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La progression de la destruction articulaire dans la polyarthrite arthrite rhumatoïde (PR) débutante est variable d'un patient à l'autre et elle est difficile à prédire par les facteurs de risque classiques (ACPA, CRP, DAS28, score radiologique). L'objectif de cette étude est d'analyser la valeur prédictive du dosage sérique de Col3-4, un nouveau marqueur biologique de la dégradation des collagènes synoviaux (type III et IV), chez les patients atteints de PR débutante de la cohorte ESPOIR. La concentration sérique de Col 3-4 a été mesurée au temps de base par dosage ELISA (brevet INSERM, reproductibilité intra et inter dosage < 10 et 15 %) chez la totalité des patients de la cohorte ESPOIR disposant d'un prélèvement sérique (n = 788, 82 % de PR, 18 % de patients avec une arthrite indifférenciée, présence de symptômes < 6 mois, naïfs de traitements par DMARDs et corticoïdes). Les associations entre les valeurs de base de Col3-4 et la progression radiologique (score de Sharp/van der Heijde, > 1 unité à 1 an et 5 unités à 5 ans) ont été analysées par régression logistique avant et après ajustement par les facteurs de risque classiques. Au temps de base, Col3-4 était plus élevé chez les PR (p = 0,0001) et chez les patients ACPA positifs (p = 0,0001). Col3-4 était significativement corrélé à la protéine C-réactive (CRP) (p < 0,0001), au DAS28 (p < 0,0001) et très faiblement au score d'érosion (r2 = 0,0081, p = 0,017). Le Tableau 1 montre le risque de progression radiologique à 5 ans pour une augmentation d'un écart-type du Col 3-4 sérique au temps de base. Les patients avec les taux de Col3-4 les plus élevés (5e quintile de la population) avaient un odds-ratio (OR, 95 % CI) de progression du score total à 5 ans de 2,93 (1,79–4,73) par rapport aux autres malades (quintiles 1 à 4) ; ceux présentant une érosion osseuse un OR (95 % CI) de 2,26 (1,38–3,70). Les patients présentant à la fois un Col3-4 élevé et une érosion osseuse avaient un OR (95 %CI) de progression à 5 ans de 7,16 (2,31–22) par rapport à l'ensemble des autres malades. Des résultats similaires ont été observés pour la prédiction de la progression à 1 an et lorsque les analyses étaient limitées aux patients PR. Des taux sériques augmentés de Col3-4 sont associés à un risque élevé de progression structurale à 1 et 5 ans dans la PR débutante, indépendamment des facteurs de risque classiques. En association avec le score radiologique d'érosion, Col 3-4 pourrait être utile pour améliorer l'identification des patients à risque élevé de destruction. L'utilité de cette combinaison pour la prise en charge individuelle de la maladie reste à être testée de manière prospective. [ABSTRACT FROM AUTHOR]

Summary: Sclerostin is a key regulator of bone formation. In a population of 572 postmenopausal women (mean age, 67 years) followed prospectively for a median of 6 years, there was no significant association between baseline levels of serum sclerostin and incidence of all fractures which occurred in 64 subjects. Introduction: Sclerostin, an osteocyte soluble factor, is a major negative regulator of osteoblastic activity. Circulating sclerostin levels were reported to increase with age and to be modestly associated with bone mineral density (BMD) and bone turnover, but there are no data on the association with fracture risk. Methods: We investigated 572 postmenopausal women (mean age, 67 ± 8.5 years) from the OFELY population-based cohort. The associations of serum sclerostin measured with a new two-site ELISA and spine and hip BMD by DXA, serum β-isomerized C-terminal crosslinking of type I collagen (CTX), intact N-terminal propeptide of type I collagen (PINP), intact PTH, 25-hydroxyvitamin D [25(OH)D], estradiol, testosterone, and fracture risk were analyzed. At the time of sclerostin measurements, 98 postmenopausal women had prevalent fractures. After a median of 6 years (interquartile range, 5-7 years) follow-up, 64 postmenopausal sustained an incident fracture. Results: Serum sclerostin correlated positively with spine ( r = 0.35, p < 0.0001) and total hip ( r = 0.25, <0.0001) BMD. Conversely, serum sclerostin was weakly negatively associated with the bone markers PINP ( r = −0.10, p = 0.014) and CTX ( r = −0.13, p = 0.0026) and with intact PTH ( r = −0.13, p = 0.0064). There was no significant association of serum sclerostin with 25(OH)D, estradiol, free estradiol index, or testosterone. Serum sclerostin considered as a continuous variable or in quartiles was not significantly associated with the risk of prevalent or incident fracture. Conclusion: Serum sclerostin is weakly correlated with BMD, bone turnover, and PTH in postmenopausal women. It was not significantly associated with the risk of all fractures, although the number of incident fractures recorded may not allow detecting a modest association. [ABSTRACT FROM AUTHOR]

Abstract: Osteoarthritis (OA) is considered as a chronic disease with a long “silent” period. The diagnosis is generally based on clinical symptoms and radiographic changes. However X-ray has a poor sensitivity and a relatively large precision error that does not allow an early detection of OA or the monitoring of joint damage progression. The limitations of the tools that are currently available for OA assessment have been the impetus to identify specific biological markers that reflect quantitative and dynamic variations in joint remodeling. Research has focused on the structural components of cartilage matrix, especially type II collagen degradation markers. In spite of a significant increase of some markers in individuals with early stage of OA, the large overlap with control subjects indicates that the current biomarkers used alone have limited diagnostic potential. However, the combination of specific markers seems to improve the prediction of disease progression at the individual level. Several types of treatment have been investigated but the lack of medications with definitively demonstrated chondroprotective activity has limited the assessment of the potential role of biomarkers for monitoring patients'' responses to the treatment of OA. In this review, we will use the BIPED classification that appeared in 2006 for OA markers to describe the potential usage of a given marker [5]. This article is part of a Special Issue entitled "Osteoarthritis". [Copyright &y& Elsevier]

