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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., (© 2024. The Author(s).)

Competing Interests: Les auteurs déclarent n’avoir aucun lien d’intérêts.

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.

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 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.

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.

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.

Introduction: Paget's disease (PDB) is a focal disorder of bone remodeling that occurs commonly in older people with decreasing prevalence reported in European countries. This disease is most often asymptomatic, but it can cause a variety of medical complications resulting in considerable morbidity and reduced quality of life. There is little information regarding the epidemiology of PDB in Poland. To the best of the authors' knowledge, this is the first large epidemiological analysis of this disease in Poland., Objective: The aim of this study was to analyze factors that may be related to the PDB epidemiology among hospitalized patients in Poland., Material and Methods: The analysis was conducted on the basis of population-based administrative data, taken from a Polish hospital morbidity study carried out by the National Institute of Public Health between January 2008 - December 2014., Results: Analyzed data covered 662 hospitalization records. The final study sample comprised 94 (41.8%) male and 131 (58.2%) female patients with first-time hospitalizations for PDB, with a significant predominance of females (P<0.02), and the predominance of patients living in urban (73%) than in rural areas (27%), P<0.001. The average age of the sample was 56.8 years (CI: 54.3-59.3; SD 18.8; range 1-93 years). The number of PDB cases hospitalized in Poland significantly decreased during the analyzed period of time., Conclusions: PDB is a rare disease with decreasing trends observed among hospitalized patients in Poland. The study results may suggest the existence of environmental risk factors for the development of PDB.

Paget's disease is a chronic focal high turnover bone disorder that is primarily present in middle-aged or older adults. It seems to be restricted to humans and has no clear parallels with other diseases. Although much has been learnt about its pathology and epidemiology, and treatment is now highly effective we still lack a complete understanding of its etiology and biology. This review focusses on the natural history of the disorder, in particular its changing epidemiology, recent discoveries about its genetic basis and current approaches to diagnosis and treatment. While there is strong evidence for genetic predisposition to Paget's disease, there is also compelling evidence that it is becoming less prevalent, the age of patients at presentation is increasing and that the extent of skeletal involvement is diminishing, implying that there is an important, but as yet unidentified, environmental factor in its etiology. Contemporary patients are typically elderly and have few bones involved. Treatment with potent intravenous bisphosphonates provides prolonged remission and many will require only once in a lifetime treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Juvenile Paget disease (JPD) is a rare disorder, mainly caused by mutations in the gene TNFRSF11B that encodes osteoprotegerin (OPG). Loss of OPG action causes generalized, extremely rapid bone turnover. The clinical manifestations are both skeletal - progressive skeletal deformity that develops in childhood - and extra-skeletal, including hearing loss, retinopathy, vascular calcification and internal carotid artery aneurysm formation. The severity of the phenotype seems to be related to the severity of TNFRSF11B gene deactivation. JPD is characterized biochemically by very high alkaline phosphatase activity, as well as other bone turnover markers. Bisphosphonates are commonly used to reduce the greatly accelerated bone turnover and can ameliorate the skeletal phenotype, if started early enough in childhood and continued at least until growth is complete. Limited evidence from patients treated with recombinant OPG or denosumab also provided favorable results. Recombinant OPG would represent a replacement treatment, but it is unavailable for clinical use. It seems that life-long treatment with anti-resorptives is required, since the disease is reactivated after treatment discontinuation. An international collaborating network for the continuous registration and follow-up of JPD patients could be helpful in the future., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Paget's disease of bone is the second most common metabolic bone disease after osteoporosis. Its pathogenesis is not yet clearly understood. Geographic distribution and epidemiological variations suggest a role of genetic and environmental factors in its pathophysiology. The frequency of the Paget's disease of bone increases with age. Its discovery can be fortuitous. Prognosis mainly depends on the occurrence of complications involving bones and joints, neurological, cardiovascular or metabolic systems. Treatment of symptomatic forms currently relies on bisphosphonates that have transformed its prognosis., (Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Objectives: To report a contemporary review from a single-institution series on Paget's disease of the temporal bone (PDTB)., Study Design: Retrospective chart review of patients evaluated from 1998 to 2016., Setting: Quaternary referral center., Patients: Patients with radiographically confirmed PDTB., Main Outcome Measures: Clinical, audiological, and radiological features and management strategies of PDTB., Results: A total of 50 temporal bones in 27 patients (15 men) were diagnosed with PDTB. Symptoms at presentation included hearing loss (n = 23, 85%), headache (n = 18, 67%), dizziness (n = 14, 52%), tinnitus (n = 5, 19%), chronic otitis media (n = 2, 7%), hemifacial spasm without facial paralysis (n = 1, 4%), multiple cranial neuropathies (n = 1, 4%), and neoplastic transformation (n = 1, 4%). Of the 23 ears with audiometric data available for review, 65% exhibited sensorineural hearing loss, and 35% mixed hearing loss. Long-term audiometric follow-up was available on two patients, both of whom demonstrated hearing loss at a rate greater than would be expected for normal aging. Two patients underwent successful cochlear implantation, achieving open-set speech recognition. Radiographic features of temporal bone involvement are reviewed and illustrated., Conclusion: This is the largest single-institution clinical series examining patients with PDTB in the English literature. Variable patterns of temporal bone involvement by Paget's disease are observed leading to a diverse set of clinical symptoms, including slowly progressive hearing loss, tinnitus, compressive cranial neuropathies, and benign or malignant tumorigenesis. Involvement typically begins in the petrous apex and progresses laterally. Otic capsule bone demineralization occurs late in the disease process. Cochlear implantation appears to be an effective management strategy for patients with severe-to-profound hearing loss.

