosarcoma.

MicroRNAs are genetic molecules that control how active our genes are and contribute to almost all genetic diseases ever studied. Specific microRNA patterns are used to determine different disease types and the findings in this study correlate with modern-day microRNA patterns of bone cancer. 
Analysis of ancient microRNAs has also opened up an entirely new field of research using archaeological samples, as microRNAs were thought to be unstable and usually have to be studied in fresh samples. 
Dr Darrell Green, from the University of East Anglia’s Norwich Medical School, received the Allan Reid Student Research Bursary Award from the Paget’s Association to investigate osteosarcoma, which is today, a very rare but devastating complication of Paget’s disease. Dr Green analysed the skeleton affected by osteosarcoma and said: “MicroRNAs have never been investigated in ancient samples before because it seemed patently obvious that given their genetic structure they would degrade very quickly.

We developed a new, more sensitive technique to capture microRNAs in all types of samples and were surprised to find we detected microRNAs in the 600 year old bone cancer. This shows that given the correct preservation conditions, microRNAs are more stable than anybody thought so our new technique could be applied to museum samples that hold a wealth of data on biological and medical history.”

Lynn Smith, Senior Keeper at Norton Priory Museum and Gardens said “The results of the scientific research into an ancient form of Paget’s here at Norton Priory have been a real surprise and are adding a huge amount to our knowledge and understanding of this unique medieval population. It is very rare for an archaeological collection to be used in such cutting-edge research and as such it has been both a privilege and a career highlight for me. The results will not only help re-work our interpretation of the site and the individuals that had connections with the Priory but will also help inform modern medical practice and future research”.

By further applying the methods developed in the project the researchers also hope to gain a better understanding of what daily life was like for our ancestors affected by this, and other, ancient bone disorders.

The next stage of the research will be to determine what the ancient environmental triggers for Paget’s disease might have been, which may help doctors understand the fall in incidence of modern-day disease observed over the past few decades. The Paget’s Association will watch with interest this developing project, which may lead to information crucial to preventing Paget’s disease from developing in those susceptible to it.

DOCUMENTARY

Specially produced for Paget's Awareness Day, this exciting Research documentary below explores the above findings as we interview the researchers.

* Proceedings of the National Academy of Sciences of the United States of America (PNAS)

If you are interested in looking at the original research paper it can be assessed at the PNAS website.  Visit information on the University of Nottingham website for more information about their work.

New Gene for Paget's Disease

It has long been recognised that genetic factors play an important role in Paget’s disease. Over the past twenty years, advances in human molecular genetics have resulted in the identification of variants in thirteen genes that predispose to the disease. Recently, a group of researchers from the Institute of Genetics and Biophysics in Naples, Italy, added another gene to the list. The researchers performed genome sequencing in a large family where several members were affected by Paget’s disease, and identified an abnormality in the PFN1 gene, as the cause of the disease.

Further studies showed that the abnormality in PFN1 caused the gene to malfunction, leading to increased activity of the bone resorbing cells (osteoclasts), which accounted for the occurrence of Paget’s disease. They also found that about 1.8% of individuals with Paget’s disease in this region of Italy were deficient in a copy of this gene.  An interesting aspect of this study is the fact that PFN1 abnormalities had previously been identified in people with certain rare forms of neurological disease and muscle weakness. Therefore, PFN1 joins a growing list of genes where abnormalities can, in some people, cause Paget’s disease but in others cause disease of the nervous system or muscle.  

It is unclear, as yet, whether PFN1 mutations occur in other populations such as the UK, or are relatively specific to the Italian population but this will be investigated in the Genetic Analysis to Predict the Development of Paget’s Disease (GAPDPD) study, which was featured in the August 2020 edition of the Paget's News magazine.

Reference
Scotto di Carlo F, Pazzaglia L, Esposito T, Gianfrancesco F. (2020). The Loss of Profilin 1 Causes Early Onset Paget's Disease of Bone. J Bone Miner Res. 35:1387-1398. doi: 10.1002/jbmr.3964.

This summary was published in Paget's News, the magazine of the Paget's Association, in 2020.

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.

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

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,  the magazine of the Paget's Association in Nov. 2014.

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 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

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

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 into 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 into 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

Bone cancer associated with Paget’s Disease of Bone

Dr Darrell Green, from Norwich, 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). Their 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)
 

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