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Context Vertebral fracture (VF) prevalence up to 24% has been reported among young people with type 1 diabetes (T1D). If this high prevalence is confirmed, individuals with T1D could benefit from preventative VF screening. Objective We compared the prevalence of VFs between adults with T1D and nondiabetic controls. Methods This cross-sectional study included 127 adults with T1D, and 65 controls with a similar age, sex, and BMI distribution, from outpatient clinics of 2 tertiary care centers. Vertebral fracture assessment (VFA) by dual-energy x-ray absorptiometry (DXA) was used for prevalent VFs. The modified algorithm-based qualitative (mABQ) method was applied. Bone mineral density (BMD) and trabecular bone score (TBS) were assessed by DXA. Serum bone turnover markers and sclerostin were measured in a subgroup of participants. Results Participants with T1D (70 women, 57 men) had a mean age of 42.8 ± 14.8 years, median diabetes duration of 25.8 (15.8-34.4) years, mean BMI of 26.6 ± 5.4 kg/m2 and mean HbA1c over the past 3 years of 7.5 ± 0.9%. Controls (35 women, 30 men) had mean age of 42.2 ± 15.9 years and mean BMI of 26.1 ± 5.1 kg/m2. VF prevalence was comparable between groups (2.4% vs 3.1%, P = 0.99). TBS, BMD at the total hip and femoral neck, and bone formation and resorption markers were lower while sclerostin levels were similar in participants with T1D vs controls. Conclusion Our VFA results using the mABQ method do not confirm increased prevalence of VFs in men and women with relatively well-controlled T1D.

Objectives: This study aims to determine whether patients with active rheumatoid arthritis (RA), either starting on or changing biological or targeted synthetic disease-modifying antirheumatic drugs (DMARDs), demonstrate better self-management safety skills three months after receiving a multidisciplinary educational intervention compared to patients receiving usual care. Patients and methods: Between October 2015 and October 2018 , this open-label, randomized-controlled trial included a total of 107 RA patients (27 males, 80 females; mean age: 60.2±10.4 years; range, 54 to 71 years) who were on treatment or in whom treatment was changed with a biological or targeted synthetic DMARD. The patients were randomized into two groups: Group 1 (n=57) received additional intervention with educational DVD and one teleconference session and Group 2 (n=55) received usual care and were offered the intervention at three months. All patients underwent a final visit at six months. At each visit, the patients completed the BioSecure questionnaire measuring the self-care safety skills, a behavioral intention questionnaire, and the Beliefs about Medicines Questionnaire (BMQ). Results: No significant difference was observed in the Biosecure score at three months between the two groups (p=0.08). After pooling the first three-month data in Group 1 and the last three-month data in Group 2, the mean score of the BioSecure questionnaire increased to 7.10±0.92 in the group receiving educational intervention (p Conclusion: The development of an educational DVD followed by a teleconference seem to improve self-care safety skills of the patients in practical situations.

In Canadian medicine faculties, an average of 2.3% of the medical curriculum is dedicated to musculoskeletal problems with a focus on orthopedic conditions. The goal of this descriptive study was to assess the educational preferences in rheumatology of family medicine residents and to identify their preferred methods of learning.From September 2017 to December 2017, two hundred and thirty-six first- and second-year family medicine residents from Université Laval were asked to complete an electronic anonymous survey assessing their confidence in doing different rheumatology tasks. They were also consulted on their favorite methods of learning and their preferred periods throughout their medical cursus to learn the different skills related to rheumatology.Eighty-five family medicine residents completed the survey. The residents were rather confident when evaluating mono-arthritis but less confident for oligo/polyarthritis and even less confident with connective tissue diseases. The family medicine residents mentioned preferring traditional lecture classes and clinical cases. They wanted to learn the majority of rheumatology education during medical school training. As residents, they wanted only small capsules, seminars, or memory aids. Interestingly, men preferred learning rheumatology skills during the residency, whereas women preferred learning it in medical school.The lack of confidence of family medicine residents when evaluating systemic inflammatory diseases compared to mechanical musculoskeletal problems highlights the importance of rheumatology teaching through general medical training and through family medicine residency. Key Points • Family medicine residents are less confident when evaluating systemic inflammatory diseases than musculoskeletal disorders. • Family medicine residents prefer traditional lecture classes and clinical cases. • Family medicine residents prefer learning rheumatology during medical school training.

Background We identified two families with Paget's disease of bone (PDB) linked to the p.Pro392Leu mutation within the SQSTM1 gene displaying a possible digenism. This study aimed at identifying this second genetic variant cosegregating with the p.Pro392Leu mutation and at characterizing its impact on the clinical and cellular phenotypes of PDB. Methods Whole exome sequencing was performed in one patient per family and two healthy controls. We compared clinical characteristics of PDB in 14 relatives from the two families. The osteoclastic phenotype was compared in in vitro differentiated osteoclasts from 31 participants carrying the DOCK6 and/or SQSTM1 variants. Tridimensional models of SQSTM1 and DOCK6 proteins were generated to evaluate the impact of these variants on their stability and flexibility. Statistical analyses were performed with Graphpad prism. Results Whole-exome sequencing allowed us to identify the p.Val45Ile missense variant in the DOCK6 gene in patients. In both families, the mean age at PDB diagnosis was delayed in pagetic patients carrier of the p.Val45Ile variant alone compared to those carrying the p.Pro392Leu mutation alone (67 vs. 44 years, P = 0.03). Although both p.Val45Ile and p.Pro392Leu variants gave rise to a pagetic phenotype of osteoclast versus healthy controls, the p.Val45Ile variant was found to attenuate the severity of the osteoclastic phenotype of PDB caused by the p.Pro392Leu mutation when both variants were present. The DOCK6 mRNA expression was higher in carriers of the p.Val45Ile variant than in pagetic patients without any mutations and healthy controls. Structural bioinformatics analyses suggested that the p.Pro392Leu mutation might rigidify the UBA domain and thus decrease its possible intramolecular interaction with a novel domain, the serum response factor–transcription factor (SRF-TF)-like domain, whereas the p.Val45Ile variant may decrease SRF-TF-like activity. Conclusion The p.Val45Ile variant may attenuate the severity of the clinical phenotype of PDB in patient carriers of both variants. In vitro, the rare variant of the DOCK6 may have a modifier effect on the p.Pro392Leu mutation, possibly via its effect on the SRF-TF-like.

