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International audience; Calcium accumulation in atherosclerotic plaques predicts cardiovascular mortality, but the mechanisms responsible for plaque calcification and how calcification impacts plaque stability remain debated. Tissue-nonspecific alkaline phosphatase (TNAP) recently emerged as a promising therapeutic target to block cardiovascular calcification. In this study, we sought to investigate the effect of the recently developed TNAP inhibitor SBI-425 on atherosclerosis plaque calcification and progression. TNAP levels were investigated in ApoE-deficient mice fed a high-fat diet from 10 weeks of age and in plaques from the human ECLAGEN biocollection (101 calcified and 14 non-calcified carotid plaques). TNAP was inhibited in mice using SBI-425 administered from 10 to 25 weeks of age, and in human vascular smooth muscle cells (VSMCs) with MLS-0038949. Plaque calcification was imaged in vivo with 18F-NaF-PET/CT, ex vivo with osteosense, and in vitro with alizarin red. Bone architecture was determined with µCT. TNAP activation preceded and predicted calcification in human and mouse plaques, and TNAP inhibition prevented calcification in human VSMCs and in ApoE-deficient mice. More unexpectedly, TNAP inhibition reduced the blood levels of cholesterol and triglycerides, and protected mice from atherosclerosis, without impacting the skeletal architecture. Metabolomics analysis of liver extracts identified phosphocholine as a substrate of liver TNAP, who's decreased dephosphorylation upon TNAP inhibition likely reduced the release of cholesterol and triglycerides into the blood. Systemic inhibition of TNAP protects from atherosclerosis, by ameliorating dyslipidemia, and preventing plaque calcification.

Recently, the bone strain index (BSI), a new index of bone strength based on a finite element model (FEA) from dual X-ray absorptiometry (DXA), has been developed. BSI represents the average equivalent strain inside the bone, assuming that a higher strain level (high BSI) indicates a condition of higher risk. Our study aimed to analyze the relationship between BSI and age, BMI and areal BMD in pre- and postmenopausal women and to prospectively investigate fracture prediction (Fx) by BSI in postmenopausal women. Methods. At the 14th annual follow-up of the OFELY study, BSI was measured at spine (Spine BSI) and femoral scans (Neck and Total Hip BSI), in addition to areal BMD with DXA (Hologic QDR 4500) in 846 women, mean (SD) age 60 yr (15). The FRAX® (fracture risk assessment tool) for major osteoporotic fractures (MOF) was calculated with FN areal BMD (aBMD) at baseline; incident fragility fractures were annually registered until January 2016. Results. In premenopausal women (n = 261), Neck and Total Hip BSI were slightly negatively correlated with age (Spearman r = -0.13 and -0.15 respectively, p = 0.03), whereas all BSIs were positively correlated with BMI (r = +0.20 to 0.37, p 0.01) and negatively with BMD (r = -0.69 to -0.37, p 0.0001). In postmenopausal women (n = 585), Neck and Total Hip BSI were positively correlated with age (Spearman r = +0.26 and +0.31 respectively, p 0.0001), whereas Spine BSI was positively correlated with BMI (r = +0.22, p 0.0001) and all BSIs were negatively correlated with BMD (r = -0.81 to -0.60, p 0.0001). During a median [IQ] 9.3 [1.0] years of follow-up, 133 postmenopausal women reported an incident fragility Fx, including 80 women with a major osteoporotic Fx (MOF) and 26 women with clinical vertebral Fx (VFx). Each SD increase of BSI value was associated with a significant increase of the risk of all fragility Fx with an age-adjusted HR of 1.23 for Neck BSI (p = 0.02); 1.27 for Total Hip BSI (p = 0.004) and 1.35 for Spine BSI (p 0.0001). After adjustment for FRAX®, the association remained statistically significant for Total Hip BSI (HR 1.24, p = 0.02 for all fragility Fx; 1.31, p = 0.01 for MOF) and Spine BSI (HR 1.33, p 0.0001 for all fragility Fx; 1.33, p = 0.005 for MOF; 1.67, p = 0.002 for clinical VFx). In conclusion, spine and femur BSI, an FEA DXA derived index, predict incident fragility fracture in postmenopausal women, regardless of FRAX®.

Tamoxifen is a selective estrogen receptor modulator used to activate the CREERT2 recombinase, allowing tissue-specific and temporal control of the somatic mutagenesis to generate transgenic mice. Studies integrating development and metabolism require a genetic modification induced by a neonatal tamoxifen administration. Here, we investigate the effects of a neonatal tamoxifen administration on energy homeostasis in adult male and female C57BL/6J mice. C57BL/6J male and female mouse pups received a single injection of tamoxifen 1 day after birth (NTT) and were fed a high-fat/high-sucrose diet at 6 weeks of age. We measured weight, body composition, glucose and insulin tolerance, basal metabolism, and tibia length and weight in adult mice. The neonatal tamoxifen administration exerted long-term, sex-dependent effects on energy homeostasis. NTT female mice became overweight and developed impaired glucose control in comparison to vehicle-treated littermates. NTT females exhibited 60% increased fat mass, increased food intake, decreased physical activity and energy expenditure, impaired glucose and insulin tolerance, and fasting hyperglycemia and hyperinsulinemia. In contrast, NTT male mice exhibited a modest amelioration of glucose and insulin tolerance and long-term decreased lean mass linked to decreased bone weight. These results suggest that the neonatal tamoxifen administration exerted a marked and sex-dependent influence on adult energy homeostasis and bone weight and must therefore be used with caution for the development of transgenic mouse models regarding studies on energy homeostasis and bone biology.

Many fractures occur in individuals with normal areal Bone Mineral Density (aBMD) measured by Dual X-ray Absorptiometry (DXA). High Resolution peripheral Quantitative Computed Tomography (HR-pQCT) allows for non-invasive evaluation of bone stiffness and strength through micro finite element (?FE) analysis at the tibia and radius. These ?FE outcomes are strongly associated with fragility fractures but do not provide clear enhancement compared with DXA measurements. The objective of this study was to establish whether a change in loading conditions in standard ?FE analysis assessed by HR-pQCT enhance the discrimination of low-trauma fractured radii (n = 11) from non-fractured radii (n = 16) obtained experimentally throughout a mechanical test reproducing a forward fall. Micro finite element models were created using HR-pQCT images, and linear analyses were performed using four different types of loading conditions (axial, non-axial with two orientations and torsion). No significant differences were found between the failure load assessed with the axial and non-axial models. The different loading conditions tested presented the same area under the receiver operating characteristic (ROC) curves of 0.79 when classifying radius fractures with an accuracy of 81.5%. In comparison, the area under the curve (AUC) is 0.77 from DXA-derived ultra-distal aBMD of the forearm with an accuracy of 85.2%. These results suggest that the restricted HR-pQCT scanned region seems not sensitive to loading conditions for the prediction of radius fracture risk based on ex vivo experiments (n = 27).

INTRODUCTION Recent technological advances with dual-energy quantitative computed tomography (DEQCT) allow to combine two images of different level of energy to obtain simulated mono-energetic images at 60 keV (SIM60KeV-QCT) with improved image contrast in clinical practice. This study includes three topics: (1) compare bone mineral content (BMC), areal and volumetric bone mineral density (aBMD, vBMD) obtained with SIM60KeV-QCT, single-energy QCT (SEQCT), and dual X-ray absorptiometry (DXA); (2) compare ash density and weight with respective vBMD and BMC assessed on SIM60KeV-QCT, SEQCT, and DXA; and (3) compare the influence of reconstruction kernels on the accuracy of vBMD and BMC using ash density and ash weight as the reference values. METHODS DXA, SEQCT, and DEQCT acquisitions were performed ex vivo on 42 human femurs. Standard kernel (SK) and bone kernel (BK) were applied to each stack of images. Ten diaphyses and 10 femoral necks were cut, scanned, and reconstructed using the techniques described above. Finally, the bone specimens were calcined to obtain the ash weight. RESULTS QCT analysis (SEQCT, SIM60KeV-QCT) underestimated BMC value compared to DXA. For femoral necks, all QCT analyses provided an unbiased estimate of ash weight but underestimated ash density regardless of the kernel used. For femoral diaphysis, SEQCT BK, SIM60KeV-QCT BK, and SK underestimated ash weight but not ash density. CONCLUSION BMC and vBMD quantifications with the SIM60KeV-QCT gave similar results as the SEQCT. Further studies are needed to optimize the use of SIM60KeV-QCT in clinical situations. SK should be used given the effect of kernels on QCT assessment.

