Françoise Debiais

Compliance and treatment satisfaction of post menopausal women treated for osteoporosis. Compliance with osteoporosis treatment

BackgroundAdherence 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.MethodsThis 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.Results785 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.ConclusionCompliance to anti-osteoporosis treatments is poor. Reduction of dosing regimen frequency and patient education may be useful ways of improving compliance.

Prevalence and distribution of juvenile idiopathic arthritis in a region of Western France

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.

The gap junction protein Cx43 is involved in the bone-targeted metastatic behaviour of human prostate cancer cells.

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.

Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing

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.

Management of osteoporosis and associated quality of life in post menopausal women

BackgroundThe 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.MethodsThis 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.ResultsData 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.ConclusionsA high proportion of women diagnosed with osteoporosis had been evaluated by densitometry, in agreement with national guidelines. Treatment choice varied between physician groups.

Effect of endothelin-1 on osteoblastic differentiation is modified by the level of connexin43: comparative study on calvarial osteoblastic cells isolated from Cx43+/−and Cx43+/+ mice

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.

Sjögren's syndrome with ANCA-associated crescentic extramembranous glomerulonephritis

A 49-year-old woman with a 1-year history of Sjögrens 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 Sjögrens 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.

[Bone targeting agents: bisphosphonates].

Malignant tumor osteolysis is a frequent complication in many cancers. It can cause skeletal-related events with alteration of quality of life and survival. Bisphosphonates play an important role in the management of this malignant osteolysis, via an inhibition of osteoclast-mediated bone resorption, and a potential direct antitumor activity. Their use constitutes an important therapeutic advance in patients with bone metastases so as to reduce or delay the appearance of these skeletal events. They are also useful for the treatment of hypercalcemia, which could arise in these patients. Their interest as adjuvant therapy before the onset of bone metastases is currently being evaluated.

New treatments for myeloma.

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.

Connexins, important players in the dissemination of prostate cancer cells

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.