Background Individuals with type 1 diabetes (T1D) have a two- to threefold increase in fracture risk at any site, and up to a sevenfold increase in hip fracture risk compared to those without diabetes. Reduced bone quality appears to contribute to the increased fracture risk observed in this population. Advanced glycation end products (AGEs) tissue accumulation, which reflects long-term glycemic control, may influence bone quality in T1D. Objective We aimed to determine if skin AGEs, as a surrogate marker for bone AGEs, are associated with vertebral trabecular bone score (TBS),anindex of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images and evaluating bone quality. Methods We present preliminary data from subjects with T1D who participated in a cross-sectional study aiming at comparing the prevalence of vertebral fractures between adult subjects with T1D from two tertiary care centers and age-, sex- and BMI-matched controls without diabetes. TBS and bone mineral density (BMD) were assessed using DXA. Skin AGEs were measured by skin autofluorescence. Simple and multiple linear regression analyses were used to explore the factors associated with TBS. Results One hundred and six subjects with T1D (52.8% women; mean age 42.7±14.7 years; mean BMI 26.9±5.6 kg/m 2; mean diabetes duration 27.6±12.3 years; 48.1% with a microvascular complication; mean HbA 1C in the preceding 3 years 7.5±0.9%; mean skin AGEs 2.15±0.54 units; mean TBS 1.428±0.113) were included. Higher skin AGEs were associated with a lower TBS in simple regression analysis (p=0. 012). In multiple linear regression, older age, male sex, higher BMI, current smoking, higher serum calcium, lower lumbar spine and femoral neck BMD, but not skin AGEs, were significantly associated with a lower TBS (model adjusted R 2 =0.65). Conclusion In this population with relatively well-controlled T1D, skin AGEs were not independently associated with TBS. Presentation: No date and time listed

The myeloid inhibitory receptor CLEC12A negatively regulates inflammation. Reduced CLEC12A expression enhances inflammation in CLEC12A knock-out mice with collagen antibody-induced arthritis. Moreover, CLEC12A internalisation augments human neutrophil activation. We thus postulated that CLEC12A expression on circulating myeloid cells of rheumatoid arthritis patients is associated with disease manifestations. Cell-surface, CLEC12A receptor expression was determined on circulating neutrophils and monocytes of eRA patients and of healthy donors. Generalized estimating equations model, Student’s t-test and Spearman’s correlations were performed to compare CLEC12A expression between groups and test its association with disease activity and clinical parameters. Plasma cytokines were measured by multiplex immunoassay. Patients with reduced neutrophil or monocyte CLEC12A expression at baseline and at 3 months have an increased simple disease activity index. Low baseline CLEC12A expression also correlates with a higher SDAI at 6 months. In contrast, positive correlations were observed between baseline CLEC12A expression and several cytokines. Moreover, neutrophil and monocyte CLEC12A expression is significantly higher in early rheumatoid arthritis patients at baseline than healthy controls. Circulating neutrophil and monocyte CLEC12A expression correlates with disease activity at baseline and is predictive of SDAI at later stages of the disease indicative of a regulatory role for CLEC12A in RA.

Bisphosphonates (BPs) are the most widely used drugs for the treatment of osteoporosis but prolonged use of BPs might increase the risk of atypical femur fracture (AFF). There are only a few studies that address the bone material quality in patients on long-term BP treatment with or without AFFs. We analyzed 52 trans-iliac bone biopsies from patients on long-term BP therapy with (n = 26) and without (n = 26) AFF. At the microscopic level, the degree of mineralization of bone (DMB) was assessed on whole bone by X-ray digitized microradiography while microhardness by Vickers microindentation, and bone matrix characteristics by Fourier transform infrared microspectroscopy (FTIRM) (mineral/organic ratio, mineral maturity and crystallinity, and collagen maturity) were measured at random focal areas. The AFF patients were treated longer than non-AFF patients (9.7 ± 3.3 years versus 7.9 ± 2.7 years). As expected, bone remodeling was low in both groups, without difference between them. The AFF group had significantly higher DMB in cortical bone (+2.9%, p = .001), which remained so after adjusting for treatment duration (p = .007), and showed a trend in cancellous bone (+1.6%, p = .05). Consistent with higher DMB, heterogeneity index (HI) was lower in the AFF than in the non-AFF group, illustrating lower heterogeneity of mineralization in the AFF group. A significant positive correlation between the duration of treatment and DMB in cortical bone was found in AFF, and not in the non-AFF group. Microhardness and bone matrix characteristics were similar between groups. We conclude that the AFF group had a duration-dependent increase in DMB leading to a significantly higher DMB than the non-AFF. Because BPs have high affinity to bone mineral and lining the walls of the osteocyte lacunae, the accumulation of matrix-bound BPs in AFF could lead to inhibition of the osteocyte cytoskeleton blunting their response to mechanical strains, a hypothesis to be further investigated. © 2021 American Society for Bone and Mineral Research (ASBMR).

