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International audience; With intermittent vitamin D supplementation, serum 25-hydroxyvitamin D (25OHD) levels may remain stable only if the dosing interval is shorter than 3 months, the ideal perhaps being about 1 month. Recent data support moderate daily vitamin D doses instead of high intermittent doses, notably in elderly patients prone to falls. The level of evidence is low, however, with no head-to-head comparisons of clinical outcomes such as fractures and falls in groups given identical dosages daily versus intermittently. A challenge to daily vitamin D supplementation in France is the absence of a suitable pharmaceutical formulation. In addition, daily dosing carries a high risk of poor adherence. Until suitable vitamin D3 formulations such as tablets or soft capsules each containing 1000 or 1500 IU become available, we suggest intermittent supplementation according to 2011 GRIO guidelines. Among the available dosages, the lowest should be preferred, with the shortest possible interval, e.g., 50,000 IU monthly rather than 100,000 every two months.

Background Pregnancy and breastfeeding are associated with bone density loss. Fracture occurrence during pregnancy and post-partum, and its determinants, remain poorly known in Osteogenesis Imperfecta (OI). The aim of this study was to characterize fractures that occurred during pregnancy and post-partum in OI patients. Results We conducted a retrospective multicentric study including a total of 50 previously pregnant OI women from 10 Bone Centers in France. Among these patients, 12 (24%) patients experienced fractures during pregnancy or in the 6 months following delivery, and 38 (76%) did not experience any fracture. The most frequent localizations were: proximal femur (25%), spine (25%), distal femur (12.5%), and pelvis (12.5%). Fractures during pregnancy occurred during the third trimester and post-partum fractures occurred with a mean delay of 2 months following delivery. No fractures occurred during childbirth. We next compared the 12 patients with pregnancy or post-partum fractures with the 38 patients without fractures. Mean age at pregnancy was 32.7 ± 3.1 years-old in the fractured group, vs 29.3 ± 5.0 years-old in the non-fractured group (p = 0.002). Breastfeeding was reported in 85.7% of patients in the fractured group, vs 47.1% in the non-fractured group (p = 0.03). All patients with post-partum fractures were breastfeeding. Bone mineral density was significantly lower in patients with pregnancy-related fractures compared with other patients: spine Z-score − 2.9 ± 1.6DS vs − 1.5 ± 1.7DS (p = 0.03), and total hip Z-score − 2.0 ± 0.7DS vs − 0.5 ± 1.4DS (p = 0.04). At least one osteoporosis-inducing risk factor or disease other than OI was identified in 81.8% vs 58.6% of fractured vs non-fractured patients (not significant). Fracture during pregnancy or post-partum was not associated with the severity of OI. Bisphosphonates before pregnancy were reported in 16.7% and 21.1% of patients with pregnancy-related fractures and non-fractured patients, respectively (not significant). Conclusions OI management during pregnancy and post-partum should aim for optimal control of modifiable osteoporosis risk factors, particularly in patients with low BMD. Breastfeeding should be avoided.

Standard adjuvant therapies for breast cancer such as chemotherapy or aromatase inhibitor and LH-RH agonist hormone therapy are associated with significant survival gains but also induce bone loss by aggravating the estrogen deprivation. The bone loss may be substantial, notably during early treatment, and occurs regardless of the baseline bone mineral density values. The objective of developing these recommendations was to achieve a practical consensus among various scientific societies, based on literature review, about osteoporosis prevention and treatment in these patients. The following scientific societies contributed to the work: Société Française de Rhumatologie (SFR), Groupe de Recherche et d'Information sur les Ostéoporoses (GRIO), Groupe Européen d'Etudes des Métastases Osseuses (GEMO), Association Francophone pour les Soins Oncologiques de Support (AFSOS), Société Française de Sénologie et de Pathologie Mammaire (SFSPM), Société Française de Radiothérapie Oncologique (SFRO). Drug prescription and reimbursement modalities in France were taken into account. These recommendations apply to postmenopausal women taking systemic chemotherapy and/or aromatase inhibitor therapy, non-postmenopausal women taking LH-RH agonist therapy, and non-postmenopausal women with persistent amenorrhea 1 year after chemotherapy completion. All women in these three categories should undergo an evaluation of bone health and receive interventions to combat risk factors for bone loss. Patients with a history of severe osteoporotic fracture and/or a T-score value-2.5 should receive osteoporosis drug therapy. The FRAX® score should be used to guide treatment decisions in patients whose T-score is between -1 and -2.5. General osteoporosis prevention measures should be applied in patients without criteria for osteoporosis drug therapy, who should undergo bone mineral density measurements 18-24 months later if the baseline T-score is-1 and 3-5 years later if the baseline T-score is-1. The anti-tumor effect of bisphosphonates and denosumab was not considered when establishing these recommendations.