It has been suggested that normalization of bone turnover may improve clinical outcome in Paget's disease of bone (PDB) by preventing complications such as fractures and the development of osteoarthritis. Here we investigated the long-term effects of a treatment strategy that aimed to normalize bone turnover in PDB with that of symptomatic treatment. The study group comprised 502 subjects who were enrolled into a 3-year extension of the Paget's Disease: Randomized Trial of Intensive versus Symptomatic Management (PRISM) study. Intensive bisphosphonate therapy was continued in 270 of these subjects with the aim of normalizing bone turnover using zoledronic acid as the treatment of first choice. Symptomatic treatment continued in 232 subjects in whom bisphosphonates were only given for the treatment of bone pain. The primary outcome was fracture and secondary outcomes were orthopedic procedures, quality of life, and bone pain, adjusted for baseline characteristics. Serum total alkaline phosphatase (ALP) concentrations were significantly lower in the intensive group on entry to the study and the differences between groups increased as the study progressed. There were no clinically important differences in quality of life measures or bone pain between the treatment groups. Intensive treatment was associated with a nonsignificant increase in fracture risk (hazard ratio = 1.90; 95% CI, 0.91 to 3.98; p = 0.087), orthopedic procedures (1.81; 95% CI, 0.71 to 4.61; p = 0.214), and serious adverse events (relative risk 1.28; 95% CI, 0.96 to 1.42). We conclude that long-term intensive bisphosphonate therapy confers no clinical benefit over symptomatic therapy and is associated with a nonsignificant increase in the risk of fractures, orthopedic events, and serious adverse events. The results of this study suggest that in patients with established PDB, bisphosphonate therapy should focus on control of symptoms rather than suppression of bone turnover. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