Paget's disease of bone (PDB) is a common chronic bone disorder. In the French-Canadian population, the p.Pro392Leu mutation within the SQSTM1 gene is involved in 46% of familial forms. In New Zealand, the emergence of PDB in offspring inheriting SQSTM1 mutations was reported to be delayed by a decade compared to their parents. We aimed at assessing the clinical phenotype of offspring carriers of this mutation in our French-Canadian cohort. We reviewed research records from adult offspring carriers of this mutation aged

This study evaluated early and medium-term changes in bone turnover markers, and their associations with weight loss, total bone mineral density (BMD), and hormonal changes after biliopancreatic diversion (BPD). Ancillary study from a one-year prospective cohort of 16 individuals assessed before, 3 days, 3 and 12 months after BPD. Bone turnover markers (C-terminal telopeptide (CTX), intact osteocalcin (OC), sclerostin, and osteoprotegerin (OPG)) and several hormones were measured at each visit. Total BMD by DXA was assessed at baseline, 3 and 12 months after BPD. Three participants were lost to follow-up. CTX increased significantly at 3 days (+ 66%), 3 months (+ 219%), and 12 months (+ 295%). OC decreased at 3 days (− 19%) then increased at 3 months (+ 69%) and 12 months (+ 164%). Change in sclerostin was only significant between 3 days and 3 months (+ 13%), while change in OPG was significant between baseline and 3 days (+ 48%) and baseline and 12 months (+ 45%). CTX increase correlated negatively with weight loss at 3 (r = − 0.63, p = 0.009) and 12 months (r = − 0.58, p = 0.039), and total BMD decrease (r = − 0.67, p = 0.033) at 12 months. Change in insulin and adiponectin correlated with changes in bone turnover markers independently of weight loss. BPD causes an earlier and greater increase in bone resorption over bone formation markers and a decrease in total BMD. Sclerostin did not increase as expected following extensive weight loss. Changes in insulin and adiponectin seem to play a role in the activation of bone remodeling after BPD.

Bisphosphonate use has been associated with atypical femoral fractures (AFFs), defined by the American Society of Bone and Mineral Research (ASBMR) Task Force criteria, which currently exclude periprosthetic fractures. The objectives of this study were to establish the prevalence of atypical periprosthetic femoral fractures (APFFs) in patients with hip and knee arthroplasties and to determine the clinical and radiological risk factors associated with these fractures. We performed a retrospective radiological review of all femoral fractures between January 1, 2006, and March 31, 2015, in Quebec City, Canada. Patients who sustained a periprosthetic femoral fracture (PFF) were identified and included in this study. We used the ASBMR Task Force criteria to identify atypical fractures and establish their prevalence. Data from medical records and radiological assessments of the femoral anatomy, the characteristics of the fracture, and the positioning of the prosthesis were collected. The prevalence of APFFs among PFFs was 8.3% (11/133). A strong association with bisphosphonates (p = 0.007) was observed, as well as an increased risk of APFFs among alendronate users compared to risedronate users (p = 0.04). A transverse fracture (p < 0.0001), a periosteal thickening of the lateral cortex at the fracture (p < 0.0001), a unicortical fracture (p = 0.02), and prodromal symptoms (p = 0.03) were associated with APFFs. The type of implant, its positioning, and the femoral geometry did not appear to be risk factors for APFFs compared to PFFs. © 2018 American Society for Bone and Mineral Research.

Resume Objectifs La mutation du gene SQSTM1 la plus frequemment retrouvee dans la maladie osseuse de Paget (MOP), p.Pro392Leu, reproduit certaines caracteristiques phenotypiques de la MOP mais semble insuffisante pour aboutir au phenotype pagetique complet, ce qui suggere la possible implication de facteurs environnementaux dans la pathogenese de la MOP. Nous avons mene une etude exploratoire afin d’identifier les facteurs environnementaux potentiellement associes aux formes familiales et non familiales de MOP dans la population canadienne-francaise. Methodes Nous avons recherche les facteurs environnementaux a partir d’un questionnaire adresse a 176 patients pagetiques dont 86 atteints d’une forme familiale et a 147 temoins sains. Tous les participants residaient dans la meme zone geographique et dans un rayon de 120 km autour de la ville de Quebec. Les associations entre les facteurs environnementaux et les formes familiales et non familiales de MOP ont ete recherchees. Resultats Dans un modele multivarie ajuste sur la correlation intrafamiliale, la MOP etait associee au chauffage au bois durant l’enfance et/ou l’adolescence (OR = 2,10 ; IC 95 % 1,13–3,90, p = 0,02). Dans l’analyse multivariee, sans prise en compte de la correlation intrafamiliale, la forme familiale de MOP etait associee a la presence d’une mine a proximite du lieu de residence (OR = 11,70 ; IC 95 % 2,92–46,80, p Conclusions En conclusion, la MOP etait significativement associee au chauffage au bois durant l’enfance et/ou l’adolescence, qu’il s’agisse des formes familiales ou non.

Context: Individuals with type 1 diabetes (T1D) have a two- to threefold increase in fracture risk at any site, and up to a sevenfold increase in hip fracture risk compared to those without diabetes. The mechanisms accounting for this bone fragility are not yet fully understood. Objectives: 1) To determine factors associated with low bone mineral density (BMD) in patients with T1D; 2) To assess the association between skin advanced glycation end products (AGEs) and low BMD in patients with T1D. Methods: These are preliminary data from patients with T1D included in a cross-sectional study aiming at comparing the prevalence of vertebral fractures between adult patients with T1D from two tertiary care centers and age- and sex-matched controls without diabetes. Patients were eligible if they were aged ≥20 years and had a diagnosis of T1D for at least 5 years. Patients were classified as having a low BMD if Z-score was ≤-2.0 at any site (lumbar spine, femoral neck, total hip, radius) in patients aged Results: 106 patients with T1D were included (mean age 45.2±15.0 years; mean BMI 26.3±5.1 kg/m2; 54.7% women; mean duration of diabetes 28.2±13.6 years; 44.3% with a microvascular complication). Mean HbA1C over the past 3 years was 7.5±0.8%. A third of the patients (31.1%) had a low BMD (3 patients using Z-score; 30 patients using T-score). Patients with a low BMD were older (58.3 vs 39.3 years, p Conclusion: In this population with T1D, a low BMD was independently associated with older age, abnormal ACR and, unexpectedly, with a lower mean HbA1C over the past 3 years, but not with skin AGEs.

