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Objective: Strontium ranelate (SR) increases bone mineral density (BMD) in postmenopausal osteoporotic women and reduces vertebral and non-vertebral fracture incidence. Hip fracture reduction has also been observed during 3-year treatment with SR in osteoporotic women at high risk of hip fracture. The objective of this study is to analyse the association between BMD changes and hip fracture incidence during treatment with SR. Material and Methods: In this post-hoc analysis, 465 women aged over 74 years with low BMD at the femoral neck (T-score < or = -2.4 according to NHANES normative values) were selected from the population of a recently published study (the Treatment of Peripheral Osteoporosis Study - TROPOS). BMD was assessed at the femoral neck at baseline and after a follow-up of 3 years. Hip fractures were reported by study investigators. Results: After adjusting for age, body mass index, femoral neck BMD at baseline and number of prevalent vertebral fractures, we found that for each 1% increase in femoral neck BMD observed after 3 years, the risk to experience a hip fracture after 3 years decreased by 7% (95% CI: 1-14%) (p = 0.04). In patients experiencing a hip fracture over 3 years of treatment with SR, femoral neck BMD increased by (mean [SE]) 3.41 (1.02)% compared to 7.23 (0.81)% in patients without hip fracture (p = 0.02). Conclusion: In this post-hoc analysis of women undergoing 3 years of SR treatment, an increase in femoral neck BMD is associated with a decrease in hip fracture incidence. [ABSTRACT FROM AUTHOR]

Objectives: Spousal concordance has already been observed for several other diseases but it has not yet been studied for bone loss. Our aim was to determine whether or not bone changes were the same within spouses who have shared the same environment for many decades.Methods: We conducted a prospective study on an average of 5±3 years in a single center. We evaluated in the 104 spouses who came at least twice and had more than 1 year of follow-up the changes in bone mineral density (BMD) at femoral neck adjusted on weight and height, and on hormone replacement therapy use and duration for women. Lifestyle characteristics and biological parameters were evaluated at baseline.Results: The mean (±SD) baseline age of wives was 63±5 years and that of their husbands was 66±5 years. They had been living together for 40±8 years. Most of the environmental baseline factors were correlated within partners: BMI (r=0.26, P<0.01), 25-OHD(3) (r=0.32, P<0.01), daily calories (r=0.52, P<0.001) and calcium intake (r=0.31, P<0.01), physical activity (r=0.43, P<0.0001). Bone loss was observed in wives (-0.0023 g/cm(2)/yr, P<0.01) but not in their husbands (0.0016 g/cm(2)/yr, P=0.10). Changes of BMD were not correlated within spouses (r=0.0004, P=0.99). In women, 25-OHD(3) and interactions of tobacco with 25-OHD(3) and calories intake explained 37% of the bone loss variance (P<0.01).Conclusion: Environmental factors do not appear to influence changes in bone density in the same manner in subjects of different genders. [ABSTRACT FROM AUTHOR]

Context: Men with congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) have both low circulating testosterone and estradiol levels. Whether bone structure is affected remains unknown., Objective: To characterize bone geometry, volumetric density and microarchitecture in CHH/KS., Methods: This cross-sectional study, conducted at a single French tertiary academic medical center, included 51 genotyped CHH/KS patients and 40 healthy volunteers. Among CHH/KS men, 98% had received testosterone and/or combined gonadotropins. High-resolution peripheral quantitative computed tomography (HR-pQCT), dual-energy x-ray absorptiometry (DXA), and measurement of serum bone markers were used to determine volumetric bone mineral density (vBMD) and cortical and trabecular microarchitecture., Results: CHH and controls did not differ for age, body mass index, and levels of vitamin D and PTH. Despite long-term hormonal treatment (10.8 ± 6.8 years), DXA showed lower areal bone mineral density (aBMD) in CHH/KS at lumbar spine, total hip, femoral neck, and distal radius. Consistent with persistently higher serum bone markers, HR-pQCT revealed lower cortical and trabecular vBMD as well as cortical thickness at the tibia and the radius. CHH/KS men had altered trabecular microarchitecture with a predominant decrease of trabecular thickness. Moreover, CHH/KS men exhibited lower cortical bone area, whereas total and trabecular areas were higher only at the tibia. Earlier treatment onset (before age 19 years) conferred a significant advantage for trabecular bone volume/tissue volume and trabecular vBMD at the tibia., Conclusion: Both vBMD and bone microarchitecture remain impaired in CHH/KS men despite long-term hormonal treatment. Treatment initiation during adolescence is associated with enhanced trabecular outcomes, highlighting the importance of early diagnosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Syncytin-A and -B are envelope genes of retroviral origin that have been captured in evolution for a role in placentation. They trigger cell-cell fusion and were shown to be essential for the formation of the syncytiotrophoblast layer during mouse placenta formation. Syncytin-A and -B expression has been described in other tissues and their highly fusogenic properties suggested that they might be involved in the fusion of other cell types. Here, taking advantage of mice knocked out for syncytin-B , SynB -/- mice, we investigated the potential role of syncytin-B in the fusion of cells from the monocyte/macrophage lineage into multinucleated osteoclasts (OCs) -in bone- or multinucleated giant cells -in soft tissues. In ex vivo experiments, a significant reduction in fusion index and in the number of multinucleated OCs and giant cells was observed as soon as Day3 in SynB -/- as compared to wild-type cell cultures. Interestingly, the number of nuclei per multinucleated OC or giant cell remained unchanged. These results, together with the demonstration that syncytin-B expression is maximal in the first 2 days of OC differentiation, argue for syncytin-B playing a role in the fusion of OC and giant cell mononucleated precursors, at initial stages. Finally, ex vivo , the observed reduction in multinucleated OC number had no impact on the expression of OC differentiation markers, and a dentin resorption assay did not evidence any difference in the osteoclastic resorption activity, suggesting that syncytin-B is not required for OC activity. In vivo , syncytin-B was found to be expressed in the periosteum of embryos at embryonic day 16.5, where TRAP-positive cells were observed. Yet, in adults, no significant reduction in OC number or alteration in bone phenotype was observed in SynB -/- mice. In addition, SynB -/- mice did not show any change in the number of foreign body giant cells (FBGCs) that formed in response to implantation of foreign material, as compared to wild-type mice. Altogether the results suggest that in addition to its essential role in placenta formation, syncytin-B plays a role in OCs and macrophage fusion; yet it is not essential in vivo for OC and FBGC formation, or maintenance of bone homeostasis, at least under the conditions tested., Competing Interests: None.

