BACKGROUND: The bone is among the most frequently chosen sites for the metastatic spread of breast cancer. The prediction of biomarkers for BM (Bone Metastasis) and PDB (Paget\'s disease of bone) initiated from breast cancer could be critically important in categorizing individuals with a higher risk and providing targeted treatment for PDB and BM.
OBJECTIVE: This research aims to investigate the common key candidate biomarkers that contribute to BM-BCa (Bone metastasis of breast cancer) and PDB by employing network decomposition and functional enrichment studies.
RESULTS: This research analyzed high-throughput transcriptome sequencing (RNA-Seq). For this work, the dataset (GSE121677) was downloaded from GEO (Gene Expression Omnibus), and DEGs were identified using Galaxy and R script 4.3. Using STRING (Search Tool for the Retrieval of Interacting Genes), high-throughput research created a protein-protein interaction network (PPIN). The BM-PDB-interactome was created using Cytoscape 3.9.1 and PDB biomarkers, with the top 3% DEGs from BM-BCa. Functional Enrichment Analysis (Funrich 3.1.3) and DAVID 6.8 performed functional and gene set enrichment analysis (GSEA) of putatively essential biomarkers. TCGA (The Cancer Genome Atlas) validated the discovered genes. Based on our research, we identified 1262 DEGs; among these DEGs, 431 genes were upregulated, and 831 genes were downregulated. During the third growth of the interactome, 20 more genes were pinned to the BM-PDB interactome. RAC2, PIAS1, EP300, EIF2S1, and LRP6 are among the additional 25% of genes identified to interact with the BM-PDB interactome. To corroborate the findings of the research presented, additional functional and gene set enrichment analyses have been performed.
CONCLUSIONS: Of the five reported genes (RAC2, PIAS1, EP300, EIF2S1, and LRP6), RAC2 was identified to function as the common key potential biomarker in the BM-PDB interactome analysis and validated by TCGA in the study presented.

Paget\'s disease of bone (PDB) is a focal disorder of skeletal remodeling leading to alteration of bony structures and properties, uncommonly reported in people under the age of 40 years, particularly in the Southeast Asia region. In the literature, PDB has been well reported in regions of Europe, in contrast to Asia where there has been limited records of prevalence of PDM especially in the younger age population. Here, we report a 21-year-old male patient presenting with an advanced disease with complaints of auditory impairment, bone pain, and neurological signs due to compression of the interverbal disc developed progressively over two months, having an elevated serum alkaline phosphatase level of 601 IU/L. The patient was administered zoledronic acid that brought significant improvement in his health. We aim to signify the advanced presentation of PDB in our region to create awareness about the condition among physicians and aid in the prompt diagnosis and prevention of the most dreaded complications of the disease, such as osteosarcoma, secondary osteoarthritis, and fractures.

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.
We aimed at examining the evolution of the prevalence and incidence of PDB in Quebec (Canada) by analyzing health administrative databases.
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.
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.
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.

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.

BACKGROUND: Paget\'s disease of bone (PDB) is the second most frequent metabolic bone disease affecting about 3 percent of the Caucasian population older than 55 years. Its etiopathogenesis is unknown .while viral agents like measles and respiratory syncytial virus has been proposed, the role of genetic susceptibilities loci such as SQSTM1/p62 gene mutations have been confirmed. A new inhibitory mechanism against osteoprotegerin (OPG) via autoantibodies has been revealed in a patient with occult celiac disease (CD) with a phenotype similar to juvenile Paget\'s disease, which suggests an immunological mechanism for Paget\'s disease-like disorders other than genetic causes. But there is no report in the literature searching for shared immunologic mechanisms underlying classic PDB, CD and psoriasis Case Presentation: I report the case of a 50-year-old Caucasian man who presented with progressive bilateral hearing loss. The patient had a history of total blindness which had developed shortly after a cranial osteotomy for optic nerve decompression without any specific diagnosis 15 years ago. He had also been suffering chronic psoriasis vulgaris. Because of his enlarged skull, a diagnosis of bone Paget\'s disease was suspected and plain radiographs revealed a polyostotic Paget\'s disease with characteristic radiologic signs. In searching for his refractory constipation causes, an elevated level of tissue transglutaminase IgA (tTG IgA) antibody was demonstrated. Alendronate sodium 40 mg daily was started and a gluten-free diet was recommended to him but he was not adherent to the treatments and lost to follow-up.
CONCLUSIONS: This case further supports the idea of considering PDB as an osteoimmunologic disorder, such as psoriasis and CD, because of similar biochemical features, including elevated levels of Cytokines such as interleukin-6 and tumor necrosis factor- α as well as bone resorption markers such as OPG and urinary deoxypyridinoline. So, the treatment of Paget\'s disease of the bone may benefit from progresses in osteoimmunology-targeted therapies. Also a probable causal relationship between PDB and CD by the production of neutralizing antibodies in CD against OPG or by inducing PDB in genetically susceptible patients through oxidative stress, has been postulated here.