We performed a study to identify potential causes and risk factors of vertebral fracture cascade. Vertebral fracture cascade is a severe clinical event in patients with bone fragility. Only half of patients have an identified cause of secondary osteoporosis. Vertebral fracture (VF) is the most common osteoporotic fracture, and a strong risk factor of subsequent VFs leading to VF cascade (VFC). We prompted a study to identify potential causes and risk factors of VFC. VFC observations were collected retrospectively between January 2016 and April 2017. VFC was defined as an occurrence of at least three VFs within 1 year. We included in 10 centers a total of 113 patients with VFC (79.6% of women, median age 73, median number of VFs in the cascade, 5). We observed 40.5% and 30.9% of patients with previous major fractures and a previous VF, respectively, and 68.6% with densitometric osteoporosis; 18.9% of patients were currently receiving oral glucocorticoids and 37.1% in the past. VFC was attributed by the physician to postmenopausal osteoporosis in 54% of patients. A secondary osteoporosis associated with the VFC was diagnosed in 52 patients: glucocorticoid-induced osteoporosis (25.7%), non-malignant hemopathies (6.2%), alcoholism (4.4%), use of aromatase inhibitors (3.6%), primary hyperparathyroidism (2.7%), hypercorticism (2.7%), anorexia nervosa (2.7%), and pregnancy and lactation-associated osteoporosis (1.8%). A total of 11.8% of cases were reported following a vertebroplasty procedure. A total of 31.5% patients previously received an anti-osteoporotic treatment. In six patients, VFC occurred early after discontinuation of an anti-osteoporotic treatment, in the year after the last dose effect was depleted: five after denosumab and one after odanacatib. The results of this retrospective study showed that only half of VFC occurred in patients with a secondary cause of osteoporosis. Prospective studies are needed to further explore the determinants of this severe complication of osteoporosis.

Highlights • The SFR selected the most critical questions Rheumatologists must contend in the management of their patients with rheumatic diseases during COVID-19 pandemic • A group of 10 experts from SFR and CRI boards proposed responses based on the current knowledge of May 2020. • In most circumstances, there is no contraindication to the initiation or continuation of anti-inflammatory drugs as well as DMARDs. • If signs suggestive of infection (coronavirus or other) occurs, treatments should be discontinued and resumed, if necessary, after 2 weeks without any symptoms., Background: Rheumatologists must contend with COVID-19 pandemic in the management of their patients and many questions have been raised on the use of both anti-inflammatory drugs and disease-modifying anti-rheumatic drugs (DMARD). The French Society of Rheumatology (SFR) selected the most critical ones to the daily practice of a rheumatologist and a group of 10 experts from SFR and Club Rheumatism and Inflammation (CRI) boards proposed responses based on the current knowledge of May 2020. Basic procedure: Following the availability of the first 18 questions and statements, 1400 individuals consulted the frequently asked questions between the March 31, 2020 and April 12, 2020. As a result, 16 additional questions were forwarded to the SFR, and answered by the board. An additional round of review by email and video conference was organized, which included updates of the previous statements. The scientific relevance of 5 of the questions led to their inclusion in this document. Each response received a final assessment on a scale of 0–10 with 0 meaning no agreement whatsoever and 10 being in complete agreement. The mean values of these votes for each question are presented as the levels of agreement (LoA) at the end of each response. This document was last updated on April 17, 2020. Main findings: Based on current scientific literature already published, in most circumstances, there is no contraindication to the initiation or continuation of anti-inflammatory drugs as well as DMARDs. If signs suggestive of infection (coronavirus or other) occurs, treatments should be discontinued and resumed, if necessary, after 2 weeks without any symptoms. Only, some signals suggest that people taking an immunosuppressive dose of corticosteroid therapy are at greater risk of developing severe COVID-19. Intra-articular injections of glucocorticoids are allowed when there is no reasonable therapeutic alternative, and providing that precautions to protect the patient and the practitioner from viral contamination are adopted, included appropriate information to the patient. Principal conclusions: Currently available data on managing patients with rheumatic diseases during the COVID-19 pandemic are reassuring and support continuing or initiating symptomatic as well as specific treatments of these diseases, the main target of their management remaining their appropriate control, even during this pandemic.

The current health crisis caused by COVID-19 is a challenge for oncology treatment, especially when it comes to radiotherapy. Cancer patients are already known to be very fragile and COVID-19 brings about the risk of severe respiratory complications. In order to treat patients safely while protecting medical teams, the entire health care system must optimize the way it approaches prevention and treatment at a time when social distancing is key to stemming this pandemic. All indications and treatment modalities must be re-discussed. This is particularly the case for radiotherapy of bone metastases for which it is possible to reduce the number of sessions, the frequency of transport and the complexity of treatments. These changes will have to be discussed according to the organization of each radiotherapy department and the health situation, while medical teams must remain vigilant about the risks of complications of bone metastases, particularly spinal metastases. In this short piece, the members of the GEMO (the European Study Group of Bone Metastases) offer a number of recommendations to achieve the above objectives, both in general and in relation to five of the most common situations on radiation therapy for bone metastases., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: Recent studies have highlighted multicolumn spinal cord stimulation (SCS) efficacy, hypothesizing that optimized spatial neural targeting provided by new-generation SCS lead design or its multicolumn programming abilities could represent an opportunity to better address chronic back pain (BP). OBJECTIVE: To compare multicolumn vs. monocolumn programming on clinical outcomes of refractory postoperative chronic BP patients implanted with SCS using multicolumn surgical lead. MATERIALS AND METHODS: Twelve centers included 115 patients in a multicenter, randomized, double-blind, controlled trial. After randomization, leads were programmed using only one or several columns. The primary outcome was change in BP visual analogic scale (VAS) at six months. All patients were then programmed using the full potential of the lead up until 12-months follow-up. RESULTS: At six months, there was no significant difference in clinical outcomes whether the SCS was programmed using a mono or a multicolumn program. At 12 months, in all patients having been receiving multicolumn SCS for at least six months (n = 97), VAS decreases were significant for global pain (45.1%), leg pain (55.8%), and BP (41.5%) compared with baseline (p

