Effect of C282Y genotype on self-reported musculoskeletal complications in hereditary hemochromatosis

Objective Arthropathy that mimics osteoarthritis (OA) and osteoporosis (OP) is considered a complication of hereditary hemochromatosis (HH). We have limited data comparing OA and OP prevalence among HH patients with different hemochromatosis type 1 (HFE) genotypes. We investigated the prevalence of OA and OP in patients with HH by C282Y homozygosity and compound heterozygosity (C282Y/H63D) genotype. Methods A total of 306 patients with HH completed a questionnaire. Clinical and demographic characteristics and presence of OA, OP and related complications were compared by genotype, adjusting for age, sex, body mass index (BMI), current smoking and menopausal status. Results In total, 266 of the 306 patients (87%) were homozygous for C282Y, and 40 (13%) were compound heterozygous. The 2 groups did not differ by median age [60 (interquartile range [IQR] 53 to 68) vs. 61 (55 to 67) years, P=0.8], sex (female: 48.8% vs. 37.5%, P=0.18) or current smoking habits (12.4% vs. 10%, P=0.3). As compared with compound heterozygous patients, C282Y homozygous patients had higher median serum ferritin concentration at diagnosis [1090 (IQR 610 to 2210) vs. 603 (362 to 950) mu g/L, P<0.001], higher median transferrin saturation [80% (IQR 66 to 91%) vs. 63% (55 to 72%), P<0.001]) and lower median BMI [24.8 (22.1 to 26.9) vs. 26.2 (23.5 to 30.3) kg/m2, P<0.003]. The overall prevalence of self-reported OA was significantly higher with C282Y homozygosity than compound heterozygosity (53.4% vs. 32.5%; adjusted odds ratio [aOR] 2.4 [95% confidence interval 1.2-5.0]), as was self-reported OP (25.6% vs. 7.5%; aOR 3.5 [1.1-12.1]). Conclusion Patients with C282Y homozygosity may be at increased risk of musculoskeletal complications of HH.Association Rhumatisme et Travail (Centre Viggo Petersen, Hospital Lariboisiere, Paris

Targeting Bone Alleviates Osteoarthritis in Osteopenic Mice and Modulates Cartilage Catabolism

Subchondral bone modifications occur early in the development of osteoarthritis (OA). The level of bone resorption might impact cartilage remodeling. We therefore assessed the in vivo and in vitro effects of targeting bone resorption in OA and cartilage metabolism.OA was induced by meniscectomy (MNX) in ovariectomized osteopenic mice (OP) treated with estradiol (E2), pamidronate (PAM), or phosphate buffered saline (PBS) for 6 weeks. We assessed the subchondral bone and cartilage structure and the expression of cartilage matrix proteases. To assess the involvement of bone soluble factors in cartilage metabolism, supernatant of human bone explants pre-treated with E2 or PAM were transferred to cartilage explants to assess proteoglycan release and aggrecan cleavage. OPG/RANKL mRNA expression was assessed in bone explants by real-time quantitative PCR. The role of osteoprotegerin (OPG) in the bone-cartilage crosstalk was tested using an OPG neutralizing antibody.Bone mineral density of OP mice and osteoclast number were restored by E2 and PAM (p<0.05). In OP mice, E2 and PAM decreased ADAMTS-4 and -5 expression, while only PAM markedly reduced OA compared to PBS (2.0±0.63 vs 5.2±0.95; p<0.05). OPG/RANKL mRNA was increased in human bone explants treated with both drugs (2.2-3.7-fold). Moreover, supernatants from bone explants cultured with E2 or PAM reduced aggrecan cleavage and cartilage proteoglycan release (73±8.0% and 80±22% of control, respectively, p<0.05). This effect was reversed with osteoprotegerin blockade.The inhibition of bone resorption by pamidronate in osteopenic mice alleviates the histological OA score with a reduction in the expression of aggrecanases. Bone soluble factors, such as osteoprotegerin, impact the cartilage response to catabolic factors. This study further highlights the importance of subchondral bone in the regulation of joint cartilage damage in OA

Intérêt de l' échographie osthéoaticulaire dans les polyarthrites débutantes (résultats de l' étude échographique d'espoir)

