Epidemiology and characteristics of Paget's disease of bone in a French nationwide HIV cohort.

Paget's disease of bone (PDB) has rarely been reported in people with HIV (PWH). We describe the prevalence and characteristics of patients with PDB in the French multicenter Dat'AIDS cohort. Among 49 698 PWH actively followed in 2022, 9 had a diagnosis of PDB. The overall prevalence of PDB was 0.02% [95% confidence interval (CI) 0.01-0.03]. The prevalence of PDB in PWH is very low and does not appear to differ from the non-HIV population.

Adolescent-onset multisystem proteinopathy due to a novel VCP variant.

Valosin-containing protein (VCP) pathogenic variants are the most common cause of multisystem proteinopathy presenting with inclusion body myopathy, amyotrophic lateral sclerosis/frontotemporal dementia, and Paget disease of bone in isolation or in combination. We report a patient manifesting with adolescent-onset myopathy caused by a novel heterozygous VCP variant (c.467G > T, p.Gly156Val). The myopathy manifested asymmetrically in lower limbs and extended to proximal, axial, and upper limb muscles, with loss of ambulation at age 35. Creatine kinase value was normal. Alkaline phosphatase was elevated. Electromyography detected mixed low amplitude, short duration and high amplitude, long duration motor unit potentials. Muscle biopsy showed features of inclusion body myopathy, which in combination with newly diagnosed Paget disease of bone, supported the VCP variant pathogenicity. In conclusion, VCP-multisystem proteinopathy is not only a disease of adulthood but can have a pediatric onset and should be considered in differential diagnosis of neuromuscular weakness in the pediatric population.

Enfermedad ósea de Paget: 1877-2023. Etiología y abordaje de una enfermedad en transición epidemiológica / Paget's disease of bone: 1877–2023. Etiology, and management of a disease on epidemiologic transition

La enfermedad ósea de Paget se caracteriza por la alteración, en una o varias localizaciones óseas, del equilibrio entre formación y resorción ósea. Este desequilibrio da lugar a un hueso ensanchado, desorganizado, en muchos casos con una densidad ósea aumentada, aunque más frágil. Existiría una predisposición genética para su desarrollo, que explicaría entre un 5 y un 40% de los casos, sobre la que actuarían distintos factores ambientales. La enfermedad ósea de Paget fue considerada clásicamente la segunda enfermedad metabólica ósea más frecuente. Sin embargo, durante las últimas décadas presenta un marcado descenso tanto de la incidencia como de la gravedad clínica, lo que ha llevado a especular sobre la disminución o desaparición de la influencia de algún factor ambiental. Este descenso en la incidencia no debe servir como excusa para el abandono de su estudio, sino ser la razón para tratar de entender mejor su patogenia (AU)

Paget's disease of bone is characterized by the alteration, in one or several bone locations, of the equilibrium between bone formation and bone resorption. This imbalance results in a disorganized, widened bone, in many cases with increased bone density, although more fragile. A genetic predisposition for Paget's disease of bone could explain between 5% and 40% of the cases. Different environmental factors should explain the rest of the cases. Paget's disease of bone was classically considered the second most common metabolic bone disease. However, in recent decades there has been a marked decrease in both incidence and clinical severity. These changes have led to believe that the influence of some environmental factor may have diminished or even disappeared. This decrease in incidence should not be an excuse for abandoning Paget's disease of bone research, but rather it should be the reason to remain searching to try to understand better its pathogenesis(AU)

[Paget's disease of bone: 1877-2023. Etiology, and management of a disease on epidemiologic transition]. / Enfermedad ósea de Paget: 1877-2023. Etiología y abordaje de una enfermedad en transición epidemiológica.

Paget's disease of bone is characterized by the alteration, in one or several bone locations, of the equilibrium between bone formation and bone resorption. This imbalance results in a disorganized, widened bone, in many cases with increased bone density, although more fragile. A genetic predisposition for Paget's disease of bone could explain between 5% and 40% of the cases. Different environmental factors should explain the rest of the cases. Paget's disease of bone was classically considered the second most common metabolic bone disease. However, in recent decades there has been a marked decrease in both incidence and clinical severity. These changes have led to believe that the influence of some environmental factor may have diminished or even disappeared. This decrease in incidence should not be an excuse for abandoning Paget's disease of bone research, but rather it should be the reason to remain searching to try to understand better its pathogenesis.