Periostin is a matricellular glutamate-containing protein expressed during ontogenesis and in adult connective tissues submitted to mechanical strains including bone and, more specifically, the periosteum, periodontal ligaments, tendons, heart valves, or skin. It is also expressed in neoplastic tissues, cardiovascular and fibrotic diseases, and during wound repair. Its biological functions are extensively investigated in fields such as cardiovascular physiology or oncology. Despite its initial identification in bone, investigations of periostin functions in bone-related physiopathology are less abundant. Recently, several studies have analyzed the potential role of periostin in bone biology and suggest that periostin may be an important regulator of bone formation. The aim of this article is to provide an extensive review on the implications of periostin in bone biology and its potential use in benign and metabolic bone diseases. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the effects of tocilizumab (TCZ) added to a stable dosage of methotrexate (MTX) on biochemical markers of bone and cartilage metabolism in patients in the multicenter double-blind, placebo-controlled OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) study who have moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: Included in this study were 416 of the 623 patients with active RA enrolled in the OPTION study. Patients were randomized to receive TCZ (4 mg/kg or 8 mg/kg) or placebo intravenously every 4 weeks, with MTX continued at the stable prestudy doses (10-25 mg for 20 weeks, with a final followup at week 24). Serum biochemical markers of bone formation (osteocalcin, N-terminal propeptide of type I collagen [PINP]), bone resorption (C-terminal crosslinking telopeptide of type I collagen [CTX-I] and C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases [ICTP]), cartilage metabolism (N-terminal propeptide of type IIA collagen [PIIANP]), collagen helical peptide [HELIX-II]), and matrix metalloproteinase 3 (MMP-3) were measured at baseline and at weeks 4, 16, and 24. RESULTS: TCZ induced marked dose-dependent reductions in PIIANP, HELIX-II, and MMP-3 levels at week 4 that were maintained until week 24, an effect associated with increased levels of bone formation markers that were significant as compared with placebo only for PINP and only at 4 weeks (P < 0.01 for both TCZ doses). TCZ induced significant decreases in the bone degradation markers CTX-I and ICTP, providing initial evidence of a beneficial effect on bone turnover. TCZ-treated patients who met the American College of Rheumatology 50% improvement criteria (achieved an ACR50 response) or achieved clinical remission (as determined by a Disease Activity Score in 28 joints <2.6) at week 24 had greater reductions in ICTP, HELIX-II, and MMP-3 levels as compared with ACR50 nonresponders. CONCLUSION: TCZ combined with MTX reduces systemic bone resorption, cartilage turnover, and proteolytic enzyme MMP-3 levels, which provides evidence of a limitation of joint damage and possible beneficial effects on skeletal structure in patients with established moderate-to-severe RA. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Biochemical markers of bone turnover (BTMs) are important in determining fracture risk in postmenopausal women; high levels being associated with increased risk. A proposed goal of anti-resorptive therapy is to reduce BTMs to the lower half of the reference range for healthy young pre-menopausal women. Our aims were a) to establish reference ranges for bone alkaline phosphatase (bone ALP), crosslinked C- and N-telopeptides of type I collagen (βCTX, NTX), osteocalcin (OC) and procollagen type I N propeptide (PINP) in pre-menopausal women and b) to investigate the determinants of these BTMs. Methods: BTMs were measured in peripheral blood and second morning void urine collected from 200 healthy pre-menopausal women ages 30 to 45 years. Each subject completed a short medical and lifestyle questionnaire. Results: BTMs were higher before the age of 35 years than after it. BTMs were higher in women with low BMI (βCTX and OC), low alcohol consumption (PINP), current smoking habit (bone ALP and NTX), and around time of ovulation (NTX). Conclusions: We recommend that the age range 35 to 45 years should be used when establishing BTM reference ranges in women. [Copyright &y& Elsevier]

Abstract: Introduction : Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D3 have yielded conflicting results. The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D (25-OH D), bone turnover markers, bone mineral density (BMD), radius bone loss and incidence of fracture in postmenopausal women. Methods : 669 postmenopausal women (mean age: 62.2 years) belonging to a population-based cohort were followed prospectively for a median of 11.2 years. At baseline, 25-OH D levels, BMD, bone turnover markers and clinical risk factors of osteoporosis were assessed. BMD loss at the radius was estimated by annual measurements of BMD and all incident fractures which occurred in 134 women were confirmed by radiographs. Results : 73% and 35% of women had serum 25-OH D levels below 75 and 50 nmol/l which correspond respectively to the median and lowest optimal values recently proposed for fracture prevention. 11% of women had levels below 30 nmol/l. Serum 25-OH D correlated modestly with intact PTH (r 2 =0.023, p <0.0001), but not with bone turnover markers or BMD at the hip and radius after adjustment for age. When levels of 25-OH D were considered as a continuous variable, there was no significant association between 25-OH D levels and radius BMD loss or fracture risk. After adjustment for age, there was no significant difference in incidence of fracture, BMD, radius BMD loss, bone turnover markers, grip strength and the percentage of fallers in the previous year between women with 25-OH D levels below or above 75, 50 or 30 nmol/l. Conclusions: In a population of home-dwelling healthy postmenopausal women with few of them with severe vitamin D deficiency, vitamin D status may not be an important determinant of bone health. [Copyright &y& Elsevier]

Bone is a complex tissue of which the principal function is to resist mechanical forces and fractures. Bone strength depends not only on the quantity of bone tissue but also on the quality, which is characterized by the geometry and the shape of bones, the microarchitecture of the trabecular bones, the turnover, the mineral, and the collagen. Different determinants of bone quality are interrelated, especially the mineral and collagen, and analysis of their specific roles in bone strength is difficult. This review describes the interactions of type I collagen with the mineral and the contribution of the orientations of the collagen fibers when the bone is submitted to mechanical forces. Different processes of maturation of collagen occur in bone, which can result either from enzymatic or nonenzymatic processes. The enzymatic process involves activation of lysyl oxidase, which leads to the formation of immature and mature crosslinks that stabilize the collagen fibrils. Two type of nonenzymatic process are described in type I collagen: the formation of advanced glycation end products due to the accumulation of reducible sugars in bone tissue, and the process of racemization and isomerization in the telopeptide of the collagen. These modifications of collagen are age-related and may impair the mechanical properties of bone. To illustrate the role of the crosslinking process of collagen in bone strength, clinical disorders associated with bone collagen abnormalities and bone fragility, such as osteogenesis imperfecta and osteoporosis, are described. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Using radiography to assess the efficacy of a disease-modifying osteoarthritis (OA) drug on joint structure is challenging. Subchondral bone marrow abnormalities determined by magnetic resonance imaging (MRI) and urinary excretion of C-terminal crosslinking telopeptide of type II collagen (CTX-II) have recently been shown to be predictors of radiographic progression in patients with knee OA, suggesting that these may represent valuable biomarkers with increased sensitivity compared with findings on radiography. The aims of this investigation were to analyze, in patients with knee OA, whether the values associated with these 2 OA biomarkers can change within 3 months, and to investigate the relationships between bone marrow abnormalities and CTX-II. METHODS: Knee MRI scans were obtained in 377 patients with painful knee OA (76% women, mean age 63 years, mean disease duration 6.6 years) at both baseline and 3 months. The femoral and tibial condyles and the patella were divided into 8 sites for the scoring of bone marrow abnormalities. A bone marrow abnormality was defined as an area of increased signal on T2-weighted images of the subchondral bone. All scans were reviewed centrally and scored by a single trained radiologist using a validated 4-point scoring method. Fasting urine and serum samples were also collected from all patients at baseline, month 1, month 2, and month 3, in order to measure the levels of urinary CTX-II and serum CTX-I, a biochemical marker of bone resorption. RESULTS: At baseline, 82% of patients had MRI evidence of bone marrow abnormalities. Bone marrow abnormality scores correlated significantly with CTX-II levels (P < 0.0001). Within 3 months, the bone marrow abnormality score decreased in 37 patients (9.8%), increased in 71 patients (18.8%), and did not change in the majority of patients (71.4%). Patients with baseline urinary CTX-II levels in the highest tertile had a relative risk of 2.4 (95% confidence interval 1.1-5.0) of worsening bone marrow abnormalities at 3 months compared with patients with levels in the lowest tertile, after adjustment for age, sex, and body mass index. In patients who showed a decrease in the bone marrow abnormality score at 3 months, urinary CTX-II levels decreased significantly (mean -75 ng/mmole creatinine), whereas levels increased (mean +23 ng/mmole creatinine) in patients showing an increase in the bone marrow abnormality score (P = 0.01 between the 2 groups). No significant association between bone marrow abnormalities and serum CTX-I was observed. CONCLUSION: In patients with painful knee OA, bone marrow abnormalities on MRI can change within only 3 months in approximately 30% of patients. Reduction in the extent of bone marrow abnormalities is associated with a decrease in cartilage degradation. [ABSTRACT FROM AUTHOR]