The osteopetroses and related sclerosing bone dysplasias can have a broad range of manifestations. Especially in the milder forms, sandwich vertebrae are an easily recognizable and reliable radiological hallmark. We report on four patients from three families presenting with sandwich vertebrae and platyspondyly. The long bone phenotypes were discordant with one patient showing modeling defects and patchy osteosclerosis, while the second displayed only metaphyseal sclerotic bands, and the third and fourth had extreme metaphyseal flaring with uniform osteosclerosis. Two of the four patients had experienced pathological fractures, two had developmental delay, but none showed cranial nerve damage, hepatosplenomegaly, or bone marrow failure. According to these clinical features the diagnoses ranged between intermediate autosomal recessive osteopetrosis and dysosteosclerosis. After exclusion of mutations in CLCN7 we performed gene panel and exome sequencing. Two novel mutations in SLC29A3 were found in the first two patients. In the third family a TCIRG1 C-terminal frameshift mutation in combination with a mutation at position +4 in intron 2 were detected. Our study adds two cases to the small group of individuals with SLC29A3 mutations diagnosed with dysosteosclerosis, and expands the phenotypic variability. The finding that intermediate autosomal recessive osteopetrosis due to TCIRG1 splice site mutations can also present with platyspondyly further increases the molecular heterogeneity of dysosteosclerosis-like sclerosing bone dysplasias., (Copyright © 2018 Elsevier Inc. All rights reserved.)

SOST encodes sclerostin, an inhibitor of bone formation that antagonizes canonical Wnt signaling. Variations of SOST expression have an impact on bone mineral density (BMD) and bone strength. We hypothesized that genetic and epigenetic DNA modifications have an impact on SOST gene expression. By analyzing 43 bone samples from women, we found that rs851054 (G/A) is associated with SOST mRNA expression, donors with one or two G allele(s) displaying higher SOST expression (p<0.05). Beside this polymorphism, we also investigated the role of CpG methylation in SOST mRNA expression, and analyzed methylation variation at 13 CpG sites on the 1st exon of SOST in 14 human bone samples. Principal component analysis identified three groups of CpG sites that explained most of the methylation variation. We calculated the percentage of methylation in the main group of CpGs, and showed that higher rates of methylated CpGs are associated with higher SOST mRNA expression. To demonstrate that change in SOST expression might be related to human bone disease, we analyzed 131 patients with osteogenesis imperfecta (OI), a rare disease characterized by low BMD, bone fragility, and marked intra-familial variability of bone phenotypes. We found an association between rs851054 of the SOST promoter and the fracture rate only during childhood (p<0.01). In conclusion, genetic and epigenetic changes contribute to variation in SOST expression in human bone. Our data also indicate that these variations may be related to the severity of OI., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: HIV-infected individuals are at increased risk of incident fractures. Evaluation of trabecular bone micro-architecture is an important tool to assess bone strength, but its use has not yet been reported in middle-aged HIV-infected male individuals. The aim of the study was to compare bone micro-architecture between HIV-infected and HIV-uninfected men., Methods: In this cross-sectional study, 53 HIV-infected male individuals with a mean (± standard deviation) age of 49 ± 9 years who had been receiving antiretroviral therapy including tenofovir disoproxil fumarate (DF) for at least 60 months were compared with 50 HIV-uninfected male controls, matched for age and ethnic origin. We studied the volumetric bone density and micro-architecture of the radius and tibia using high-resolution peripheral quantitative computed tomography (HR-p QCT)., Results: Volumetric trabecular bone density was 17% lower in the tibia (P < 10(-4) ) and 16% lower in the radius (P < 10(-3) ) in HIV-infected patients compared with controls. By contrast, the cortical bone density was normal at both sites. The tibial trabecular micro-architecture differed markedly between patients and controls: bone volume/total volume (BV/TV) and trabecular number were each 13% lower (P < 10(-4) for both). Trabecular separation and inhomogeneity of the network were 18% and 24% higher in HIV-infected patients than in controls, respectively. The radial BV/TV and trabecular thickness were each 13% lower (P < 10(-3) and 10(-2) , respectively). Cortical thickness was not different between the two groups., Conclusions: The findings of lower volumetric trabecular bone density and disrupted trabecular micro-architectural parameters in middle-aged male HIV-infected treated patients help to explain bone frailty in these patients., (© 2016 British HIV Association.)

