Vertebral fractures cascade: potential causes and risk factors.

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. INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Oxytocin and bone status in men: analysis of the MINOS cohort.

UNLABELLED: Oxytocin, a neurohypophysial hormone, regulates bone metabolism in animal studies and postmenopausal women. In men, oxytocin is not associated with bone mineral density, bone turnover markers, or prevalent fractures, but weakly negatively with incident fragility fracture requiring further studies. INTRODUCTION: We previously showed that serum oxytocin (OT) level is associated with bone mineral density (BMD) and bone turnover rate in postmenopausal women. The aim of our study was to assess the relationship between circulating OT levels and bone status in men. METHODS: In 552 men aged 50 and older from the MINOS cohort, we measured serum levels of OT. We assessed the association of serum OT levels with BMD (lumbar, femoral neck, total hip), bone turnover markers (BTM) (serum N-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (bone ALP), and C-terminal telopeptide of type I collagen (CTX-I)) and fracture risk. RESULTS: In the univariate analysis, serum OT level was not associated with BMD at any site, BTM levels, or with prevalent or incident fracture. OT was significantly correlated with body mass index (BMI) (r = 0.17, p < 0.001), total or bioavalaible 17ß-estradiol (r = 0.09, p = 0.04 and r = 0.20, p < 0.001, respectively), free testosterone (r = 0.17, p < 0.001), and leptin (r = 0.16, p < 0.001). Multivariate analysis did not show significant relationship between serum OT and BMD. After adjustment for age, BMI, interaction BMI/age, history of fall in the last year, and BMD, OT and prevalent fracture were not associated. By contrast, the same analysis with additional adjustment for prevalent fracture showed a weakly significant negative association between OT and incident fracture, e.g., after adjustment for femoral neck BMD, HR = 0.73, 95 %CI 0.55-0.99, p = 0.04. CONCLUSION: In men, serum OT levels are not associated with BMD, bone turnover rate, or prevalent fractures. The weak negative relationship with fracture risk requires further studies.

Denosumab use in bone fibrous dysplasia refractory to bisphosphonate: A retrospective multicentric study.

INTRODUCTION: Increased RANKL expression is observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS). In one animal model of FD/MAS, the inhibition of RANKL reduced tumor volume. A beneficial effect of denosumab on pain in patients refractory to bisphosphonates has been reported, but without systematic quantification of pain improvement. This work describes the clinical experience of our group on the efficacy on pain of denosumab treatment, along with safety, in FD/MAS patients refractory to bisphosphonates. MATERIALS AND METHODS: We have conducted a retrospective multicenter study in 6 academic rheumatology centers in France. We have collected patients and FD/MAS characteristics, duration of prior exposure to bisphosphonates, denosumab treatment modalities (dosage - administration regimen - number of courses); evolution of pain evaluated by Visual Analogic Scale (VAS). RESULTS: 13 patients were included (10 women and 3 men) 45 years on average, 5 MAS, 4 monostotic and 4 polyostotic forms. The average duration post-diagnosis of FD/MAS was 25 years and the mean duration of prior exposure to bisphosphonates was 4.7 years. Pain could be analyzed in 7 patients, showing a significant improvement from a mean VAS of 7.8 to 2.9 (-4.9 points, p = 0.003). In one patient with fronto-orbital FD/MAS, a 30 % decrease in lesional volume, assessed by MRI, was observed within 6 months of treatment, that was sustained over the following 12 months. Treatment regimens were heterogeneous. No hypercalcemia was observed after treatment cessation and the clinical tolerance was good. DISCUSSION: This study suggests that denosumab reduces pain in patients with DF/MAS refractory to bisphosphonates, and quantifies this improvement for the first time in a multicenter study. In our cohort, no patients who discontinued denosumab developed hypercalcemia and clinical tolerance was overall good. This study also provides encouraging data regarding lesion volume control. Further controlled studies are required to determine the place and modalities of the denosumab treatment of FD/MAS. CONCLUSION: Denosumab significantly decreased pain in FD/MAS refractory to bisphosphonate. This study paves the way for a randomized clinical trial to validate and standardize the prescription of denosumab in FD/MAS.

Validation of the adherence evaluation of osteoporosis treatment (ADEOS) questionnaire for osteoporotic post-menopausal women.