Abstract: In the skeleton of elderly men, two opposite activities occur: bone loss at the endosteal envelope, which increases bone fragility, and periosteal apposition, which improves bending strength of bone. Both may contribute to serum bone formation markers although they have an opposite effect on bone fragility. The aim of this study was to determine if circulating bone formation markers reflect periosteal bone formation and endosteal bone remodelling in 640 men aged 55–85 years belonging to the MINOS cohort. We measured biochemical markers of bone formation (osteocalcin, bone alkaline phosphatase, N-terminal extension propeptide of type I collagen) and bone resorption (urinary and serum β-isomerised C-terminal telopeptide of collagen type I, total and free deoxypyridinoline). Parameters of bone size (cross-sectional surface of third lumbar vertebral body measured by X-ray, projected areas of total hip, femoral neck, radius and ulna measured by dual-energy X-ray absorptiometry) increased with age (r = 0.20–0.32, P &#60; 0.0001). In contrast, parameters related to bone loss (areal bone mineral density [aBMD], volumetric bone mineral density [vBMD] and cortical thickness) and determined mainly by bone resorption, decreased with ageing (r = −0.14 to −0.23, P &#60; 0.005–0.0001). Men in the highest quartile of bone resorption markers had lower aBMD (3.8–10.2%, P &#60; 0.05–0.0001), lower vBMD (3.9–13.0%, P &#60; 0.05–0.0001), and lower cortical thickness (1.5–9.6%, P &#60; 0.05–0.0001) than men in the lowest quartile. Markers of bone resorption were not significantly associated with estimates of bone size at any skeletal site. Markers of bone formation were not associated with estimates of periosteal formation after adjustment for covariates. In contrast, men in the highest quartile of the bone formation markers had significantly lower aBMD (4.0–11.7%, P &#60; 0.05–0.0001), lower vBMD (4.2–16.3, P &#60; 0.05–0.0001) and lower cortical thickness (4.0–7.4%, P &#60; 0.05–0.0001) than men in the lowest quartile. In summary, serum levels of bone formation markers are negatively correlated with the estimates of endosteal bone loss. In contrast, they disclose no association with parameters reflecting periosteal apposition. Thus, in elderly men, bone formation markers reflect endosteal bone remodelling, probably because of the coupling between resorption and formation activities. In contrast, they do not reflect the periosteal bone formation, probably because the periosteal surface is smaller and has a slower remodelling rate than the endosteal surface. [Copyright &y& Elsevier]

Background: Post-menopausal hormone therapy (pHT) induces changes in both body composition and bone mineral density (BMD).Methods: In 109 post-menopausal women beginning either tibolone 2.5 mg (n=29), tibolone 1.25 mg (n=42) or estradiol 2 mg plus norethisterone acetate 1 mg (E2 + NETA) (n=38), we assessed body composition, total and regional BMD by dual energy X-ray absorptiometry, and the serum bone alkaline phosphatase (BAP), osteocalcin and the urinary excretion to type I collagen C-telopeptide (CTX) at baseline and after 2 years.Results: At baseline, BMD at all sites correlated negatively with age and years since menopause, and positively with lean mass and fat mass (r=0.42, P<0.001 and r=0.26, P=0.006 at the total femur). During treatment, BMD increased at all sites (P<0.001), and serum BAP, osteocalcin, and urinary CTX decreased in all groups (P<0.001). Lean mass increased whereas android fat and android obesity index decreased. The increase in BMD at all sites correlated positively with changes of lean mass at 2 years.Conclusions: Both fat mass and lean mass are related to BMD in post-menopausal women, the relationship being strongest with lean mass; an increase in lean mass and a change in distribution of body fat are observed during treatment with E2 + NETA and tibolone. [ABSTRACT FROM AUTHOR]

Type I collagen fragments are the most sensitive markers of bone resorption in osteoporosis. Currently, all available type I collagen-related bone resorption markers detect in serum and/or urine fragments arising from the telopeptide region of the molecule. Our aim was to evaluate the technical and clinical performances of a new assay detecting in urine a degradation fragment originating from the helical part of type I collagen and consisting of the 620–633 sequence of the α1 chain. Urinary helical peptide was measured with a new ELISA (Metra Helical peptide, Quidel Corporation). Results were compared with those of urinary C-terminal cross-linking type I collagen of type I collagen (CTX), an established bone resorption marker. We measured urinary helical peptide levels in 89 healthy women (age 31–89 years) and in 59 postmenopausal women involved in two randomized studies of the efficacy of alendronate (10 mg/day; n = 20) and transdermal 17β estradiol (50 μg/day; n = 39). The within-run and between-run CVs were ≤ 7.3 and 8.7%, respectively. In 59 healthy women, urinary helical peptide levels highly correlated with those of urinary CTX (r = 0.78, P < 0.0001). The long-term intraindividual variability assessed over 6 months in 18 untreated postmenopausal women was 24%. Compared to 24 premenopausal women, urinary helical peptide was 42% (P < 0.0001) higher in 65 postmenopausal women (mean age, 60 years), an increase comparable to that of urinary CTX (+ 47%, P < 0.0001). Urinary helical peptide levels decreased by 72% (P < 0.0001) after 3 months of alendronate treatment and by 59% (P < 0.0001) after 6 months of transdermal estrogen therapy. These changes were of similar magnitude to those of urinary CTX (−69 and −62%, respectively; NS compared with changes in helical peptide). In women treated with transdermal 17β estradiol, the percentage of change of urinary helical peptide and urinary CTX at 6 months significantly correlated with the change in spinal bone mineral density after 2 years (r = −0.58, P = 0.002, and r = −0.52, P = 0.006, for urinary helical peptide and CTX, respectively). This new assay for type I collagen helical peptide has demonstrated adequate analytical performance and was highly correlated with urinary CTX, an established type I collagen C-telopeptide bone resorption marker. The test was a sensitive indicator of the antiresorptive effects of bisphosphonate and estrogens in postmenopausal women. This new bone resorption marker should be useful for the clinical investigation of patients with osteoporosis. [Copyright &y& Elsevier]