Rheumatoid arthritis is a chronic disease that results in a disabling and painful condition as it progresses to destruction of the articular cartilage and ankylosis of the joints. Although the cause of the disease is still unknown, evidence argues that autoimmunity plays an important part. There are increasing but contradictory views regarding serotonin being associated with activation of immunoinflammatory pathways and the onset of autoimmune reactions. We studied serotonin's involvement during collagen-induced arthritis in wild-type and Tph1(-/-) mice, which have markedly reduced peripheral serotonin levels. In wild-type mice, induction of arthritis triggered a robust increase in serotonin content in the paws combined with less inflammation. In Tph1(-/-) mice with arthritis, a marked increase in the clinical and pathologic arthritis scores was noticed. Specifically, in Tph1(-/-) mice with arthritis, a significant increase in osteoclast differentiation and bone resorption was observed with an increase in IL-17 levels in the paws and in Th17 lymphocytes in the draining lymph nodes, whereas T-regulatory cells were dampened. Ex vivo serotonin and agonists of the 5-HT2A and 5-HT2B receptors restored IL-17 secretion from splenocytes and Th17 cell differentiation in Tph1(-/-) mice. These findings indicate that serotonin plays a fundamental role in arthritis through the regulation of the Th17/T-regulatory cell balance and osteoclastogenesis., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

An association between atherosclerosis and osteoporosis has been reported in several studies. This association could result from local intraosseous atherosclerosis and ischemia, which is shown by limb osteoporosis in patients with peripheral artery disease (PAD), but also could result from bidirectional communication between the skeleton and blood vessels. Systemic bone disorders and PAD are frequent in ESRD. Here, we investigated the possible interaction of these disorders. For 65 prevalent nondiabetic patients on hemodialysis, we measured ankle-brachial pressure index (ABix) and evaluated mineral and bone disorders with bone histomorphometry. In prevalent patients on hemodialysis, PAD (ABix<0.9 or >1.4/incompressible) was associated with low bone turnover and pronounced osteoblast resistance to parathyroid hormone (PTH), which is indicated by decreased double-labeled surface and osteoblast surface (P<0.001). Higher osteoblast resistance to PTH in patients with PAD was characterized by weaker correlation coefficients (slopes) between serum PTH and double-labeled surface (P=0.02) or osteoblast surface (P=0.03). The correlations between osteoclast number or eroded surface and serum mineral parameters, including PTH, did not differ for subjects with normal ABix and PAD. Common vascular risk factors (dyslipidemia, smoking, and sex) were similar for normal, low, and incompressible ABix. Patients with PAD were older and had high C-reactive protein levels and longer hemodialysis vintage. These results indicate that, in prevalent nondiabetic patients with ESRD, PAD associates with low bone turnover and pronounced osteoblast resistance to PTH., (Copyright © 2015 by the American Society of Nephrology.)

Osteopetrosis is a rare genetic disorder characterized by an increase of bone mass due to defective osteoclast function. Patients typically displayed spontaneous fractures, anemia, and in the most severe forms hepatosplenomegaly and compression of cranial facial nerves leading to deafness and blindness. Osteopetrosis comprises a heterogeneous group of diseases as several forms are known with different models of inheritance and severity from asymptomatic to lethal. This review summarizes the genetic and clinical features of osteopetrosis, emphasizing how recent studies of this disease have contributed to understanding the central role of the skeleton in the whole body physiology. In particular, the interplay of bone with the stomach, insulin metabolism, male fertility, the immune system, bone marrow, and fat is described.

In chronic kidney disease the excessive production of parathyroid hormone increases the bone resorption rate and leads to histologic bone signs of secondary hyperparathyroidism. However, in other situations, the initial increase in parathyroid hormone and bone remodeling may be slowed down excessively by a multitude of factors including age, ethnic origin, sex, and treatments such as vitamin D, calcium salts, calcimimetics, steroids, and so forth, leading to low bone turnover or adynamic bone disease. Both high and low bone turnover diseases actually are observed equally in chronic kidney disease patients treated by dialysis, and all types of renal osteodystrophy are associated with an increased risk of skeletal fractures, reduced quality of life, and poor clinical outcomes. Unfortunately, the diagnosis of these bone abnormalities cannot be obtained correctly by current clinical, biochemical, and imaging methods. Therefore, bone biopsy has been, and still remains, the gold standard analysis for assessing the exact type of renal osteodystrophy. It is also the unique way to assess the mechanisms of action, safety, and efficacy of new bone-targeting therapies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: Wilson's disease is characterized by copper deposition, especially in the liver and central nervous system. We assessed the prevalent fractures and bone mineral density (BMD) and related risk factors in 85 patients. BMD was normal, but patients with severe neurological involvement, low BMI, and/or amenorrhea are at risk for fractures., Introduction: Wilson's disease (WD) is characterized by copper deposition, especially in the liver and central nervous system. Two studies showed a high prevalence of osteoporosis in WD patients. We wanted to assess the prevalent fractures and bone mineral density (BMD) and to identify risk factors for bone loss and fractures in a large group of WD patients., Methods: In this prospective cross-sectional survey at National center of reference for WD, we included 85 patients, 47 women, and 38 men, with a mean age of 35 ± 10 years, and mean time from diagnosis to study of 21 ± 9 years; 57 (67%) patients had neurological signs. Peripheral fractures, prevalent radiological vertebral fractures (VFx), and dual-energy X-ray absorptiometry BMD measurements at the femoral neck (FN) and lumbar spine (LS) were studied., Results: Mean LS and FN Z-score was normal (-0.37 ± 1.20 at LS and -0.06 ± 1.20 at FN). BMI <19 kg/m(2) and amenorrhea were associated with low BMD. Prevalent peripheral fractures were noted in 43 (51%) and VF in 7 (8%) patients. Severity of neurological involvement and male sex was associated with peripheral fractures, whereas older age, severe neurological involvement, and low BMD and Z-score values were associated with VF., Conclusion: Our data showing normal BMD overall do not support routine bone status evaluation in adults with WD. However, patients with severe neurological involvement, low BMI, and/or amenorrhea are at risk factors for fractures and may require specific monitoring.