International audience; Over the past 50years, increasing experimental evidences have established that connexins (Cxs) and gap junctional intercellular communication (GJIC) ensure an important role in both the onset and development of cancerous processes. In the present review, we focus on the impact of Cxs and GJIC during the development of prostate cancer (PCa), from the primary growth mainly localized in acinar glands and ducts to the distant metastasis mainly concentrated in bone. As observed in several other types of solid tumours, Cxs and especially Cx43 exhibit an ambivalent role with a tumour suppressor effect in the early stages and, conversely, a rather pro-tumoural profile for most of invasion and dissemination steps to secondary sites. We report here the current knowledge on the function of Cxs during PCa cells migration, cytoskeletal dynamics, proteinases activities and the cross talk with the surrounding stromal cells in the microenvironment of the tumour and the bones. In addition, we discuss the role of Cxs in the bone tropism even if the prostate model is rarely used to study the complete sequence of cancer dissemination compared to breast cancer or melanoma. Even if not yet fully understood, these recent findings on Cxs provide new insights into their molecular mechanisms associated with progression and bone targeted behaviour of PCa. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.

Resume Ces dernieres annees, de nouveaux traitements ont permis une amelioration du pronostic du myelome multiple, mais l’atteinte osseuse reste une preoccupation chez ces patients. L’atteinte osseuse du myelome multiple est caracterisee par une augmentation de la resorption osseuse et une diminution de la formation osseuse. Les lesions osseuses au cours de cette affection sont des lesions lytiques, souvent associees avec des douleurs, des fractures pathologiques, une hypercalcemie, une compression medullaire et une augmentation de la mortalite. Leur prise en charge necessite une approche multidisciplinaire. Elle comporte l’association du traitement antitumoral a un traitement inhibiteur de la resorption, et si necessaire a un traitement local des atteintes osseuses. Les bisphosphonates sont recommandes pour diminuer les complications de ces lesions osseuses. La radiotherapie ou la chirurgie peuvent etre necessaires en cas de douleur mal controlee, de fractures pathologiques ou de compression medullaire. Une vertebroplastie ou une cyphoplastie peuvent etre envisagees en cas de fractures vertebrales symptomatiques. D’autres traitements ciblant notamment dickkopf-1, activin-A ou BAFF sont en cours d’etude.

Resume Les traitements inhibiteurs de la resorption osseuse jouent un role important dans la prise en charge des metastases osseuses. Bisphosphonates et denosumab ont montre une efficacite pour retarder la survenue des complications osseuses chez les patients ayant des metastases osseuses. Dans d’importantes etudes randomisees, le denosumab a montre une superiorite par rapport a l’acide zoledronique pour retarder la survenue de la premiere complication osseuse en cas de cancer du sein ou de prostate avec metastases osseuses, et une non-inferiorite a ete retrouvee dans l’etude concernant les autres tumeurs. Des questions concernant la duree du traitement, le meilleur rythme d’administration des traitements persistent. L’interet de ces traitements en adjuvant avant la survenue des metastases osseuses est en cours d’evaluation ; des donnees recentes avec l’utilisation des bisphosphonates en traitement adjuvant chez les patientes ayant un cancer du sein, pourraient changer la pratique clinique, en particulier chez les femmes menopausees ayant un cancer du sein a haut risque de rechute.

Resume Le myelome multiple (MM) se distingue des autres hemopathies lymphoides malignes B par une atteinte osseuse caracteristique : au cours de leur maladie, plus de 80 % des patients souffriront de cette osteolyse myelomateuse ou de ses complications parfois revelatrices. L’evaluation de la maladie osseuse liee au MM est importante : elle participe a la decision d’instauration du traitement antitumoral. Les radiographies standard (mais de plus en plus le scanner corps entier faibles doses) et l’imagerie par resonance magnetique (IRM) conventionnelle pelvirachidienne ou de preference corps entier restent les examens de reference pour l’evaluation au diagnostic et a la rechute. La tomodensitometrie (TDM) intervient, si necessaire, en complement. Le role de la tomographie par emission de positron (TEP) couplee a la TDM se precise dans l’evaluation de la reponse therapeutique et le depistage de la maladie residuelle. L’avenir precisera le role des IRM dynamiques et de diffusion, ou de nouveaux examens d’imagerie en developpement tels que la TEP couplee a l’IRM.