Decline in clinical severity of Paget's disease of bone: Comparison between a contemporary cohort and a historical cohort.

BACKGROUND: European and Australian studies have reported a decrease in the prevalence, incidence and clinical severity of Paget's disease of bone (PDB). There are no studies on the current clinical characteristics of PDB in Quebec, Canada. AIMS: The purpose of this study was to describe the characteristics of unrelated patients with PDB diagnosed after the year 2000 in our region and to compare them to a historical cohort diagnosed before 2000. METHODS: In this retrospective descriptive cohort study, socio-demographic data and clinical characteristics for the contemporary cohort were collected from electronic medical records of patients with PDB followed at our university hospital. For the historical cohort, the same data were collected from the research files of PDB participants in our research program. Inclusion criteria were: age > 18 years, having PDB diagnosed by a rheumatologist, and being followed in our hospital. Exclusion criteria were: having a relative with PDB participating in this study. Variables were reported as mean, standard deviation, frequency and percentage. Chi-square tests were used to compare categorical variables. Continuous values were compared with Wilcoxon-Mann-Whitney tests. Unadjusted p-values and adjusted p-values with the Bonferroni correction method were calculated. A p-value <0.05 was considered statistically significant. RESULTS: Among the 195 patients with PDB in the contemporary cohort, 53.3 % were men, 60.5 % had monostotic involvement, 14.2 % were symptomatic at diagnosis. In comparison to the historical cohort of 173 patients, patients in the contemporary cohort were older at diagnosis (68.7  10.7 vs. 58.5  10.1; p < 0.0001) and had less family history of PDB (13.8 % vs. 33.6 %; p = 0.0024). They also had lower total alkaline phosphatase levels at diagnosis (118.0 (85.0-184.0)) vs. 184.0 (115.0-312.0)); p = 0.0006), a lower pagetic bone number (1.0 (1.0-3.0) vs. 2.0 (1.0-5.0); p < 0.0001), lower pagetic bone fractures (6.7 % vs. 36.7 %; p = 0.0078) and lower bone deformities (13.0 % vs. 54.0 %; p < 0.0001). There was no significant difference for pagetic bone pain (52.0 % vs. 52.6 %; p = 1.0000), percentage of patients who had orthopedic surgery related to PDB complications (8.8 % vs. 28.6 %; p = 1.0000), secondary osteoarthritis (43.0 % vs. 51.6 %; p = 1.0000), and hearing impairment (51.9 % vs. 61.1 %; p = 0.1000). CONCLUSION: The contemporary cohort is characterized by an older age at diagnosis, a majority of monostotic disease and fewer complications of PDB. This decline in clinical severity of PDB in Quebec is consistent with studies reported in other countries.

Updates on Paget's Disease of Bone.

Paget's disease of the bone is a prevalent bone disease characterized by disorganized bone remodeling; however, it is comparatively uncommon in East Asian countries, including China, Japan, and Korea. The exact cause still remains unknown. In genetically susceptible individuals, environmental triggers such as paramyxoviral infections are likely to cause the disease. Increased osteoclast activity results in increased bone resorption, which attracts osteoblasts and generates new bone matrix. Fast bone resorption and formation lead to the development of disorganized bone tissue. Increasing serum alkaline phosphatase or unique radiographic lesions may serve as the diagnostic indicators. Common symptoms include bone pain, bowing of the long bones, an enlarged skull, and hearing loss. The diagnosis is frequently confirmed by radiographic and nuclear scintigraphy of the bone. Further, bisphosphonates such as zoledronic acid and pamidronate are effective for its treatment. Moreover, biochemical monitoring is superior to the symptoms as a recurrence indicator. This article discusses the updates of Paget's disease of bone with a clinical case.

