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.

Prevalence and incidence of Paget's disease of bone: Temporal trend over 20 years in the province of Quebec, Canada.

BACKGROUND: Paget's disease of bone (PDB) is a focal bone disorder characterized by an increased bone remodeling and an anarchic bone structure. A decline of prevalence and incidence of PDB has been observed in some countries. No epidemiological data are available on PDB in Canada. AIMS: We aimed at examining the evolution of the prevalence and incidence of PDB in Quebec (Canada) by analyzing health administrative databases. METHODS: PDB case definition relied on one or more hospitalizations, or one or more physician-billing claims with a diagnosis code of PDB. To identify incident cases, a 'run-in' period of four years (1996-1999) was used to exclude prevalent cases. For each fiscal year from 2000 to 2001 to 2019-2020 (population size 2,914,480), crude age and sex-specific prevalence and incidence rates of PDB among individuals aged ≥55 years were determined, and sex-specific rates were also standardized to the 2011 age structure of the Quebec population. Generalized linear regressions were used to test for linear changes in standardized prevalence and incidence rates. RESULTS: Over the study period, standardized prevalence of PDB has remained stable in Quebec, from 0.44 % in 2000/2001 to 0.43 % in 2019/2020 (mean change -0.002, p-value = 0.0935). For the 2019-2020 fiscal year, 13,165 men and women had been diagnosed with PDB and prevalence of PDB increased with age. Standardized incidence of PDB has decreased over time from 0.77/1000 in 2000/2001 to 0.28/1000 in 2019-2020 (mean change -0.228/year, p-value<0.0001), the incidence decreasing from 0.82/1000 to 0.37/1000 in men and from 0.76/1000 to 0.22/1000 in women, respectively. This decrease was observed in all age categories. CONCLUSION: With the exception of a slight increase in PDB prevalence up to 0.55 % in years 2005 to 2007, the prevalence of PDB has remained stable in Quebec over the past 20 years, 13,160 men and women being currently diagnosed with PDB. The incidence has decreased over time. Our results support the epidemiological changes of PDB reported in other countries.

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.

Prevalence of Paget's disease of bone: review of consecutive abdominopelvic CT scans and literature.

BACKGROUND: Previous studies suggest an overall decrease of Paget's disease of bone (PDB) prevalence. However, a large number of asymptomatic patients make previously reported prevalence likely underrepresented. PURPOSE: To evaluate the prevalence of PDB in our patient population. MATERIAL AND METHODS: We retrospectively identified 1295 (mean age = 59 years; age range = 18-98 years) consecutive abdominopelvic computed tomography (CT) scans over a 15-day period in 2014. Abdominopelvic CT images were reviewed to assess for the presence of PDB in the lower thoracic spine, lumbar spine, pelvis, or proximal femora. This prevalence was compared with prevalence reported in earlier literature using Fisher's exact test. RESULTS: Of the included patients, 5/1295 (0.39%) patients had imaging findings of PDB on abdominopelvic CT. Those five patients were all aged ≥55 years and had pelvic bone involvement, with one patient having additional involvement of multiple lower thoracic vertebral bodies. In our studied cohort, 812/1295 (62.7%) patients were aged ≥55 years, which corresponds to a prevalence of 0.62% (5/812) of PDB in patients aged ≥55 years. When accounting for fact that bones of the pelvis are involved in 40%-91% of patients with PDB, the prevalence is estimated at 0.43%-0.98% in the total adult population and estimated at 0.68%-1.55% in older adults. The prevalence was greater than two studies before 1960, and less than some studies during 1960-2019. CONCLUSION: We found that the prevalence of PDB on abdominopelvic CTs was 0.39% of all adult patients with an increase after the age of 55 years.

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.

Clinical Characteristics and Pathogenic Gene Identification in Chinese Patients With Paget's Disease of Bone.