Background Dual X-ray absorptiometry body composition measurements are widely used for clinical and research settings. It is well known that measurements vary across instruments, needing caution for longitudinal monitoring or multicentric studies. This study was to quantify intra- and inter-center variability of bone mineral content, bone mineral density, fat and lean body composition measurements between Hologic Discovery models in order to calculate the corrective factors to be applied for multicenter research projects. Materials and methods A whole body phantom composed of materials representing the thickness and percentage of bone, lean and fat mass in the human physiological range was analyzed ten times in three different centers using dual energy X-ray absorptiometry scanners (Two Hologic Discovery QDR A and one QDR W). In addition, we used a morphometric vertebral phantom to monitor stability and a three steps block phantom to check accuracy. Results We found a good long-term stability and accuracy for the three devices. Intra-center coefficients of variation were within the range of the manufacturer acceptable values (bone mineral density: 1.40%, bone mineral content: 1%, area: 1.50%, fat mass: 0.89%, lean mass: 0.76%, total mass: 0.12%). Whereas the inter-center coefficient of variation exceeded 8% (bone mineral density: 8.18%, bone mineral content: 3.03%, area: 8.63%: fat mass: 3,92%, lean mass: 7.89%, total mass: 2.85%). Conclusion Our study showed that the discrepancies across centers remain a major concern, particularly with regard to body composition results. Our study highlight the need of cross calibration between densitometers and proposes corrective factors evaluated from a whole body phantom to lead multicentric studies adjustment.

International audience; Lysphosphatidic acid (LPA) is a major natural bioactive lipid mediator whose biological functions affect multiple organs. These include bone as demonstrated by global Lpar1-knockout mice (Lpar1-/-) which present a bone growth defect. LPA acts on all bone cells including osteoblasts, that are responsible for bone formation, and osteoclasts, which are specialized cells that resorb bone. LPA appears as a potential new coupling molecule during bone remodeling. LPA1 is the most ubiquitous LPA receptor among the six LPA receptor family members (LPA1-6). To better understand the specific role of LPA via its receptor LPA1 in osteoblastic cell lineage we generated osteoblast-specific Lpar1 knockout mice (Lpar1-∆Ob) by crossing Lpar1flox/flox and Osx:Cre+ mouse lines. Lpar1-∆Ob mice do not recapitulate the bone defects of Lpar1-/- mice but revealed reduced bone mineralization and decreased cortical thickness, as well as increased bone porosity associated with an augmentation in the lacunae areas of osteocyte and their apoptotic yield. In vitro, primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1-/- osteoblasts revealed a remarkable premature expression of alkaline phosphatase, reduced cell proliferation associated with decreased YAP-P nuclear accumulation, and reduced mineralization activity. Osteocyte specification is markedly impaired as demonstrated by reduced expression of early (E11) and late (DMP1, DKK1, SOST) osteocyte markers ex vivo in enriched osteocytic fractions of Lpar1-∆Ob mouse bone explants. In addition, E11 expression and dendrite formation induced by FGF2 are markedly impaired in both primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1-/- osteoblasts. Taken together these results suggest a new role for LPA in bone mass control via bone mineralization and osteocyte function.

Several cross-sectional studies have shown that impairment of bone microarchitecture contributes to skeletal fragility. The aim of this study was to prospectively investigate the prediction of fracture (Fx) by bone microarchitecture assessed by high-resolution peripheral computed tomography (HR- pQCT) in postmenopausal women. We measured microarchitecture at the distal radius and tibia with HR-pQCT in the OFELY study, in addition to areal BMD with dual-energy X-ray absorptiometry (DXA) in 589 women, mean ± SD age 68 ± 9 years. During a median [IQ] 9.4 [1.0] years of follow-up, 135 women sustained an incident fragility Fx, including 81 women with a major osteoporotic Fx (MOP Fx). After adjustment for age, women who sustained Fx had significantly lower total and trabecular volumetric densities (vBMD) at both sites, cortical parameters (area and thickness at the radius, vBMD at the tibia), trabecular number (Tb.N), connectivity density (Conn.D), stiffness, and estimated failure load at both sites, compared with control women. After adjustment for age, current smoking, falls, prior Fx, use of osteoporosis-related drugs, and total hip BMD, each quartile decrease of several baseline values of bone microarchitecture at the radius was associated with significant change of the risk of Fx (HR of 1.39 for Tb.BMD [p = 0.001], 1.32 for Tb.N [p = 0.01], 0.76 for Tb.Sp.SD [p = 0.01], 1.49 [p = 0.01] for Conn.D, and 1.27 for stiffness [p = 0.02]). At the tibia, the association remained significant for stiffness and failure load in the multivariate model for all fragility Fx and for Tt.BMD, stiffness, and failure load for MOP Fx. We conclude that impairment of bone microarchitecture—essentially in the trabecular compartment of the radius—predict the occurrence of incident fracture in postmenopausal women. This assessment may play an important role in identifying women at high risk of fracture who could not be adequately detected by BMD measurement alone, to benefit from a therapeutic intervention. © 2017 American Society for Bone and Mineral Research.

International audience; OBJECTIVE : The severity of rheumatoid arthritis (RA) correlates directly with bone erosions arising from osteoclast (OC) hyperactivity. Despite the fact that inflammation may be controlled in patients with RA, those in a state of sustained clinical remission or low disease activity may continue to accrue erosions, which supports the need for treatments that would be suitable for long-lasting inhibition of OC activity without altering the physiologic function of OCs in bone remodeling. Autotaxin (ATX) contributes to inflammation, but its role in bone erosion is unknown. METHODS : ATX was targeted by inhibitory treatment with pharmacologic drugs and also by conditional inactivation of the ATX gene Ennp2 in murine OCs (ΔATXC tsk ). Arthritic and erosive diseases were studied in human tumor necrosis factor-transgenic (hTNF+/- ) mice and mice with K/BxN serum transfer-induced arthritis. Systemic bone loss was also analyzed in mice with lipopolysaccharide (LPS)-induced inflammation and estrogen deprivation. Joint inflammation and bone erosion were assessed by histology and micro-computed tomography. The role of ATX in RA was also examined in OC differentiation and activity assays. RESULTS : OCs present at sites of inflammation overexpressed ATX. Pharmacologic inhibition of ATX in hTNF+/- mice, as compared to vehicle-treated controls, significantly mitigated focal bone erosion (36% decrease; P < 0.05) and systemic bone loss (43% decrease; P < 0.05), without affecting synovial inflammation. OC-derived ATX was revealed to be instrumental in OC bone resorptive activity and was up-regulated by the inflammation elicited in the presence of TNF or LPS. Specific loss of ATX in OCs from mice subjected to ovariectomy significantly protected against the systemic bone loss and erosion that had been induced with LPS and K/BxN serum treatments (30% reversal of systemic bone loss [P < 0.01]; 55% reversal of erosion [P < 0.001]), without conferring bone-protective properties. CONCLUSION : Our results identify ATX as a novel OC factor that specifically controls inflammation-induced bone erosions and systemic bone loss. Therefore, ATX inhibition offers a novel therapeutic approach for potentially preventing bone erosion in patients with RA.