The most frequent mutation linked to Paget's disease of bone (PDB), p.Pro392Leu within SQSTM1 gene, leads to phenotypic characteristics of PDB, but this mutation is seemingly insufficient to result in complete pagetic osteoclast phenotype, suggesting that possible environmental factors play a role in PDB pathogenesis. We performed an exploratory study to identify environmental factors potentially associated with familial or non-familial form of PDB in the French-Canadian population.We investigated environmental factors through a questionnaire in 176 pagetic patients, including 86 patients with a familial form, and 147 healthy controls. All participants lived in the same geographic area, within a 120km radius of Quebec City. Associations between environmental factors and familial and non-familial forms of PDB were searched.In the multivariate model adjusted for intra-familial correlation, PDB was associated with wood fired heating in childhood and/or adolescence (OR=2.10; 95% CI 1.13-3.90, P=0.02). In the multivariate model without considering correlation for family relatedness, familial form of PDB was associated with residency near a mine (OR=11.70; 95% CI 2.92-46.80, P0.01) and hunting (OR=2.92; 95% CI 1.14-7.47, P=0.03). Wood fired heating during childhood and/or adolescence (P=0.02) was associated with both familial and non-familial forms.In conclusion, PDB was significantly associated with wood fired heating in childhood and/or adolescence, regardless of the form of PDB, familial or not.

The presence of microcalcifications in the breast microenvironment, combined with the growing evidences of the possible presence of osteoblast-like or osteoclast-like cells in the breast, suggest the existence of active processes of calcification in the breast tissue during a woman’s life. Furthermore, much evidence that osteoimmunological disorders, such as osteoarthritis, rheumatoid arthritis, or periodontitis influence the risk of developing breast cancer in women exists and vice versa. Antiresorptive drugs benefits on breast cancer incidence and progression have been reported in the past decades. More recently, biological agents targeting pro-inflammatory cytokines used against rheumatoid arthritis also demonstrated benefits against breast cancer cell lines proliferation, viability, and migratory abilities, both in vitro and in vivo in xenografted mice. Hence, it is tempting to hypothesize that breast carcinogenesis should be considered as a potential osteoimmunological disorder. In this review, we compare microenvironments and molecular characteristics in the most frequent osteoimmunological disorders with major events occurring in a woman’s breast during her lifetime. We also highlight what the use of bone anabolic drugs, antiresorptive, and biological agents targeting pro-inflammatory cytokines against breast cancer can teach us.

International audience; Lors de la mesure de densité minérale osseuse (DMO) par dual-energy X-ray absorptiometry (DXA), il n’est pas rare de retrouver des valeurs augmentées témoignant d’une hyperdensité osseuse. La définition de l’hyperdensité osseuse n’est pas consensuelle (T-scores et/ou Z-scores ≥ +2,5 ou +4 selon les auteurs). Une grande variété de pathologies est associée avec une hyperdensité osseuse avec une classification habituellement selon le caractère localisé ou généralisé ou encore selon le caractère acquis ou constitutionnel de cette hyperdensité osseuse. Une interprétation attentive du compte rendu et des images de DMO permet dans plus de la moitié des cas de retrouver une étiologie artéfactuelle (arthrose rachidienne, calcifications vasculaires, syndesmophytose…) ou localisée (métastases condensantes, localisation pagétique…). Les causes d’hyperdensité osseuse diffuses et acquises sont nombreuses et variées (fluorose, ostéosclérose diffuse liée à l’ostéodystrophie rénale, hémopathies, hépatite C…) et nécessitent parfois des investigations cliniques et paracliniques supplémentaires pour parvenir à un diagnostic (imagerie, tryptase sérique, sérologie hépatite C…). Enfin, il existe de nombreuses maladies génétiques entraînant une hyperdensité osseuse. Les principales sont les ostéopétroses et les maladies liées à une mutation du gène SOST (sclérostéose et maladie de van Buchem) ou du corécepteur de Wnt, LDL-R-Related Protein 5 (LRP5).

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.

Paget’s disease (PD) is characterized by focal and dramatic bone resorption and formation. Treatments that target osteoclasts (OCLs) block both pagetic bone resorption and formation; therefore, PD offers key insights into mechanisms that couple bone resorption and formation. Here, we evaluated OCLs from 3 patients with PD and determined that measles virus nucleocapsid protein (MVNP) was expressed in 70% of these OCLs. Moreover, transgenic mice with OCL-specific expression of MVNP (MVNP mice) developed PD-like bone lesions that required MVNP-dependent induction of high IL-6 expression levels in OCLs. In contrast, mice harboring a knockin of p62P394L (p62-KI mice), which is the most frequent PD-associated mutation, exhibited increased bone resorption, but not formation. Evaluation of OCLs from MVNP, p62-KI, and WT mice revealed increased IGF1 expression in MVNP-expressing OCLs that resulted from the high IL-6 expression levels in these cells. IL-6, in turn, increased the expression of coupling factors, specifically ephrinB2 on OCLs and EphB4 on osteoblasts (OBs). IGF1 enhanced ephrinB2 expression on OCLs and OB differentiation. Importantly, ephrinB2 and IGF1 levels were increased in MVNP-expressing OCLs from patients with PD and MVNP-transduced human OCLs compared with levels detected in controls. Further, anti-IGF1 or anti-IGF1R blocked Runx2 and osteocalcin upregulation in OBs cocultured with MVNP-expressing OCLs. These results suggest that in PD, MVNP upregulates IL-6 and IGF1 in OCLs to increase ephrinB2-EphB4 coupling and bone formation.