Enlivening the radiographic features of Paget disease.

Paget disease often presents as a rare asymptomatic lesion of the bone until it progresses into the advanced stages. A senile man was diagnosed with Paget disease of bone on routine dental radiographic analysis. His history of fractures, periodical ill-fitting dentures and frequent pain in the long bones were contributing to the diagnosis. The patient was referred to a general physician where whole body radiographs were taken, which showed several of the classic features of Paget disease. Biochemical analysis was also done in which serum alkaline phosphatase was elevated with all other values within normal limits, confirming the diagnosis. The patient was treated with single-infusion bisphosphonate followed by other required dental procedures. Early diagnosis and prompt management gave a good prognosis, preventing the potential complications.

Multisystem Proteinopathy Due to VCP Mutations: A Review of Clinical Heterogeneity and Genetic Diagnosis.

In this work, we review clinical features and genetic diagnosis of diseases caused by mutations in the gene encoding valosin-containing protein (VCP/p97), the functionally diverse AAA-ATPase. VCP is crucial to a multitude of cellular functions including protein quality control, stress granule formation and clearance, and genomic integrity functions, among others. Pathogenic mutations in VCP cause multisystem proteinopathy (VCP-MSP), an autosomal dominant, adult-onset disorder causing dysfunction in several tissue types. It can result in complex neurodegenerative conditions including inclusion body myopathy, frontotemporal dementia, amyotrophic lateral sclerosis, or combinations of these. There is also an association with other neurodegenerative phenotypes such as Alzheimer-type dementia and Parkinsonism. Non-neurological presentations include Paget disease of bone and may also include cardiac dysfunction. We provide a detailed discussion of genotype-phenotype correlations, recommendations for genetic diagnosis, and genetic counselling implications of VCP-MSP.

Clinical features, diagnostic evaluation and responses to treatment in Paget's disease of bone in a center specialized in bone metabolism.

The epidemiology of Paget's disease of bone (PDB) has changed in the last years but there is no update data on its clinical presentation, diagnosis and management in Latin America. Our aim was to describe its clinical features, diagnostic evaluation and responses to treatment in a group of PDB patients treated between June 2012 and December 2019 in an institution specialized in bone diseases, in Buenos Aires, Argentina. The frequency of PDB (180/10 714) was 1.68%. Median age was 67 (range 39-97) years and 59.5% were women. Most patients were asymptomatic (58.6%) and had monostotic disease (54.3%). Favorable responses were obtained in all patients who were treated with zoledronate (n = 36), in 10 out of 14 treated with pamidronate, in 9 out of 10 who received intravenous ibandronate and in 12 out of 13 who received oral bisphosphonates. The response rates were not significantly different when we compared monostotic vs. polyostotic disease. Among the biochemical parameters, mean values of bone specific and total alkaline phosphatase, and C-terminal crosslinked telopeptide of type I collagen decreased significantly after treatment with bisphosphonates. It seems that our results reflect the change in PDB epidemiology towards a more indolent disease. In the future, this would probably allow physicians to use lower doses of bisphosphonates than the ones historically recommended for these patients.

La epidemiología de la enfermedad de Paget ósea (EPO) ha cambiado en los últimos años. Son necesarios datos actualizados sobre su forma de presentación clínica, diagnóstico y tratamiento en nuestra región. Nuestro objetivo fue describir las características clínicas, evaluación diagnóstica y respuestas al tratamiento de un grupo de pacientes con EPO en un centro especializado en salud ósea de Buenos Aires, Argentina. Se evaluaron todos los pacientes que fueron atendidos en nuestra institución por enfermedades óseas entre junio de 2012 y diciembre de 2019. La frecuencia de EPO (180/10 714) fue de 1.68%. La mediana de edad fue de 67 (rango 39-97) años. El 59.5% eran mujeres. La mayoría se encontraba asintomático (58.6%) y tenían enfermedad monostótica (54.3%). Se objetivaron respuestas favorables en todos los que recibieron zoledronato (n = 36), en 10 de 14 pacientes que recibieron pamidronato, en 9 de 10 que utilizaron ibandronato endovenoso y en 12 de 13 con bifosfonatos orales. Los porcentajes de respuesta no variaron significativamente entre pacientes con formas monostóticas y poliostóticas. Entre los parámetros bioquímicos, los valores de fosfatasa alcalina total y ósea y de Β cross-laps disminuyeron significativamente luego del tratamiento con bifosfonatos. Nuestros resultados reflejarían un cambio en la epidemiología de la EPO hacia una forma de presentación más indolente. Esto permitiría probablemente el uso de dosis más bajas de bifosfonatos que las históricamente recomendadas para estos pacientes.