SUMMARY: We developed and validated a specific 12-item questionnaire to evaluate adherence to oral antiresorptive medication by post-menopausal osteoporotic women in everyday practice. Over the following 9 months, an index of ≤16 was associated with an increase in the risk of treatment discontinuation of 1.69 and of 2.10 for new patients who had started treatment within the previous year. INTRODUCTION: Adherence to medication in osteoporosis is poor. The goal of this study was to develop and validate a disease-specific questionnaire to evaluate adherence to treatment of women with post-menopausal osteoporosis taking oral antiresorptive medication. METHODS: A prototype adherence questionnaire with 45 items developed from patient interview, literature review, and physician opinion was evaluated in a sample of 350 post-menopausal women with osteoporosis treated in primary care. Item responses were matched against scores on the Morisky Medication Adherence Scale (MMAS). The most discriminant items were retained in the final questionnaire. Concurrent and predictive validity were assessed. RESULTS: Twelve items were associated with MMAS score at a probability level of 0.05. These were retained in the final questionnaire which provided an adherence index ranging from 0 to 22. An index of ≥20 was associated with a high probability of persistence and an index ≤ 16 with a high probability of treatment discontinuation in the following 9 months. CONCLUSIONS: The ADEOS-12 is a simple patient-reported measure to determine adherence to osteoporosis treatments with good concurrent and discriminant validity. This is the first disease-specific adherence measure to have been developed for osteoporosis.

Immune changes in post-menopausal osteoporosis: the Immunos study.

UNLABELLED: The phenotypic and functional characteristics of immune cells of osteoporotic women compared to healthy controls similar for age and estrogen level showed for the first time significant changes in several B lymphocytes populations in postmenopausal osteoporosis, related to bone mineral density (BMD) and fractures, and a significant lower basal secretion of interferon-gamma (IFN-gamma) by CD4(+). INTRODUCTION: To investigate the interactions between bone and immune system, we studied the phenotypic and functional characteristics of immune cells of 26 postmenopausal women with osteoporotic (OP) fractures compared to 24 healthy controls. METHODS: We analyzed surface markers of peripheral B, CD4(+) and CD8(+) lymphocytes and cytokine secretion in supernatants of these cells cultured with or without stimulation. Body composition was assessed by dual energy X-ray absorptiometry. RESULTS: The two groups were similar for age and estrogen level. OP women had a significantly lower body mass index, fat mass, and lean mass. The number of CD19(+), CD19(+)/CD27(+), CD19(+)/CD27(+)/CD5(-)/CD38(+) and CD19(+)/CD27(+)/RANK(+), CD4(+)/CD27(+)/CD45RA(-)/RANK(+), and CD4(+)/CD27(+)/CD45RA(-)/CD28(+) was lower in OP women and positively correlated to BMD. In OP women, under basal conditions, CD4(+) secreted less IFN-gamma and B lymphocytes more granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF was positively correlated to fracture rate and negatively to BMD. CONCLUSIONS: Our results suggest that, regardless of age and estrogen status, postmenopausal OP is associated with immune changes, highlighting a possible role of IFN-gamma in the pathophysiology of OP and reporting, for the first time, changes in several B lymphocyte populations. These alterations may reflect the frailty observed after fracture, providing new insight into the mechanisms of morbidity and mortality associated with OP fractures.

[Uveitis treated with biotherapy and/or DMARD: Analysis from the French Pharmacovigilance Study Base]. / Uvéites sous biothérapies et/ou DMARDs en rhumatologie : analyse de la base de données déclarative de la pharmacovigilance nationale française.

PURPOSE: To report the characteristics of uveitis cases occurring while on biologic therapy or disease-modifying antirheumatic drugs (DMARDs) reported to the French national pharmacovigilance database. METHODS: All the uveitis cases occurring in patients with chronic rheumatologic diseases, chronic inflammatory intestinal diseases or connective tissue diseases, while treated with DMARDs and/or biologic therapies between 2000 and 2015 and reported to the French National Pharmacovigilance Database were collected. RESULTS: During the study period, 32 cases of uveitis were reported (15 men, 17 women). Two patients were treated with one DMARD alone, 24 with biologic therapy alone, and six with both treatments. Anterior uveitis was diagnosed in 19 patients (8 cases were bilateral); intermediate uveitis was found (unilaterally) in one patient; posterior and diffuse uveitis occurred in 5 and 2 cases respectively. Five cases were inconclusive with regard to the anatomical type of uveitis. The uveitis was of infectious origin in 5 cases: 2 toxoplasmosis, 2 herpes virus and 1 tuberculosis. In the 27 other cases, it was not possible to state whether the uveitis was associated with the underlying disease (uncontrolled) or a side effect of the biologic/DMARD treatments. The occurrence of the uveitis led to 9 switches in biologic therapy and 13 discontinuations of treatment (8 complete discontinuations, 5 discontinuations only until uveitis remission was obtained). In 4 cases, the treatments were not modified. The database does not specify the ultimate course or rheumatologic disease activity at the time of the uveitis. CONCLUSIONS: The presence of uveitis while on biologic therapy must not be taken to indicate a therapeutic failure, especially if the ocular manifestation is isolated. In the case of uveitis occurring in patients treated with biologic therapies and/or DMARDs, infectious complications should be ruled out.