Genetic factors play an important role in determining bone mass and several genes are involved in this process. Interleukin-6 (IL-6) is a candidate gene for regulation of bone mineral density (BMD) and it has been suggested recently that novel IL-6 −174 G/C allelic variants may be associated with peak BMD in young men and with bone resorption in elderly women. In this study, we assessed the relationships between IL-6 gene polymorphism, peak BMD, rate of postmenopausal BMD loss, and bone turnover in women. BMD was measured by dual-energy X-ray absorptiometry in 255 healthy premenopausal women, aged 31–57 years. BMD loss at the forearm was measured over 4 years in 298 healthy untreated postmenopausal women, 50–88 years (mean 64 years). We also measured levels of serum osteocalcin, bone alkaline phosphatase, and N-propeptide of type I collagen for bone formation and three markers of bone resorption, including urinary and serum C-terminal cross-linking telopeptide of type I collagen and urinary N-terminal telopeptide of type I collagen, in both pre- and postmenopausal women at baseline. In premenopausal women we found a significant association between IL-6 genotypes and BMD at the whole body (analysis of variance [ANOVA], p = 0.03), femoral neck (p = 0.03), trochanter (p = 0.014), Ward’s triangle (p = 0.03), and total hip (p = 0.006), with subjects having the CC genotype showing 3%–7% higher BMD levels than their GG counterparts. However, after matching women with CC and GG genotypes for body height the differences decreased (2%–4%), and were no longer significant (p = 0.10–0.23). In postmenopausal women the mean rate of loss at the ultradistal radius was significantly associated with IL-6 genotypes (ANOVA, p = 0.049), with women having the CC genotype showing a significantly greater rate of bone loss (p < 0.05) compared with their GC and GG counterparts. After adjustment for weight changes, the difference in the rate of ultradistal radius bone loss between genotypes decreased and was not significant (p = 0.06 for CC vs. GG). A similar trend was observed for distal radius bone loss (p = 0.10, ANOVA), but not for the middle radius. We found no significant association between genotypes, bone turnover markers in premenopausal women, and either bone turnover or BMD in postmenopausal women. We conclude that this new functional IL-6 polymorphism was weakly associated with level of peak BMD and the rate of forearm trabecular postmenopausal bone loss in this cohort of healthy French women. IL-6 genotypes accounted only for a small proportion of the interindividual variation of both peak BMD and rate of bone loss and were not significant after adjustment for height and changes in body weight, respectively, suggesting that part of the effect may have been due to the differences in body size. Larger long-term studies are necessary to assess adequately the relationships between IL-6 genotype, rate of bone loss, and risk of fracture. [Copyright &y& Elsevier]

Although increased bone formation is a prominent feature of patients with osteosclerotic metastases from prostate cancer, there is also some evidence for increased bone resorption. The aim of this study was to compare the clinical utility of new bone resorption markers to that of bone formation in patients with bone metastases from prostate cancer before and after bisphosphonate treatment. Thirty-nine patients with prostate cancer and bone metastasis, nine patients with prostate cancer without bone metastases, nine patients with benign prostatic hyperplasia and 355 healthy age-matched men were included. Urinary non-isomerized (α CTX) and β isomerized (β CTX) type I collagen C-telopeptides (CTX) and a new assay for serum CTX were used to assess bone resorption. Bone formation was determined by serum osteocalcin, serum total (T-ALP) and bone (BAP) alkaline phosphatase and serum type I collagen C-terminal propeptide (PICP). Fourteen patients with bone metastases were also evaluated 15 days after a single injection of the bisphosphonate pamidronate (120 mg). Levels of all bone formation and bone resorption markers were significantly (P < 0.006-0.0001) higher in patients with prostate cancer and bone metastasis than in patients with benign prostatic hyperplasia, patients with prostate cancer without bone metastases and healthy controls. In patients with bone metastases the median was increased by 67% for serum osteocalcin, 128% for T-ALP, 138% for BAP, 79% for PICP, 220% for urinary α CTX, 149% for urinary β CTX and 214% for serum CTX. After bisphosphonate treatment all three resorption markers significantly decreased by an average of 65% (P = 0.001), 71% (P = 0.0010) and 61% (P = 0.0015) for urinary α CTX, urinary β CTX and serum CTX, respectively, whereas no significant change was observed for any bone formation markers. Patients with prostate cancer and bone metastases exhibit a marked increase in bone resorption, which... [ABSTRACT FROM AUTHOR]

The link between serum insulin-like growth factor 1 (IGF-1) and postmenopausal osteoporosis remains controversial. In this study of healthy postmenopausal women, decreased serum concentrations of IGF-1 were strongly associated with an increased risk of osteoporotic fractures independently of bone-mineral density. [ABSTRACT FROM AUTHOR]

The article presents an abstract of a research paper that attempts develop an ELISA for fecal S100A12 and investigate its utility for the clinical investigation of patients with ulcerative colitis (UC) and Crohn's disease (CD), submitted at the 5th European Workshop on Immune-Mediated Inflammatory Diseases in Sitges-Barcelona, Spain from December 1-3, 2010.