Background:Excessive bone formation in the entheses is one of the features of peripheral spondyloarthritis. Biomechanical stress is proposed to occupy a central place in spondyloarthritis pathophysiology, but the precise molecular and cellular mechanisms underlying the pathological response of the enthesis are still largely unknown [1]. Besides, physical therapy and exercise are recommended as non-pharmacologic therapies for patients. We focused on the effect of exercising on enthesis ossification.Objectives:We aimed to develop and characterize an in vivo model in mice to study the impact of mechanical stimulation on the enthesis of the Achilles tendon.Methods:DBA/1 mice were subjected to voluntary running exercise by the use of activity wheels for two weeks, and compared to mice housed in standard conditions (n=17 per group). The running performances were recorded. mRNAs were extracted from the long bones (flushed tibia and femur) and the ankles’ entheses for real-time PCR analysis. µCT was performed on the femurs. Alkaline phosphatase activity was detected by histology on the anchorage of the Achilles tendon to the calcaneum, and by enzymatic assay in serum samples. Luminex analysis was also conducted on serum samples for Il-6 and Il-8/Kc detection.Results:Free access to the activity wheel resulted in a running exercise of 5.5±0.8 km/day (approximately 80 km in total) at 14.5±0.5 m/min. No effect was detected on the femur architecture by µCT. Sclerostin (Sost) gene expression was monitored as a mechanosensitive marker. Its expression was expectedly reduced by half in entheseal tissues, but no modulation was observed in long bones (Figure 1). Similarly, exercise-induced regulation of Osterix and Runx2 expressions was observed only in enthesis samples. This tissue-specific pattern was also verified for key genes of the sphingosine-1 phosphate metabolic pathway, which we recently implicated in spondyloarthritis pathophysiology [2]. The in situ staining of alkaline phosphatase activity suggested the presence of more positive cells in the anchorage of Achilles tendon of running mice, compared to control ones. However, alkaline phosphatase activity in serum samples and its gene expression in rough tissue extracts were unchanged. No inflammatory response was detected as Il-8/Kc serum levels were similar in the control and the exercising group (59±14 vs 57±14 pg/mL). In addition, Il-6 was not detected in the serum and its expression was very faint and constant in the tissue extracts.Conclusion:This work is still in progress for a more complete characterization of the model. We believe that this experimental design will be useful to study the role of mechanical stimulation specifically in the enthesis and that it can help to better understand the spondyloarthritis pathophysiology.References:[1]Cambré, et al. Nat Commun, 2018; [2] El Jamal, et al. J Bone Miner Res, 2019Figure 1.Expression level of the mechanosensitive gene Sclerostin (Sost). It dropped in response to exercise in entheseal tissues, but not in long bones, revealing a tissue-specific response to mechanical stimulation.Acknowledgements:Société Arthritis R&D (2020)Disclosure of Interests:None declared

Introduction L’outil d’evaluation du risque de fracture (FRAX®) identifie la probabilite de fractures (Fx) osteoporotiques majeures (MOF) et/ou de fractures de la hanche (HF) au cours des 10 annees suivantes, mais l’evolution de FRAX au cours du temps n’a pas encore ete evaluee. Materiels et methodes Nous avons collige les fractures par fragilite chez 579 femmes (âge moyen, 67 ± 11 ans) entre le 14e et le 20e suivi annuel de l’etude prospective OFELY et avons calcule l’evolution du score FRAX au cours de ces six annees. Nous avons regarde si cette evolution etait associee au risque ulterieur de fracture. Toutes les fractures de fragilite, confirmees radiologiquement, ont ete enregistrees prospectivement depuis l’inclusion dans l’etude jusqu’au 28e suivi annuel. Resultats Les probabilites FRAX etaient fortement correlees a 6 ans d’intervalle avec un coefficient de Spearman entre 0,90 et 0,97 pour MOF et HF avec et sans DMO. La variation des probabilites FRAX exprimees en difference absolue (mediane [IQR]) etait de 1,7 [0,5–3,5] pour MOF FRAX avec DMO, de 3,0 [0,6–6,4] pour MOF FRAX sans DMO, de 0,7 [0,1–1,9] pour HF FRAX avec DMO et de 1,7 [0,2–4,3] pour HF FRAX sans DMO. Les plus fortes augmentations de FRAX (p. ex., quartile superieur de la difference pour MOF sans DMO) etaient moderement associees a un âge plus avance avec un OR [IC a 95 %] de 1,24 [1,19–1,30] par an et a un IMC plus faible (OR de 0,93 [0,89–0,98] par unite), et fortement associees a la survenue de fracture depuis l’evaluation de FRAX 6 ans plus tot (OR de 21,9 [8,3–57,9]). Au cours d’un suivi median [IQR] de 7 ans (6,9–7,3), 104 femmes ont eu des fractures incidentes, dont 14 HF et 28 Fx vertebrales. A l’aide d’un modele de Cox, le quartile superieur de la difference absolue pour MOF FRAX sans DMO (6,9–28) etait associe a un risque accru de Fx avec un hazard ratio (IC a 95 %) de 2,0 (1,3–3,0), p = 0,001. Parmi 502 femmes situees en dessous du seuil d’intervention pour MOP FRAX avec DMO, seules 20 femmes (4 %) passaient au-dessus du seuil 6 ans plus tard. Conclusion Sur une periode de 6 ans, le FRAX evolue peu chez la plupart des femmes. La survenue d’une fracture est le principal facteur predictif de l’augmentation du score de FRAX. En l’absence de nouvelle fracture, recalculer le FRAX apres 6 ans ne changera pas la decision de traiter dans la plupart des cas.

La croissance post-natale est dependante des apports energetiques et des facteurs de croissance constituant l’axe somatotrope. Le microbiote intestinal, via sa production d’acides gras a courtes chaines, a recemment ete implique dans la regulation de la croissance chez les nouveau-nes. Chez l’adulte, les acides gras a courtes chaines ameliorent l’homeostasie energetique par induction de la neoglucogenese intestinale (NGI). Cette fonction presentant un pic d’induction 7 jours apres la naissance, nous avons teste si le pic neonatal de NGI pouvait affecter la croissance. Nous avons suivi le poids, la taille des tibias et dose l’expression genique et proteique du facteur de croissance Insuline-like-growth-factor-1 (IGF-1) et de son transporteur IGF-binding-protein-3 (IGFBP-3) chez des souris invalidees pour la NGI au 1er (I-G6pc−/−.P1) ou 12e jour post-natal (I-G6pc−/−.P12). A 8 jours, les souris I-G6pc−/−.P1 presentent une concentration plasmatique d’IGF1 et une expression hepatique d’Igf1 et d’Igfbp3 reduites de 40 % (p

In humans, the middle ear contains a chain of three ossicles with a major highly specific mechanical property (transmission of vibrations) and modeling that stops rapidly after birth. Their bone quality has been rarely studied either in noninflammatory ossicles or in those from ears with chronic inflammation. Our primary goal was to assess bone microarchitecture, morphology and variables reflecting bone quality from incuses, in comparison with those from human femoral cortical bone as controls. Secondly, the impact of chronic inflammation on quality of ossicles was documented. The study was performed on 15 noninflammatory incuses from 15 patients (35±32 years, range: 2-91). Comparisons were performed with 13 inflammatory incuses from 13 patients (55±20 years, range: 1-79) with chronic inflammation of the middle ear, essentially cholesteatoma. Microarchitecture and bone mineral density (BMD) were assessed by microcomputed tomography. Microhardness was measured by microindentation. Mineral and organic characteristics were investigated by Fourier transform infrared microspectroscopy. Noninflammatory incuses were composed of a compact, well mineralized bone without bone marrow and with sparse vessels. Remodeling activity was rarely observed. Woven or lamellar textures and numerous osteocytes were observed. In inflammatory incuses, architecture was degraded, organic tissue was abundant and bone cavities contained fibrocellular tissue and adipocytes. BMD of noninflammatory incuses was significantly higher than BMD from both control bones (4 embedded cortical femoral bone samples; age: 72±15 years, range: 50-85) and inflammatory incuses. Noninflammatory incuses were less hard than both control bone (8 cortical femoral bone samples; age: 49±18 years, range: 24-74) and inflammatory incuses. All incuses were more mineralized and less mature than controls. In conclusion, bone quality of incuses (dense, well mineralized, hard) is well adapted to their function of sound transmission. In inflammatory condition, incuses were degraded, thus explaining the decline of hearing. Moreover, microhardness was found higher than in noninflammatory incuses. Compared to bone with remodeling, the mineralization index in incuses does not explain variation of microhardness. Interestingly, a linear multiple regression model indicated that a combination of two variables, i.e., crystallinity index (crystal size/perfection) and carbonation (incorporation of carbonate ions in apatite) explains 26% of the increase in microhardness variability. Because the low remodeling level of ossicles could not prevent the reversibility of their degradation which impacts audition quality, an early management of ear inflammation in chronic otitis is recommended.