Despite the multitude of studies published on atypical femoral fractures (AFFs), a profile for patients at risk does not exist. This study aimed first at estimating AFF incidence over a 19-month-period in Quebec City using the ASBMR Task force criteria to define AFF. The medical records of patients hospitalized for hip or femoral fracture between June 1, 2009, and December 31, 2010, were reviewed. Thirty-six cases of atypical fractures were identified during the 19-month period, representing an AFF incidence of 7.0 (range, 4.7 to 9.3) cases per 100,000 person-years. In the second part of the study, data regarding the characteristics suspected of increasing the risks of AFF were collected from medical and pharmacological records, proximal femur radiographs, and patient interviews. The data regarding each patient with an AFF during years 2008-2011 were compared to two controls with a hip or femoral fragility fracture or a traumatic fracture, paired for age and sex. Twenty patients with AFF were added to the 36 patients with AFF selected in the first part, thereby 56 patients with AFF were investigated. The association between the occurrence of AFF and bisphosphonates (BPs) use was proven statistically significant in multivariate analysis, odds ratio (OR) = 10.39 (95% CI, 2.22 to 48.58; p = 0.0029). Compared to controls, patients with AFF had excessive femoral offset (43.1 mm versus 38.3 mm, p = 0.0007), proximal femoral neck angle in varus (128.9 degrees versus 134.0 degrees, p < 0.0001), and had greater proximal cortical thickness. This retrospective study confirms the low incidence of AFF, confirms its significant association with exposure to BPs, and reveals the possible contribution of proximal femoral geometry in AFF occurrence.

We report the case of a 53-year-old female, treated by bisphosphonate for 12 years, who presented atraumatic fractures of both fibulas. Her X-rays showed bilateral distal fibula fractures with radiological features similar to atypical femur fractures. The distal fibula should be considered as a potential site for stress fractures in bisphosphonate users. Bisphosphonates are the most widely used drugs in the treatment of osteoporosis. During the last decade, the occurrence of atypical fractures, mostly subtrochanteric and diaphyseal femoral fractures, has been acknowledged in patients with long-term use of bisphosphonates. We report the case of a 53-year-old female on alendronate therapy for the past 12 years who presented with a few months history of atraumatic right, and subsequently left, lateral ankle pain. Her X-rays showed bilateral distal fibula fractures with radiological features similar to atypical femur fractures. She had been treated conservatively with walking boots and her treatment with bisphosphonate had been stopped 5 months prior to the fractures. Callus was progressively seen on serial follow-up X-rays, and both fractures healed completely within a reasonable period of 1 year. Investigations did not reveal any secondary causes of osteoporosis or metabolic bone disorders. To our knowledge, this is the first reported case of bilateral distal fibula fractures in a patient on long-term bisphosphonate therapy.

RESUME La maladie osseuse de Paget (MP) est une affection a revelation tardive dont la prevalence actuelle atteint jusqu’a 3 % de la population apres l’âge de 55 ans. Entre les annees 1970 et 1990, un declin de prevalence de la MP d’environ 60 % a ete rapporte en Angleterre, particulierement dans le Lancashire ayant connu la plus haute prevalence initialement. Malgre d’importantes variations regionales, une meta-analyse recente a confirme le declin global de prevalence de la MP. Le declin seculaire de la MP est en lien avec une moindre mortalite suite a la disparition des degenerescences sarcomateuses sur os pagetique. Le phenotype clinique pagetique semble aussi moins severe actuellement avec un âge moyen au diagnostic augmentant progressivement de 4 ans tous les 10 ans. Chez les descendants porteurs de mutation dans SQSTM1 , la MP est detectable environ 10 ans plus tard par rapport a leurs parents, avec un phenotype attenue : faible augmentation des phosphatases alcalines et extension osseuse moindre. Les causes de ce declin sont mal comprises possiblement en lien avec certains facteurs environnementaux : correction d’insuffisance en calcium et/ou vitamine D pendant l’enfance, mode de vie moins rural, le contact avec des animaux domestiques ou la consommation de visceres de bovides pendant l’enfance moins repandu ? L’exposition a des toxiques lies a l’industrialisation ou issus de produits de combustion dans l’enfance est aussi suspectee. Enfin, le role des paramyxovirus comme le virus de la rougeole, classiquement implique dans la pathogenie de la MP, demeure controverse dans la litterature.

Resume La maladie osseuse de Paget (MP) est une affection a revelation tardive dont la prevalence atteint jusqu’a 3 % de la population caucasienne apres l’âge de 55 ans. En Angleterre et en Nouvelle-Zelande, deux pays ayant eu la plus forte prevalence de la MP rapportee a ce jour, une diminution de l’incidence de cette maladie a ete notee entre les annees 1990–2006. Actuellement, les prevalences dans ces pays se situent aux alentours de 3 %, ce qui est similaire a ce qui est observe ailleurs en Europe de l’Ouest. Une meta-analyse des changements seculaires de prevalence de la MP a demontre une diminution significative de cette prevalence dans la derniere decennie (odds ratio : 0,64 [0,45 ; 0,91]). Ces resultats suggerent davantage une harmonisation de la prevalence de la MP avec la disparition des foyers de haute prevalence. A l’exception de la region de la Campanie en Italie, on note une diminution de la severite clinique de la MP, se traduisant par des atteintes monostotiques plus frequentes, un âge au diagnostic plus tardif, une moindre mortalite et une moindre frequence et severite des complications de la MP. Cette diminution rapide de l’incidence et de la severite de la MP est vraisemblablement en rapport avec des changements environnementaux qui modifient l’expressivite du phenotype de la MP, via un effet sur l’autophagie. Toutefois, les cliniciens doivent demeurer vigilants et garder en memoire que les mutations causales impliquees dans les formes familiales de la MP, qui concernent un tiers des patients pagetiques, continuent d’etre transmises aux descendants.