International audience; Androgen-deprivation therapy (ADT) in patients with prostate cancer can be achieved surgically or chemically, notably by prescribing LHRH analogs. Major bone loss occurs rapidly in both cases, due to the decrease in testosterone levels, and can increase the fracture risk. The objective of developing these recommendations was to achieve a practical consensus among various scientific societies, based on a literature review, about osteoporosis prevention and treatment in patients on ADT. The following scientific societies contributed to the work: Société Française de Rhumatologie (SFR), Groupe de Recherche et d’Information sur les Ostéoporoses (GRIO), Groupe Européen d’Etudes des Métastases Osseuses (GEMO), Association Francophone pour les SOins de Support (AFSOS), Association Française d’Urologie (AFU), Société Française de Radiothérapie Oncologique (SFRO). Medication prescription and reimbursement modalities in France were taken into account. The recommendations state that a fracture-risk evaluation and interventions targeting risk factors for fractures should be provided to all patients on ADT. Those patients with a history of severe osteoporotic fracture and/or a T-score

International audience; Objectives - To update the 2012 recommendations on pharmacotherapy for postmenopausal osteoporosis, under the aegis of the Bone Task Force of the French Society for Rheumatology (SFR) and of the Osteoporosis Research and Information Group (GRIO), in collaboration with scientific societies (Collège national des généralistes enseignants, Collège national des gynécologues et obstétriciens français, Fédération nationale des collèges de gynécologie médicale, Groupe d'étude de la ménopause et du vieillissement hormonal, Société française de chirurgie orthopédique, Société française d'endocrinologie, and Société française de gériatrie et de gérontologie). Methods - Updated recommendations were developed by a task force whose members represented the medical specialties involved in the management of postmenopausal osteoporosis. The update was based on a literature review and developed using the method advocated by the French National Authority for Health (HAS). Discussion and conclusion - The updated recommendations place strong emphasis on the treatment of women with severe fractures, in whom the use of osteoporosis medications is recommended. All the available osteoporosis medications are suitable in patients with severe fractures; zoledronic acid deserves preference as the fist-line drug after a hip fracture. In patients with or without non-severe fractures, the decision to use osteoporosis medications is based on bone mineral density values and in challenging cases, on probabilities supplied by prediction tools such as FRAX. All osteoporosis medications are suitable; raloxifene should be reserved for patients at low risk for peripheral fractures. The fracture risk should be reevaluated every 2 to 3 years to decide on the best follow-up treatment. These updated recommendations discuss the selection of first-line osteoporosis medications and treatment sequences.

Background Vertebral fracture (VF) is the most common osteoporotic fracture, and a strong risk factor of subsequent vertebral fracture. Prospective studies have shown that a recent VF increases an imminent risk of a subsequent one, and attention has been paid recently to a possible cascade phenomenon i.e. the occurrence of multiples VFs in less than one year. Objectives This cascade could have severe consequences, and we prompted a study to identify potential causes of osteoporosis and risk factors. Methods Vertebral fractures cascade (VFC) observations were collected retrospectively between January 2016 and April 2017. VFC was defined as the occurrence of at least 3 vertebral fractures within one year. Patients with other etiologies than osteoporosis (i.e. malignant or traumatic VFs) were excluded. The cause of osteoporosis associated with VFC was the one retained by the physician at the time of diagnosis. Results Ninety-five observations of VFC (80% of women, mean age of 71 years) were collected in 10 centres (9 tertiary centres and 1 outpatient centre). The median number of incident VFs over 1 year was 4.3–11 Forty-five patients (45.9%) had a previous major fracture before the VFC and 65 (70.7%) had densitometric osteoporosis (T-Score ≤−2.5 SD either at lumbar or femoral site). Eighteen (19%) patients currently received oral glucocorticoids treatment at the time of VFC, with a mean daily dose of 20 mg. Thirty-three (35.1%) patients received systemic glucocorticoids in the past. The main comorbidities were history of cancer (n=19) and chronic inflammatory diseases (n=21) including asthma (n=7), chronic obstructive pulmonary disease (n=7) and rheumatoid arthritis (n=7). A secondary osteoporosis associated with the cascade was diagnosed in 54 patients (54.5%) with the following causes: glucocorticoid-induced osteoporosis (n=22, 23.7%), benign hemopathies (mastocytosis, MGUS) (n=7, 7.1%), use of aromatase inhibitors (n=3, 3.1%), anorexia nervosa (n=3, 3.1%), alcoholism (n=3, 3.1%), pregnancy and lactation-associated osteoporosis (n=2, 2.1%), primary hyperparathyroidism (n=2, 2.1%) and hypercorticism (n=1, 1.1%). In addition, 11 cases (11.3%) were reported following a vertebroplasty procedure. Primary either postmenopausal or idiopathic osteoporosis was diagnosed in 48 patients (51.6%). A total of 29 (29.6%) patients previously received an anti-osteoporotic treatment. In six patients (6.3%), VFC occurred early (in the year) following discontinuation of an anti-osteoporotic treatment: 5 after denosumab and one 12 months after an infusion of zoledronic acid. Conclusions The results of this retrospective study show that almost half of VFC occurred in patients with secondary osteoporosis. While they suggest that a careful management has to be given to these patients in order to prevent VFC in these circumstances, prospective studies are needed to further explore the determinants of such a severe complication of osteoporosis. Disclosure of Interest None declared

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).