Pleural amyloidosis as the first sign of IgD multiple myeloma.

We describe a case of IgD myeloma with amyloid and plasmocytic pleural localisations. At the onset of the disease it mimicked rheumatoid arthritis, which can be the first presentation of both AL amyloidosis and multiple myeloma. Pleural effusion can happen first in IgD myeloma, but our observation is of interest in that it confirms the very rare possibility of pleural amyloid and plasmocytic localisations devoid of pleural effusion.

Human osteoclast formation and activity in vitro: effects of alendronate.

Recent advances in technique have made it possible to study human osteoclast (OC) formation and activity in vitro. The object of the present study was to determine the effects of alendronate (ALN) on human OCs generated from precursors obtained from standard peripheral blood samples. Peripheral blood mononuclear cells from 14 postmenopausal women were cocultured with ST2 stromal cells on bone slices in the presence of 10(-7) M 1,25-dihydroxyvitamin D3, 10(-8) M dexamethasone, and 25 ng/ml human macrophage colony-stimulating factor. After 21 days, the cultures contained numerous OCs, which were characterized by multinuclearity, the presence of tartrate-resistant acid phosphatase, calcitonin and vitronectin receptors, and the ability to resorb substantial amounts of bone, which was inhibited by calcitonin. The percentage area of bone resorbed per slice was highly correlated (r = 0.89, p < 0.001) with the concentration of Type I collagen cross-linked C-telopeptides (CTx) released into the culture medium. When added to the medium, ALN inhibited bone resorption at concentrations < or =10(-7) M. At 10(-7) M, inhibition was achieved primarily by a reduction in OC activity without a marked effect on OC number. At the highest concentration studied (10(-5) M), both OC number and resorption were profoundly decreased. Overnight preincubation of bone slices in ALN, without further exposure to ALN, resulted in an inhibition of resorption that was similar to that seen when ALN was present in the medium throughout the entire culture period. We conclude that, except at very high concentrations, the predominant mechanism of action of ALN is to inhibit the activity of differentiated human OCs with little or no effect on recruitment. Interaction between the OC and ALN on the bone surface is an important component of the inhibitory mechanism. Measurement of CTx in tissue culture medium is a convenient method for assessment of bone resorption in human OC cultures and offers a number of advantages over morphometric analysis of the bone slice.

Occipitocervical fixation using hooks and screws for upper cervical instability.

OBJECTIVES: Occipitocervical fixation is used for the treatment of nontraumatic upper cervical instabilities. To date, plates have been fixed with screws or wires. However, these devices are not indicated in the treatment of patients with severe osteoporosis or in instances of significant thinning of the occipital bone. We performed a clinical trial of a new type of fixation that uses cervical interlaminar hooks and occipital claws with hooks or with screws (CCD type; Sofamor-Danek, Roissy, France) for the treatment of nontraumatic upper cervical instabilities. METHODS: Five women and one man ranging in age from 28 to 72 years (average age, 54 yr) were thus treated. The CCD type material had two rod plates and hooks allowing the proper placement of interlaminar and occipital claws. The occipital plate can also be directly screwed to the bone. Occipital hooks were used in four patients. The other two patients, who had occipitocervical congenital abnormalities that required an occipitocervical opening and an additional dural enlargement, underwent occipital screw fixation because of the previous opening of the foramen magnum. A cancellous iliac autograft allowed the usual fusion. RESULTS: No postoperative complications were observed, and all patients experienced significant improvement of their neck pain. Four patients had neurological symptoms. The condition of two patients improved, and the condition of the other two stabilized. CONCLUSION: This report confirms the interest of the CCD method to correct all types of upper cervical instabilities, even in cases of unusual thinning of the occipital bone or in osteoporotic states.

Gonadal dysgenesis and bone metabolism.

