Diagnosis and treatment of Paget's disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS).

INTRODUCTION: Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget's disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management. METHODS: Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice. RESULTS AND CONCLUSION: Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.

Paget's Disease of Bone: Osteoimmunology and Osteoclast Pathology.

PURPOSE OF REVIEW: The purpose of this review is to recognize clinical features of Paget's disease of bone and to describe how the osteoclast, a myeloid-derived cell responsible for bone resorption, contributes to the disease. RECENT FINDINGS: Recent studies have identified several variants in SQSTM1, OPTN, and other genes that may predispose individuals to Paget's disease of bone; studies of these genes and their protein products have elucidated new roles for these proteins in bone physiology. Understanding the pathologic mechanisms in the Pagetic osteoclast may lead to the identification of future treatment targets for other inflammatory and autoimmune diseases characterized by abnormal bone erosion and/or osteoclast activation.

Clinical features, diagnosis and treatment of Paget's disease of bone in mainland China: A systematic review.

Paget's disease of bone (PDB) is a metabolic bone disease with distinct geographical and ethnic differences in its pathogenesis. In this study, we aimed to retrospectively analyze the clinical features and the status of diagnosis and treatment of PDB in mainland China to improve the clinician's understanding of this disease. For this purpose, we conducted a systematic review of 118 articles, including a total of 332 patients with PDB. The results showed that the onset age of PDB in mainland China was 46-60 years. The number of male patients in most age groups was slightly higher than that of female patients, but there was no statistical difference (p > 0.05). The gender ratio (male to female) of PDB in mainland China was significantly different from that in Japan (p < 0.05), but not from that in the USA (p > 0.05). The clinical manifestations of PDB patients in mainland China mainly included ostealgia, bone malformation, hearing loss, and fracture, and bisphosphonate was used as the main treatment drug. These findings were similar to those in Japan, UK, and USA. Total alkaline phosphatase (TALP) level was elevated in about 89.7% of patients, and no correlation between TALP level and ostealgia was observed (p > 0.05). In addition, no difference in TALP level between males and females in each group was observed (p > 0.05).

Paget Disease of Bone for Primary Care.

Paget disease of bone is a benign disorder characterized by focal areas of increased bone turnover in one or more skeletal sites. It usually affects older adults, and men are at a higher risk than women. Any bone may be affected, but the disease has a high preference for the pelvis, spine, skull, and long bones. Pain is the most common symptom, and presentation of the disease may depend on which bones are affected, the extent of involvement, and the presence of complications. Paget disease of bone may be asymptomatic, and suspicion arises from incidental findings of elevated serum alkaline phosphatase levels on routine blood work or abnormalities on imaging tests performed for an unrelated cause. Evidence-based guidelines recommend the use of plain radiography and serum alkaline phosphatase testing for initial diagnosis and radionuclide scans for delineation of the extent of disease. Treatment with nitrogen-containing bisphosphonates is recommended in active disease or when risk of complications is possible. Complications of the disease include arthritis, gait changes, hearing loss, nerve compression syndromes, and osteosarcoma. Total serum alkaline phosphatase is the suggested marker for assessing treatment response when high bone turnover occurs, and it should be measured at three to six months to evaluate initial response. Early diagnosis of Paget disease of bone remains key to its management because patients generally have a good prognosis if treatment is initiated before major complications arise. The primary care physician may need to consult with a specialist for confirmation of diagnosis and initiation of treatment.

Paget's Disease of Bone.

Paget's disease of bone (PDB) is a chronic and focal bone disorder, characterized by increased osteoclast-mediated bone resorption and a subsequent compensatory increase in bone formation, resulting in a disorganized mosaic of woven and lamellar bone at one or more affected skeletal sites. As a result, bone pain, noticeable deformities, arthritis at adjacent joints, and fractures can occur. In a small proportion of cases neoplastic degeneration in osteosarcoma, or, less frequently, giant cell tumor has been also described at PDB sites. While recent epidemiological evidences clearly indicate a decrease in the prevalence and the severity of PDB, over the past 2 decades there have been consistent advances on the genetic mechanisms of disease. It is now clear that PDB is a genetically heterogeneous disorder, with mutations in at least two different genes (SQSTM1, ZNF687) and more common predisposing variants. As a counterpart to the genetic hypothesis, the focal nature of lesions, the decline in prevalence rates, and the incomplete penetrance of the disease among family members suggest that one or more environmental triggers may play a role in the pathophysiology of PDB. The exact nature of these triggers and how they might interact with the genetic factors are less understood, but recent experimental data from mice models suggest the implication of paramixoviral infections. The clinical management of PDB has also evolved considerably, with the development of potent aminobisphosphonates such as zoledronic acid which, given as a single intravenous infusion, now allows a long-term disease remission in the majority of patients.