Objectives To update the recommendations on the prevention and treatment of glucocorticoid-induced osteoporosis issued in 2003 by the French National Authority for Health (HAS). This update was performed under the aegis of the Bone Section of the French Society for Rheumatology (SFR) and Osteoporosis Research and Information Group (GRIO), in collaboration with four French learned societies (primary-care, gastroenterology, internal medicine, and nephrology). Methods A task force composed of members of the medical specialties involved in managing patients with glucocorticoid-induced osteoporosis conducted a systematic literature review according to the method developed by the HAS then used the results to develop updated recommendations. Results These recommendations are intended for all physicians involved in the management of patients who are scheduled to start, or are taking, long-term glucocorticoid therapy (≥ 3 months) in any dose and for any reason. In postmenopausal women and men older than 50 years of age, treatment is warranted in the presence of any of the following risk factors for fracture: history of bone frailty fracture after 50 years of age, bone mineral density T-score ≤ −2.5 at one or more sites, age ≥ 70 years, and dosage ≥ 7.5 mg/d prednisone-equivalent for longer than 3 months. Bisphosphonates can be used in all these situations; teriparatide can be given as first-line therapy in patients at high fracture risk but is reimbursed by the French statutory health insurance system only in patients having two or more prevalent vertebral fractures. The fracture risk is lower in nonmenopausal women and in men younger than 50 years of age, in whom treatment decisions should rest on a case-by-case evaluation. Conclusion These recommendations are intended to clarify the pharmacological management of glucocorticoid-induced osteoporosis.

The agreement for vertebral fracture (VF) diagnosis in men, between doctors is poor. Objectives To assess the agreement for VF diagnosis, in men, on standard radiographs, between experts, before and after consensual workshop and establishing an algorithm. Methods The agreement between thirteen experimented rheumatologists has been calculated in thirty osteoporotic men. Then, the group discussed in a workshop and 28 other radiograph sets of osteoporotic men with follow-up radiographs and incident confirmed VF, have been reviewed. The experts identified and hierarchised 18 pathological features of vertebral deformation and established an algorithm of VF diagnosis. Eleven experts have realized a second reading of the first set of radiographs. We compared the agreement between the 2 readings without and with the algorithm. Results After consensus and the use of the algorithm the results are: number of fractured patients (with at least 1 VF) according to the experts varies from 13 to 26 patients out of 30 (13 to 28 during the first reading). The agreement between the experts at the patient level is 75% (70% at the first reading). Among the 390 vertebrae analyzed by the experts, the number of VF detected varies from 18 to 59 (18 to 98 at the first reading). The agreement between the experts at the vertebral level is 92% (89% at the first reading). The algorithm allows a good improvement of the agreement, especially for 8 of the 11 experts. Discrepancies for the VF diagnosis between experts exist. The algorithm improves the agreement.

Long-term bisphosphonates exposure is a proven risk factor for atypical femoral fractures (AFF) but several cases occur in untreated patients. The identification of other risk factors for AFF is critical for the management of osteoporosis. We here assessed the genetic factors associated with AFF regardless of the treatment.Cases were identified through ICD-10 codes in 3 academic centers. Medical records were analyzed by 2 investigators that adjudicated X-rays for typical or atypical fractures. Genetic screening for ALPL, SOX9, COL1A1 and COL1A2 variants was performed after patient's information and consent.A total of 389 cases were identified and 268 were ruled out according to the ASBMR Task Force recommendations. On the remaining 121, 14 (11.6%) were AFF. Anti-osteoporotic drugs were more frequent in the AFF group compared to the typical fracture group (35% vs 5%, P0.001) but only 4 (28.6%) patients with AFF had been exposed to bisphosphonates. Genetic analysis performed in 5 patients found one with a heterozygous mutation in COL1A2 (rs72658163, NM_000089.3:c.2123GA, p.Arg708Gln). This rare variant (Minor Allele Frequency=0.0008) causes a missense mutation that alters collagen fibrillogenesis. Eight heterozygous polymorphisms for ALPL were also found in 3 patients.Genetic screening for variants in only 4 genes and 5 patients with AFF resulted in the identification of genetic variants in 3 patients including a rare variant in COL1A2, suggesting a possible genetic susceptibility to AFF. This finding should encourage clinician to further genotype patients with AFF in a collaborative multicentric project.

Resume L’utilisation des inhibiteurs de l’aromatase est frequente chez la femme menopausee en traitement adjuvant au cours du cancer du sein. Empechant la transformation d’androgenes en estrogenes, ils peuvent etre responsables d’une perte osseuse et d’une augmentation du risque fracturaire. Les analogues de la LH-RH peuvent etre utiles chez la femme non menopausee ayant un cancer du sein, ou lors d’autres indications telles que l’endometriose. Ils sont plus frequemment prescrits chez l’homme au cours du cancer de prostate afin de realiser une castration chimique ; dans ce cas ils s’accompagnent d’une perte osseuse precoce et plus importante au debut du traitement et egalement d’une augmentation du risque de fractures. La prevention de ces complications osseuses observees avec les inhibiteurs de l’aromatase et des analogues de la LH-RH au cours des cancers du sein et de la prostate necessite la recherche d’autres facteurs de risque de fracture, la realisation d’un examen osteodensitometrique, l’application de mesures hygienodietetiques avec correction des frequentes carences en calcium et vitamine D et la discussion d’un traitement, notamment par bisphosphonate en cas d’antecedent fracturaire ou de densite minerale osseuse basse.