UNASSIGNED: Paget\'s disease of bone (PDB) is a focal metabolic bone disorder characterized by an increased bone remodeling. Fifteen to 40 % of PDB patients have a familial form with an autosomal dominant inheritance. Disease-causing mutations of the SQSTM1 gene have been linked to PDB in about 40 % of families whereas genes linked to the remaining families are unknown. Several single nucleotide polymorphisms (SNPs) have been associated with PDB in unrelated patient non-carriers of a SQSTM1 mutation. The current clinical practice guidelines still recommend the measure of serum total alkaline phosphatase (sALP) for PDB screening. In unrelated individual non-carriers of SQSTM1 mutations, we previously developed a genetic test combining male sex with five genetic markers (rs499345, rs5742915, rs2458413, rs3018362, rs2234968), giving rise to an area under the curve (AUC) for PDB phenotype of 0.73 (0.69; 0.77). A combination of male sex with total calcium corrected for albumin and Procollagen type I N-terminal propeptide (P1NP), had an AUC of 0.82 (0.73; 0.92). Combining both genetic and biochemical tests increased the AUC to 0.89 (0.83; 0.95).
UNASSIGNED: This study aimed at estimating the performance of our previous test of PDB, in families not linked to SQSTM1 mutations with disease-causing genes yet unknown, and at developing a new algorithm if the performance is not satisfactory.
UNASSIGNED: We genotyped the five SNPs cited above, and measured calcium corrected for albumin and P1NP in 181 relatives, with PDB or not, from 19 PDB families not linked to SQSTM1 mutations. Bivariate and multivariate logistic regression models including male sex were fitted to search for a molecular test that could best detect PDB in these families. A receiving operating characteristics analysis was done to establish a cut-off point for continuous variables.
UNASSIGNED: Logistic regression estimates of our previous molecular test gave rise to a high sensitivity of 78 %, 97 % and 88 % for the genetic, biochemical, and combined test but the specificity was very low, 35 %, 11 % and 21 %, respectively. This poor specificity persisted even when the cut-off point was changed. We then generated in these families, new logistic regression estimates but on the same parameters as mentioned above, giving rise to an AUC of 0.65 (0.55; 0.75) for the genetic test, of 0.84 (0.74; 0.94) for the biochemical test, and 0.89 (0.82; 0.96) for the combination test, the latter having a sensitivity of 96 % and specificity of 57 %. By comparison serum P1NP alone gave rise to an AUC of 0.84 (0.73; 0.94), with a sensitivity of 71 % and a specificity of 79 %.
UNASSIGNED: In PDB families not linked to SQSTM1 mutations, the estimates of our previous molecular test gave rise to a poor specificity. Using new estimates, the biochemical and combined tests have similar predictive abilities than our former test. Serum P1NP is a bone marker of interest for the screening for PDB in families not linked to SQSTM1 mutations.

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.
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.
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.
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).
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.

Bone science has over the last decades unraveled many important pathways in bone and mineral metabolism and the interplay between genetic factors and the environment. Some of these discoveries have led to the development of pharmacological treatments of osteoporosis and rare bone diseases. Other scientific avenues have uncovered a role for the gut microbiome in regulating bone mass, which have led to investigations on the possible therapeutic role of probiotics in the prevention of osteoporosis. Huge advances have been made in identifying the genes that cause rare bone diseases, which in some cases have led to therapeutic interventions. Advances have also been made in understanding the genetic basis of the more common polygenic bone diseases, including osteoporosis and Paget\'s disease of bone (PDB). Polygenic profiles are used for establishing genetic risk scores aiming at early diagnosis and intervention, but also in Mendelian randomization (MR) studies to investigate both desired and undesired effects of targets for drug design.

Optineurin (OPTN) is involved in a variety of mechanisms, such as autophagy, vesicle trafficking, and nuclear factor kappa-B (NF-κB) signaling. Mutations in the OPTN gene have been associated with different pathologies, including glaucoma, amyotrophic lateral sclerosis, and Paget\'s disease of bone. Since the relationship between fish and mammalian OPTN is not well understood, the objective of the present work was to characterize the zebrafish optn gene and protein structure and to investigate its transcriptional regulation. Through a comparative in silico analysis, we observed that zebrafish optn presents genomic features similar to those of its human counterpart, including its neighboring genes and structure. A comparison of OPTN protein from different species revealed a high degree of conservation in its functional domains and three-dimensional structure. Furthermore, our in vitro transient-reporter analysis identified a functional promoter in the upstream region of the zebrafish optn gene, along with a region important for its transcription regulation. Site-directed mutagenesis revealed that the NF-κB motif is responsible for the activation of this region. In conclusion, with this study, we characterize zebrafish optn and our results indicate that zebrafish can be considered as an alternative model to study OPTN\'s biological role in bone-related diseases.

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.