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., (Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Multicentric giant cell tumor of the bone (MGCT) is a rare entity whose radiographic, pathological and biological features remain confusing. We retrospectively reviewed six patients (1 male, 5 female; average age, 22.33 years) treated for confirmed MGCT between 2001 and 2015. The patients' clinical information, images from radiographs (n = 14), CT (n = 13), MRI (n = 8), bone scintigraphy (n = 1) and PET-CT (n = 2), as well as histologic features, treatment and prognosis were analyzed. A total of 17 lesions were detected: 4 around the knee joint, 3 in the greater trochanter and head of the femur, 5 in the small bones of the feet, and 2 in flat bones. All these lesions occurred in an ipsilateral extremity. One patient had Paget's disease. On radiographs and CT, 12 lesions exhibited sclerotic margins or patchy sclerosis, 8 showed cortical discontinuity, and 5 showed soft tissue masses. On histopathology, 8 lesions showed signs of sarcomatous transformation and one had transformed into osteosarcoma. Ten lesions in 4 patients were initially treated with surgery, and 3 showed local recurrence. Seven lesions in 3 patients were treated with denosumab. All the patients are currently stable without metastasis. These results suggest MGCT tends to occur in uncommon sites with sclerosis. Because these lesions can be aggressive, patients should be carefully monitored for the recurrence or formation of other lesions, especially in an ipsilateral extremity.

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., (© 2015 Wiley Periodicals, Inc.)

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.

The current understanding of Paget disease of bone (PDB) has vastly changed since Paget described the first case in 1877. Medical management of this condition remains the mainstay of treatment. Surgical intervention is usually only used in fractures through pagetic bone, need for realignment to correct deformity in major long bones, prophylactic treatment of impending fractures, joint arthroplasty in severe arthritis, or spinal decompression in cases of bony compression of neural elements. Advances in surgical technique have allowed early return to function and mobilization. Despite medical and surgical intervention, a small subset of patients with PDB develops Paget sarcoma., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia is attributed to mutations in the valosin-containing protein (VCP) gene, mapped to chromosomal region 9p13.3-12. Affected individuals exhibit scapular winging and die from progressive muscle weakness and cardiac and respiratory failure in their 40s to 50s. Mutations in the VCP gene have also been associated with amyotrophic lateral sclerosis in 10-15% of individuals with hereditary inclusion body myopathy and 2-3% of isolated familial amyotrophic lateral sclerosis. Currently, there are no effective treatments for VCP-related myopathy or dementia. To determine the effects of targeted excision of the most common R155H mutation in VCP disease, we generated the Cre-ER™-VCPR155H/+ tamoxifen-inducible model. We administered tamoxifen (0.12 mg/g body weight) or corn oil (vehicle) to the pregnant dams by oral gavage and monitored survival and muscle strength measurements of the pups until 18 months of age. We confirmed efficient removal of exons 4 and 5 and recombination of the mutant/floxed VCP copies by Q-PCR analyses. The activity and specificity of Cre recombinase was confirmed by immunostaining. Herein, we report that Cre-ER™-VCPR155H/+ mice demonstrated improved muscle strength and quadriceps fibers architecture, autophagy signaling pathway, reduced brain neuropathology, decreased apoptosis, and less severe Paget-like bone changes. The Cre-ER™-VCPR155H/+ mouse model provides proof of principle by demonstrating that removal of the mutated exons could be beneficial to patients with VCP-related neurodegenerative diseases, and serves as an excellent platform in understanding the underlying pathophysiological mechanism(s) in the hopes of a promising therapeutic approach.

Paget's disease was first described more than 150 years ago, but the exact cause is still unknown--genes and the environment are both important. This article explores the basic science and clinical aspects of this intriguing condition.

Objective: The aim of this guideline was to formulate practice guidelines for the diagnosis and treatment of Paget's disease of the bone., Participants: The guideline was developed by an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer., Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence., Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence., Conclusions: We recommend that plain radiographs be obtained of the pertinent regions of the skeleton in patients with suspected Paget's disease. If the diagnosis is confirmed, we suggest that a radionucleotide bone scan be done to determine the extent of the disease. After diagnosis of Paget's disease, we recommend measurement of serum total alkaline phosphatase or, when warranted, a more specific marker of bone formation or bone resorption to assess the response to treatment or evolution of the disease in untreated patients. We suggest treatment with a bisphosphonate for most patients with active Paget's disease who are at risk for future complications. We suggest a single 5-mg dose of iv zoledronate as the treatment of choice in patients who have no contraindication. In patients with monostotic disease who have a normal serum total alkaline phosphatase, we suggest that a specific marker of bone formation and bone resorption be measured, although these may still be normal. Serial radionuclide bone scans may determine the response to treatment if the markers are normal. We suggest that bisphosphonate treatment may be effective in preventing or slowing the progress of hearing loss and osteoarthritis in joints adjacent to Paget's disease and may reverse paraplegia associated with spinal Paget's disease. We suggest treatment with a bisphosphonate before surgery on pagetic bone.