Paget's disease of bone (PDB) is the second most frequent metabolic bone disease after osteoporosis. Genetic factors play an important role in PDB, but to date PDB causing mutations were identified only in the Sequestosome 1 gene at the PDB3 locus. OPTN has been recently associated with PDB, however little is known about the effect of genetic variants in this gene in PDB pathophysiology. By sequencing OPTN in SQSTM1 non-carriers PDB patients we found 16 SNPs in regulatory, coding and non-coding regions. One of those was found to be associated with PDB in our cohort - rs2234968. Our results show that rs2238968 effect may be explained by a change in OPTN splicing that give rise to a predicted truncated protein. We also performed functional studies on the variants located in OPTN promoter - rs3829923 and the rare variant -9906 - to investigate putative regulators of OPTN. Our results show that OPTN expression seems to be regulated by SP1, RXR, E47, and the E2F family. In conclusion, our work suggests a potential pathophysiological role of SNPs in OPTN, giving a new perspective about the regulatory mechanisms of this gene. Ultimately we discovered a new variant associated with PDB in OPTN, reinforcing the relevance of this gene for the development of this bone disease. info:eu-repo/semantics/publishedVersion

International audience; A finding of high bone mineral density (BMD) from routine dual-energy X-ray absorptiometry (DXA) screening is not uncommon. No consensus exists about the definition of high BMD, and T-score and/or Z-score cutoffs of ≥+2.5 or ≥+4 have been suggested. The many disorders that can result in high BMD are usually classified based on whether the BMD changes are focal vs. generalized or acquired vs. constitutional. In over half the cases, careful interpretation of the DXA report and images identifies the cause as an artefact (e.g., degenerative spinal disease, vascular calcifications, or syndesmophytes) or focal lesion (e.g., sclerotic bone metastasis or Paget's disease). Generalized acquired high BMD may be secondary to a diverse range of disorders such as fluorosis, diffuse bone sclerosis related to renal osteodystrophy, hematological diseases, and hepatitis C. Identification of the cause may require additional investigations such as imaging studies, serum tryptase assay, or serological tests for the hepatitis C virus. Finally, high BMD is a feature of many genetic diseases, most notably osteopetrosis and the disorders caused by mutations in the sclerostin gene SOST (sclerosing bone dysplasia and van Buchem disease) or in the LRP5 gene encoding the low-density lipoprotein receptor-related protein 5 (which is the Wnt co-receptor).

Atmospheric pollution-induced cellular oxidative stress is probably one of the pathogenic mechanisms involved in most of the common autophagy-mediated aging diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, disease, as well as Paget's disease of bone with or without frontotemporal dementia and inclusion body myopathy. Oxidative stress has serious damaging effects on the cellular contents: DNA, RNA, cellular proteins, and cellular organelles. Autophagy has a pivotal role in recycling these damaged non-functional organelles and misfolded or unfolded proteins. In this paper, we highlight, through a narrative review of the literature, that when autophagy processes are impaired during aging, in presence of cumulative air pollution-induced cellular oxidative stress and due to a direct effect on air pollutant, autophagy-mediated aging diseases may occur.

Histone deacetylation, DNA methylation, and micro-RNAs (miRNAs) are the three main epigenetic mechanisms that regulate gene expression. All the physiological processes involved in bone remodeling are tightly regulated by epigenetic factors. This review discusses the main epigenetic modifications seen in tumoral and non-tumoral bone diseases, with emphasis on miRNAs. The role for epigenetic modifications of gene expression in the most common bone diseases is illustrated by drawing on the latest publications in the field. In multifactorial bone diseases such as osteoporosis, many epigenetic biomarkers, either alone or in combination, have been associated with bone mineral density or suggested to predict osteoporotic fractures. In addition, treatments designed to modulate bone remodeling by selectively targeting the function of specific miRNAs are being evaluated. Advances in the understanding of epigenetic regulation shed new light on the pathophysiology of other non-tumoral bone diseases, including genetic conditions inherited on a Mendelian basis. Finally, in the area of primary and metastatic bone tumors, the last few years have witnessed considerable progress in elucidating the epigenetic regulation of oncogenesis and its local interactions with bone tissue. These new data may allow the development of epigenetic outcome predictors, which are in very high demand, and of innovative therapeutic agents acting via miRNA modulation.

Objective.In our region in Quebec, Canada, access to rheumatologists is very limited. Sharing followup of stable patients with their primary care physicians (PCP) could increase access to rheumatologists. In our study, we assessed the feasibility and potential benefits of sharing followup of inflammatory arthritis (IA) patients with their PCP.Methods.We reviewed the clinical records of 300 patients with peripheral arthritis who presented at our rheumatology outpatient clinic between July and October 2015. We distributed questionnaires to their treating rheumatologist, asking whether a PCP could participate in the followup of the patient and whether there were any factors that would prevent shared followup. We also distributed questionnaires to PCP to assess their level of comfort in participating in the followup care of patients with arthritis.Results.Chart review was completed on 300 patients. There was no treatment modification in 49% of the cases, and 38% of the visits were deemed unnecessary by the attending rheumatologist. We found that 74% of PCP were very interested in sharing the arthritis followup care of their patients. According to PCP, the main barriers to shared followup were treatment with biological agents, active disease, and need for infiltrations. Main organizational barriers were the lack of rheumatologist availability to see patients urgently (46%) and the lack of clear guidelines for the management of IA (58%).Conclusion.Up to 38% of peripheral IA visits to a rheumatologist could have been prevented and done by a PCP. In our department, this represented up to 19 followup visits per week that could have been avoided by involving a PCP.