Le diagnostic et l évaluation précoce d une polyarthrite rhumatoïde (PR) débutante est un élément clé pour une bonne réponse thérapeutique. L échographie est une nouvelle technique d imagerie qui permet une détection plus sensible des synovites et érosions. ESPOIR est une cohorte multicentrique française de polyarthrites débutantes, qui inclue 813 adultes ayant au moins 2 arthrites depuis au moins 6 semaines et moins de 6 mois.L étude échographique d ESPOIR a porté sur 127 patients ayant eu une évaluation échographique à l inclusion, issus de 4 des 13 centres. L analyse transversale à l inclusion des données cliniques, radiographiques et échographiques a montré que l échographie était plus sensible que l examen clinique pour la détection des synovites, et retrouvait 6,8 fois plus d érosions chez 3,3 fois plus de patients que la radiographie standard. Le suivi à 2 ans de ces patients a permis de montrer que l échographie en elle-même ne suffisait pas à faire le diagnostic de PR selon les critères ACR 1987 à 2 ans ou selon les nouveaux critères ACR/EULAR 2010. En revanche, certains paramètres échographiques précoces étaient associés à un pronostique structural plus sévère. Les érosions échographiques initiales sont prédictives de la présence d une polyarthrite érosive typique de PR à 2 ans. De plus l activité Doppler initiale était associée à une progression rapide des érosions définie par une variation du score de Sharp érosion >= 5 à 1 an. Ces deux paramètres échographiques étaient également associés à la progression radiographique durant la première année en régression linéaire. A l échelle de l articulation, là encore, l activité Doppler ainsi que la présence d érosion échographique étaient des paramètres précoces associés à la présence d une érosion radiographique observée à 1 an sur la même articulation. En conclusion, cette étude issue des données de la cohorte ESPOIR a permis de montrer l intérêt de l échographie pour une détection plus sensible et précoce des synovites et érosions, sans toutefois de spécificité diagnostique pour la PR. C est surtout au plan pronostique que cet outil s avère le plus performant, l activité Doppler initiale et la présence d érosions échographiques étant des marqueurs indépendants associés à une atteinte structurale plus sévère.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Patients with osteoporosis: children of a lesser god

: Osteoporosis is a common non-communicable disease with enormous societal costs. Antiosteoporosis medications have been proven efficacious in reducing the refracture rate and mortality; moreover, we have now convincing evidence about the cost-effectiveness of antiosteoporotic medications. However, albeit preventable and treatable, osteoporosis has been somehow neglected by health authorities. Drugs approval has been unnecessarily lengthy, especially when compared with other non-communicable diseases. Herein, we discuss the issue of procrastinating drug approval in osteoporosis and future implications

Osteopetrosis and related osteoclast disorders in adults:A review and knowledge gapsOn behalf of the European calcified tissue society and ERN BOND

Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.</p

Evidence of a causal effect of estradiol on fracture risk in men

Context: Observational studies indicate that serum estradiol (E2) is more strongly associated with bone mineral density (BMD) than serum testosterone (T) is, whereas both E2 and T associate with fracture risk in men. Objective: To evaluate the possible causal effect of serum E2 and T on fracture risk in men. Design, Setting, and Participants: A Mendelian randomization (MR) approach was undertaken using individual-level data on genotypes, BMD as estimated by quantitative ultrasound of the heel (eBMD), fractures (n = 17,650), and relevant covariates of 175,583 unrelated men of European origin from the UK Biobank. The genetic instruments for serum E2 and T were taken from the most recent large-scale genome-wide association study meta-analyses on these hormones in men. Results: MR analyses demonstrated a causal effect of serum E2 on eBMD and fracture risk. A 1 SD (or 9.6 pg/mL) genetically instrumented decrease in serum E2 levels was associated with a 0.38 SD decrease in eBMD (P value: 9.7 × 10−74) and an increased risk of any fracture (OR: 1.35; 95% CI: 1.18, 1.55), nonvertebral major osteoporotic fractures (OR: 1.75; 95% CI: 1.35, 2.27), and wrist fractures (OR: 2.27; 95% CI: 1.62, 3.16). These causal effects of serum E2 levels on fracture risk were robust in sensitivity analyses and remained unchanged in stratified analyses for age, body mass index, eBMD, smoking status, and physical activity. MR analyses revealed no evidence of a causal effect of T levels on fracture risk. Conclusion: Our findings provide evidence of a robust causal effect of serum E2, but not T, on fracture risk in men

Common bone turnover markers in rheumatoid arthritis and ankylosing spondylitis: A literature review.

International audienceWe studied the impact of inflammatory rheumatism and its treatment on the most common bone turnover markers, based on six previously defined questions in a systematic literature review in order to define their place in daily clinical practice. The role of bone is currently considered of particular importance concerning cartilage damage in inflammatory rheumatism (rheumatoid arthritis and ankylosing spondylitis) and the new concept of osteoimmunology has emerged. Some bone turnover markers are available in clinical practice. In spite of rich and extensive literature on bone turnover markers, their use in inflammatory rheumatism or even osteoporosis is not clear, and a systematic literature review became necessary. In spite of a large number of different markers used in literature, few of them that are useful in common practice have been studied in the field of inflammatory rheumatism such as rheumatoid arthritis and ankylosing spondylitis. Although their study enables understanding of the physiopathological mechanisms of osteoporosis in inflammatory rheumatism, their use in current common practice cannot be recommended. Interesting data on the forecast of the structural evolution of rheumatoid arthritis has been found within the framework of clinical research, without any real practical impact today