Silvana Di Gregorio

High prevalence of and progression to low bone mineral density in HIV-infected patients: a longitudinal cohort study

Background:Low bone mineral density (BMD) is an emerging metabolic condition in HIV-infected patients; however, data on progression of this disease are scarce. Methods:We studied 671 patients with at least one dual-energy X-ray absorptiometry scan (391 of them ≥2 scans) to determine the prevalence and progression of BMD and establish related factors. Linear regression and logistic polytomic regression were used for the cross-sectional study and mixed effects and generalized estimating equations were used for the longitudinal study. Results:Osteopenia and osteoporosis were diagnosed in 47.5 and 23%, respectively. Progression to bone demineralization was observed in 28% of the patients over a median of 2.5 years (12.5% progressed to osteopenia and 15.6% to osteoporosis). In the 105 patients with at least 5 years of follow-up, progression was 47% (18% to osteopenia; 29% to osteoporosis). Factors associated with bone loss and progression were age [odds ratio (OR) 1.07; 95% confidence interval (CI) 1.05–1.08; P < 0.0001], male sex (OR 2.23; 95% CI 1.77–2.8; P < 0.0001), low body mass index (OR 1.14; 95% CI 1.11–1.17; P < 0.0001), time on protease inhibitor (OR 1.18; 95% CI 1.12–1.24; P < 0.0001), time on tenofovir (OR 1.08; 95% CI 1.03–1.14; P < 0.0019), and current use of protease inhibitors (OR 1.64; 95% CI 1.35–2.04; P < 0.0001). Conclusions:Our results show a high prevalence of and considerable progression to osteopenia/osteoporosis in our cohort. Our findings support the importance of applying adequate strategies to prevent bone demineralization and of close monitoring of BMD in HIV-infected patients, specifically in at-risk patients who are taking antiretrovirals that affect bone mineralization.

Factores de riesgo de fracturas por fragilidad en una cohorte de mujeres españolas

INTRODUCTION Fragility fractures are an important public health issue. The aim of this study was to analyze the association of the main osteoporotic risk factors related to fragility fracture in a cohort of women with an indication of bone densitometry (BD). METHODS A retrospective cohort was followed-up until a fragile fracture occurred, in a population of women aged 40 to 90 years with a first visit for BD between January 1992 and February 2008. We calculated the incidence rate of fracture per 1000 women-years of follow-up, and the hazard ratio (HR) of fragile fracture using a Cox regression model. RESULTS A total of 49,735 women were studied. The average age of participants was 57.8 years (SD: 8.5). Of these, 3631 women (7.1%) reported a new fragility fracture in post-baseline visits. Risk factors with higher adjusted HR were age ≥ 75 years compared with age < 55 years (HR: 3.8; 95% CI: 3.3-4.4) and having a BC result evaluated as osteoporosis compared to normal (HR: 2.0; 95% CI: 1.8-2.2). A personal history of humerus, hip or vertebral fractures had an adjusted HR of 1.2 (95% CI: 1.1-1.3). CONCLUSIONS The main risk factors for fragility fracture were advanced age, BD result and a personal history of fracture, although 74% of fractures were detected with a bone mineral density classified as normal or osteopenia. Other relevant factors were rheumatoid arthritis or having received prolonged corticosteroid therapy.

Effects of testosterone treatment on body composition in males with testosterone deficiency syndrome

Abstract Objective: We evaluated the safety of testosterone treatment and its efficacy on body composition in males with testosterone deficiency syndrome (TDS) over 24 months. Methods: 50 males aged 50–65 years with TDS (Aging Males Symptoms Scale [AMS] > 26 and calculated free testosterone [cFT] 250 pmol/l) were administered 50 mg testosterone gel daily for one year. During the second year, patients received 1000 mg of testosterone undecanoate every 2–3 months. Outcome measures were clinical chemistry values and total testosterone; sex hormone-binding globulin and cFT, changes in AMS and International Prostate Symptom Score; and changes in body composition measured by dual-energy-x-ray absorptiometry. Results: There were no clinically significant changes in clinical chemistry safety parameters. There were significant improvements in both total and cFT and in AMS scores after three months (p < 0.001). Lean mass increased 2.35% at 12 months and 4.5% at 24 months, but proportionally more muscle mass was gained in arms and legs than in the trunk. Fat mass decreased 4.2% at 12 months and 9.1% at 24 months. Conclusions: Testosterone treatment in males with TDS leads to body changes affecting lean and fat mass with significant improvement in AMS scores, and has an excellent safety profile.