A case of Paget's disease of bone associated with hypomyopathic dermatomyositis.

Dermatomyositis is associated with malignancies and is known to have systemic involvement. However, associations with bone diseases have not been well described in the current literature. This article describes the second reported case of the co-existence of dermatomyositis and Paget's disease of bone (PDB), but this is the first report to describe such co-existence in a specific subtype of dermatomyositis-hypomyopathic dermatomyositis. Our patient was a 51 year old woman who presented with prolonged fever, myalgia, morning stiffness, and rashes pathognomonic of dermatomyositis. There was no muscle weakness clinically, although muscle enzymes were increased and electromyogram revealed myopathic changes. Further imaging showed the incidental finding of a T11 vertebral bone lesion, of which biopsy confirmed the diagnosis of PDB. Our report illustrates the diagnostic approach to bone lesions in patients with dermatomyositis and takes a closer look at the pathophysiology and management implications of the co-occurrence of these two rare diseases.

Misdiagnosis of Paget's Disease of Bone in a Congenital Generalized Lipodystrophy Patient: Case Report.

Paget's disease of bone (PDB) is a common skeleton disorder in which the diagnosis is suggested by radiological analyses. Congenital generalized lipodystrophy (CGL) is a rare, but a radiologic differential diagnosis of Paget's disease. Patients present total or almost total lack of subcutaneous adipose tissue, leptin deficiency, and precocious ectopic lipid accumulation, which lead to intense insulin resistance, poorly controlled diabetes mellitus, and hypertriglyceridemia. CGL subtypes 1 and 2 present sclerosis and osteolytic lesions that can resemble "pagetic" lesions. The clinical correlation is, therefore, essential. We report a CGL patient with bone lesions in which the radiographic findings led to a misdiagnosis of PDB. This case report brings awareness to CGL, a life-threating condition. Its early recognition is essential to avoid clinical complications and premature death. Therefore, it is important to consider CGL as PDB's differential diagnosis, especially in countries with high prevalence of this rare disease, such as Brazil.

Juvenile Paget's Disease: Report of a successful treatment throughout the complete growth of a patient with a missense TNFRSF11B mutation.

INTRODUCTION: Juvenile Paget's Disease (JPD) is an ultra-rare inherited osteopathy featuring markedly accelerated bone turnover. Several clinical characteristics have been reported, including bone deformities developing in childhood and hearing loss. CASE REPORT: We report the case of a 2 ¾-year-old girl that presented with progressive bowing of both legs since the age of 2, lower limb pain and frequent falls with one consequent femur fracture. Plain radiographs revealed osteoectasia of the long bone's diaphysis, and laboratory tests showed extremely high serum total alkaline phosphatase levels. A missense mutation on the gene TNFRSF11B was identified in homozygosity, and the diagnosis of JPD was made. Treatment with bisphosphonates was initiated early and markedly improved lower limb bowing and pain. The patient reached adulthood with normal height, minor bone deformities, and no functional impairment. Despite the good skeletal symptom's response, bisphosphonates failed to prevent or improve sensorineural hearing loss. CONCLUSIONS: In this clinical case, early treatment with bisphosphonates was effective for the treatment of JPD skeletal deformities. New therapeutic strategies need to be developed to better control the extraskeletal manifestations of JPD.

Paget's Disease of Bone in Patients under 40 Years: Two case reports and review of the literature.