Summary: This multicenter and randomized clinical trial showed that daily oral herbal formula Xian Ling Gu Bao (XLGB) was safe in postmenopausal women over a 1-year treatment. Those patients ( n ∼ 50) treated with XLGB at the conventional dose demonstrated a statistically significant increase in dual-energy X-ray absorptiometry (DXA) bone mineral density (BMD) at lumbar spine at 6 months and a numerically increased BMD at 12 months. Introduction: The aim of this study was to examine the safety and efficacy of a herbal formula XLGB in postmenopausal women (ChiCTR-TRC-00000347). Methods: One hundred eighty healthy postmenopausal women (≥60 years old) with BMD T-score ≤ −2.0 (lumbar spine or femoral neck) were recruited from four clinical centers to receive low-dose (conventional dose) XLGB (L-XLGB group, 3 g/day, n = 61) or high-dose XLGB (H-XLGB group, 6 g/day, n = 58) or placebo (CON group, n = 61). Women received daily calcium (500 mg) and vitamin D (200 IU) supplementation. Primary endpoints were lumbar spine BMD and safety; secondary endpoints were femoral neck BMD and bone turnover markers measured at baseline and at 6 and 12 months. Results: Of 180 women recruited, 148 completed the study. The compliance in each group was comparable. Prominent adverse events were not observed in either group. In the L-XLGB group at 6 months, lumbar spine BMD by DXA increased significantly from baseline (+2.11% versus CON +0.58%, p < 0.05), but femoral neck BMD did not; at 12 months, BMD in the L-XLGB group decreased from 6-month levels yet remained higher than baseline, but without difference from the CON group. There was no dose-dependent response. Bone turnover marker levels declined during the first 6 months after XLGB treatment. There was no significant difference in the overall incidence of side effects among treatment and control groups. Conclusion: XLGB over 1-year treatment at the conventional dose demonstrated safe and only a statistically significant increase in BMD at lumbar spine at 6 months in postmenopausal women. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Bisphosphonates have slowed the progression of osteoarthritis (OA) in animal models and have decreased pain in states of high bone turnover. The Knee OA Structural Arthritis (KOSTAR) study, which is the largest study to date investigating a potential structure-modifying OA drug, tested the efficacy of risedronate in providing symptom relief and slowing disease progression in patients with knee OA. METHODS: The study group comprised 2,483 patients with medial compartment knee OA and 2-4 mm of joint space width (JSW), as determined using fluoroscopically positioned, semiflexed-view radiography. Patients were enrolled in 2 parallel 2-year studies in North America and the European Union. These studies evaluated the efficacy of risedronate at dosages of 5 mg/day, 15 mg/day, 35 mg/week (in Europe), and 50 mg/week (in North America) compared with placebo in reducing signs and symptoms, as measured by the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and patient global assessment (PGA) scores, and in slowing radiographic progression. RESULTS: A reduction of approximately 20% in signs and symptoms, as measured by WOMAC subscales and PGA scores, was observed in all groups, with no treatment effect of risedronate demonstrated. Risedronate did not significantly reduce radiographic progression as measured by decreased JSW or using a dichotomous definition of progression (joint space loss of >or=0.6 mm). Thirteen percent of patients receiving placebo demonstrated significant disease progression over 2 years. A dose-dependent reduction in the level of C-terminal crosslinking telopeptide of type II collagen, a cartilage degradation marker associated with progressive OA, was seen in patients who received risedronate. No increase in the number of adverse events was demonstrated for risedronate compared with placebo. CONCLUSION: Although risedronate (compared with placebo) did not improve signs or symptoms of OA, nor did it alter progression of OA, a reduction in the level of a marker of cartilage degradation was observed. A sustained clinically relevant improvement in signs and symptoms was observed in all treatment and placebo groups. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease-modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation. METHODS: OPG and RANKL levels, together with a parameter of inflammation (first-year time-averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5-year radiographic progression of joint damage. RESULTS: The first-year tESR and the OPG:RANKL ratio, as measured at baseline, independently predicted 5-year radiographic progression of joint damage (both P

OBJECTIVE: Type II collagen, which consists of a large helical domain and telopeptides at each end, is the most abundant protein of cartilage matrix. The aim of this study was to develop a biochemical marker reflecting the degradation of the helical region of type II collagen and to evaluate its clinical performance in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: We developed a competitive polyclonal antibody-based enzyme-linked immunosorbent assay (ELISA) using the 622-632 peptide derived from the sequence of the alpha1 chain of human type II collagen (HELIX-II) as immunogen and standard. We measured urinary levels of HELIX-II peptide and C-terminal crosslinking telopeptide of type II collagen (CTX-II) in 90 patients with knee OA (73% women; mean +/- SD age 63.0 +/- 8.0 years, mean +/- SD disease duration 6.1 +/- 6.8 years), 89 patients with early RA (disease duration /=0.5 units/year), with an odds ratio (OR) of 5.9 (95% confidence interval [95% CI] 2.0-17.2) after adjustment for serum C-reactive protein (CRP) levels and baseline joint damage. Patients with increased levels of both urinary HELIX-II and CTX-II had the highest risk of progression (OR 17.5 [95% CI 3.1-99]). CONCLUSION: The HELIX-II ELISA is specific for type II collagen degradation, has adequate technical performance, and can distinguish patients with knee OA or RA from healthy controls. Elevated HELIX-II levels are associated with increased risk of radiographic progression in RA independently of CRP levels, baseline joint damage, and urinary CTX-II levels. The HELIX-II ELISA should be useful for the clinical investigation of patients with arthritis and for identifying RA patients at higher risk of progression. [ABSTRACT FROM AUTHOR]

Hip fractures are common among older women. At the present time, major efforts are being made to identify women with low bone mineral density (BMD). However, more than half of hip fractures occur in women who would not classically be considered osteoporotic by BMD. This study aimed to identify factors associated with hip fracture in women with high BMDs. A total of 7598 French women aged over 74 participated in the EPIDOS study and had BMD measured by dual energy X-ray absorptiometry. Analysis was carried out comparing women with and without hip fractures over more than 3 years of follow-up. The participants were divided into three groups based on femoral neck BMD, so as to have equal numbers in each group (cut-off points=0.601 g/cm2, and 0.683 g/cm2). Multiple risk factors thought to be associated with hip fracture were tested in the high and low BMD groups to search for those whose effect was stronger in the high BMD group. Age adjusted Cox regression was used. Results for continuous variables are reported per standard deviation change. Positive interaction between higher BMD, hip fracture and the following factors were found: age (P<0.01), ultrasound attenuation (P<0.05), urinary deoxypyridinoline (DPD) (P<0.05), left quadriceps strength (P<0.05) and right and left foot coordination (P<0.05). The following factors had a larger hazards ratio in those in the upper third of BMD than the low and were statistically significant: femoral neck BMD, nulliparity, age, ultrasound attenuation and speed, prior fracture, urinary deoxypyridinoline, left grip strength and foot coordination. Multiple factors appear to be more strongly associated with hip fractures in women with high BMD than low. They appear to cluster as factors that may relate to bone turnover and architecture and others which are more subtle measures of left-sided coordination. [ABSTRACT FROM AUTHOR]