The Search for a New Marker of Renal Function in Older Patients with Chronic Kidney Disease Stages 3–4: Usefulness of Cystatin C-Based Equations

Background/Aim: Cystatin C (Cys C) is an endogenous marker of glomerular filtration rate (GFR) unaffected by body composition. The aim of the present study was to assess the utility of Cys C-based GFR prediction equations (Hoek, Larsson and Stevens) and creatinine (modification of diet in renal disease-isotope dilution mass spectrometry – MDRD-IDMS, and Cockcroft-Gault – CG) compared with 51Cr-EDTA. Methods: This study was carried out in 40 Caucasian older patients with advanced age (≥60) and chronic kidney disease stages 3–4. To assess the utility of prediction equations in relation to body composition, we measured lean mass (LM) with densitometry (DXA). Pearson’s, Bland-Altman and Lin’s coefficient (Rc) were used to study accuracy and precision. Results:51Cr-EDTA was 36.9 ± 9.2 ml/min/1.73 m2 (22–60). Cys C levels were 2.2 ± 0.8 mg/l (r = 0.085; p = 0.662 LM) and creatinine 2.8 ± 1.1 mg/dl (r = 0.427; p = 0.021 LM). The most accurate equations were the Hoek, Larsson and Stevens formulae, with a bias of –0.2 (Rc 0.48), –2.9 (Rc 0.44) and 2.6 ml/min/1.73 m2 (Rc 0.58). The biases obtained with MDRD-IDMS and CG were –14.6 (Rc 0.35) and –12.5 (Rc 0.40). All correlations among biases obtained with creatinine-based formulae and LM were negative and statistically significant (p < 0.05). Conclusions: The results show superiority of Cys C-based GFR formulae over the MDRD-IDMS and CG equations. This significant underestimation obtained with conventional prediction equations was directly related to the influence of LM.

3D-DXA: Assessing the Femoral Shape, the Trabecular Macrostructure and the Cortex in 3D from DXA images

The 3D distribution of the cortical and trabecular bone mass in the proximal femur is a critical component in determining fracture resistance that is not taken into account in clinical routine Dual-energy X-ray Absorptiometry (DXA) examination. In this paper, a statistical shape and appearance model together with a 3D-2D registration approach are used to model the femoral shape and bone density distribution in 3D from an anteroposterior DXA projection. A model-based algorithm is subsequently used to segment the cortex and build a 3D map of the cortical thickness and density. Measurements characterising the geometry and density distribution were computed for various regions of interest in both cortical and trabecular compartments. Models and measurements provided by the “3D-DXA” software algorithm were evaluated using a database of 157 study subjects, by comparing 3D-DXA analyses (using DXA scanners from three manufacturers) with measurements performed by Quantitative Computed Tomography (QCT). The mean point-to-surface distance between 3D-DXA and QCT femoral shapes was 0.93 mm. The mean absolute error between cortical thickness and density estimates measured by 3D-DXA and QCT was 0.33 mm and 72 mg/cm3. Correlation coefficients (R) between the 3D-DXA and QCT measurements were 0.86, 0.93, and 0.95 for the volumetric bone mineral density at the trabecular, cortical, and integral compartments respectively, and 0.91 for the mean cortical thickness. 3D-DXA provides a detailed analysis of the proximal femur, including a separate assessment of the cortical layer and trabecular macrostructure, which could potentially improve osteoporosis management while maintaining DXA as the standard routine modality.

Risk factors for fragility fractures in a cohort of Spanish women

INTRODUCTION Fragility fractures are an important public health issue. The aim of this study was to analyze the association of the main osteoporotic risk factors related to fragility fracture in a cohort of women with an indication of bone densitometry (BD). METHODS A retrospective cohort was followed-up until a fragile fracture occurred, in a population of women aged 40 to 90 years with a first visit for BD between January 1992 and February 2008. We calculated the incidence rate of fracture per 1000 women-years of follow-up, and the hazard ratio (HR) of fragile fracture using a Cox regression model. RESULTS A total of 49,735 women were studied. The average age of participants was 57.8 years (SD: 8.5). Of these, 3631 women (7.1%) reported a new fragility fracture in post-baseline visits. Risk factors with higher adjusted HR were age ≥ 75 years compared with age < 55 years (HR: 3.8; 95% CI: 3.3-4.4) and having a BC result evaluated as osteoporosis compared to normal (HR: 2.0; 95% CI: 1.8-2.2). A personal history of humerus, hip or vertebral fractures had an adjusted HR of 1.2 (95% CI: 1.1-1.3). CONCLUSIONS The main risk factors for fragility fracture were advanced age, BD result and a personal history of fracture, although 74% of fractures were detected with a bone mineral density classified as normal or osteopenia. Other relevant factors were rheumatoid arthritis or having received prolonged corticosteroid therapy.

3D reconstruction of the lumbar vertebrae from anteroposterior and lateral dual-energy X-ray absorptiometry