High resolution-peripheral quantitative computed tomography (HR-pQCT) measurements are carried out in clinical research protocols to analyze cortical bone. Micro-computed tomography (micro-CT) is a standard tool for ex vivo examination of bone in 3D. The aim of this work was to evaluate cortical measurements derived from HR-pQCT images compared to those from synchrotron radiation (SR) micro-CT in a distal position (4.2 cm from the distal pilon). Twenty-nine tibia specimens were scanned with HR-pQCT using protocols provided by the manufacturer. The standard measured outcomes included volumetric bone density (gHA/cm(3)) of the cortical region (Dcomp), and the cortical thickness (Ct.Th, mm). New features, such as cortical porosity (Ct.Po) and mean pore diameter (Ct.Po.Dm), were measured by an auto-contouring process. All tibias were harvested from the posterior region and imaged with SR micro-CT (voxel size=7.5 μm). The cortical thickness, (Ct.Thmicro-CT), porosity (PoV/TV), pore diameter, pore spacing, pore number, and degree of mineralization of bone (DMB) were obtained for SR micro-CT images. For standard measurements on HR-pQCT images, site matched analyses with micro-CT were completed to obtain Dcomplocal and Ct.Thlocal. Dcomp was highly correlated to PoV/TV (r=-0.84, p<10(-4)) but not to DMB. Dcomplocal was correlated to PoV/TV (r=-0.72, p<10(-4)) and to DMB (r=0.40, p>0.05). Ct.Thlocal and Ct.Thmicro-CT were moderately correlated (r=0.53, p<0.01). Ct.Th and Ct.Po results from the autocontouring process are influenced by the level of trabecularization of the cortical bone and need manual correction of the endosteal contour. Distal tibia is a reliable region to study cortical bone with Dcomp as the best parameter because it reflects both the micro-porosity (Havers canals) and macro-porosity (resorption lacunae) of the cortical bone., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Autosomal dominant osteopetrosis type II (ADO II) is a rare, heritable bone disorder characterized by a high bone mass and insufficient osteoclast activity. Mutations in the CLCN7 gene have been reported to cause ADO II. To gain novel insights into the pathways dysregulated in ADOII osteoclasts, we identified changes in gene expression in osteoclasts from patients with a heterozygous mutation of CLCN7. To do this, we carried out a transcriptomic study comparing gene expression in the osteoclasts of patients with ADO II and healthy donors. Our data show that, according to our selection criteria, 182 genes were differentially expressed in osteoclasts from patients and controls. From the 18 displaying the highest change in microarray, we confirmed differential expression for seven by qPCR. Although two of them have previously been found to be expressed in osteoclasts (ITGB5 and SERPINE2), the other five (CES1 (carboxyl esterase 1), UCHL1 (ubiquitin carboxy-terminal esterase L1, also known as ubiquitin thiolesterase), WARS (tryptophanyl-tRNA synthetase), GBP4 (guanylate-binding protein 4), and PRF1) are not yet known to have a role in this cell type. At the protein level, we confirmed elevated expression of ITGB5 and reduced expression of WARS, PRF1, and SERPINE2. Transfection of ClC-7 harboring the G215R mutation into osteoclasts resulted in an increased ITGB5 and reduced PRF1 expression of borderline significance. Finally, we observed that the ADO II patients presented a normal or increased serum level of bone formation markers, demonstrating a coupling between dysfunctional osteoclasts and osteoblasts. Sphingosine kinase 1 mRNA was expressed at the same level in ADO II and control osteoclasts. In conclusion, these data suggest that in addition to an acidification dysfunction caused by the CLCN7 mutation, a change in ITGB5, PRF1, WARS, and SERPINE2 expression could be part of the osteoclastic phenotype of ADO II.

Mutations in the 2Cl(-)/1H(+)-exchanger ClC-7 impair osteoclast function and cause different types of osteoclast-rich osteopetrosis. However, it is unknown to what extent ClC-7 function has to be reduced to become rate-limiting for bone resorption. In osteoclasts from osteopetrosis patients expression of the mutated ClC-7 protein did not correlate with disease severity and resorption impairment. Therefore, a series of transgenic mice expressing ClC-7 in osteoclasts at different levels was generated. Crossing of these mice with Clcn7(-/-) mutants rescued the osteopetrotic phenotype to variable degrees. One resulting double transgenic line mimicked human autosomal dominant osteopetrosis. The trabecular bone of these mice showed a reduction of osteoblast numbers, osteoid, and osteoblast marker gene expression indicative of reduced osteoblast function. In osteoclasts from these mutants ClC-7 expression levels were 20 to 30% of wildtype levels. These reduced levels not only impaired resorptive activity, but also increased numbers, size and nucleus numbers of osteoclasts differentiated in vitro. Although ClC-7 was expressed in the stomach and PTH levels were high in Clcn7(-/-) mutants loss of ClC-7 did not entail a relevant elevation of gastric pH. In conclusion, we show that in our model a reduction of ClC-7 function by approximately 70% is sufficient to increase bone mass, but does not necessarily enhance bone formation. ClC-7 does not appear to be crucially involved in gastric acid secretion, which explains the absence of an osteopetrorickets phenotype in CLCN7-related osteopetrosis., (© 2013.)