Background Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) is involved in osteoclastogenesis with a key role in mononucleated osteoclasts fusion. We reported in patients with Paget’s disease of bone (PDB) a rare variant (rs62620995) in the TM7SF4 gene, encoding for DC-STAMP, which changes a highly conserved amino acid, possibly damaging according to in silico predictions. This study aimed at determining the functional effects of this variant on osteoclast phenotype in PDB. Methods Fifty ml of peripheral blood were collected in pagetic patients carrier of this variant (n = 4) or not (n = 4) and healthy controls (n = 4). Monocytes were collected after Ficoll gradient and cultured in a medium containing RANKL (40 ng/ml) and hMCSF (25 ng/ml). At the end of the differentiation period, we assessed the osteoclast morphology and bone resorption abilities. We quantified gene expression of SQSTM1, DC-STAMP, OS9, CREB3, LAMP1, OC-STAMP, and NFATC1 genes from cell lysates. Proteins encoded by these genes were investigated by Western Blot. Statistical analyses relied on ANOVA followed by Tukey post-tests. Results After 21 days of differentiation, the mean number of nuclei per multinucleated cell was significantly higher in pagetic patients carrier of the variant than in healthy controls. Bone resorption abilities were not modified by the variant. qPCR and Western Blot analyses did not provide any differences, but DC-STAMP expression was higher in patients carrier of the variant than in patients non carrier. Conclusions This TM7SF4 rare variant may have an impact on osteoclast morphology and on DC-STAMP expression during osteoclastogenesis. Further analyses are required to understand the role of this variant during osteoclastogenesis in PDB. Electronic supplementary material The online version of this article (10.1186/s12881-017-0495-3) contains supplementary material, which is available to authorized users.

Summary Paget's disease of bone (PDB) is the second most frequent metabolic bone disease after osteoporosis. Genetic factors play an important role in PDB, but to date the only PDB causal gene identified is the Sequestosome 1 (SQSTM1) gene. Because the zebrafish has been validated as a model for human genetic diseases, the objective was to investigate if the gene structure and chromosomal environment of the SQSTM1 were similar between zebrafish and humans, thus providing a basis for developing a mutant fish capable of modeling PDB. Through a comparative in silico analysis, we confirmed that zebrafish sqstm1 shares not only the same gene structure as its fish and mammalian orthologs, but they also present, within their promoter regions, similar putative binding sites for common transcriptional factors known to affect bone metabolism. The synteny of SQSTM1 was also determined and results indicate that the cluster of surrounding genes was conserved throughout evolution. The protein comparison revealed a high degree of conservation, particularly in the functional domains of the protein. The most common mutation in PDB patients is p.Pro392Leu and the residue Pro392 was found to be 100% conserved in all species analyzed, including zebrafish, confirming its known functional relevance. In conclusion, this study demonstrated that SQSTM1 is well conserved throughout evolution and therefore fish models such as the zebrafish could be an interesting tool to further investigate the biological role of SQSTM1 in PDB and in bone development.

Joint Bone Spine - In Press.Proof corrected by the author Available online since vendredi 23 janvier 2015

Resume La genetique des lombalgies a beaucoup ete etudiee au cours des 15 dernieres annees. Dans les etudes de jumeaux, les heritabilites de la discopathie degenerative et des lombalgies sont estimees, respectivement, entre 29 % et 80 % et entre 21 % et 67 %. L’agregation familiale de la discopathie degenerative varierait entre 34 % et 61 %. Une meta-analyse d’etude pangenomique d’association a identifie une association genetique avec un variant du gene PARK2. Une revue systematique des etudes d’association genetique dans la discopathie degenerative a confirme un niveau d’evidence modere pour des variants des genes ASPN, COL11A1, GDF5, SKT, THBS2 et MMP9. Plusieurs variants de genes candidats codant pour des proteines structurelles du disque intervertebral ont ete associes aux lombalgies, notamment ACAN, COL9A2, COL9A3, ASPN, ainsi que des polymorphismes fonctionnels des genes COL11A1, SPARC, et CILP. Une association genetique a ete rapportee avec des alleles codant pour des proteines cataboliques, notamment MMP1 et MMP3. Les genes codant pour les interleukines (IL), notamment le cluster de l’IL-1, pour des facteurs de croissance et pour des proteines impliquees dans la douleur, tels que COMT, OPRM1 et GCH1 ont aussi ete rapportes. Les etudes pangenomiques d’expression genique dans l’annulus ont montre une surexpression des genes de la douleur, tels que le Bradykinin receptor B1 et le COMT. Les genes de cytokines pro-inflammatoires, de chemokines et des composantes de la matrice extracellulaire, etaient aussi differentiellement exprimes. Dans le nucleus pulposus, les disques moderement atteints surexprimaient les genes ACAN, COL2, SOX9, COL1 alors que les disques severement atteints surexprimaient l’IL-1β et le TNFα.

Increased expression of DKK1 gene was reported in pagetic osteoblasts and stromal cells, and increased serum levels of DKK1 and SOST proteins were reported in patients with Paget disease of bone (PDB). This study aimed at identifying rare genetic variants of the DKK1 and SOST genes and at testing for genetic association with PDB in the French-Canadian population. Exons, promoters, and exon-intron junctions of these genes were sequenced in patients with PDB and healthy controls. An association study of Tag SNPs of both genes was also performed in 239 pagetic patients and 297 healthy individuals. Three rare variants were identified in this study, all located in the DKK1 gene: one variant in the second exon leading to alteration in a highly conserved amino acid (p.R120L), one in the 5'-untranslated region (-50 C/A), and one in a splice site of intron 1 (IVS1 184 T/C), although none of these rare variants were associated with PDB. A genetic association of a Tag SNP of the DKK1 gene was found: the G allele of rs1569198 was significantly decreased in patients in comparison to controls (42 vs. 49 %, uncorrected P = 0.03, OR = 0.77, 95 % CI 0.61-0.98). In conclusion, this study identified three rare genetic variants in DKK1 in the French-Canadian population. In addition, a weak genetic association of a common variant of DKK1, rs1569198, which is located on a predicted new acceptor site for splicing of this gene, was observed in PDB, whereas no rare variant or genetic association was found in the SOST gene.