Background Lung adenocarcinoma regularly induces bone metastases that are responsible for impaired quality of life as well as significant morbidity, including bone pain and fractures. We aimed at identifying whether bone and metabolic biomarkers were associated with the prognosis of lung adenocarcinoma patients with synchronous bone metastases. Patients and methods POUMOS is a prospective cohort of patients diagnosed with lung adenocarcinoma and synchronous bone metastases. All patients underwent biopsy of bone metastases to confirm diagnosis, including genotyping of oncogenic drivers such as EGFR and KRAS . Whole-body composition was assessed using DEXA scan. Serum levels of C-reactive protein, HbA1C, calcaemia, sCTX, and DKK1 were also measured. Results Sixty four patients, aged (mean ± SD) 65 ± 11 years, were included. Thirty-nine (61%) patients had a good performance status (PS 0–1); 56% had >5 bone lesions, and 41% a weight-bearing bone (femour or tibia) involvement. Median overall survival was 7 months. In multivariate analysis, HbA1c (HR = 1.69 [1.10–2.63] per 0.5% decrease; p = .02), DKK1 (HR = 1.28 [1.01–1.61] per 10 ng/mL increase; p = .04), and hypercalcaemia (HR = 2.83 [1.10–7.30]; p = .03) were independently associated with poorer survival. In the subgroup of patients with DEXA, sarcopenia was also associated with poorer survival (HR = 2.96, 95%CI [1.40–6.27]; p = .005). Conclusions In patients with lung adenocarcinoma and synchronous bone metastases, bone, sarcopenia, and metabolic parameters were predictors of poor overall survival independently of common prognostic factors. We suggest that, in addition to oncological therapy, supportive treatment dedicated to bone metastases, muscle wasting, and energy metabolism are essential to improve prognosis.

Low bone mineral density (BMD) is a major determinant of fragility fractures (Fx), but its very long-term prediction is poorly documented.We analyzed the risk of Fx beyond 10 years in women.In a longitudinal cohort study (Os des Femmes de Lyon), we studied 867 women aged 40 years and older (mean age 59 ± 10 y) over 20 years.We assessed the risk of the first incident Fx according to the baseline BMD obtained by dual-energy X-ray absorptiometry, clinical risk factors, and the Fracture Risk Assessment Tool (FRAX).During a median (interquartile range) follow-up of 20 years (3), 245 women sustained one or more incident fragility Fx. Women who sustained a first Fx beyond 10 years (Fx 10-20, n = 109) were younger and had lower values of FRAX compared with those in the first 10 years (Fx 0-10, n = 136). After adjustment for age, they still had greater grip strength and BMD. Parental hip Fx was associated with an increased risk of Fx 10-20 but contrasting with Fx 0-10, the risk of Fx 10-20 was not associated with age, previous Fx, and FRAX except in women younger than 70 years. Each SD decrease of BMD at the spine, femoral neck, total hip, and ultradistal radius was associated with an increased risk of Fx 10-20 with adjusted odds ratios [95% confidence interval (CI)] of 1.43 (95% CI 1.12-1.82), 1.39 (95% CI 1.08-1.82), 1.47 (95% CI 1.14-1.89), and 2.00 (95% CI 1.47-2.7). Women with osteoporosis had an increased risk of both Fx 0-10 and Fx 10-20 compared with women with normal BMD, whereas osteopenia was not associated with a higher risk of Fx beyond 10 years.Low BMD in women is significantly associated with an increased risk of Fx over 20 years. Beyond 10 years, the prediction conferred by baseline BMD was better than that from clinical risk factors.

Clinical cone beam computed tomography (CBCT) was compared to high-resolution peripheral quantitative computed tomography (HR-pQCT) for the assessment of ex vivo radii. Strong correlations were found for geometry, volumetric density, and trabecular structure. Using CBCT, bone architecture assessment was feasible but compared to HR-pQCT, trabecular parameters were overestimated whereas cortical ones were underestimated. HR-pQCT is the most widely used technique to assess bone microarchitecture in vivo. Yet, this technology has been only applicable at peripheral sites, in only few research centers. Clinical CBCT is more widely available but quantitative assessment of the bone structure is usually not performed. We aimed to compare the assessment of bone structure with CBCT (NewTom 5G, QR, Verona, Italy) and HR-pQCT (XtremeCT, Scanco Medical AG, Bruttisellen, Switzerland). Twenty-four distal radius specimens were scanned with these two devices with a reconstructed voxel size of 75 μm for Newtom 5G and 82 μm for XtremeCT, respectively. A rescaling-registration scheme was used to define the common volume of interest. Cortical and trabecular compartments were separated using a semiautomated double contouring method. Density and microstructure were assessed with the HR-pQCT software on both modality images. Strong correlations were found for geometry parameters (r = 0.98–0.99), volumetric density (r = 0.91–0.99), and trabecular structure (r = 0.94–0.99), all p

Several cross-sectional studies have shown that impairment of bone microarchitecture contributes to skeletal fragility. The aim of this study was to prospectively investigate the prediction of fracture (Fx) by bone microarchitecture assessed by high-resolution peripheral computed tomography (HR- pQCT) in postmenopausal women. We measured microarchitecture at the distal radius and tibia with HR-pQCT in the OFELY study, in addition to areal BMD with dual-energy X-ray absorptiometry (DXA) in 589 women, mean ± SD age 68 ± 9 years. During a median [IQ] 9.4 [1.0] years of follow-up, 135 women sustained an incident fragility Fx, including 81 women with a major osteoporotic Fx (MOP Fx). After adjustment for age, women who sustained Fx had significantly lower total and trabecular volumetric densities (vBMD) at both sites, cortical parameters (area and thickness at the radius, vBMD at the tibia), trabecular number (Tb.N), connectivity density (Conn.D), stiffness, and estimated failure load at both sites, compared with control women. After adjustment for age, current smoking, falls, prior Fx, use of osteoporosis-related drugs, and total hip BMD, each quartile decrease of several baseline values of bone microarchitecture at the radius was associated with significant change of the risk of Fx (HR of 1.39 for Tb.BMD [p = 0.001], 1.32 for Tb.N [p = 0.01], 0.76 for Tb.Sp.SD [p = 0.01], 1.49 [p = 0.01] for Conn.D, and 1.27 for stiffness [p = 0.02]). At the tibia, the association remained significant for stiffness and failure load in the multivariate model for all fragility Fx and for Tt.BMD, stiffness, and failure load for MOP Fx. We conclude that impairment of bone microarchitecture-essentially in the trabecular compartment of the radius-predict the occurrence of incident fracture in postmenopausal women. This assessment may play an important role in identifying women at high risk of fracture who could not be adequately detected by BMD measurement alone, to benefit from a therapeutic intervention. © 2017 American Society for Bone and Mineral Research.

The relationships between body composition and bone mineral density are well established but the contribution of body composition to the risk of fracture (Fx) has rarely been evaluated prospectively. We analyzed the risk of Fx by body composition in 595 postmenopausal women (mean age 66±8years) from a longitudinal cohort study (Os des Femmes de Lyon). We assessed the risk of the first incident fragility Fx according to body composition obtained from whole-body DXA: abdominal visceral (VFAT) and subcutaneous fat mass (SFAT), total body fat mass (FM), lean mass index (LMI) and appendicular skeletal muscle mass index (ASMI). During a median [IQ] follow-up of 13.1years [1.9], 138 women sustained a first incident Fx, including 85 women with a major osteoporotic Fx (MOP Fx: hip, clinical spine, humerus or wrist). After adjustment for age, women who sustained Fx had lower BMI (-4%, p=0.01), LMI (-6%, p=0.002) and ASMI (-3%, p=0.003), compared with women without Fx. After adjustment for age, prevalent Fx, physical activity, incident falls and FN BMD, each SD increase of baseline values of LMI and ASMI was associated with decreased Fx risk with adjusted hazard ratios of 0.76 for both of p≤0.02. Those associations were similar after accounting for the competing risk of death. VFAT and SFAT were associated with Fx risk in the multivariate model only for MOP Fx and the association did not persist after consideration of competing mortality. We conclude that lean mass and appendicular muscle mass indexes are associated with the risk of fracture in postmenopausal women independently of BMD and clinical risk factors.

Data on age-related differences in fat mass and distribution in men are scarce. We performed a cross-sectional analysis of age-related differences in fat distribution in men. In a cohort of 1133 men aged 20–87 yr, body composition was assessed using a Hologic Discovery A device. We assessed fat mass (FM) and FM indices adjusted for height. Interindividual variability was calculated as standard deviation, interquartile range, and difference between the 95th and 5th percentiles in 5-yr age groups. After adjustment for lifestyle factors, the FM and FM index of appendicular, gynoid, central, android, and subcutaneous abdominal compartments increased with age. Their variability did not vary with age. Visceral FM was 181% higher in men aged >80 yr compared to men aged 20–30 yr, and the variability increased with age. FM in the central, android, subcutaneous abdominal, and visceral compartments correlated with age significantly more strongly before the age of 70 than after this age. The relative differences between the elderly and younger men were greater for visceral FM than for subcutaneous (abdominal and appendicular) fat. The interindividual variability in visceral FM is higher in elderly men. The association between visceral FM and age is stronger before the age of 70.