Abstract: Iliac crest bone biopsies are used to assess the mechanism of action of drug treatments, yet there are little data comparing this site to sites prone to fracture. The purpose of this study was to compare the delay and the amplitude of responses to treatment in two different bone sites. The short‐term effects of zoledronic acid and teriparatide on microarchitecture, collagen crosslinks and bone remodeling were evaluated in iliac crest and lumbar vertebrae. Aged ewes (n=8/gr) received either vehicle (CTRL) or a single injection of zoledronic acid (ZOL, 10mg) or daily injections of teriparatide (TPTD, 20μg/d) for 3months. Blood samples were collected monthly for assessing bone turnover markers. At the end of the study, a transiliac bone biopsy (IC) and L1 lumbar vertebrae (LV1) were collected to assess bone microarchitecture; pyridinoline (PYD), deoxypyridinoline (DPD), pentosidine (PEN) content, static and dynamic parameters of bone remodeling. In CTRL, Tb-BV/TV was significantly higher in LV1 than IC (p<0.0001). This was associated with a trend of higher Tb.N, Tb.Th, DA, an inferior Conn.D and a lower bone turnover as shown by the decreases of osteoid parameters, MS/BS, Ac.f in LV1 when compared to IC. In addition, the ratio PYD/DPD was 4 times higher in LV1 than IC. After 3months, significant decreases of sALP (p<0.001) and sCTX (p<0.001) were observed in the ZOL-group whereas in TPTD-group, after transient increases, they returned to baseline values. When compared to their respective CTRL, ZOL induced significant increases in Tb.BV/TV, Conn.D, Tb.N and Tb.Sp, in IC but not in LV1. Regardless of the site, ZOL markedly depressed the bone turnover: The static parameters of bone formation significantly decreased and the diminution of MS/BS, BFR/BS and Ac.f varied from −94 to −98% vs CTRL (p<0.01 to 0.001). It was associated with a diminution of the DPD content and the PYD/DPD ratio mainly in IC cortices. In contrast, after 3months, TPTD did not modify the 3D structure and microarchitecture in IC and LV1, except a trend of higher Conn.D in IC, compared to IC-CTRL. TPTD treatment induced a significant increase in cortical porosity in LV1 (p<0.05) when compared to LV1-CTRL. Static parameters of bone formation and resorption were augmented in both sites, significantly only in LV1 (p<0.05) with a trend of increases in MS/BS and BFR/BS, compared to LV1-CTRL. In conclusion, in adult ewes, the bone mass, microarchitecture, remodeling and collagen crosslink content differ according to the bone site (iliac crest and vertebra). Furthermore, after 3months, the responses to ZOL and TPTD were of different magnitude and delay between the two bone sites. The distinction of bone sites to study the early effects of anti-osteoporotic therapies appears meaningful in order to approach their site-specific anti-fracture efficacy. [Copyright &y& Elsevier]

Summary: The International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommend that a marker of bone formation (serum procollagen type I N propeptide, s-PINP) and a marker of bone resorption (serum C-terminal telopeptide of type I collagen, s-CTX) are used as reference analytes for bone turnover markers in clinical studies. Introduction: Bone turnover markers (BTM) predict fracture risk, and treatment-induced changes in specific markers account for a substantial proportion of fracture risk reduction. The aims of this report were to determine their clinical potential in the prediction of fracture risk and for monitoring the treatment of osteoporosis and to set an appropriate research agenda. Methods: Evidence from prospective studies was gathered through literature review of the PUBMED database between the years 2000 and 2010 and the systematic review of the Agency for Healthcare Research and Quality up to 2001. Results: High levels of BTMs may predict fracture risk independently from bone mineral density in postmenopausal women. They have been used for this purpose in clinical practice for many years, but there is still a need for stronger evidence on which to base practice. BTMs provide pharmacodynamic information on the response to osteoporosis treatment, and as a result, they are widely used for monitoring treatment in the individual. However, their clinical value for monitoring is limited by inadequate appreciation of the sources of variability, by limited data for comparison of treatments using the same BTM and by inadequate quality control. IOF/IFCC recommend one bone formation marker (s-PINP) and one bone resorption marker (s-CTX) to be used as reference markers and measured by standardised assays in observational and intervention studies in order to compare the performance of alternatives and to enlarge the international experience of the application of markers to clinical medicine. Conclusion: BTM hold promise in fracture risk prediction and for monitoring treatment. Uncertainties over their clinical use can be in part resolved by adopting international reference standards. [ABSTRACT FROM AUTHOR]

Abstract: We describe a novel high performance liquid chromatography–electrospray ionization mass spectrometry (HPLC–ESI-MS) method for the simultaneous quantification of enzymatic immature (dihydroxylysinonorleucine DHLNL, hydroxylysinonorleucine HLNL) and mature (pyridinoline PYD, deoxypyridinoline DPD) collagen crosslinks in connective tissues. The crosslinks were separated on a C18 Atlantis® T3 reversed-phase column with heptafluorobutyric acid (HFBA) as volatile ion-pairing reagent in an acetonitrile–water mobile phase. Detection was carried out by electrospray ionization mass spectrometry in a positive ion mode with selected ion recording (SIR). This method is more sensitive and selective than ion exchange chromatography with post-column ninhydrin detection which is the reference method used for the simultaneous quantification of collagen enzymatic divalent and trivalent crosslinks. The intra and inter-day precision errors were less than 3.4 and 7.7%, respectively for DHLNL, 3.5 and 5.9%, respectively for HLNL, 4.0 and 5.2%, respectively for PYD, 8.2 and 10.7%, respectively for DPD. This novel technique should be useful to quantify simultaneously DHLNL, HLNL, PYD and DPD in connective tissues and to evaluate the maturation of collagen by determination of the ratio between immature and mature enzymatic crosslinks. [Copyright &y& Elsevier]

The World Health Organization defines osteoporosis as a systemic disease characterized by decreased bone tissue mass and microarchitectural deterioration, resulting in increased fracture risk. Since this statement, a significant amount of data has been generated showing that these two factors do not cover all risks for fracture. Other independent clinical factors, such as age, as well as aspects related to qualitative changes in bone tissue, are believed to play an important role. The term “bone quality” encompasses a variety of parameters, including the extent of mineralization, the number and distribution of microfractures, the extent of osteocyte apoptosis, and changes in collagen properties. The major mechanism controlling these qualitative factors is bone remodeling, which is tightly regulated by the osteoclast/osteoblast activity. We focus on the relationship between bone remodeling and changes in collagen properties, especially the extent of one posttranslational modification. In vivo, measurements of the ratio between native and isomerized C-telopeptides of type I collagen provides an index of bone matrix age. Current preclinical and clinical studies suggests that this urinary ratio provides information about bone strength and fracture risk independent of bone mineral density and that it responds differently according to the type of therapy regulating bone turnover. [ABSTRACT FROM AUTHOR]

Bioavailability and pharmacological effects of tiludronate were compared when administered as an intravenous (i.v.) bolus at a dosage of 0.1 mg/kg body weight (b.w.) once daily for 10 consecutive days (group 1, n = 6) and as a single constant rate infusion (CRI) at a total dose of 1 mg/kg b.w. (group 2, n = 6) in healthy adult horses. Tiludronate and carboxy-terminal cross-linking telopeptide of type I collagen (CTX-1) were measured in plasma and urine. There was no statistically significant difference in area under the curve ( AUC) and clearance ( Cl) between the two groups. Bioavailability of the CRI was 103% (not significantly different) that of the 10 daily i.v. bolus doses. Cumulative urine tiludronate excretion could not be compared between groups because of poor sensitivity of the assay in urine. Plasma and urine CTX-1 levels were not different between groups throughout the study. However, interindividual variations were greater in group 1 than in group 2. A significant decrease in CTX-1 levels was observed in plasma after the first administration in group 1, but not in urine; while in group 2, a significant decrease in CTX-1 concentrations was observed after treatment in both plasma and urine. In conclusion, both dosage regimens of tiludronate produced similar plasma exposure and pharmacological effects in adult healthy horses. [ABSTRACT FROM AUTHOR]

The article presents a study which determined the association between individual biochemical markers and radiographic features. Serum and urinary biochemical markers were assessed in patients with predominantly tibiofemoral knee osteoarthritis (OA). Results of principal components analysis suggest that biochemical marker combinations may be more sensitive than individual marker for reflecting structural damage in patients with knee OA.