Gonadal dysgenesis is defined as congenital hypogonadism related to abnormalities of the sex chromosomes. Because sex steroids play a central role in the acquisition and maintenance of bone mass, studies have been done to investigate bone status in patients with gonadal dysgenesis, particularly Turner's syndrome and Klinefelter's syndrome, which are the two most common types. The severe estrogen deficiency characteristic of Turner's syndrome (44, X0) is associated with a significant bone mass decrease ascribable to increased bone turnover, as shown by histological studies and assays of bone turnover markers. Estrogen therapy is followed by a significant bone mass gain and a return to normal of bone turnover markers, suggesting that it is the estrogen deficiency rather than the chromosomal abnormality that causes the bone mass deficiency, although abnormalities in the renal metabolism of vitamin D have been reported. Combined therapy with estrogens and growth hormone seems beneficial during the prepubertal period. In Klinefelter's syndrome (47XXY), serum testosterone levels are at the lower end of the normal range and dihydrotestosterone levels are low. Histological studies show depressed osteoblast function and a decrease in 5-alpha-reductase activity responsible for partial tissue resistance to androgens. Assays of bone turnover markers show evidence of increased bone turnover. The bone deficiency is most marked at the femoral neck and seems correlated with serum testosterone and estradiol levels. Androgen therapy has favorable effects on the bone only if it is started before puberty. Recent data suggest that estrogens may contribute to the development of demineralization in KS and that bisphosphonate therapy may be beneficial.

[Prevention of pathological aging. The arterial hypertension example]. / Prévention du vieillissement pathologique. L'exemple de l'hypertension artérielle.

Studies conducted during the last decade have made it increasingly easier to distinguish between normal and pathological ageing. Previous studies on general populations had established a dogma: most of the major body functions, such as cardiac output, glomerular clearance, muscular strength, visual acuity and so forth, were supposed to decline with age. However, in recent studies on the effects of age on cardiac output all subjects with heart disease were excluded and as a result the negative correlation found between cardiac output and age disappeared, which shows that a phenomenon attributed to ageing was in fact caused by disease. This does not mean that there is no such thing as fundamental ageing, and indeed the mechanisms that maintain cardiac output are different in young and elderly subjects. These data are of more than theoretical interest, since it may be presumed that prevention, the instruments of which are already available in some fields, will modify the profile of ageing. The risk of arterial hypertension is not restricted to the classical cardiovascular diseases: it extends to other diseases, such as vascular dementia, which are potent factors of pathological ageing. Most of the controlled trials carried out in arterial hypertension have demonstrated that treating certain types of hypertension significantly reduces the morbidity and/or mortality of cardiovascular diseases. The specific properties of new antihypertensive drugs, such as angiotensin-converting enzyme inhibitors, open stimulating vistas on arterial ageing.

[Etanercept--infliximab switch in rheumatoid arthritis 14 out of 131 patients treated with anti TNFalpha]. / Switch étanercept--infliximab dans la polyarthrite rhumatoïde. 14 patients sur 132 traités par anti-TNFalpha.

OBJECTIVE: Patients with severe rheumatoid arthritis and resistant to at least three DMARDS can benefit from anti-TNFalpha (tumor necrosis factor) therapy. In some patients, because of inefficacy or adverse events, treatment with one of the two available TNFalpha drugs (etanercept and infliximab) must be stopped. In this study, we explored the results in efficacy and tolerance of switching from one anti-TNFalpha to the other. PATIENTS: Between August 1999 and January 2002, we administered one of the two anti TNFalpha drugs to 131 patients: 67 patients received infiximab and 64 etanercept. RESULTS: Among the 67 patients treated with infliximab, 17 patients had to stop treatment. In 8 of them (4 allergies, 2 infections and 2 non responders) the switch from infliximab to etanercept was beneficial for 5 patients, 2 patients did not respond and 1 patient withdrew for personal reasons. Among the 64 patients treated with etanercept, 13 had to stop treatment. In 6 of them (2 adverse events, 4 failures) the switch from etanercept to infliximab was beneficial for 3 patients, 2 did not respond and 1 withdrew because of adverse events. CONCLUSION: In all, 14 patients with severe rheumatoid arthritis and treated by one of the two TNFalpha drugs (and in whom treatment was stopped because of adverse events or inefficacy) benefited from the switch to the other anti- TNFalpha, with excellent response in 8 out of 14 patients.

Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)-alpha therapy.