Eighty one women with vertebral osteoporosis were treated for up to 2 years with fluoride administered either as monofluorophosphate (MFP, 200 mg/day, i.e., 26.4 mg fluoride-ion) or sodium fluoride (NaF, 50 mg/day, i.e., 22.6 mg fluoride-ion). All patients received calcium supplementation (1 g of Ca2+/day) taken apart from NaF and in the same tablet for MFP. Despite almost similar fluoride dosage of both regimens, the early increase in the bone mineral density (BMD) of the lumbar spine was higher with MFP than with NaF, reaching 11% and 4%, respectively, at 1 year (p = 0.007), and 21% and 6%, respectively, at 18 months (p less than 0.001). The incidence of lower extremity pain syndrome related to benign stress microfractures was also higher with MFP than with NaF (35% and 15%, respectively, p less than 0.01). Urinary fluoride levels were higher in the MFP than in the NaF group (9.6 +/- 3.5 vs. 6.8 +/- 3.4 at one year, p = 0.003), suggesting that this difference in efficacy and tolerance is related to a better bioavailability of fluoride provided by MFP than by NaF. The occurrence of a stress microfracture could not be predicted by any clinical, biochemical, or densitometric parameter before treatment, but patients presenting with a stress microfracture during the course of the treatment had a higher gain in bone mass than those without stress fractures (at 1 yr+11 vs. +5%, p = 0.03 and at 18 months +18 vs. +6.9%, p less than 0.02). In conclusion, there is a clear correlation between the efficacy and the occurrence of side effects of fluoride therapy in osteoporosis.(ABSTRACT TRUNCATED AT 250 WORDS)

We previously showed that circulating undercarboxylated osteocalcin (ucOC) is elevated in elderly women and is a powerful marker of the subsequent risk of hip fracture in elderly institutionalized women (J Clin Invest 1993; 91:1769). To investigate the relationship between bone mass and ucOC, we measured bone mineral density (BMD) of the hip with dual-energy x-ray absorptiometry in 98 elderly institutionalized women, 81.4 +/- 6.0 years old. ucOC was negatively correlated with BMD at all sites (r = -0.26 to -0.38, p0.001 to p0.0001), even after exclusion of the effect of age by partial correlation (for the femoral neck, r = -0.26, p0.01) and after controlling for serum parathyroid hormone. BMD was significantly lower at all sites of measurement in women with elevated ucOC (1.65 ng/ml, upper limit of the normal range in young women) than in those with normal ucOC (for the neck, 0.58 +/- 0.13 versus 0.43 +/- 0.13 g/cm2, p0.001). Similar results were obtained for ucOC expressed as the fraction of total OC (ucOC%). Multiple regression showed that ucOC has the highest predictive value for BMD when including age and body weight in the equation. In summary, our data indicate that serum ucOC is an independent determinant of BMD of the hip in elderly women. The mechanism by which serum ucOC is related to bone mass is unclear and should be addressed in further studies. However, our data suggest that ucOC level may be an interesting marker in the investigation of bone status in the elderly.

We measured the heels of 43 women who had recently sustained a hip fracture and 86 age matched controls, using an Achilles ultrasound device. Average BUA, SOS, and Stiffness were significantly lower in fractured patients (p < 0.0001). We also estimated ultrasound parameters for patients as a function of controls and found the mean BUA to be -1.09 SD compared with controls, the mean SOS -0.89 SD, and the mean Stiffness -0.98 SD. Femoral BMD measured at the neck, Ward's triangle, and the trochanter with a DPX Plus was also significantly lower in fractured patients (p < 0.0001). The increased risk of hip fracture associated with low ultrasound values was estimated with logistic regression analysis for each bone parameter, adjusted for height and weight. The adjusted regression coefficients associated with BUA, SOS, Stiffness, and BMD were all significant (p < 0.0001) demonstrating the influence of all ultrasound and DXA parameters on the risk of hip fracture. After adjusting the logistic regressions for BMD neck, BUA, SOS, and Stiffness were still significant independent predictors of hip fracture. Sensitivity and specificity of all measures were analyzed with the area under the ROC curve which were for BUA, 0.77 +/- 0.04; for SOS, 0.75 +/- 0.04; for Stiffness, 0.78 +/- 0.04; and for BMD, 0.74 +/- 0.04. We determined the range for the best compromise between sensitivity and specificity of BUA, 97-98 dB/MHz; SOS, 1482-1487 m/s; Stiffness 59-62% Young Adult; and of BMD, 0.64-0.69 g/cm2. The area under the ROC curves of BUA, SOS, Stiffness, and DXA were compared and no statistically significant difference was found.(ABSTRACT TRUNCATED AT 250 WORDS)

We describe a quasistatic method for mechanical characterization of tissue-mimicking material used in elastography. We demonstrate that it is possible to assess the elasticity modulus with a reasonable reproducibility using simple and easy tools and methods. Possessing a simple relevant technique with evaluated relative error to assess Young's modulus of these phantoms could deeply improve the quality of the research in the field of elastography. The method was tested and validated with four samples of polyvinyl alcohol (PVA) cryogel with different elasticity values corresponding to those of stiffer soft biological tissues. Young's moduli, varying from 70 to 180 kPa depending on the number of freeze-thaw cycles (two to five), were measured within strict measurement conditions and found to have a reproducibility varying from 4% to 8%. Relative error, estimated as the ratio between observed and reference values, varied from 16% to 32%. Besides, measurement stability over 4 months was evaluated. The method demonstrated good feasibility and acceptable reproducibility for mechanically characterizing and controlled over time phantoms used for validating new potential ultrasound imaging techniques in the field of elastography. Nevertheless, in this study, investigation was performed on gel possessing young's modulus values ranging from 80 to 215 kPa. Some tissue values of Young'modulus were reported to be lower, ranging from 0.6 to 28 kPa as liver or glandular values. Consequently, further validation of this static method for mechanical characterization of phantom gels should be performed using softer PVA cryogel.

The increase in bone fragility after menopause results from reduced periosteal bone formation and increased endocortical resorption. Women with highest remodeling had greatest loss of bone mass and estimated bone strength, whereas those with low remodeling lost less bone and maintained estimated bone strength. Introduction: Bone loss from the inner (endocortical) surface contributes to bone fragility, whereas deposition of bone on the outer (periosteal) surface is believed to be an adaptive response to maintain resistance to bending. Materials and Methods: To test this hypothesis, changes in bone mass and estimated indices of bone geometry and strength of the one-third distal radius, bone turnover markers, and fracture incidence were measured annually in 821 women 30–89 years of age for 7.1 ± 2.5 years. The analyses were made in 151 premenopausal women, 33 perimenopausal women, 279 postmenopausal women, and 72 postmenopausal women receiving hormone replacement therapy (HRT). Results: In premenopausal women, periosteal apposition increased the radius width, partly offsetting endocortical resorption; therefore, the estimated cortical thickness decreased. Outward displacement of the thinner cortex maintained bone mass and cortical area and increased estimated bending strength. Estimated endocortical resorption accelerated during perimenopause, whereas periosteal apposition decreased. Further cortical thinning occurred, but estimated bending strength was maintained by modest outward cortical displacement. Endocortical resorption accelerated further during the postmenopausal years, whereas periosteal apposition declined further; cortices thinned, but because outward displacement was minimal, estimated cortical area and bending strength now decreased. Women with highest remodeling had the greatest loss of bone mass and strength. Women with low remodeling lost less bone and maintained estimated bone strength. In HRT-treated women, loss of bone strength was partly prevented. These structural indices predicted incident fractures; a 1 SD lower section modulus doubled fracture risk. Conclusions: Periosteal apposition does not increase after menopause to compensate for bone loss; it decreases. Bone fragility of osteoporosis is a consequence of reduced periosteal bone formation and increased endocortical resorption. Understanding the mechanisms of the age-related decline in periosteal apposition will identify new therapeutic targets. On the basis of our results, it may be speculated that the stimulation of periosteal apposition will increase bone width and improve skeletal strength.