Osteoclast (OCL) precursors from many Paget's disease (PD) patients express measles virus nucleocapsid protein (MVNP) and are hypersensitive to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3; also know as calcitriol). The increased 1,25-(OH)2D3 sensitivity is mediated by transcription initiation factor TFIID subunit 12 (TAF12), a coactivator of the vitamin D receptor (VDR), which is present at much higher levels in MVNP-expressing OCL precursors than normals. These results suggest that TAF12 plays an important role in the abnormal OCL activity in PD. However, the molecular mechanisms underlying both 1,25-(OH)2D3's effects on OCL formation and the contribution of TAF12 to these effects in both normals and PD patients are unclear. Inhibition of TAF12 with a specific TAF12 antisense construct decreased OCL formation and OCL precursors' sensitivity to 1,25-(OH)2D3 in PD patient bone marrow samples. Further, OCL precursors from transgenic mice in which TAF12 expression was targeted to the OCL lineage (tartrate-resistant acid phosphatase [TRAP]-TAF12 mice), formed OCLs at very low levels of 1,25-(OH)2D3, although the OCLs failed to exhibit other hallmarks of PD OCLs, including receptor activator of NF-κB ligand (RANKL) hypersensitivity and hypermultinucleation. Chromatin immunoprecipitation (ChIP) analysis of OCL precursors using an anti-TAF12 antibody demonstrated that TAF12 binds the 24-hydroxylase (CYP24A1) promoter, which contains two functional vitamin D response elements (VDREs), in the presence of 1,25-(OH)2D3. Because TAF12 directly interacts with the cyclic adenosine monophosphate–dependent activating transcription factor 7 (ATF7) and potentiates ATF7-induced transcriptional activation of ATF7-driven genes in other cell types, we determined whether TAF12 is a functional partner of ATF7 in OCL precursors. Immunoprecipitation of lysates from either wild-type (WT) or MVNP-expressing OCL with an anti-TAF12 antibody, followed by blotting with an anti-ATF7 antibody, or vice versa, showed that TAF12 and ATF7 physically interact in OCLs. Knockdown of ATF7 in MVNP-expressing cells decreased cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) induction by 1,25-(OH)2D3, as well as TAF12 binding to the CYP24A1 promoter. These results show that ATF7 interacts with TAF12 and contributes to the hypersensitivity of OCL precursors to 1,25-(OH)2D3 in PD.

Objective To search for association with environmental factors and to determine SQSTM1/p62 mutations prevalence in French families with Paget's disease of bone (PDB). Methods Unrelated patients with a confirmed diagnosis of PDB were recruited in three Rheumatology departments and informed consent obtained. First- and second-degree relatives of each index case had a physical examination, blood taken for DNA extraction and biochemical measurements, and a whole-body bone scan. Exons 7 and 8 and exon-intron boundaries of SQSTM1/p62 (p62) gene were PCR-amplified before sequencing. Haplotype carriers of the p62 P392L mutation were determined. Comparisons between PDB patients and healthy relatives were performed. Results We investigated 18 families consisting of 83 individuals: 20 patients with known PDB, three relatives with newly-diagnosed PDB and 60 healthy relatives. Index cases and/or relatives with Dupuytren's disease were found in eight (44.4%) out of the 18 families. Forty-three percent of PDB patients were former or current tobacco users versus 18% of healthy relatives ( P = 0.02; OR = 3.37 (1.04–11.09)). Five index cases (27.8%) were carriers of SQSTM1/p62 mutations: three p62 P392L mutations, one p62 P392L / A390X double mutation and one p62 A390X mutation. The p62 P392L mutation was carried by haplotype 2 in all four index cases. Conclusion Accurate phenotypic assessment of PDB patients’ relatives allowed for diagnosing PDB in three asymptomatic relatives. There was evidence for an aggregation of Dupuytren's disease in PDB families (not associated with SQSTM1/p62 mutation), and for an association between PDB and tobacco use. Half of PDB familial forms carried a SQSTM1/p62 mutation, p62 P392L mutation being the most frequent.

Resume Objectif Rechercher une association avec des facteurs environnementaux et determiner la prevalence des mutations de SQSTM1/p62 dans des familles francaises avec maladie osseuse de Paget (MOP). Methodes Des patients non apparentes avec un diagnostic confirme de MOP ont ete recrutes dans trois services de rhumatologie et un consentement eclaire a ete obtenu. Les apparentes au premier et second degre de chaque cas index ont eu un examen clinique, une prise de sang pour extraction de l’ADN et dosages biochimiques, et une scintigraphie osseuse corps entier. Les exons 7 et 8 et les jonctions exon-intron du gene SQSTM1/p62 (p62) ont ete amplifies par PCR avant sequencage. Les haplotypes porteurs de la mutation p62P392L ont ete determines. Des comparaisons entre les patients avec MOP et les apparentes sains ont ete effectuees. Resultats Nous avons investigue 18 familles totalisant 83 individus : 20 patients avec MOP connue, trois apparentes avec un diagnostic nouveau de MOP et 60 apparentes sains. Des cas index et/ou des apparentes avec la maladie de Dupuytren ont ete trouves dans huit (44,4 %) des 18 familles. Quarante-trois pour cent des patients avec MOP etaient des consommateurs de tabac actuels ou passes contre 18 % des apparentes sains (p = 0,02 ; OR = 3,37 [1,04–11,09]). Cinq cas index (27,8 %) etaient porteurs de mutations de SQSTM1/p62 : trois mutations p62P392L, une double mutation p62P392L/A390X et une mutation p62A390X. La mutation p62P392L etait portee par l’haplotype 2 chez les quatre cas index. Conclusion Un phenotypage precis des apparentes de patients avec MOP a permis de diagnostiquer la MOP chez trois apparentes asymptomatiques. Des elements en faveur d’une agregation familiale de la maladie de Dupuytren dans les familles de MOP (non associee avec les mutations de SQSTM1/p62) et d’une association entre la MOP et l’usage du tabac ont ete identifies. La moitie des formes familiales portait des mutations de SQSTM1/p62, la mutation p62P392L etant la plus frequente.