Osteoporosis is due to an imbalance between decreased bone formation by osteoblasts and increased resorption by osteoclasts. Deciphering factors controlling bone formation is therefore of utmost importance for the understanding and the treatment of osteoporosis. Our previous in vivo results showed that bone formation is reduced in the absence of the serotonin receptor 5-HT2B, causing impaired osteoblast proliferation, recruitment, and matrix mineralization. In this study, we investigated the signaling pathways responsible for the osteoblast defect in 5-HT2BR(-/-) mice. Notably, we investigated the phospholipase A2 pathway and synthesis of eicosanoids in 5-HT2BR(-/-) compared to wild type (WT) osteoblasts. Compared to control osteoblasts, the lack of 5-HT2B receptors was only associated with a 10-fold over-production of prostacyclin (PGI2). Also, a specific prostacyclin synthase inhibitor (U51605) rescued totally osteoblast aggregation and matrix mineralization in the 5-HT2BR(-/-) osteoblasts without having any effect on WT osteoblasts. Prostacyclin is the endogenous ligand of the nuclear peroxisome proliferator activated receptor ß/δ (PPAR-ß/δ), and its inhibition in 5-HT2BR(-/-) cells rescued totally the alkaline phosphatase and osteopontin mRNA levels, cell-cell adhesion, and matrix mineralization. We conclude that the absence of 5-HT2B receptors leads to the overproduction of prostacyclin, inducing reduced osteoblast differentiation due to PPAR-ß/δ -dependent target regulation and defective cell-cell adhesion and matrix mineralization. This study thus reveals a previously unrecognized cell autonomous osteoblast defect in the absence of 5-HT2BR and highlights a new pathway linking 5-HT2B receptors and nuclear PPAR- ß/δ via prostacyclin.

We report on a family affected by Camurati-Engelmann disease, characterized by radiological signs limited to the tibia, and associated with overweight or obesity, which is not a known feature of this disorder. The affected patients were heterozygous for a c.466C > T mutation (which predicts p.Arg156Cys) in the latency associated protein (LAP)-coding domain of the TGFB1 gene. This mutation had previously been reported once in another family with a similar, atypical phenotype, which suggests a possible phenotype/genotype relationship., (Copyright © 2013 Wiley Periodicals, Inc.)

Diastrophic dysplasia (DTD) is a chondrodysplasia caused by mutations in the SLC26A2 gene, leading to reduced intracellular sulfate pool in chondrocytes, osteoblasts and fibroblasts. Hence, proteoglycans are undersulfated in the cartilage and bone of DTD patients. To characterize the bone phenotype of this skeletal dysplasia we used the Slc26a2 knock-in mouse (dtd mouse), that was previously validated as an animal model of DTD in humans. X-rays, bone densitometry, static and dynamic histomorphometry, and in vitro studies revealed a primary bone defect in the dtd mouse model. We showed in vivo that this primary bone defect in dtd mice is due to decreased bone accrual associated with a decreased trabecular and periosteal appositional rate at the cell level in one month-old mice. Although the osteoclast number evaluated by histomorphometry was not different in dtd compared to wild-type mice, urine analysis of deoxypyridinoline cross-links and serum levels of type I collagen C-terminal telopeptides showed a higher resorption rate in dtd mice compared to wild-type littermates. Electron microscopy studies showed that collagen fibrils in bone were thinner and less organized in dtd compared to wild-type mice. These data suggest that the low bone mass observed in mutant mice could possibly be linked to the different bone matrix compositions/organizations in dtd mice triggering changes in osteoblast and osteoclast activities. Overall, these results suggest that proteoglycan undersulfation not only affects the properties of hyaline cartilage, but can also lead to unbalanced bone modeling and remodeling activities, demonstrating the importance of proteoglycan sulfation in bone homeostasis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To determine biochemical, radiological and micro-architectural bone factors related to fragility fractures in idiopathic male osteoporosis (IMO) patients. IMO is a rare disorder characterized by low areal bone mineral density (aBMD) (Z-score<-2) occurring in men after excluding secondary causes of low BMD., Methods: We conducted a case-control study in 31 patients with fragility fracture (IMO F+) that had occurred after the age of 40 years and 37 without fracture (IMO F-). We first compared IMO group to 40 age-matched disease-free men. We measured aBMD and bone micro-architectural indices at distal radius and tibia sites with a HR-pQCT scan (XtremeCT) using standard and extended cortical analysis. Urine and blood samples were collected in order to determine the levels of bone-turnover markers and the potential determinant of bone fragility. Models of analysis of covariance, including age, height and weight as adjustment factors, were used to compare the groups., Results: Compared to their controls, IMO patients showed marked disturbance of their micro-architectural parameters at tibia and radius affecting both trabecular and cortical parameters. IMO F+ subjects were significantly older than IMO F- subjects (58 ± 8 vs. 53 ± 9 yrs, p=0.01). BMD Z-score at the total-hip was significantly lower in IMO F+ (-1.3 ± 0.5 vs. -0.9 ± 0.8 g/cm(2), p=0.01). After adjustment, trabecular micro-architectural parameters, biochemical markers and hormonal parameters were not different in the 2 groups. At distal tibia, cortical v-BMD was significantly lower in IMO F+ patients (799 ± 73 vs. 858 ± 60 mg/cm(3), p=0.03), while cortical thickness was not different., Conclusion: Our results show that patients with IMO display a marked disturbance of trabecular and cortical bone micro-architecture, and that age and low cortical density are determinants of the fracture occurrence., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Unlabelled: We have examined the effect of oral monthly ibandronate on distal radius and tibia microarchitecture with high-resolution peripheral quantitative tomography compared with placebo, in women with osteopenia, and found that ibandronate did not significantly affect trabecular bone but improved cortical density and thickness at the tibia., Methods: We have examined the effect of ibandronate on bone microarchitecture with peripheral high-resolution quantitative computed tomography (HR-pQCT) in a randomized placebo-controlled trial among 148 women with osteopenia. Patients received either oral 150 mg monthly ibandronate or placebo over 24 months. Bone microarchitecture was assessed at baseline, 6, 12, and 24 months, using HR-pQCT at the distal radius and tibia; areal bone mineral density (aBMD) was measured with DXA at the spine, hip, and radius., Results: At 12 months, there was no significant difference in trabecular bone volume at the radius (the primary end point) between women on ibandronate (10.8 ± 2.5%) and placebo (10.5 ± 2.9%), p = 0.25. There was no significant difference in other radius trabecular and cortical microarchitecture parameters at 12 and 24 months. In contrast, at the tibia, cortical vBMD in the ibandronate group was significantly greater than in the placebo group at 6, 12, and 24 months, with better cortical thickness at 6, 12, and 24 months. With ibandronate, aBMD was significantly increased at the hip and spine at 12 and 24 months but at the radius was significantly superior to placebo only at 24 months. Most of the adverse events related to ibandronate were expected with bisphosphonate use, and none of them were serious., Conclusion: We conclude that 12 months of treatment with ibandronate in women with osteopenia did not affect trabecular bone microarchitecture, but improved cortical vBMD at the tibia at 12 and 24 months, and preserved cortical thickness at the tibia.