Management of Paget's Disease of the Calcaneum.

The calcaneum is not the most common site for Paget's disease of bone, with only a few reports of monostotic involvement. We present 2 cases of Paget's disease of bone affecting the calcaneus, present an overview of the published data, and describe our management of these interesting cases.

Biology and Treatment of Paget's Disease of Bone.

Paget's disease of bone (PDB) is a common skeletal disorder characterized by increased and disorganized bone remodeling affecting one or more skeletal sites. Although some patients are asymptomatic others develop complications such as bone pain, deformity, nerve compression syndromes, and fragility fractures. Genetic factors play an important role in the pathogenesis of PDB and there is strong evidence that susceptibility is determined by variants within or close to genes that regulate osteoclast function. Environmental factors also play a key role but the nature of the environmental triggers is less clear. Bisphosphonates are a highly effective treatment for the elevations in bone turnover that are characteristic of PDB but it is unclear at present if they alter the natural history of the disease. Here, we review the epidemiology, clinical, cellular, and molecular abnormalities in PDB as well as environmental and genetic triggers, and current available treatment options.

Paget's Disease of Bone: Progress Towards Remission and Prevention.

Paget's disease of bone is a focal disorder of bone remodelling leading to areas of enlarged weakened bone manifesting with chronic pain, bone deformity, and fracture. Predominantly a disease of older adults, its prevalence is strongly linked to European ancestry. Pre-disposing factors include exposure to viruses such as measles and mutations in the SQSTM1 gene. PDB is diagnosed on plain radiograph, the extent of disease is delineated by radionuclide bone imaging, the degree of activity is quantified biochemically, and it is treated with a nitrogen-containing bisphosphonate, most effectively by a single intravenous infusion of zoledronate 5mg. Lifelong specialist follow-up is advocated because some patients require repeated infusions. Current clinical research is focusing on genetic factors in order to identify patients suitable for prevention.

Paget's disease.

Paget's disease of bone is the most common metabolic bone disease after osteoporosis and affects 2-4% of adults over 55 years of age. Its etiology is only partly understood and includes both genetic and environmental factors. The disease may be asymptomatic and can be uncovered incidentally on x-ray or in biochemical tests performed for another condition. It can also manifest itself with bone pain, deformity, fracture or other complications. Paget's disease is diagnosed by x-rays and in general has very typical radiological features, but occasionally the clinical picture may be unusual and a differential diagnosis of sclerotic or lytic metastases needs to be considered. Plasma total alkaline phosphatase activity is the most clinically useful indicator of disease activity. It is elevated in most untreated patients, but may be within the normal range in patients with monostotic or limited disease. Bisphosphonate therapy is indicated for patients with symptoms and should also be considered in patients with disease sites that suggest a risk of complications, such as long bones, vertebrae or base of the skull. Orthopedic surgery in Paget's disease patients includes almost exclusively the correction of fractures and arthroplasty.

[Multilocular Paget's disease in IBMPFD syndrome. A case report with 14-year follow-up]. / Multilokulärer Morbus Paget bei IBMPFD-Syndrom. Darstellung eines Krankheitsverlaufes über 14 Jahre.

Paget's osteodystrophia deformans is a monoostotic or polyostotic disease of the skeletal system with increased bone remodelling, structural modifications and skeletal deformation, typically arranged like a chessboard. The unusual case of a patient is described who had suffered from generalized Paget's disease of the bone for 14 years and also developed progressive myopathy and a behavioural variant frontotemporal dementia. Further cytogenetic diagnostics revealed a point mutation in the valosin-containing protein (VCP, p97) gene on chromosome 9p13-p12 consistent with the finding of inclusion body myopathy with early onset Paget's disease and frontotemporal dementia (IBMPFD syndrome). A causal therapy of this disease is not known. Conservative treatment with bisphosphonate therapy, intensive physiotherapeutic exercise and psychotherapeutic treatment was performed to retard the progression of the disease.

A case of Paget's disease in hemodialysis.

Paget's disease is the second most common bone disease after osteoporosis and causes an excessive bone turnover. Moreover, chronic kidney failure causes an impairment of bone mineral metabolism and electrolytes and PTH homeostasis. As far as we know, this is the first reported case of Paget's disease in a hemodialysis patient: the patient was also affected by secondary hyperparathyroidism and was successfully treated with clodronate, cinacalcet and paracalcitol. The safety and efficacy of this combined therapy was periodically revised in a 12-month follow-up considering the common markers of bone turnover as well as the dosage of OPG, RANKL, IL-6 and MCSF, involved in the pathophysiology of Paget's disease.