Resume L’importance des facteurs genetiques dans la survenue de l’osteoporose est bien connue. Leur identification permettrait de mieux comprendre la physiopathologie de cette affection et peut-etre de mieux predire le risque de fractures et d’envisager de nouveaux traitements. Un grand nombre d’etudes concernant les genes candidats impliques dans differentes voies du metabolisme osseux et plus recemment des etudes d’association a l’echelle du genome ont ete realisees, mais la contribution des genes actuellement identifies reste modeste. Des progres ont ete effectues dans la comprehension de la pathogenie des osteomalacies ou rachitismes hereditaires hypophosphatemiques avec la decouverte de mutations de differents genes ( PHEX, FGF23, DMP1, SLC34A3 ) et de l’hypophosphatasemie qui s’accompagne d’une mutation du gene de la phosphatase alcaline non tissu specifique.

Resume L’apparition de nouveaux agents tels que l’inhibiteur du proteasome bortezomib et les immunomodulateurs thalidomide et lenalidomide constitue un reel progres dans la prise en charge du myelome. Apres avoir considerablement ameliore le pronostic du myelome en phase avancee, ils ont radicalement transforme le traitement initial de cette affection : les associations melphalan-prednisone-thalidomide et melphalan-prednisone-bortezomib sont devenus les nouveaux traitements de reference des sujets âges ou non eligibles pour une intensification ; l’introduction de ces agents dans le traitement d’induction, le conditionnement de l’intensification et le traitement postgreffe laisse esperer une amelioration de la survie globale des sujets jeunes en augmentant le taux et la qualite des reponses obtenues. Si la guerison du myelome reste encore illusoire, il devient possible de vivre longtemps avec cette hemopathie.

Resume Objectif Determiner la prevalence et la distribution des differentes formes d’arthrites juveniles idiopathiques (AJI) dans la region Poitou-Charentes. Methodes Il s’agit d’une etude retrospective sur une periode d’un an allant de janvier a decembre 2006. La population de l’etude a concerne les enfants de moins de 16 ans residant en Poitou-Charentes (n = 305 198) avec un diagnostic d’AJI selon les criteres de l’International League of Association for Rheumatology. Un questionnaire a ete envoye a l’ensemble des rhumatologues et pediatres de la region, suivi d’un contact telephonique. Resultats Quarante-huit enfants suivis pour AJI ont ete inclus avec une prevalence evaluee a 15,7/100 000. La moyenne d’âge des enfants au moment du diagnostic est de 6,6 ans. Les formes oligoarticulaires sont les plus frequentes avec 20 cas sur 48, soit 41,6 % de la population. La moyenne d’âge au moment du diagnostic est de 4,9 ans avec 80 % de filles. Cette forme constitue la forme la plus benigne avec seulement deux patients (10 %) qui ont eu recours a un traitement de fond. Les enthesites avec arthrites representent 16,6 % des enfants avec une moyenne d’âge au moment du diagnostic de 10,7 ans et 75 % de garcons. Neuf et sept enfants presentent respectivement une forme polyarticulaire et systemique d’AJI et representent les formes les plus severes avec seulement deux enfants sur 16 qui ne recoivent ni corticoides ni traitement de fond. Conclusion Notre etude permet de retrouver une prevalence de l’AJI en Poitou-Charentes proche des prevalences retrouvees dans d’autres regions francaises.

International audience; Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of HPP is performed by sequencing the ALPL gene by Sanger methodology. Osteogenesis imperfecta (OI) and campomelic dysplasia (CD) are the main differential diagnoses of severe HPP, so that in case of negative result for ALPL mutations, OI and CD genes had often to be analyzed, lengthening the time before diagnosis. We report here our 18-month experience in testing 46 patients for HPP and differential diagnosis by targeted NGS and show that this strategy is efficient and useful. We used an array including ALPL gene, genes of differential diagnosis COL1A1 and COL1A2 that represent 90% of OI cases, SOX9, responsible for CD, and 8 potentially modifier genes of HPP. Seventeen patients were found to carry a mutation in one of these genes. Among them, only 10 out of 15 cases referred for HPP carried a mutation in ALPL and 5 carried a mutation in COL1A1 or COL1A2. Interestingly, three of these patients were adults with fractures and/or low BMD. Our results indicate that HPP and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases.

Until recently, the only therapeutic agents available for postmenopausal osteoporosis acted by inhibiting bone resorption and decreased the fracture risk by no more than 50%. Teriparatide, the recombinant 1–34 fragment of human parathyroid hormone, is a bone formation enhancer that has recently been licensed for use in established postmenopausal osteoporosis. Intermittent parathyroid hormone administration preferentially stimulates bone formation. The resultant increase in bone mass and improvement in bone architecture translate into a large decrease in the fracture risk that constitutes a major advance in the treatment of postmenopausal osteoporosis. Further work is needed to define the role for teriparatide in the therapeutic strategy for postmenopausal osteoporosis and to determine whether this agent is best used alone or in synchronous or sequential combination with bone resorption inhibitors.