Paget's disease of bone (PDB) is a focal disorder of accelerated skeletal remodelling that is uncommon in patients under the age of 40 years; it is more prevalent in older individuals. We report two cases of PDB diagnosed in early adulthood at the Mohamed Kassab Institute of Orthopedics, La Manouba, Tunisia. The first case was a 35-year-old male patient who presented in 2011 with a seven-month history of hip pain. The second case was a 39-year-old female patient who presented 2014 with chronic lower back pain. The PDB diagnosis was confirmed with clinical, biological and radiological investigations. Both patients were doing well on follow-up. Some previous cases have been reported in the literature, differing from the presented cases in some aspects; data of PDB features at differing ages is still insufficient. Early recognition of this clinical entity in young patients is important as early treatment can affect the progression of the disease.

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.

Incidence of Paget's disease of bone in the UK: evidence of a continuing decline.

OBJECTIVES: To characterize the incidence of clinically diagnosed Paget's disease of bone in the UK during 1999-2015 and to determine variations in the incidence of disease by age, sex, geography and level of deprivation. METHODS: Incident cases of Paget's disease occurring between 1999 and 2015 were identified from primary care records. Overall crude incidence and incidence stratified by age and sex was calculated each year from 1999 to 2015. Direct age- and sex-standardized incidence was also calculated. We used Poisson regression to look at variations in incidence by deprivation and UK region. RESULTS: A total of 3592 incident cases of Paget's disease were identified between 1999 and 2015. Incidence increased with age and at all ages was greater in men than women. In women and men, respectively, crude incidence increased from 0.037 and 0.074/10 000 population per year among those 45-49 years of age to 3.7 and 6.3/10 000 population per year among those ≥85 years. The overall standardized incidence decreased from 0.75/10 000 person-years in 1999 to 0.20/10 000 person-years in 2015. After adjustment for age and sex, incidence was >30% higher in the most- compared with least-deprived quintile of deprivation. There was evidence of geographic variation, with the highest incidence in the North West of England, which persisted after adjustment for age, sex and level of deprivation. CONCLUSION: The incidence of clinically diagnosed Paget's disease has continued to decrease since 1999. The reason for the decline in incidence remains unknown, although the rapidity of change points to an alteration in one or more environmental determinants.

Decreasing severity of Paget's disease of bone in northern Italy over the last two decades: results of a monocentric study on 391 patients.

Patients with Paget's disease of bone recruited over the last 20 years by a single centre were evaluated to find possible clinical changes. All markers of severity showed consistent downward trends. A reduced disease incidence could seemingly refer to lower sensitivity of the diagnostic tools owing to lower severity. INTRODUCTION: This study aimed to evaluate if the severity of Paget's disease of bone (PDB) is decreasing and whether a milder phenotype can have affected the results of studies on disease prevalence. METHODS: From August 2007 to August 2019, 167 patients with PDB were referred to our centre. Demographic and clinical characteristics were collected and compared with those of a sample of 224 patients enrolled in the same setting between January 2000 and July 2007. Multivariate analyses on 391 patients as a whole were performed assuming the year of presentation as explanatory variable. RESULTS: Patients of newer sample were diagnosed at a significantly older age (64.0 ± 11.3 vs 61.1 ± 11.6; p = 0.01). By comparing clinical features acknowledged as markers of disease severity, the mean number of involved bones, the proportion of skeletal involvement, and pre-treatment serum alkaline phosphatase (SAP) values all showed significant decreases (p < 0.001) in the more recent sample. Multivariate analyses confirmed these results for the latter two indices. Further markers of disease severity such as the prevalence of monostotic disease and normal SAP at diagnosis showed the same trend. The sensitivity of tools allowing incidental diagnosis in asymptomatic patients showed a reduced sensitivity: -11% for radiological assessments and -33% for SAP. CONCLUSIONS: Allowing for referral differences, our study provides information on reduced severity of PDB over the last two decades. A milder phenotype affects the age at onset and impairs the sensitivity of the diagnostic tools contributing to reduce the prevalence of PDB patients incidentally discovered.