Objective: To evaluate the clinical features of sporadic Paget's disease of bone (PDB) in China and further explore the underlying genetic abnormalities of the disease. Methods: Clinical characteristics, biochemical indices, bone turnover markers and radiographic examinations of the patients were collected. Genomic DNA was extracted from peripheral blood and whole-exome sequencing was carried out to identify the potential pathogenic genes. The pathogenicity of the variants was thereafter investigated by bioinformatics analysis. Results: A total of 50 patients (57.20 ± 15.52 years, male/female: 1.63: 1) with PDB were included and the mean onset age was 48.34 years (48.34 ± 17.24 years). 94.0% of the patients exhibited symptomatic patterns described as bone pain (86.0%), elevated skin temperature at the lesion site (26.0%), bone deformity (22.0%) and local swelling (18.0%). The most frequently involved lesion sites were pelvis (52.0%), femur (42.0%), tibia (28.0%), skull (28.0%) and spine (18.0%), respectively. Additionally, 40.0% of them accompanied with osteoarthritis, 14.0% with pathological fractures, and the misdiagnosis rate of PDB was as high as 36.0%. Serum level of alkaline phosphatase was significantly increased, with the mean value of 284.00 U/L (quartiles, 177.00-595.00 U/L). Two heterozygous missense mutations of SQSTM1 gene (c.1211T>C, M404T) and one novel heterozygous missense mutation in HNRNPA2B1 gene (c.989C>T, p. P330L) were identified in our study. Moreover, several potential disease-causing genes were detected and markedly enriched in the pathways of neurodegeneration (including WNT16, RYR3 and RYR1 genes) and amyotrophic lateral sclerosis (ALS, including NUP205, CAPN2, and NUP214 genes). Conclusion: In contrast to Western patients, Chinese patients have an earlier onset age, more severe symptoms, and lower frequency of SQSTM1 gene mutation (4.0%). Moreover, a novel heterozygous missense mutation in HNRNPA2B1 gene was identified in one male patient with isolated bone phenotype. As for other genetic factors, it was indicated that WNT16, RYR3, RYR1, NUP205, CAPN2 and NUP214 genes may be potential pathogenic genes, pathways of neurodegeneration and ALS may play a vital role in the pathogenesis of PDB.

Complications of Paget Bone Disease: A Study of 69 Patients.

INTRODUCTION: Paget bone disease (PBD) is characterized by a disorder in the bone remodeling activity at sites of involvement. This can produce dramatic alterations of local bone architecture and causes most of the complications. We aimed to focus on the characteristics of complications of PDB among hospitalized patients. MATERIAL AND METHODS: A retrospective study was conducted, on PBD patients hospitalized in two rheumatology centers from 1994 to 2019. Characteristics of the PBD complications were studied. RESULTS: Sixty-nine patients were collected with a sex ratio of 0.76 and a mean age of 75.4±6.4 years [43-101]. The diagnosis of PBD was established in the average age of 64.2±11.5 years. The primary reason for consultation was pain (78.3%). The PBD was localized in the pelvis (58%), lower limb (42%), spine (36.2%), skull (23.2%) and upper limb (5.8%). It was polyostotic in 44.9% of cases. Dosage of ALP was 324 [68-8390]. The PDB complication rate was 52.2% and it decreased over time. The main complication was osteoarthritis (23.2%), followed by deafness (17.4%), fracture (15.9%), hydrocephalus (7.2%), neurological disease (7.2%) and osteosarcoma (1.4%). The presence of complications was significantly associated with the polyostotic form (p=0.01), the skull localization (p=0.04), an increased ALP (p=0.02). CONCLUSION: According to our study, the incidence rate of PBD among hospitalized cases is higher among elderly women and decreases over time. Complications related to PDB are frequent (52%). It concerns patients with a polyostotic form, skull localization and high ALP.

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.

Paget's Disease in Primary Total Hip Arthroplasty Is Associated With Greater In-Hospital Lengths of Stay, Costs, and Complications.