The aim of this study was to determine whether Dickkopf-1 (Dkk-1) expression in breast cancer was associated with bone metastases. We first analysed Dkk-1 expression by human breast cancer cell lines that induce osteolytic or osteoblastic lesions in animals. Dickkopf-1 levels were then measured in the bone marrow aspirates of hind limbs from eight NMRI mice inoculated with breast cancer cells that induced bone metastases and 11 age-matched non-inoculated control animals. Finally, Dkk-1 was measured in the serum of 17 women with breast cancer in complete remission, 19 women with breast cancer and bone metastases, 16 women with breast cancer and metastases at non-bone sites and 16 healthy women. Only breast cancer cells that induce osteolytic lesions in animals produced Dkk-1. There was a six-fold increase in Dkk-1 levels in the bone marrow from animals inoculated with MDA-B02 cells when compared with that of control non-inoculated animals (P=0.003). Median Dkk-1 levels in the serum of patients with breast cancer and bone metastases were significantly higher than levels of patients in complete remission (P=0.016), patients with breast cancer having metastases at non-bone sites (P<0.0001) and healthy women (P=0.047), although there was a large overlap in individual levels between the different groups. In conclusion, Dkk-1 is secreted by osteolytic human breast cancer cells lines and increased circulating levels are associated with the presence of bone metastases in patients with breast cancer. Measurements of circulating Dkk-1 levels may be useful for the clinical investigation of patients with breast cancer and bone metastases.British Journal of Cancer (2007) 97, 964–970. doi:10.1038/sj.bjc.6603959 www.bjcancer.com Published online 18 September 2007 [ABSTRACT FROM AUTHOR]

In a 5-year study involving 119 postmenopausal women, zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. BMD increased significantly. Bone turnover markers decreased from baseline and were maintained within premenopausal reference ranges. After completion of the core study, two consecutive, 2-year, open-label extensions investigated the efficacy and safety of zoledronic acid 4 mg over 5 years in postmenopausal osteoporosis. In the core study, patients received 1 to 4 mg zoledronic acid or placebo. In the first extension, most patients received 4 mg per year and then patients entered the second extension and received 4 mg per year or calcium only. Patients were divided into three subgroups according to years of active treatment received (2, 3 or 5 years). Changes in BMD and bone turnover markers (bone ALP and CTX-I) were assessed. All subgroups showed substantial increases in BMD and decreases in bone markers. By the end of the core study, 37.5% of patients revealed a suboptimal reduction (< 30%) of bone ALP levels. After subsequent study drug administration during the extensions, there was no evidence of progressive reduction of bone turnover markers. Furthermore, increased marker levels after treatment discontinuation demonstrates preservation of bone remodelling capacity. This study showed that zoledronic acid 4 mg once-yearly was well tolerated and effective in reducing biomarkers over 5 years. Detailed analysis of bone marker changes, however, suggests that this drug regimen causes insufficient reduction of remodelling activity in one third of patients. [ABSTRACT FROM AUTHOR]

Abstract: Introduction : Tiludronate, a bisphosphonate, has recently been introduced in veterinary medicine to treat orthopedic conditions in the horse. This study was designed to evaluate its effects on biochemical biomarkers of bone metabolism and on bone density and structure in an experimental model of disuse osteoporosis induced by cast application in horses. Methods : Two groups of eight horses were immobilized during 8 weeks. The first group (P-group) received a placebo, and the second group (T-group) received tiludronate 1 mg/kg by slow IV infusion. Both treatments were administered twice, 28 days apart. Immobilization consisted of stall rest with the left forelimb packed in a fiberglass cast. It was followed by a 4-week remobilization period and an 8-week standardized training protocol. One biomarker of bone resorption, the C-telopeptides of type I collagen cross-links (CTX-1) and one biomarker of bone formation, the bone isoenzyme of alkaline phosphatase (bone ALP), were assessed. Metacarpus III (MCIII) bone mineral density (BMD) and speed of sound (SOS) were evaluated respectively by dual energy X-ray absorptiometry (DEXA) and quantitative ultrasonography (QUS). Lameness was regularly assessed during the remobilization and training periods. Group- and time-related effects were tested by analysis of variance on repeated measurements. Results : A rapid, transient and significant decrease in CTX-1 concentration was seen after each treatment in the T-group only. No significant differences between groups were seen in the evolution of bone ALP activity. At the end of the experiment, the loss of MCIII BMD measured by DEXA in the immobilized limb was significantly less in the T-group than in the P-group. The MCIII SOS measured by QUS did not significantly vary within or between groups throughout the study. Discussion and conclusions : Tiludronate was found to significantly reduce bone resorption during immobilization, as well as to prevent long-term osteopenia in the immobilized limb. Disuse osteopenia did not affect the lateral superficial cortex of MCIII. [Copyright &y& Elsevier]

Objectives. The 5-yr longitudinal study tested the hypothesis that serum and urinary markers of type II collagen metabolism would be associated with radiological progression of disease in patients with mild-to-moderate knee osteoarthritis (OA). [ABSTRACT FROM PUBLISHER]

Complex biological pathways including angiogenesis, invasion, osteoclastic activation and bone matrix degradation are involved in the formation of bone metastasis (BM). The aim of our study was to investigate the cross-sectional and longitudinal associations of a panel of 12 serum biochemical markers reflecting biological pathways underlying BM development. In a cross-sectional study, we investigated 29 patients with primary breast carcinoma without BM (BC/BM-), 28 patients with breast carcinoma and BM (BC/BM+) and 15 healthy women. In longitudinal analyses, we investigated 34 patients for whom serum was obtained a two different time points: at the time of primary BC diagnosis and after a median time of 3 years. During this follow-up, 15 patients developed BM, whereas the other 19 remained free of BM. In patients who developed BM, the second samples were obtained before BM was documented by bone scan. The cross-sectional analyses have shown all biochemical markers to be significantly elevated in patients with BM, when compared to the patients without BM and healthy controls, except TGFβ1 that was significantly decreased. Multivariable analyses showed that only the bone resorption markers TRACP 5b, CTX and ICTP, and the marker of angiogenesis VEGF were independently associated with BM. Those markers correctly distinguished 85% of BC patients with or without BM from normal individuals. Longitudinal analyses showed that patients with primary BC who developed BM during follow-up had higher levels of TRACP5b (+95%, P=0.08) at the time of primary diagnosis, those patients had also a higher increases of ICTP (P=0.006), MMP-7 (P=0.004) and TIMP-1 (P=0.017) during follow-up than patients who did not progress toward bone metastasis. This study provides evidence of increase and interrelationship of circulating markers of angiogenesis, invasion and bone resorption in patients with BC with and without BM. Markers of bone resorption have the highest independent diagnostic value for detecting and potentially predicting BM in breast carcinoma patients. [ABSTRACT FROM AUTHOR]