The risk of fragility fractures in elderly men is only partly explained by areal bone mineral density (aBMD) measured by dual X-ray absorptiometry (DXA). Several studies suggest the importance of bone morphology for the risk of fracture. The aim of this study was to assess the value of bone size and estimated structural parameters for the prediction of incident fractures in a large cohort of men. This study was made in 759 men aged 50-85 from the MINOS cohort. During a 90-month follow-up, 74 men sustained incident vertebral and peripheral fractures. Areal BMD was measured by DXA at femoral neck, distal radius and distal ulna. Estimates of structural bone parameters and volumetric BMD (vBMD) were derived from aBMD measured by DXA. Given the limited number of fractures, the predictive value of investigated parameters was assessed for peripheral and vertebral fractures jointly by using logistic regression. Men who sustained the fractures had, at baseline, lower aBMD (3.5-6.5%), lower bone mineral content (BMC 5.4-8.7%) and lower cortical thickness (3.5-6.9%) compared with the men without fracture. At all the three skeletal sites, aBMD, BMC, width, cortical area and thickness, cross-sectional moment of inertia (CSMI), and section modulus predicted incident fractures (O.R. = 1.28-1.92 per 1 SD decrease, P0.05-0.0001). Fracture risk was weakly associated with vBMD for ulna (O.R. = 1.25 per 1 SD decrease, P0.05) but not for femoral neck or radius. After adjustment for aBMD, bone width remained a significant predictor of fractures (O.R. = 1.37-1.48 per 1 SD decrease, P0.02-0.01). Men with osteopenia (BMD T score-1) and low bone width (T score-1) had the fracture incidence similar to that observed in men with BMD T score-2. Bone width and aBMD of the femoral neck and radius were predictive of fractures in 49 men with the incident peripheral fractures, whereas their O.R. did not attain the level of statistical significance in 25 men with the incident vertebral fractures. Men, who had both low aBMD and low CSMI ( both T scores-1), had the fracture risk 3.8 to 4.2 higher than the reference group (both T scoresor= -1). Men, who had both low aBMD and low section modulus (both T scores-1), had the fracture risk 2.1 to 4.1 higher than the reference group (both T scoresor= -1). In conclusion, men who sustained a fragility fracture during a 90-month follow-up had, at baseline, lower BMC because they had narrower bones but not necessarily less dense. In elderly men, small bone width, low BMC and poor resistance to bending may increase bone fragility. Low bone width seems to be associated with an increased fracture risk in elderly men regardless of aBMD.

Mechanical behavior of bone depends on its mass and architecture, and on the material properties of the matrix, which is composed of a mineral phase and an organic component mainly constituted of type I collagen. Mineral accounts largely for the stiffness of bone, whereas type I collagen provides bone its ductility and toughness, i.e., its ability to undergo deformation and absorb energy after it begins to yield. The molecular mechanisms underlying the effect of alterations in type I collagen on bone mechanical properties are unclear. We used an in vitro model of fetal bovine cortical bone specimens (n = 44), where the extent of type I collagen cross-linking was modified by incubation at 37 degrees C for 0, 60, 90 and 120 days, keeping constant the architecture and the mineral content. At each incubation time, the following parameters were determined: (1) the bone concentration of enzymatic (pyridinoline; PYD and deoxypyridinoline, DPD) and non-enzymatic (pentosidine) crosslinks by HPLC, (2) the extent of aspartic acid isomerization of the type I collagen C-telopeptide (CTX) by ELISA of native (alpha CTX) and isomerized (beta CTX) forms, (3) the mineral density by DXA, (4) the porosity by micro-computed tomography and (5) the bending and compressive mechanical properties. Incubation of bone specimens at 37 degrees C for 60 days increased the level (per molecule of collagen) of PYD (+98%, P = 0.005), DPD (+42%, P = 0.013), pentosidine (+55-fold, P = 0.005), and the degree of type I collagen C-telopeptide isomerization (+4.9-fold, P = 0.005). These biochemical changes of collagen were associated with a 30% decrease in bending and compressive yield stress and a 2.5-fold increase in compressive post-yield energy absorption (P0.02 for all), with no significant change of bone stiffness. In multivariate analyses, the level of collagen cross-linking was associated with yield stress and post-yield energy absorption independently of bone mineral density, explaining up to 25% of their variance. We conclude that the extent and nature of collagen cross-linking contribute to the mechanical properties of fetal bovine cortical bone independently of bone mineral density.

The International Society for Clinical Densitometry (ISCD) has developed Official Positions to assist healthcare providers in addressing some of the issues inherent with the use of bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA) to diagnose osteoporosis, apply World Health Organization (WHO) T-score classifications, and monitor BMD changes over time. Differences exist, however, between the ISCD Official Position statement and that of the International Osteoporosis Foundation with respect to WHO criteria for skeletal sites. Consequently, a subcommittee of the ISCD was directed to address the application of the WHO classifications to specific skeletal sites and regions of interest. In 2005, the ISCD Position Development Conference reviewed the findings and prepared Official Positions, which address whether or not: (1) the lowest T-score of the total proximal femur, femoral neck, trochanter, and spine should continue to be used for diagnosis; (2) the WHO classification may be applied to a single vertebral body T-score; and (3) the ISCD should endorse the use of the National Health and Nutrition Examination Survey database for proximal femur T-score derivation. The resulting ISCD Official Positions, with their corresponding rationales and evidence are provided here, as well as questions that will need to be addressed in the future.

Rationale Hip fractures can be separated into cervical and trochanteric fractures. Trochanteric fractures have been associated with up to twice the short-term mortality of cervical fractures in the elderly. There is also evidence suggesting that the mechanisms are different. Evidence from the literature remains limited on the predictive power of bone mineral density (BMD) and quantitative ultrasounds (QUS) for both types of hip fractures. Methods 5703 elderly women aged 75 years or more, who were recruited from the voting lists in the EPIDOS study, and had baseline calcaneal ultrasounds (QUS) and DXA measurements at the hip and the whole body, were analyzed in this paper. Among those, 192 hip fractures occurred during an average follow-up of 4 years, 108 cervical and 84 trochanteric fractures. Results Femoral neck, trochanteric and whole body BMD were able to predict trochanteric hip fracture (RR’s and 95% CI were, respectively, 3.2 (2.4–4.2); 4.8 (3.5–6.6); and 2.8 (2.2–3.6)) more accurately than cervical fractures (respectively, 2.1 (1.7–2.7); 2.3 (1.8–3.0); 1.2 (1.0–1.6)). All ultrasound parameters, SOS, BUA, and stiffness index (SI) were significant predictors of trochanteric (RR’s respectively 3.0 (2.2–4.1), 2.5(2.0–3.1), and 3.5(2.6–4.7)) but not cervical fractures. After adjustment for femoral neck or trochanteric BMD ultrasound parameters were still significant predictors of trochanteric fracture, and stiffness tended to be a better predictor of trochanteric fractures than either BUA or SOS with a relative risk of 2.25 (1.6–3.1). Conclusions A significant decrease of all bone measurements, BMD and QUS, was highly predictive of trochanteric fractures, whereas a decrease of femoral neck and trochanteric BMD were only associated with a slight increase in cervical fracture risk and a low total body BMD or QUS parameters were not significant predictors of cervical fractures. In women who sustained a hip fracture, the decrease of BMD and QUS values increases the risk of trochanteric fracture as compared to cervical fracture. Trochanteric fractures were mostly a consequence of a generalized low BMD and QUS, whereas other parameters might be involved in cervical fractures.

Diagnosis of vertebral fracture is critical for management of osteoporosis, as existence of such deformities substantially increases the risk of subsequent fracture. Thus, accurate and precise techniques allowing detection of such deformities are essential to clinicians. So far, this detection has been performed by spinal lateral X-rays. More advanced techniques have recently been developed, based on dual energy X-ray absorptiometry (DXA). This review describes these different techniques and discusses the effectiveness of the DXA technique to assess vertebral deformities compared to X-ray. The use of DXA detection of vertebral fracture for clinical practice and clinical trials is discussed. Specifically, vertebral morphometry using DXA provides an excellent specificity, with moderate sensitivity. The major limitation of the DXA vertebral assessment is the poor quality of images of thoracic vertebrae. The clinical utility of vertebral morphometry using densitometry may help screening patients with vertebral fracture, but technological improvements are necessary to improve image quality.