BACKGROUND: There are few well-powered studies investigating the association of Paget's disease of bone on patients undergoing primary total hip arthroplasty (THA). This study utilized a nationwide database to determine whether Paget's patients undergoing primary THA are associated with higher rates of (1) lengths of stay (LOS); (2) costs; and (3) complications (medical/surgical and implant-related). METHODS: Using International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes, Paget's patients undergoing primary THA were identified and matched to non-Paget's patients in a 1:5 ratio by age, sex, and comorbidities utilizing the PearlDiver database. This resulted in 21,714 patients in Paget's (n = 3619) and non-Paget's (n = 18,095) cohorts. Outcomes assessed included LOS, episode-of-care costs, medical/surgical complications, and implant-related complications. A P value less than .003 was considered statistically significant. RESULTS: Compared to the matched cohort, Paget's patients undergoing primary THA had significantly longer LOS (P < .0001), higher 90-day total global episode-of-care costs (P < .0001), higher 90-day medical and surgical complications (P < .0001), and higher implant-related complications (P < .0001). CONCLUSION: We found that Paget's was associated with higher rates of LOS, costs, and complications. Although there was an association found, the risk appears reasonably low compared to the matched cohort. The study can be utilized by orthopedic professionals to counsel and educate these patients of potential complications which may occur following their procedure.

Paget's Disease of Bone and Cardiovascular Risk: A Pilot Study.

BACKGROUND: The association between Paget's disease of bone (PDB) and increased cardiovascular (CV) risk has been suggested, but the literature is conflicting. OBJECTIVE: Our study aimed to evaluate two markers of CV risk, namely, common carotid artery intimamedia thickness (cIMT) and the aortic pulse wave velocity (PWV) in patients with PDB. METHODS: We enrolled 12 patients with PDB and 58 control subjects, matched for age. The diagnosis of PDB was based on clinical, radiological and biochemical parameters. RESULTS: Patients with PDB showed higher PWV values than the controls, whereas cIMT was slightly but not significantly increased. CONCLUSION: These findings, although limited by the small study population, represent an original observation that deserves further study. The higher arterial stiffness in PDB could be related to the increased bone turnover or the high levels of oxidative stress that characterize this population.

Increased Prevalence of Nephrolithiasis and Hyperoxaluria in Paget Disease of Bone.

CONTEXT: Nephrolithiasis (NL) and primary hyperparathyroidism (HPTH) are metabolic complications of Paget disease of bone (PDB), but recent data regarding their prevalence in PDB patients are lacking. OBJECTIVES: Study 1: To compare the prevalence of primary HPTH and NL in 708 patients with PDB and in 1803 controls. Study 2: To evaluate the prevalence of NL-metabolic risk factors in 97 patients with PDB and NL, 219 PDB patients without NL, 364 NL patients without PDB, and 219 controls, all of them without HPTH. DESIGN: Cross-sectional multicentric study. SETTING: Italian referral centers for metabolic bone disorders. PARTICIPANTS: Patients with PDB from the Associazione Italiana malati di osteodistrofia di Paget registry. Participants in the Olivetti Heart and the Siena Osteoporosis studies. MAIN OUTCOME MEASURES: HPTH; NL; NL-metabolic risk factors. RESULTS: Patients with PDB showed higher prevalence of primary HPTH and NL compared with controls (P < 0.01). The NL recurrence occurs more frequently in patients with polyostotic PDB. About one-half of patients with PDB but without NL showed 1 or more NL-related metabolic risk factors. The hyperoxaluria (HyperOx) prevalence was higher in patients with PDB and NL compared with patients with NL but without PDB and in patients with PDB without NL compared with controls (P = 0.01). Patients with PDB and HyperOx showed a longer lapse of time from the last aminobisphosphonate treatment. CONCLUSIONS: NL and HPTH are frequent metabolic complication of PDB. The NL occurrence should be evaluated in patients with PDB, particularly in those with polyostotic disease and/or after aminobisphosphonate treatment to apply an adequate prevention strategy.

Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort.

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p < .0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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).

Genetic Variation in RIN3 in the Belgian Population Supports Its Involvement in the Pathogenesis of Paget's Disease of Bone and Modifies the Age of Onset.

Paget's disease of bone (PDB) is a common, late-onset bone disorder characterized by focal increase of bone turnover. Mutations in the SQSTM1 gene are found in up to 40% of patients and recent GWAS have led to novel associations with several loci. RIN3, the candidate gene located at the associated 14q32 locus, has recently been studied in a British cohort to elucidate its contribution to the pathogenesis. In this study, we performed a genetic screening of RIN3 in an unrelated cohort to validate these findings and to further explore genetic variation in this gene in the context of PDB. In our screening, we examined the 5' untranslated region (UTR), the exonic regions and the intron-exon boundaries of the gene in a control cohort and a patient cohort. Our findings show clustering of variation similar to the British cohort and support a protective role for common genetic variation (rs117068593, p.R279C) in the proline-rich region and a functionally relevant role for rare genetic variation in the domains that mediate binding and activation of its interaction partner, Rab5. Additive regression models, fitted for the common variants, validated the association of the rs117068593 variant with the disease (OR+/+ 0.315; OR+/- 0.562). In addition, our analyses revealed a potentially modifying effect of this variant on the age of onset of the disease. In conclusion, our findings support the involvement of genetic variation in RIN3 in PDB and suggest a role for RIN3 as a potential modifier of the age of onset of the disease.