Besides its action as a neurotransmitter, serotonin has multiple physiological functions in several peripheral organs. Recently, Yadav et al. suggested that peripheral serotonin produced in the gut was a major negative regulator of osteoblast proliferation. These data were challenged by Cui et al. that showed no change in bone density in mature mice with a global invalidation of tryptophan hydroxylase 1, the enzyme responsible of serotonin synthesis in the periphery. In this context, we showed that osteoclasts are able to synthetize serotonin that acts locally to induce osteoclast precursors differentiation. Our data and previous results from others suggest that rather than acting as a hormone, serotonin produced in the bone could act locally on osteoclast and osteoblast realizing in the bone a complete micro-serotoninergic system.

Purpose: Degenerative scoliosis usually begins at menopause and lateral rotatory olisthesis (LRO) might be a triggering factor in the onset of degenerative scoliosis in postmenopausal women. We set out to evaluate the influence of hormone replacement therapy (HRT) on degenerative scoliosis and on LRO., Methods: A cross-sectional study was conducted in 146 postmenopausal women: 75 women had received HRT for more than 1 year (HRT > 1) and 71 women had never received HRT or less than 1 year (HRT < 1). Scoliotic curve, LRO, sacral slope, lordosis, kyphosis were measured. The excess risk of LRO associated with age, BMI, isometric strength of brachial biceps, bone mineral density, lean mass and HRT was evaluated using a multiple logistic regression model., Results: No difference was found in sacral slope, lumbar lordosis or thoracic kyphosis between both groups or in the presence of scoliosis. The prevalence of LRO was significantly lower in HRT >1 than HRT <1 (8 vs. 30%) while the risk was dependent on age, HRT and their interaction. LRO increased with age only in HRT <1 (11% when aged ≤66 years vs. 39% when aged >66 years, p = 0.013), whereas the prevalence of LRO remained stable in HRT >1., Conclusions: LRO was significantly lower in women who received HRT. The excess risk of LRO was dependent on both age and HRT status. These findings suggest that HRT might prevent the onset of LRO, and therefore might contribute to the prevention of low back pain.

The fibroblast growth factor receptor 3 (FGFR3) plays a critical role in the regulation of endochondral ossification. Fgfr3 gain-of-function mutations cause achondroplasia, the most common form of dwarfism, and a spectrum of chondrodysplasias. Despite a significant number of studies on the role of FGFR3 in cartilage, to date, none has investigated the influence of Fgfr3-mediated effects of the growth plate on bone formation. We studied three mouse models, each expressing Fgfr3 mutation either ubiquitously (CMV-Fgfr3(Y367C/+)), in chondrocytes (Col II-Fgfr3(Y367C/+)) or in mature osteoblasts (Col I-Fgfr3(Y367C/+)). Interestingly, we demonstrated that dwarfism with a significant defect in bone formation during growth was only observed in mouse models expressing mutant Fgfr3 in the cartilage. We observed a dramatic reduction in cartilage matrix mineralization and a strong defect of primary spongiosa. Anomalies of primary spongiosa were associated with an increase in osteoclast recruitment and a defect of osteoblasts at the mineralization front. A significant decrease in bone volume, trabecular thickness and number was also observed in the trabecular bone. Interestingly, no anomalies in proliferation and differentiation of primary osteoblasts from CMV-Fgfr3(Y367C/+) mice were observed. Based on these data, we excluded a potential function of Fgfr3 directly on osteoblasts at 3 weeks of age and we obtained evidence that the disorganization of the growth plate is responsible for the anomalies of the trabecular bone during bone formation. Herein, we propose that impaired FGFR3 signaling pathways may affect trabecular bone formation via a paracrine mechanism during growth. These results redefine our understanding of endochondral ossification in FGFR3-related chondrodysplasias.