OBJECTIVES: Anti-tumour necrosis factor (TNF)-alpha therapies are considered category B drugs for pregnancy. Although sometimes prescribed to women of reproductive age, data in humans are limited with regard to safety for a developing fetus. The objectives of the present article are to report experience of anti-TNF-alpha use in pregnancy, and review the international literature. METHODS: Since 1999 the present authors have used anti-TNF-alpha (infliximab, etanercept, adalimumab) to treat patients with various chronic rheumatic conditions. All patients were prospectively followed during their treatment time and data were systematically collected. RESULTS: In a group of 442 patients treated with anti-TNF, three women with RA unexpectedly became pregnant One treated with etanercept chose a therapeutic termination at two and a half months, despite of any ultrasound anomaly, and satisfactory fetal growth. The other two patients (one with adalimumab exposure and one with etanercept exposure) delivered healthy infants. The following perinatal complications were observed: prematurity, neonatal jaundice, neonatal urinary Escherichia coli infection and adrenal congenital hyperplasia of probable hereditary origin. CONCLUSIONS: To date, there is no evidence that TNF-alpha antagonists are associated with embryo toxicity, teratogenicity or increased pregnancy loss. However, caution should be taken when anti-TNF agents are used during pregnancy, as human experience is still extremely limited, particularly in patients with rheumatic diseases among whom there are several alarming reports. The potential risk should be balanced against the known risks associated with DMARDs and steroid therapy. Large registries will be necessary before firm conclusions can be drawn.

Safety of anti-TNF-alpha therapy in rheumatoid arthritis and spondylarthropathies with concurrent B or C chronic hepatitis.

OBJECTIVE: To assess the safety of anti-tumour necrosis factor (TNF)-alpha therapy in patients with rheumatoid arthritis (RA) or spondylarthropathies (SA) and concurrent chronic hepatitis B or C. METHODS: Records concerning 480 outpatients attending the Rheumatology Department of the University Hospital of Nice (France) for RA or SA were retrospectively reviewed for the duration of disease, treatment, serological status and biological data. RESULTS: Six relevant cases were identified: two of RA with chronic hepatitis B; one of SA with chronic hepatitis B and three of RA with chronic hepatitis C. Five patients had received etanercept and one infliximab; two had been given adalimumab after an unsuccessful trial of etanercept. Patients with concurrent chronic hepatitis B were also given lamivudine. In none of the cases had changes in serum aminotransferases or viral load been reported. CONCLUSION: The use of anti-TNF-alpha therapy (plus lamivudine in the presence of concurrent underlying hepatitis B viral infection) appeared to be safe in that it had no effect on serum aminotransferases and/or viral load. However, repeated monitoring is necessary throughout the treatment period.

Reactive arthritis induced by Strongyloides stercoralis.

Reactive arthritis induced by Strongyloides is exceedingly rare. A case in a 53-year-old man from the Guadeloupe (French Antilles) is reported. The outcome was rapidly favorable under thiabendazole therapy. The cycle of Strongyloides is reviewed, and the contribution of parasites to reactive arthritis in patients with genetic risk factors is discussed. Establishing the correct diagnosis is sometimes difficult but is essential in order to avoid inappropriate administration of corticosteroids that can lead to fatal, multivisceral dissemination of the parasite, particularly in patients with strongyloidiasis.

Localization of rat cathepsin K in osteoclasts and resorption pits: inhibition of bone resorption and cathepsin K-activity by peptidyl vinyl sulfones.

We have localized cathepsin K in rat osteoclasts and within exposed resorption pits by immuno-fluorescence microscopy. Intracellular staining using an antibody raised against recombinant mouse cathepsin K was vesicular and uniformly distributed throughout the cell. Confocal microscopy analysis did not reveal an accumulation of cathepsin K containing vesicles opposing the ruffled border and the resorption lacuna. Exposed resorption pits exhibited a uniform distribution of cathepsin K, and no differences were observed between the edges and the centers of the pits. The immunostaining of resorption pits with anti-cathepsin K antibodies demonstrates that the protease is secreted into the sub-osteoclastic compartment. Cathepsin K-specific inhibition using peptidyl vinyl sulfones as selective cysteine protease inactivators reduced bone resorption by 80% in a dose-dependent manner at sub-micromolar concentrations. No reduction of bone resorption was observed at those low concentrations using a potent cathepsin L, S, B-specific inhibitor. That the inhibition of bone resorption can be attributed to cathepsin K-like protease inhibition was corroborated by the selective inhibition of the osteoclastic Z-Gly-Pro-Arg-MbetaNA hydrolyzing activity by the cathepsin K, L, S, B-inhibitor, but not by the cathepsin L, B, and S inhibitor. Z-Gly-Pro-Arg-MbetaNA is efficiently hydrolyzed by cathepsin K but only poorly by cathepsins L, S, and B. On the contrary, the intracellular hydrolysis of the cathepsin B-specific substrate, Z-Arg-Arg-MbetaNA, was prevented by both types of inhibitors. The identification of cathepsin K in resorption pits and the inhibition of bone resorption and intracellular cathepsin K activity by selective vinyl sulfone inhibitors indicate the critical role of the protease in osteoclastic bone resorption.