Low body mass index (BMI) is a well-documented risk factor for future fracture. The aim of this study was to quantify this effect and to explore the association of BMI with fracture risk in relation to age, gender and bone mineral density (BMD) from an international perspective using worldwide data. We studied individual participant data from almost 60,000 men and women from 12 prospective population-based cohorts comprising Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo, EPIDOS, OFELY, Kuopio, Hiroshima, and two cohorts from Gothenburg, with a total follow-up of over 250,000 person years. The effects of BMI, BMD, age and gender on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson regression model in each cohort separately. The results of the different studies were then merged. Without information on BMD, the age-adjusted risk for any type of fracture increased significantly with lower BMI. Overall, the risk ratio (RR) per unit higher BMI was 0.98 (95% confidence interval [CI], 0.97–0.99) for any fracture, 0.97 (95% CI, 0.96–0.98) for osteoporotic fracture and 0.93 (95% CI, 0.91–0.94) for hip fracture (all p <0.001). The RR per unit change in BMI was very similar in men and women ( p >0.30). After adjusting for BMD, these RR became 1 for any fracture or osteoporotic fracture and 0.98 for hip fracture (significant in women). The gradient of fracture risk without adjustment for BMD was not linearly distributed across values for BMI. Instead, the contribution to fracture risk was much more marked at low values of BMI than at values above the median. This nonlinear relation of risk with BMI was most evident for hip fracture risk. When compared with a BMI of 25 kg/m2, a BMI of 20 kg/m2 was associated with a nearly twofold increase in risk ratio (RR=1.95; 95% CI, 1.71–2.22) for hip fracture. In contrast, a BMI of 30 kg/m2, when compared with a BMI of 25 kg/m2, was associated with only a 17% reduction in hip fracture risk (RR=0.83; 95% CI, 0.69–0.99). We conclude that low BMI confers a risk of substantial importance for all fractures that is largely independent of age and sex, but dependent on BMD. The significance of BMI as a risk factor varies according to the level of BMI. Its validation on an international basis permits the use of this risk factor in case-finding strategies. [ABSTRACT FROM AUTHOR]

Objective To compare the effects of a 12-week treatment with 17ß-estradiol given alone and in sequential combination with 3.75?mg of nomegestrol acetate (Naemis ® ), or a placebo on biochemical markers of bone turnover in menopausal women. Patients and methods A double-blind, randomized, placebo and estradiol-controlled multicenter study was conducted. A total of 176 patients who had been menopausal for 1–10 years, hysterectomized or not, having no contraindications to hormone replacement therapy, without any risks factors for osteoporosis, received one of these treatments during 12 weeks: placebo, 1.5?mg estradiol (E2) or 1.5?mg E2/3.75?mg nomegestrol acetate (E2 /NOMAC). The primary efficacy variables were the change in bone markers (total alkaline phosphatase, bone alkaline phosphatase and osteocalcin; urinary type-I collagen peptides). Results The four biochemical markers decreased only in the E2/NOMAC group. Bone alkaline phosphatase, osteocalcin and urinary type-I collagen peptides decreased in the E2 group. For both active treatment groups compared to the placebo group, the changes were statistically significant after a 12-week treatment. There were no statistically significant differences between the E2 and the E2/NOMAC groups except for total serum alkaline phosphatase, whose mean value decreased in the E2/NOMAC group but increased slightly in the E2 group ( p < 0.001). Furthermore, after a 6-week treatment, the changes in biochemical markers of bone turnover were similar to those found after 12 weeks. Safety data were satisfactory with regard to estradiol given alone or in combination with nomegestrol acetate. Conclusion These results demonstrated that 1.5?mg E2 is effective in reducing bone turnover in postmenopausal women and proved that the combination of 1.5?mg E2 and 3.75?mg nomegestrol acetate has no deleterious effect on bone remodelling. [ABSTRACT FROM AUTHOR]

Previous fracture is a well-documented risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the relationship of this risk with age, sex, and bone mineral density (BMD). We studied 15 259 men and 44 902 women from 11 cohorts comprising EVOS/EPOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and two cohorts from Gothenburg. Cohorts were followed for a total of 250 000 person-years. The effect of a prior history of fracture on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age, sex, and BMD. The results of the different studies were merged by using the weighted β-coefficients.A previous fracture history was associated with a significantly increased risk of any fracture compared with individuals without a prior fracture (RR = 1.86; 95% CI = 1.75–1.98). The risk ratio was similar for the outcome of osteoporotic fracture or for hip fracture. There was no significant difference in risk ratio between men and women. Risk ratio (RR) was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any fracture (8%) and for hip fracture (22%). The risk ratio was stable with age except in the case of hip fracture outcome where the risk ratio decreased significantly with age.We conclude that previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by measurement of BMD. Its validation on an international basis permits the use of this risk factor in case finding strategies. [Copyright &y& Elsevier]

This paper presents an overview of the FRENCH plasma propulsion activities. The main existing and future projects are described. The field of application of plasma propulsion is the station keeping and the orbit raising of geostationary telecommunication satellites (STENTOR) and the transfer of interplanetary vehicles such as Mars Sample Return.The works done in the frame of the preparation of the first commercial spacecraft as well as the preparation of the future and the associated Research and Technology program are described.The scientific activity supporting the development of Hall thrusters is on-going in the frame of the GDR (Groupement de Recherche) CNRS/CNES/Snecma Moteurs /ONERA on Plasma Propulsion. Several Russian entities are also involved: the MIREA (Moscow Institute of Radioelectronics and Automatics), of the RIAME MAI (Research Institute of Applied Mechanics and Electrodynamics - Moscow Aviation Institute) and of the SPT « father a˚ Professor MOROZOVThe industrial development activities are jointly conducted by Snecma Moteurs and Russian manufacturer FAKEL.The future developments are mainly dedicated to the use of electric propulsion for the orbit raising of telecommunications satellites which leads to the development of thrusters with higher thrust than those existing today.Works are also performed to develop and improve the tools necessary to evaluate the plume effects of plasma thrusters. [Copyright &y& Elsevier]