Background Many studies have demonstrated the efficacy of spinal cord stimulation (SCS) for chronic neuropathic radicular pain over recent decades, but despite global favourable outcomes in failed back surgery syndrome (FBSS) with leg pain, the back pain component remains poorly controlled by neurostimulation. Technological and scientific progress has led to the development of new SCS leads, comprising a multicolumn design and a greater number of contacts. The efficacy of multicolumn SCS lead configurations for the treatment of the back pain component of FBSS has recently been suggested by pilot studies. However, a randomized controlled trial must be conducted to confirm the efficacy of new generation multicolumn SCS. Evaluation medico-economique de la STImulation MEdullaire mulTi-colonnes (ESTIMET) is a multicentre, randomized study designed to compare the clinical efficacy and health economics aspects of mono- vs. multicolumn SCS lead programming in FBSS patients with radicular pain and significant back pain. Materials and methods FBSS patients with a radicular pain VAS score ≥ 50 mm, associated with a significant back pain component were recruited in 14 centres in France and implanted with multicolumn SCS. Before the lead implantation procedure, they were 1:1 randomized to monocolumn SCS (group 1) or multicolumn SCS (group 2). Programming was performed using only one column for group 1 and full use of the 3 columns for group 2. Outcome assessment was performed at baseline (pre-implantation), and 1, 3, 6 and 12 months post-implantation. The primary outcome measure was a reduction of the severity of low back pain (bVAS reduction ≥ 50%) at the 6-month visit. Additional outcome measures were changes in global pain, leg pain, paraesthesia coverage mapping, functional capacities, quality of life, neuropsychological aspects, patient satisfaction and healthcare resource consumption. Trial status Trial recruitment started in May 2012. As of September 2013, all 14 study centres have been initiated and 112/115 patients have been enrolled. Preliminary results are expected to be published in 2015. Trial registration Clinical trial registration information-URL: www.clinicaltrials.gov . Unique identifier NCT01628237

International audience; For decades, cancer was associated with gap-junction defects. However, more recently it appeared that the gap junction proteins (connexins) could be re-expressed and participate to cancer cell dissemination during the late stages of tumor progression. Since primary tumors of prostate cancer (PCa) are known to be connexin deficient, it was interesting to verify whether their bone-targeted metastatic behaviour could be influenced by the re-expression of the connexin type (connexin43) which is originally present in prostate tissue and highly expressed in bone where it participates to the differentiation of osteoblastic cells. Thus, we investigated the effect of the increased Cx43 expression, by retroviral infection, on the metastatic behaviour of two well-characterized cell lines (PC-3 and LNCaP) representing different stages of PCa progression. It appeared that Cx43 differently behaved in those cell lines and induced different phenotypes. In LNCaP, Cx43 was functional, localized at the plasma membrane and its high expression was correlated with a more aggressive phenotype both in vitro and in vivo. In particular, those Cx43-expressing LNCaP cells exhibited a high incidence of osteolytic metastases generated by bone xenografts in mice. Interestingly, LNCaP cells were also able to decrease the proliferation of cocultured osteoblastic cells. In contrast, the increased expression of Cx43 in PC-3 cells led to an unfunctional, cytoplasmic localization of the protein and was correlated with a reduction of proliferation, adhesion and invasion of the cells. In conclusion, the localization and the functionality of Cx43 may govern the ability of PCa cells to metastasize in bones.

(IF : 2,74); International audience; Bone is a dynamic tissue that undergoes a precise remodeling process involving resorptive osteoclastic cells and bone-forming osteoblastic (OB) cells. The functional imbalance of either of these cell types can lead to severe skeletal diseases. The proliferation and differentiation of OB cells play a major role in bone development and turnover. These cellular processes are coordinated by connexin43 (Cx43)-based gap-junctional intercellular communication (GJIC) and by soluble factors such as endothelin-1 (ET-1). We have used the Cx43 heterozygous (Cx43(+/-)) murine model to study the possible cross-talk between Cx43 and ET-1 in cultured calvarial OB cells. On microcomputed tomographic analysis of 3-day-old pups, Cx43(+/-) mice showed hypomineralized calvaria in comparison with their Cx43(+/+) littermates. Characterization of cultured OB cells clearly demonstrated the effect of the partial deletion of the Cx43 gene on its expression, on GJIC, and subsequently on OB differentiation. In this model, ET-1 (10(-8) M) lost its mitogenic action in Cx43(+/-) OB cells compared with Cx43(+/+) cells. Moreover, a correlation between the inhibition of cell differentiation by ET-1 and the decreased amount and function of Cx43 was found in Cx43(+/+) OB cells but not in their Cx43(+/-) counterparts. Thus, as Cx43 is linked to OB differentiation, our data indicate that this mitogenic ET-1 peptide has pronounced effects on fully differentiated OB cells. With respect to roles in mechanotransduction and OB differentiation, Cx43 might modulate osteoblastic sensitivity to soluble factors.