Peripheral serotonin, synthesized by tryptophan hydroxylase-1 (TPH(1)), has been shown to play a key role in several physiological functions. Recently, controversy has emerged about whether peripheral serotonin has any effect on bone density and remodeling.We therefore decided to investigate in detail bone remodeling in growing and mature TPH(1) knockout mice (TPH(1)(-/-)). Bone resorption in TPH(1)(-/-) mice, as assessed by biochemical markers and bone histomorphometry, was markedly decreased at both ages. Using bone marrow transplantation, we present evidence that the decrease in bone resorption in TPH(1)(-/-) mice is cell-autonomous. Cultures from TPH(1)(-/-) in the presence of macrophage colony-stimulating factor and receptor activator for NF-KB ligand (RANKL) displayed fewer osteoclasts, and the decreased differentiation could be rescued by adding serotonin. Our data also provide evidence that in the presence of RANKL, osteoclast precursors express TPH(1) and synthesize serotonin. Furthermore, pharmacological inhibition of serotonin receptor 1B with SB224289, and of receptor 2A with ketanserin, also reduced the number of osteoclasts. Our findings reveal that serotonin has an important local action in bone, as it can amplify the effect of RANKL on osteoclastogenesis.

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

Objectives: Treatment for degenerative rotator cuff disease of the shoulder includes physiotherapy. Dynamic humeral centering (DHC) aims at preventing subacromial impingement, which contributes to the disease. The goal of this study was to assess the effectiveness of DHC., Method: 69 patients with shoulder pain and impingement syndrome were prospectively included in a single-centre randomised trial with a 12-month follow-up. Patients and assessor were blinded to the study hypothesis and treatment, respectively. DHC and non-specific mobilisation as control were performed for 6 weeks, in 15 supervised individual outpatient sessions, and patients performed daily home exercises. The planned primary outcome was the Constant score including subscores for pain, activity, mobility and strength at 3 months. Secondary outcomes were the Constant score and subscores at 12 months, and medication use for pain at 3 and 12 months., Results: The DHC group did not differ from the control group in the total Constant score at 3 months. However, the DHC group showed a higher Constant subscore for pain (12.2 (SD 2.8) vs 9.9 (2.9), least square means difference 2.1, 95% CI 0.7 to 3.5, p=0.004). At 3 months, the DHC group also showed a higher rate of no medication use (96.7% vs 71%, proportional difference 25.7, 95% CI 3.7 to 51.9, p=0.012). There was no other intergroup difference., Conclusions: There was no difference in the total Constant score between DHC and controls. However, pain was improved at 3 months after DHC. The differences found in subscores for pain should be explored in future studies. Trial registration clinicaltrials.gov Identifier: NCT 01022775.

Hepatitis C-associated osteosclerosis (HCAO) is characterized by increased bone mass following hepatitis C infection. We report here a case of HCAO that lasted 8 years before the patient received antiviral hepatitis treatment. Seven years after the antiviral treatment, the evolution of radiographs and densitometry showed skeletal recovery of osteosclerosis. This case strengthens the relationship between viral infection and osteosclerosis., (Copyright © 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Young mice overexpressing Runx2 specifically in cells of the osteoblastic lineage failed to gain bone mass and exhibited a dramatic increase in bone resorption, leading to severe osteopenia and spontaneous vertebral fractures. The objective of the current study was to determine whether treatment with a bisphosphonate (risedronate, Ris), which reduces fractures in postmenopausal as well as in juvenile osteoporosis, was able to improve bone quality and reduce vertebral fractures in mice overexpressing Runx2. Four-week-old female Runx2 mice received Ris at 2 and 10 μg/kg subcutaneously twice a week for 12 weeks. Runx2 and wild-type mice received vehicle (Veh) as control. We measured the number of new fractures by X-ray and bone mineral density (BMD) by DEXA. We evaluated bone quality by histomorphometry, micro-CT, and Fourier transform infrared imaging (FTIRI). Ris at 20 μg/kg weekly significantly reduced the average number of new vertebral fractures compared to controls. This was accompanied by significantly increased BMD, increased trabecular bone volume, and reduced bone remodeling (seen in indices of bone resorption and formation) in the vertebrae and femoral metaphysis compared to Runx2 Veh. At the femur, Ris also increased cortical thickness. Changes in collagen cross-linking seen on FTIRI confirmed that Runx2 mice have accelerated bone turnover and showed that Ris affects the collagen cross-link ratio at both forming and resorbing sites. In conclusion, young mice overexpressing Runx2 have high bone turnover-induced osteopenia and spontaneous fractures. Ris at 20 μg/kg weekly induced an increase in bone mass, changes in bone microarchitecture, and decreased vertebral fractures.