Osteoporosis in men is becoming a public health problem in developed countries. Fracture incidence increases with age, and the number of fractures increases because of the ageing of the population. We assessed the predictive value of bone mineral density (BMD) for osteoporotic fractures evaluated prospectively in a large cohort of elderly men and assessed the sensitivity of the T-score =−2 to detect men who will sustain a fracture. Fracture incidence was evaluated for 90 months in 759 men from the MINOS cohort aged 50 and over at baseline. In 74 men, 77 incident vertebral and peripheral fractures occurred. BMD was measured at baseline at the lumbar spine, hip, whole body and distal forearm. The incidence of osteoporotic fractures increased with age and with decreasing body weight. In men with low BMD (T-score

Structural failure becomes increasingly likely as the load on bone approximates or exceeds the bone’s ability to withstand it. The vertebral fracture risk index (FRI) expresses the risk for structural failure as a ratio of compressive stress (load per unit area) to estimated failure stress, and so should be a more sensitive and specific predictor of vertebral fracture than spine areal BMD (aBMD) or volumetric BMD (vBMD), surrogates of bone strength alone. To address this issue, we analyzed the results of a case-control study of 89 postmenopausal women with vertebral fractures and 306 controls in Melbourne, Australia, and a 10-year community-based prospective study in which 30 postmenopausal women who had incident vertebral fractures were compared with 150 controls in Lyon, France. The FRI and vBMD of the third lumbar vertebral body and spine aBMD were derived using dual X-ray absorptiometry. In the cross-sectional analysis, each SD increase in FRI was associated with 2.1-fold (95% confidence interval [CI], 1.55–2.73) increased vertebral fracture risk, while each SD decrease in aBMD or vBMD was associated with 4.0-fold (95% CI, 2.69–6.18 and 2.65–6.94, respectively) increase in risk. Using receiver operating characteristic (ROC) analysis, the FRI was less sensitive and specific than aBMD in discriminating cases and controls (area under ROC, 0.76 vs 0.84, p

Hip fracture is the most disastrous osteoporotic fracture, characterized by high mortality, morbidity and institutionalization for the patient and by high economic costs for the health care system. The morphology of the upper part of the femur can influence the risk of hip fracture, e.g., a longer femoral neck is associated with a higher risk of cervical fractures, but not trochanteric ones. In this study, we evaluated the prediction of hip fracture risk by morphological parameters estimated from DXA measurements, and we compared their predictive value for cervical and trochanteric fractures in elderly women by reanalyzing previously published data (Duboeuf et al. J Bone Miner Res 1997 12 1895). This nested case-control study was performed in 232 elderly community-dwelling women from the EPIDOS cohort, including 65 women who sustained a hip fracture. After adjustment for confounding variables, women who sustained a cervical fracture had lower areal bone mineral density (aBMD), lower cortical thickness and a higher average buckling ratio (P0.005 for all) as well as longer femoral neck (P0.01) than controls. Women who sustained a trochanteric fracture had lower aBMD, lower cortical thickness and higher buckling ratio than controls (P0.0001) and than women who sustained a cervical fracture (P0.05). Their bending resistance (cross-sectional moment of inertia-CSMI, section modulus) was significantly lower in comparison with controls (P0.05-0.001). A decrease in aBMD, cortical thickness, CSMI and section modulus as well as an increase in buckling ratio were predictive of all hip fractures (OR -1.42-2.46 per 1 SD, P0.05-0.0001), but the ORs for all structural parameters were markedly higher for trochanteric than for cervical fractures. CSMI and section modulus were predictive of trochanteric, but not cervical fractures. However, aBMD was strongly correlated with the CSA, cortical thickness and buckling ratio (r20.74), which suggests that they convey the same information. CSMI and section modulus correlated with aBMD more weakly, but their OR lost statistical significance after adjustment for aBMD. In conclusion, low femoral neck aBMD, CSA and cortical thickness as well as a high buckling ratio are associated with the higher risk of hip fracture, especially trochanteric ones. These indices are highly correlated with aBMD and convey the same message. The calculated CSMI and section modulus predict trochanteric fractures, but not cervical fractures, and their statistical significance is lost after adjustment for aBMD, indicating that they reflect mainly aBMD, not mechanical properties. Thus, the independent contribution of the external diameter of the femoral neck to the risk of hip fracture cannot be reliably estimated by this technique.

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 beta-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, P0.0001). 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, P0.005-0.0001). Men in the highest quartile of bone resorption markers had lower aBMD (3.8-10.2%, P0.05-0.0001), lower vBMD (3.9-13.0%, P0.05-0.0001), and lower cortical thickness (1.5-9.6%, P0.05-0.0001) 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%, P0.05-0.0001), lower vBMD (4.2-16.3, P0.05-0.0001) and lower cortical thickness (4.0-7.4%, P0.05-0.0001) 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.

Background: Aging-related sarcopenia is characterized by a loss of muscle mass and strength and increased fatigability. However, studies of its determinants in elderly men are scarce. Objective: We investigated risk factors for sarcopenia in a large cohort of men. Design: We analyzed 845 men aged 45– 85 y who belonged to the MINOS cohort. Lifestyle factors (physical activity, tobacco smoking, alcohol intake, caffeine intake) were evaluated by using a standardized questionnaire. Appendicular skeletal muscle mass (ASM) was estimated by using dual-energy X-ray absorptiometry. The relative appendicular skeletal muscle mass index (RASM) was calculated as ASM/body height 2.3 . Apparent free testosterone concentration (AFTC) and free testosterone index (FTI) were calculated on the basis of concentrations of total testosterone and sex hormone– binding globulin. Results: RASM decreased with age (r 0.29, P 0.0001). Current smokers had lower RASM than did subjects who never smoked (3.2%; P 0.003). RASM increased with the intensity of physical activity at work (P for trend 0.001). Men who participated in regular exercise during leisure time had 2.2% higher RASM than did those who did not (P 0.03). Men whose values for AFTC, FTI, or 25-hydroxycholecalciferol [25(OH)D] were 2 SDs below the mean for young men had significantly lower RASM than did men with higher values. Men with sarcopenia, defined as the lowest quartile of RASM in the studied cohort (6.32 kg/m 2.3 ), were significantly older than men with normal RASM, weighed significantly less, smoked more, and spent significantly less time on leisure-time activities. Sarcopenic men also had lower values for testosterone, AFTC, FTI, and 25(OH)D. Conclusion: In elderly men, low physical activity, tobacco smoking, thinness, low testosterone (AFTC and FTI), and decreased 25(OH)D concentrations are risk factors for sarcopenia. Am J Clin Nutr 2004;80:496 –503.

While the potential of quantitative ultrasound (QUS) in the management of osteoporosis has been accepted, its interaction with follow-up time has never been investigated. The aim of our study is to prospectively evaluate the influence of follow-up time on the prediction of hip fracture by ultrasound parameters in the elderly as compared to bone mineral density (BMD) and to establish a long-term fracture prediction model. In the multicenter prospective study EPIDOS, 5898 Caucasian healthy women, aged 75 and over, had femoral dual-energy X-ray absorptiometry (DXA) and heel ultrasound measurements at baseline. A survey of fracture occurrence was conducted every 4 months. Statistical analyses were performed for three different average lengths of follow-up, namely, 1.5, 2.5 and 3.5 years. Relative risks per standard deviation decrease (RR) and the area under the receiver operating characteristic (AUC) curves were given. Estimates of the long-term hip fracture prediction by DXA and QUS were extrapolated. During an average of 3.5 years follow-up, 227 women sustained their first non-traumatic hip fracture. For the three categories of follow-up, low values of both calcaneal ultrasound and hip BMD were associated with a significant increased risk of hip fracture [e.g. ultrasound Stiffness index RR = 2.8 (2.1-3.8), 2.1 (1.7-2.6) and 1.9 (1.7-2.3) for 1.5, 2.5 and 3.5 years of follow-up, respectively]. The combination of femoral neck BMD with the Stiffness showed an improvement of the hip fracture prediction model. Using extrapolation, the prediction of hip fracture by the Stiffness remained significant up to 7.5 years [RR = 1.2 (1.03-1.41)], whereas the limit of significance was reached at 10 years for the femoral neck BMD [RR = 1.25 (1.04-1.52)]. Our results indicate that the Stiffness tends to be the best short- and long-term predictor of hip fracture among ultrasound parameters. This paper provides additional information on the long-term prediction of hip fracture, which has always been an important issue in routine clinical practice as it influences the management of the disease. Our model should give a relatively good estimation of the fracture risk prediction at 5 years with the ultrasound and 10 years for the femoral neck BMD.