Background Adherence to anti-osteoporosis treatments is poor, exposing treated women to increased fracture risk. Determinants of poor adherence are poorly understood. The study aims to determine physician- and patient- rated treatment compliance with osteoporosis treatments and to evaluate factors influencing compliance. Methods This was an observational, cross-sectional pharmacoepidemiological study with a randomly-selected sample of 420 GPs, 154 rheumatologists and 110 gynaecologists practicing in France. Investigators included post-menopausal women with a diagnosis of osteoporosis and a treatment initiated in the previous six months. Investigators completed a questionnaire on clinical features, treatments and medical history, and on patient compliance. Patients completed a questionnaire on sociodemographic features, lifestyle, attitudes and knowledge about osteoporosis, treatment compliance, treatment satisfaction and quality of life. Treatment compliance was evaluated with the Morisky Medication-taking Adherence Scale. Variables collected in the questionnaires were evaluated for association with compliance using multivariate logistic regression analysis. Results 785 women were evaluated. Physicians considered 95.4% of the sample to be compliant, but only 65.5% of women considered themselves compliant. The correlation between patient and physician perceptions of compliance was low (κ: 0.11 [95% CI: 0.06 to 0.16]). Patient-rated compliance was highest for monthly bisphosphonates (79.7%) and lowest for hormone substitution therapy (50.0%). Six variables were associated with compliance: treatment administration frequency, perceptions of long-term treatment acceptability, perceptions of health consequences of osteoporosis, perceptions of knowledge about osteoporosis, exercise and mental quality of life. Conclusion Compliance to anti-osteoporosis treatments is poor. Reduction of dosing regimen frequency and patient education may be useful ways of improving compliance.

The management of multiple myeloma has benefited substantially from the introduction of three new drugs, namely, the proteasome inhibitor bortezomib and the immunomodulators thalidomide and lenalidomide. These drugs were initially shown to improve the outcome of advanced myeloma and were subsequently found to transform the treatment of patients with previously untreated myeloma. Melphalan and prednisone combined with thalidomide or bortezomib is the new treatment of reference for patients who are elderly or ineligible for intensification. The introduction of these new drugs into induction regimens, intensified conditioning regimens, and posttransplantation regimens may improve overall survival among young patients by increasing the rate and quality of the treatment responses. Although myeloma remains incurable, prolonged survival is now a reasonable objective.

Objective To determine the prevalence and distribution of the various forms of juvenile idiopathic arthritis (JIA) in the Poitou-Charentes region of Western France. Methods We surveyed all the practicing rheumatologists and pediatricians in the study region for cases of JIA meeting ILAR criteria seen in 2006 among the population of 305,198 children younger than 16 years of age who resided in the study region. The survey was conducted by means of a questionnaire followed by a phone call. Cases of JIA identified by the survey were reviewed retrospectively. Results We identified 48 children with JIA, which yielded a prevalence of 15.7/100,000. Mean age at diagnosis was 6.6 years (range, 1–15 years). Oligoarticular disease was the most common pattern, with 20 (41.6%) patients, a mean age of 4.9 years at diagnosis, and 80% of females. Oligoarticular disease was associated with the best outcomes, and only two (2/20, 10%) patients in this subgroup required disease-modifying therapy. Enthesitis-related arthritis contributed eight (16.6%) patients, with a mean age at diagnosis of 10.7 years and 75% of males. There were nine patients with polyarticular disease and seven with systemic disease; disease severity was greatest in these 16 patients, of whom only two were not taking disease-modifying drugs or glucocorticoids. Conclusion The prevalence of JIA in Poitou-Charentes was similar to the prevalences reported in other regions of France.

A 49-year-old woman with a 1-year history of Sjogren's syndrome was diagnosed with cutaneous leukocytoclastic vasculitis and necrotizing crescentic membranous glomerulonephritis. Antineutrophil cytoplasmic antibodies targeting myeloperoxidase were found. She reported a transient episode of nephritis 4 years earlier. This pattern of kidney disease is not typical of Sjogren's syndrome. Methylprednisolone boluses followed by oral glucocorticoid therapy were given in combination with mycophenolate mofetil. Renal function stabilized after 2 months, and tests for anti-myeloperoxidase reverted to negative.

Background The study aimed to describe the characteristics of women treated for recently-diagnosed osteoporosis, to identify variables associated with different treatment regimens and to assess impact on quality of life. Methods This is an observational, cross-sectional pharmacoepidemiological study performed in France. A random sample of 684 general practitioners, gynaecologists and rheumatologists included the first three post-menopausal osteoporotic women consulting in the previous six months on the basis of densitometry or fracture. Data on osteoporosis, fracture risk factors, treatments and comorbidities was collected with a physician questionnaire. Data on quality of life was collected using the SF-12. Results Data were analysed for 1,306 patients, of whom 1,117 (85.5%) had been evaluated by densitometry within the previous six months and 554 (42.4%) had experienced a fracture, most frequently of the spine or wrist within the previous six months. Osteoporotic fracture risk factors were reported in 1,028 women (78.7%). 746 women (57.1%) were currently receiving treatment, most frequently weekly or monthly bisphosphonates. Five variables were associated with prescription choice: age (p < 0.0001), physician speciality (p < 0.0001), previous fracture history (p = 0.0002), ongoing treatment at the time of consultation (p = 0.0091) and paraclinical investigations performed in the previous six months (p = 0.0060). SF-12 scores were lower in women complaining of pain, with recent fractures and with spine or hip fractures and in women consulting rheumatologists. Conclusions A high proportion of women diagnosed with osteoporosis had been evaluated by densitometry, in agreement with national guidelines. Treatment choice varied between physician groups.