Paget's disease of bone is a common disorder characterized by increased but disorganized bone remodelling. Some patients are asymptomatic but others present with bone pain or other complications such as fracture and deformity. Major advances have been made in understanding the pathophysiology of Paget's disease in recent years and highly effective agents are now available with which to suppress the abnormal bone turnover that causes the disease. Here we review recent advances in the epidemiology, pathogenesis, clinical features and management of Paget's disease. We also reflect upon the future challenges that remain to be overcome to explain the unusual distribution of the disease and to favourably alter the natural history and prevent the development of complications., (© The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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.

Paget's disease is an osteoclastic-mediated disorder of bone that results in abnormal bone resorption associated with inadequate remodeling that leads to mechanically weakened bone. Demonstrating variable geographic prevalence, it is becoming less frequent and age of onset is lengthening in areas of once high prevalence prior to the institution of effective medical therapies, suggesting its etiology involves both environmental as well as genetic factors. Insights into its pathophysiology are helping to clarify other inherited osteolytic disorders of bone by providing additional insights into related cellular processes., (© 2014 Elsevier B.V. All rights reserved.)

Paget's disease of bone (PDB) is characterized by focal areas of aberrant and excessive bone turnover, specifically increased bone resorption and disorganized bone formation. Germline mutations in the sequestosome 1/p62 (SQSTM1/p62) gene are common in PDB patients, with most mutations affecting the ubiquitin-associated domain of the protein. In vitro, osteoclast precursor cells expressing PDB-mutant SQSTM1/p62 protein are associated with increases in nuclear factor κB activation, osteoclast differentiation, and bone resorption. Although the precise mechanisms by which SQSTM1/p62 mutations contribute to disease pathogenesis and progression are not well defined, it is apparent that as well as affecting nuclear factor κB signaling, SQSTM1/p62 is a master regulator of ubiquitinated protein turnover via autophagy and the ubiquitin-proteasome system. Additional roles for SQSTM1/p62 in the oxidative stress-induced Keap1/Nrf2 pathway and in caspase-mediated apoptosis that were recently reported are potentially relevant to the pathogenesis of PDB. Thus, SQSTM1/p62 may serve as a molecular link or switch between autophagy, apoptosis, and cell survival signaling. The purpose of this review is to outline recent advances in understanding of the multiple pathophysiological roles of SQSTM1/p62 protein, with particular emphasis on their relationship to PDB, including challenges associated with translating SQSTM1/p62 research into clinical diagnosis and treatment.

One of the serious complications of Paget's disease (PD) is a significant increase in the risk of developing osteosarcoma. Approximately 1% of the patients with PD develop osteosarcoma. This contributes significantly to the mortality and morbidity of the patients with PD. We present the case of an elderly person, who developed osteosarcoma 1 year after being diagnosed to have PD. The patient had been diagnosed to have lymphoma 8 years prior to the diagnosis of PD. The association between PD and follicular lymphoma is discussed.

Study Design: This article presents a case of Paget's disease of the cervical spine., Objectives: To report a very rare case of Paget's disease of the cervical spine and review the literature., Methods: We report a case of Paget's disease of the cervical spine in a 51-year-old male presenting with neck pain post RTA. Routine radiographs revealed enlarged sclerotic bodies of C2-C5 with normal alignment. CT revealed a fracture of the lateral mass of C2 with extensive sclerotic changes in the bodies of C2-C5 with periosteal apposition, endosteal resorption "pumice stone" type focal periosteal apposition consistent with Paget's disease. Laboratory investigations were consistent with a diagnosis of Paget's disease. Isotope bone scan revealed isolated uptake in the cervical spine. He was commenced on biosphosphonate therapy. Following 12 weeks of immobilisation his orthosis was removed and rehabilitation commenced., Results: At 12-month follow-up he is asymptomatic with no radiological change., Conclusion: This case illustrates the investigation and successful management of a very rare case of Paget's disease of the cervical spine.