Current vertebral fracture prevention measures use Dual-energy X-ray Absorptiometry (DXA) to quantify the density of the vertebrae and subsequently determine the risk of fracture. This modality however only provides information about the projected Bone Mineral Density (BMD) while the shape and spatial distribution of the bone determines the strength of the vertebrae. Quantitative Computed Tomography (QCT) allows for the measurement of the vertebral dimensions and volumetric densities, which have been shown to be able to determine the fracture risk more reliably than DXA. However, for the high cost and high radiation dose, QCT is not used in clinical routine for fracture risk assessment. In this work, we therefore propose a method to reconstruct the 3D shape and density volume of lumbar vertebrae from an anteroposterior (AP) and lateral DXA image used in clinical routine. The method is evaluated for the L2, L3 and L4 vertebra. Of these vertebrae a statistical model of the vertebral shape and density distribution is first constructed from a large dataset of QCT scans. All three models are then simultaneously registered onto both AP and lateral DXA image. The shape and volumetric BMD at several regions of the reconstructed vertebrae is then evaluated with respect to the ground truth QCT volumes. For the L2, L3 and L4 vertebrae respectively the shape was reconstructed with a mean (2RMS) point-to-surface distance of 1.00 (2.64) mm, 0.93(2.52) mm and 1.34(3.72) mm and a strong correlation (r > 0.82) was found between the trabecular volumetric BMD extracted from the reconstructions and from the same subject QCT scans. These results indicate that the proposed method is able to accurately reconstruct the 3D shape and density volume of the lumbar vertebrae from AP and lateral DXA, which can potentially improve the fracture risk estimation accuracy with respect to the currently used DXA derived areal BMD measurements.

Genetic Analysis of High Bone Mass Cases from the BARCOS Cohort of Spanish Postmenopausal Women

The aims of the study were to establish the prevalence of high bone mass (HBM) in a cohort of Spanish postmenopausal women (BARCOS) and to assess the contribution of LRP5 and DKK1 mutations and of common bone mineral density (BMD) variants to a HBM phenotype. Furthermore, we describe the expression of several osteoblast-specific and Wnt-pathway genes in primary osteoblasts from two HBM cases. A 0.6% of individuals (10/1600) displayed Z-scores in the HBM range (sum Z-score >4). While no mutation in the relevant exons of LRP5 was detected, a rare missense change in DKK1 was found (p.Y74F), which cosegregated with the phenotype in a small pedigree. Fifty-five BMD SNPs from Estrada et al. [NatGenet 44:491-501,2012] were genotyped in the HBM cases to obtain risk scores for each individual. In this small group of samples, Z-scores were found inversely related to risk scores, suggestive of a polygenic etiology. There was a single exception, which may be explained by a rare penetrant genetic variant, counterbalancing the additive effect of the risk alleles. The expression analysis in primary osteoblasts from two HBM cases and five controls suggested that IL6R, DLX3, TWIST1 and PPARG are negatively related to Z-score. One HBM case presented with high levels of RUNX2, while the other displayed very low SOX6. In conclusion, we provide evidence of lack of LRP5 mutations and of a putative HBM-causing mutation in DKK1. Additionally, we present SNP genotyping and expression results that suggest additive effects of several genes for HBM.

Age-Related changes in vertebral morphometry by statistical shape analysis

The morphological changes of the vertebrae associated with normal aging are still subject of debate, whereas this knowledge is important in detecting vertebral fractures and degenerative shape changes. The aim of this study is to present a method to statistically analyze the vertebral shape and determining the morphometric changes related to normal aging. The analysis is performed on the L2 lumbar vertebrae from a large dataset of Computed Tomography scans. The surface meshes of all vertebrae, with a groupwise vertex correspondence between them, are first acquired by an intensity based registration process onto a segmented reference. Principal component analysis then reduces the dimensionality to the main modes of variation which were subsequently analyzed by multiple linear regression to acquire the global shape variations with respect to the age of the subjects. In addition, the correlation with age of the deformation at each mesh vertex is analyzed, giving a significance map of the age related changes. This analysis shows several shape changes which are in agreement with previous studies while also giving a more detailed global shape analysis. Understanding the normal shape changes allows for a better diagnosis of vertebral fractures and spinal pathologies.

Structural Parameters of the Proximal Femur by 3-Dimensional Dual-Energy X-ray Absorptiometry Software: Comparison With Quantitative Computed Tomography

Structural parameters of the proximal femur evaluate the strength of the bone and its susceptibility to fracture. These parameters are computed from dual-energy X-ray absorptiometry (DXA) or from quantitative computed tomography (QCT). The 3-dimensional (3D)-DXA software solution provides 3D models of the proximal femur shape and bone density from anteroposterior DXA scans. In this paper, we present and evaluate a new approach to compute structural parameters using 3D-DXA software. A cohort of 60 study subjects (60.9 ± 14.7 yr) with DXA and QCT examinations was collected. 3D femoral models obtained by QCT and 3D-DXA software were aligned using rigid registration techniques for comparison purposes. Geometric, cross-sectional, and volumetric structural parameters were computed at the narrow neck, intertrochanteric, and lower shaft regions for both QCT and 3D-DXA models. The accuracy of 3D-DXA structural parameters was evaluated in comparison with QCT. Correlation coefficients (r) between geometric parameters computed by QCT and 3D-DXA software were 0.86 for the femoral neck axis length and 0.71 for the femoral neck shaft angle. Correlation coefficients ranged from 0.86 to 0.96 for the cross-sectional parameters and from 0.84 to 0.97 for the volumetric structural parameters. Our study demonstrated that accurate estimates of structural parameters for the femur can be obtained from 3D-DXA models. This provides clinicians with 3D indexes related to the femoral strength from routine anteroposterior DXA scans, which could potentially improve osteoporosis management and fracture prevention.