Our specific aims were to evaluate the power of bivariate analysis and to compare its performance with traditional univariate analysis in samples of unrelated subjects under varying sampling selection designs. Bivariate association analysis was based on the seemingly unrelated regression (SUR) model that allows different genetic models for different traits. We conducted extensive simulations for the case of two correlated quantitative phenotypes, with the quantitative trait locus making equal or unequal contributions to each phenotype. Our simulation results confirmed that the power of bivariate analysis is affected by the size, direction and source of the phenotypic correlations between traits. They also showed that the optimal sampling scheme depends on the size and direction of the induced genetic correlation. In addition, we demonstrated the efficacy of SUR-based bivariate test by applying it to a real Genome-Wide Association Study (GWAS) of Bone Mineral Density (BMD) values measured at the lumbar spine (LS) and at the femoral neck (FN) in a sample of unrelated males with low BMD (LS Z-scores ≤ -2) and with high BMD (LS and FN Z-scores >0.5). A substantial amount of top hits in bivariate analysis did not reach nominal significance in any of the two single-trait analyses. Altogether, our studies suggest that bivariate analysis is of practical significance for GWAS of correlated phenotypes.

Unlabelled: Young mice over-expressing Runx2 fail to gain bone relative to wild type mice with growth and present spontaneous fractures. It allows, for the first time in rodents, direct assessment of anti-fracture efficacy of strontium ranelate which was able to decrease caudal vertebrae fracture incidence through an improvement of trabecular and cortical architecture., Introduction: The aim was to investigate whether strontium ranelate was able to decrease fracture incidence in mice over-expressing Runx2, model of severe developmental osteopenia associated with spontaneous vertebral fractures., Methods: Transgenic mice and their wild type littermates were treated by oral route with strontium ranelate or vehicle for 9 weeks. Caudal fracture incidence was assessed by repeated X-rays, resistance to compressive loading by biochemical tests, and bone microarchitecture by histomorphometry., Results: Transgenic mice receiving strontium ranelate had significantly fewer new fractures occurring during the 9 weeks of the study (-60%, p < 0.05). In lumbar vertebrae, strontium ranelate improves resistance to compressive loading (higher ultimate force to failure, +120%, p < 0.05) and trabecular microarchitecture (higher bone volume and trabecular number, lower trabecular separation, +60%, +50%, -39%, p < 0.05) as well as cortical thickness (+17%, p < 0.05). In tibiae, marrow cavity cross-section area and equivalent diameter were lower (-39%, -21%, p < 0.05). The strontium level in plasma and bone was in the same range as the values measured in treated postmenopausal women., Conclusions: This model allows, for the first time, direct assessment of anti-fracture efficacy of strontium ranelate treatment in rodents. In these transgenic mice, strontium ranelate was able to decrease caudal vertebral fracture incidence through an improvement of trabecular and cortical architecture.

Objective: To evaluate the efficacy of a functional restoration program for patients with chronic low back pain, using overall disability and work ability as the primary evaluation criteria., Patients and Methods: We prospectively studied patients aged 18 years or older who had been on sick leave because of nonspecific low back pain for at least 3 months and whose job position was still open. The program was delivered on a day-hospital basis 5 days a week for 5 weeks. Patients were followed up for 1 year., Results: We included 39 patients, 11 females and 28 males with a mean (± SD) age of 43 ± 8 years and a mean sick-leave duration of 10 ± 7 months. After 1 year, 26 (67%) patients reported improvements and 25 (64%) had returned to work. Compared to the year before the program, the number of sick leave days was decreased by 51% (120 ± 140 vs. 244 ± 114, P < 0.05). The work-and-leisure-activities subscore of the validated French version of the Dallas Pain Questionnaire (DRAD) was significantly improved (57 ± 24 vs. 70 ± 17 at baseline, P < 0.05). The patients still on sick leave after 1 year were older and had greater alterations in baseline DRAD subscores for anxiety/depression and daily activities, compared to the patients who had returned to work., Conclusions: Our functional restoration program was effective and allowed two-thirds of patients to resume work. Factors associated with failure to resume work were well-known correlates of chronicity. Our results support the use of functional restoration programs in patients with incapacitating low back pain. They suggest that functional restoration may deserve to be started earlier, after only 3 months with chronic pain, in patients who are unable to work., (Copyright © 2010. Published by Elsevier SAS.)

Background: fractures may have serious implications in an elderly individual, and fracture prevention may include a careful choice of medications., Design: the Hypertension in the Very Elderly Trial (HYVET) was a double-blind placebo-controlled trial of a thiazide-like diuretic (indapamide 1.5 mg SR) with the optional addition of the angiotensin-converting enzyme (ACE) inhibitor (perindopril 2-4 mg). Fracture was a secondary end point of the trial., Setting: HYVET recruited participants from Eastern and Western Europe, China, Australasia, and Tunisia., Subjects: all participants were > or =80 years of age and hypertensive., Methods: participants were randomised to receive a thiazide-like diuretic (indapamide 1.5 mg SR) +/- ACE inhibitor (perindopril 2-4 mg) or matching placebos. Incident fractures were validated and analysed based on time to first fracture., Results: there were 3,845 participants in HYVET and a total 102 reported fractures (42 in the active and 60 in the placebo group). When taking only validated first fractures, 90 were included in the analyses (38 in the active and 52 in the placebo group). Cox proportional hazard regression, adjusted for key baseline risk factors, resulted in a point estimate of 0.58 (95% CI 0.33-1.00, P = 0.0498)., Conclusions: despite the lowering of blood pressure, treatment with a thiazide-like diuretic and an ACE inhibitor does not increase and may decrease fracture rate.