Gene-environment interactions in Paget's disease of bone.

OBJECTIVES: This study explored the role of outdoor and indoor air pollutants in Paget's disease of bone (PDB). METHODS: We performed a survey in 140 French-Canadian patients with PDB, including 39 carriers of p.Pro392Leu mutation (SQSTM1 gene) and 113 healthy not mutated controls. The survey covered outdoor air pollution near the residence and indoor air pollutants by focusing on heating fuels and exposure to tobacco smoke. In a subgroup of patients, urinary concentrations of 17 heavy metals and 11 polycyclic aromatic hydrocarbons were measured by mass spectrometry. In light of what we learned from the survey and urinary assays, we explored the in vitro effects of certain toxics on osteoclasts in PDB. We conducted in vitro monocytes differentiation from peripheral blood of more than 40 participants, whose osteoclasts were treated with or without the toxic. The morphology of osteoclasts, their bone resorption abilities, gene and protein expression levels, and cellular oxidative stress levels were assayed. RESULTS: An inhibitory effect of cigarette smoke condensate and heavy metals was observed on morphology and bone resorption activity of patients' osteoclasts. SQSTM1 gene expression was upregulated in osteoclasts from patients with PDB versus healthy controls in presence of cadmium, and SQSTM1 protein expression was upregulated in presence of bismuth and tobacco smoke condensates, in particular in osteoclasts from carriers of the SQSTM1 mutation. Furthermore, high levels of oxidative stress in patients' osteoclasts were observed. CONCLUSIONS: Our in vitro experiments suggest an interaction between SQSTM1 gene and exposure to cadmium and tobacco smoke condensates.

Increased frequency of impaired fasting glucose and isolated systolic hypertension in Paget's disease of bone.

PURPOSE: Scanty data about glucose metabolism and hypertension have been reported in Paget's disease of bone (PDB) to be related with increased cardiovascular mortality. The aim of the present study was to evaluate glucose and blood pressure levels in PDB, looking for their association with disease severity. METHODS: We performed an observational cross-sectional study in 54 patients with PDB and 54 age, sex and BMI-matched controls. Glucose and blood pressure levels and parameters of bone and mineral metabolism were assessed. RESULTS: Patients with PDB showed increased glucose levels (6.3 ± 1.7 vs 5.3 ± 1.4 mmol/l, p < 0.001) and prevalence of impaired fasting glucose (14.8%, 5.3-24.3 vs 1.9%, 0-5.4, p < 0.02) as well as enhanced systolic blood pressure (145.9 ± 21.3 vs 132.9 ± 18.9 mmHg, p < 0.005), pulse pressure (69.6 ± 20.0 vs 56.0 ± 16.9 mmHg, p < 0.01) and prevalence of isolated systolic hypertension (46.3%, 33.0-59.6 vs 16.7%, 6.7-26.6, p < 0.003) in comparison to controls. Moreover, we found a positive association of (1) glucose levels with ionized calcium and bone alkaline phosphatase; (2) both systolic and pulse pressure with total and bone alkaline phosphatase (p < 0.05). By multiple linear regression analysis (R2 = 0.26; p < 0.05) serum ionized calcium correlated with glucose levels (ß = 0.44; p < 0.04), after adjusting for age and BMI. CONCLUSIONS: Our study shows increased fasting glucose, systolic and pulse pressure levels as well as enhanced prevalence of impaired fasting glucose and isolated systolic hypertension in PDB, potentially accounting for increased cardiovascular mortality. Furthermore, our findings suggest high serum calcium and/or increased bone alkaline phosphatase as a link between PDB and cardio-metabolic disorders.