Paget's disease of bone is the paradigm of bone focal distortion with accelerated bone turnover. Over the years, a number of different drugs have been used to control its activity but, since biphosphonates were introduced for the treatment of the disease, they have become the preferred treatment. This review will update the therapeutic indications, available drugs and therapeutic response monitoring., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

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.

Objectives: Paget's disease of bone (PDB), with a prevalence of 2 to 5% in Caucasians >55 years, is the second most frequent metabolic bone disease, after osteoporosis. PDB characteristics are bone lesions with an imbalanced bone remodeling, resulting in disorganized and nonfully fledged new bone. PDB etiology is not completely understood. In this review, current views on the etiology, clinical aspects, and PDB treatment are summarized and discussed., Methods: The PubMed database was searched using the keywords PDB, sequestosome1 (SQSTM1), valosin-containing protein (VCP), receptor activator of nuclear factor-κB (RANK), osteoprotegerin (OPG), RANK ligand (RANKL), mutation, genetic variants, virus, osteosarcoma, bisphosphonates, and denosumab., Results: Environmental evidence (e.g. viruses) and also genetic risk factors have been found for PDB. Until now, SQSTM1 was the only PDB-causing gene identified. However, PDB patients without SQSTM1 mutations seem to have susceptibility genetic polymorphisms in regions containing the CaSR, ESR1, TNFRSF11B (OPG), TNFRSF11A (RANK), CSF1 (M-CSF), OPTN, TM7SF4 (DC-STAMP), VCP, NUP205, RIN3, PML, and GOLGA6A genes, resulting in an increased risk of developing PDB. The nature of these genes indicates that the regulation of osteoclastogenesis is a key process in PDB pathogenesis. Furthermore, with the involvement of SQSTM1 and VCP in autophagy and in forming protein aggregates, this might also indicate that a disturbance of these processes might be a risk factor., Conclusions: Unraveling the PDB genetic background is instrumental to understanding the PDB pathogenesis and the role of slow viruses. Furthermore, it might make early detection and subsequently treatment of risk individuals possible., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Paget's disease of bone (PDB) is a progressive monostotic or polyostotic metabolic bone disease characterized by focal abnormal bone remodeling, with increased bone resorption and excessive, disorganized, new bone formation. PDB rarely occurs before middle age, and it is the second most frequent metabolic bone disorder after osteoporosis, affecting up to 3% of adults over 55 years of age. One of the most striking and intriguing clinical features is the focal nature of the disorder, in that once the disease is established within a bone, there is only local spread within that bone and no systemic dissemination. Despite many years of intense research, the etiology of PDB has still to be conclusively determined. Based on a detailed review of genetic and viral factors incriminated in PDB, we propose a unifying hypothesis from which we can suggest emerging strategies and therapies. PDB results in weakened bone strength and abnormal bone architecture, leading to pain, deformity or, depending on the bone involved, fracture in the affected bone. The diagnostic assessment includes serum total alkaline phosphatase, total body bone scintigraphy, skull and enlarged view pelvis x-rays, and if needed, additional x-rays. The ideal therapeutic option would eliminate bone pain, normalize serum total alkaline phosphatase with prolonged remission, heal radiographic osteolytic lesions, restore normal lamellar bone, and prevent recurrence and complications. With the development of increasingly potent bisphosphonates, culminating in the introduction of a single intravenous infusion of zoledronic acid 5 mg, these goals of treatment are close to being achieved, together with long-term remission in almost all patients. Based on the recent pathophysiological findings, emerging strategies and therapies are reviewed: ie, pulse treatment with zoledronic acid; denosumab, a fully human monoclonal antibody directed against RANK ligand; tocilizumab, an interleukin-6 receptor inhibitor; odanacatib, a cathepsin K inhibitor; and proteasome and Dickkopf-1 inhibitors.

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.