Agnes Ostertag

Cortical measurements of the tibia from high resolution peripheral quantitative computed tomography images: A comparison with synchrotron radiation micro-computed tomography

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.

A case–control study of fractures in men with idiopathic osteoporosis: Fractures are associated with older age and low cortical bone density

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.

Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD

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.

Variations of SOST mRNA expression in human bone are associated with DNA polymorphism and DNA methylation in the SOST gene

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.

Efficacy of dynamic humeral centering according to Neer test results: a stratified analysis of a randomized-controlled trial.

The aim of this study was to assess the efficacy of dynamic humeral centering (DHC) according to Neer test results. The study was a stratified analysis of a previously reported randomized trial. The patients included had shoulder pain with impingement syndrome. Interventions were DHC or nonspecific mobilization for control. The primary outcome was the Constant score including subscores for pain, activity, mobility, and strength at 3 months. All patients improved at follow-up, with better results after DHC. There was no interaction between Neer test results, treatments, and time. However, a trend toward higher effect sizes was observed after DHC in patients with a positive Neer test in comparison with negative patients. Patients with a positive Neer test showed improvement after DHC for rotator cuff disease compared with nonspecific mobilization.

Anterior Skull Base and Pericranial Flap Ossification after Frontofacial Monobloc Advancement

Background: Frontofacial monobloc advancement creates a communication between the anterior cranial fossa and nasal cavities. To tackle this issue, transorbital pericranial pedicled flaps are routinely performed in the authors’ center. This study aimed to assess the postoperative ossification of the anterior skull base and pedicled flaps following frontofacial monobloc advancement, and to identify factors influencing this ossification. Methods: Measurements of the skull base only and of the ossified pedicled flaps together with the skull base were performed on computed tomographic scans at the nasofrontal and the nasoethmoid frontal junctions. The total thickness of the skull vault was measured and a qualitative defect score for the anterior skull base was computed. Results: Twenty-two patients who underwent frontofacial monobloc advancement at a median age of 3.1 years (range, 1.9 to 3.6 years) were included: 14 with Crouzon, five with Pfeiffer, and three with Apert syndrome. One year and 5 years after surgery, the distraction gap was completely ossified in the anterior skull base midline in all patients. Ossified pedicled flaps together with the skull base were thicker in patients than in controls at these two time points (p < 0.005 and p < 0.02). Patients with Pfeiffer syndrome had a significantly thicker skull base only and ossified pedicled flaps together with the skull base thicknesses (p = 0.01 and p = 0.03) and lower defect scores than patients with Crouzon or Apert syndrome (p = 0.03) 1 year postoperatively. Conclusion: As ossification of the pedicled flaps and total reossification of the anterior skull base midline were observed in all patients, the authors indicate that performing pedicled flaps in frontofacial monobloc advancement surgery could promote the reossification of the anterior skull base. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.