The purpose of this longitudinal in-field study was to evaluate the influence of exercise, age, and gender on superficial cortical bone of the third metacarpal bone (MC III) in young Thoroughbreds by measuring speed of sound (SOS) values with an axial transmission technique (Omnisense, Sunlight Ltd, Israel). Both MC III of 75 racehorses, 2 to 4 years old, were monitored with SOS measurements in 5- to 7-week intervals during a 9- month physical exercise period. Medical data and training programs (slow gallop, canter, and high-speed work) of each horse were recorded. SOS measurements began before 2-year-old horses started high-speed training. SOS values of the dorsal aspect of MC III were significantly lower in comparison with values obtained at the lateral and the medial aspect of MC III, and SOS values were inversely correlated with measurement cycles. Significant limb-associated differences in dorsal MC III SOS values were observed at measurement cycles 2, 3, and 4. SOS values obtained at the lateral and medial aspect of MC III increased with age. SOS values obtained at the dorsal aspect of MC III, decreased with age. Mares had significantly higher SOS values at the dorsal aspect of MC III, when compared with corresponding values in stallions. In 2-year-old Thoroughbreds SOS values of the dorsal MC III were significantly different between cycles 1 and 2, between cycles 3 and 4, and between cycles 4 and 5. Three-year-old horses showed significant differences between SOS values of the dorsal MC III obtained at cycles 3 and 4. Training intensities did not significantly influence SOS values. The results indicate that young exercising Thoroughbred racehorses have age-, gender-, and measurement-cycle-dependent variations in SOS values of MC III, which probably reflect adaptive variations in superficial cortical bone properties of MC III.

The beneficial effects of hormone replacement therapy (HRT) on bone mineral density (BMD) and bone turnover are well documented but whether HRT withdrawal is followed by an accelerated rate of bone loss is still controversial. We analyzed 26 women who have withdrawn HRT during a 6-year follow-up of the OFELY cohort. They were compared with three groups of women from the same cohort: one hundred four healthy postmenopausal women who continued HRT during the 6-year follow-up, 78 untreated postmenopausal women matched for age, and 31 untreated women within 5 years of menopause. Bone markers [serum osteocalcin (Intact OC), bone alkaline phosphatase (Bone ALP), and serum CTX] were performed annually during 4 years and bone mineral density (BMD) was measured at the forearm (DXA) during 6 years. Withdrawal of HRT was followed by a significant bone loss with an annual rate ranged from -0.7 to -1.6% at the radius according to the skeletal site and by a marked increase of bone markers after 6 months: +36 % for osteocalcin, +23% for bone alkaline phosphatase, and +120% for serum CTX (P < 0.05 to P < 0.001). In contrast, in the HRT continuing group, there was no bone loss and no substantial change of bone markers over 4 years. The rate of bone loss after withdrawal of HRT was significantly greater than in postmenopausal women matched for age who never received HRT (2.2 to 2.8 times higher according to the radius area) and not different as compared to the accelerated bone loss observed in untreated women within 5 years of menopause. We conclude that in postmenopausal women who have been on HRT for 6 years, cessation of treatment results in a rapid increase of bone turnover and a rate of bone loss similar to early postmenopausal women during the subsequent 4 years and greater than untreated women of the same age.

The purpose of this ex vivo study was to analyse two commonly established methods of mechanical bone property assessment for application in horses: Quantitative ultrasound (QUS), which depends on the bone's density and Young's modulus, and dual energy X-ray absorptiometry (DXA), which depends on the areal bone mineral density (BMD). The third metacarpal bone (MC III) of horses was selected as examination region for practical reasons. An interrelationship between QUS- and DXA-values was examined. Both MC III of eleven randomly selected equine cadavers were divided in nine regions of interest (ROI). A multi-site QUS device was used for axial transmission speed of sound (SOS) measurements and a DXA device was used for BMD evaluation. Full cortical thickness BMD (FcBMD), overall aspect BMD and 4 mm cortical border slice BMD (4 mmBMD) were evaluated. In addition, each ROI of one MC III was measured 10 times to determine QUS- and DXA-measurement precision. SOS values and BMD values obtained at different aspects of MC III were different (P < 0.001). FcBMD and overall BMD obtained at different levels were different (P < 0.001). SOS data correlated with FcBMD-, overall BMD- and 4 mmBMD-data at various ROI. FcBMD-, overall BMD- and 4 mmBMD-data were strongly correlated. The intra-operator coefficient of variation was 1.3% for SOS-measurements and ranged between 1.94 and 10.3% for BMD-measurements. Multi-site axial transmission QUS as well as DXA can be used to precisely measure bone characteristics of MC III in horses. However, both techniques do not measure the same bone properties. It is therefore concluded, that QUS and DXA techniques are complementary for application in horses.

Objective—To evaluate the usefulness of multisite quantitative ultrasonography for noninvasive assessment of bone in horses.Sample Population—12 healthy horses and both forelimbs from 8 clinically normal horses.Procedure—For in vivo measurements, various regions of interest (ROI) were examined on the third metacarpal bone, radius, and tibia. Precision error for speed of sound (SOS) measurements was obtained by measuring each ROI of 4 horses 10 times with probe repositioning. Additionally, 3 operators measured each aspect of the third metacarpal bone of 6 horses 5 times each. For ex vivo measurements, third metacarpal bones were examined at 9 ROI, and SOS measurements were performed before and after soft tissue removal. One ROI of a single forelimb was subjected to 96 ex vivo measurements with 3 different contact media.Results—The lateral aspect of the third metacarpal bone had significantly higher SOS values than the dorsal and medial aspect of the third metacarpal bone. No difference was obtained between SOS values of the lateral and medial aspect of the radius. The tibia had significantly higher SOS values than the lateral aspect of the radius and the dorsal and medial aspect of the third metacarpal bone. Intraoperator coefficients of variation ranged from 0.62 to 3.15%, and interoperator coefficients of variation ranged from 0.78 to 2.70%. Values of SOS were highest when silicone oil was used as the contact medium.Conclusions and Clinical Relevance—Speed of sound measurements obtained by quantitative ultrasonography in axial transmission mode can be used to precisely measure superficial cortical bone properties of third metacarpal bone, radius, and tibia in horses. (Am J Vet Res2002;63:1464–1469)

Although the long-term outcomes of osteoporosis (Op) such as fracture, kyphosis, and pain are well known, the physical, psychological, and social consequences, beyond fracture and pain, are less clear. The Osteoporosis-targeted Quality-of-life (OPTQoL) questionnaire aimed at assessing the physical difficulty, fears, and adaptations to one's daily life was developed as a cross-sectional instrument to characterize the burden of Op within a community. The purpose of this study was to assess the impact of Op and related factors on community women participating in the OFELY study in France. Femoral neck bone mineral density (BMD) and OPTQoL questionnaire data were collected from women randomly selected from a large insurance company. Data were obtained for 756 women (mean age 59 years, range 36-92), most of whom were white. Women were classified into five groups based on the extent of physical manifestations and family history of Op. Women who had prior fractures, height loss, and/or kyphosis or both reported greater physical difficulty, more adaptations to their lives, and greater fears than women reporting no such changes. Scores on the Physical Difficulty domain, however, did not differ significantly based on BMD alone (BMD T score

Tobacco was found to be a risk factor for osteoporosis, mainly in postmenopausal women. We studied the effect of smoking on bone mineral density (BMD) and bone turnover in a cohort of 719 men, aged 51-85 yr, composed of 83 current smokers, 405 former smokers, and 231 men who never smoked. Most current and former smokers were moderate smokers (median, 10 cigarettes/d). Current smokers were younger, thinner, and drank more coffee and more alcoholic beverages. After adjustment for age, body weight, alcohol intake, and caffeine intake, current and former smokers had similar BMD, except at the forearm. Former smokers had lower BMD compared with never-smokers at most skeletal sites. Men who had smoked more than 7120 packs (third quartile) had lower BMD of total hip (P < 0.01) and distal forearm (P = 0.03) compared with men in the 2 lower tertiles. In the 3 groups, levels of bone formation markers did not differ. After adjustment for confounding variables, levels of urinary markers of bone resorption (beta-isomerized C-terminal telopeptide, free and total deoxypyridinoline) were higher in the current smokers than in former smokers and never-smokers. Concentrations of T, total 17beta-E2, and androstenedione were higher, whereas that of 25-hydroxyvitamin D was lower, in current smokers. When men were divided according to tertiles of body weight, increased bone resorption, decreased BMD and biochemical indexes of secondary hyperparathyroidism were observed in current smokers in the lowest tertile of body weight (