Paget disease of bone.

Despite significant advances in management, Paget disease remains an enigmatic disorder. There are no animal models, and while its end result --a focal disorder of accelerated bone turnover--is easily recognized, the causes and evolution of the disorder remain uncertain. Recent evidence strongly implicates both genetic and environmental factors in its etiology. The authors consider some of the unresolved questions surrounding Paget disease, including the attenuating prevalence and severity of the disease; how these observations might be reconciled with an apparently highly penetrant genetic susceptibility; what the putative environmental triggers of Paget disease might be; and what relapse after treatment tells us. Most observations seem to fit best with the idea that Paget disease behaves as a multifocal benign neoplasm.

[Documentation of outpatient treatment of Paget's disease in Westphalia-Lippe. Descriptive analysis of statutory health insurance data for the year 2005]. / Dokumentation der ambulanten Morbus-Paget-Behandlung am Beispiel der Region Westfalen-Lippe: Deskriptive Analyse der Abrechnungsdaten gesetzlich Krankenversicherter für das Jahr 2005.

GOAL: Inpatient health care data are often used as a source of information for health reporting in Germany, despite the fact that a lot of diseases are predominantly treated in the outpatient sector. This study provides a first overview of the outpatient care situation in relation to Paget's disease. METHOD: Outpatient care data from the Association of Statutory Health Insurance Physicians constituted the database for a descriptive analysis, capturing the state of medical care for the rare rheumatic illness Paget's disease (Osteodystrophia deformans) in the region of East Westphalia-Lippe in 2005. RESULTS: While the health report of North Rhine-Westphalia documents a total of 56 cases of M. Paget discharged from hospital for the year 2003, 166 patients suffering from Paget's disease consulted an practice-based physician in 2005 in the district of Detmold alone. The latter figure corresponds to 8.0 treated patients per 100.000 inhabitants. The treatment rates of men and women are comparable. The probability of treatment increases with advancing age. On average, patients with Paget's disease are 65.6 years old (SD=15.4 years). Almost 90% of the diagnoses of Paget's disease are classified as M88.9 according to ICD 10; more exact localisations are provided only for relatively few cases. Nearly a quarter of the cases (24.1%) are treated by general practitioners and internists. Anaesthetists treated 17.5% of the patients and orthopaedists 16.9%. In addition, ophthalmologists treat a considerable proportion of cases (12.0%). CONCLUSION: Consistent with the rareness of Paget's disease, the treatment data are as low as expected. However, the results show that routinely collected health care data allow insights into morbidity structures within the outpatient sector. It follows that for statutory health insurants (approximately 90% of the population) there should be an extension of health reporting to diseases that are mainly treated in outpatient settings.

Juvenile Paget's disease.

Juvenile Pagets disease (JPD), a rare genetic disorder characterized by markedly accelerated bone turnover, presents in early childhood. We report a child with typical features of JPD who remained undiagnosed till 15 years of age. Rarity of this disease in Indian literature and need for early diagnosis to prevent progression of disease prompted us to report this case.

Paget's disease 2: exploring diagnosis, management and support strategies.

This is the second of a two-part unit on Paget's disease. Part 1 outlined the epidemiology, pathophysiology, causes and clinical features of the condition. This part outlines advice on diagnosis, drug therapy, surgery, other management options and emotional support.

Paget's disease of bone: updates for clinicians.

PURPOSE OF REVIEW: To provide clinicians an overview to the diagnosis, treatment, and management of Paget's disease, including recent guideline recommendations, with comparison of the Endocrine Society Clinical Practice Guideline (JCEM 2014) with the new Clinical Guideline review endorsed by the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the European Calcified Tissues Society, and the United Kingdom Bone Research Society (JBMR 2019). RECENT FINDINGS: Radionuclide bone scans are recommended for assessing the extent of Paget's disease. Bisphosphonates remain the mainstay for therapy with evidence of reducing symptomatic bone pain. One 5 mg intravenous dose of zoledronic acid is the current standard therapy for Paget's disease. SUMMARY: Paget's disease of the bone is characterized by focal increased bone remodeling activity, resulting in sclerotic or lytic lesions and poor bone quality at one or more sites. Patients may be symptomatic with bone pain, or may be asymptomatic, and identified through unexplained elevations in serum alkaline phosphatase. Diagnosis is through plain film imaging, with radionuclide bone scan to determine the extent. A single dose of IV zoledronic acid typically results in extended suppression of bone turnover and amelioration of bone pain. There remains a lack of evidence regarding efficacy of this treatment with regards to other complications of Paget's, but in general, bisphosphonate treatment is recommended.