Variation of trabecular architecture in proximal femur of postmenopausal women

This investigation of microstructure in the human proximal femur probes the relationship between the parameters of the FRAX index of fracture risk and the parameters of bone microstructure. The specificity of fracture sites at the proximal femur raises the question of whether trabecular parameters are site-specific during post-menopause, before occurrence of fragility fracture. The donated proximal femurs of sixteen post-menopausal women in the sixth and seventh decades of life, free of metabolic pathologies and therapeutic interventions that could have altered the bone tissue, constituted the material of the study. We assessed bone mineral density of the proximal femurs by dual energy X-ray absorptiometry and then sectioned the femurs through the center of the femoral head and along the femoral neck axis. For each proximal femur, morphometry of trabeculae was conducted on the plane of the section divided into conventional regions and sub-regions consistent with the previously identified trabecular families that provide regions of relatively homogeneous microstructure. Mean trabecular width and percent bone area were calculated at such sites. Our findings indicate that each of mean trabecular width and percent bone area vary within each proximal femur independently from each other, with dependence on site. Both trabecular parameters show significant differences between pairs of sites. We speculate that a high FRAX index at the hip corresponds to a reduced percent bone area among sites that gives a more homogeneous and less site-specific quality to the proximal femur. This phenomenon may render the local tissue less able to carry out the expected mechanical function.     

Estimation of 3D shape, internal density and mechanics of proximal femur by combining bone mineral density images with shape and density templates

Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) alone is only a moderate predictor of fracture risk. Finite element analysis (FEA) of bone mechanics, based on DXA images, may improve the prediction of fracture risk. We developed a method to estimate the 3D shape and density distribution of the proximal femur, using a 2D BMD image and a femur shape template. Proximal femurs of eighteen human cadavers were imaged using computed tomography and divided into two sets (N = 9 + 9). The template was created from the samples in first set by using 3D generalized Procrustes analysis and thin-plate splines. Subsequently, the template and 2D BMD image were utilized to estimate the shape and internal density distribution of the femurs in the second set. Finally, FEA was conducted based on the original and the estimated bone models to evaluate the effect of geometrical and density distributional errors on the mechanical strength. The volumetric errors induced by the estimation itself were low (<1.4%). In the estimation of bones in the second set, the mean distance difference between the estimated and the original bone surfaces was 0.80 ± 0.19 mm, suggesting feasible estimation of the femoral shape. The mean absolute error in voxel-by-voxel BMD was 120±8 mg cm?3. In FEA, the stiffness of the proximal femur differed by -7±16% between the original and estimated bones. The present method, in comparison with methods used in previous studies, improved the prediction of the geometry, the BMD distribution and the mechanical characteristics of the proximal femur. Potentially, the proposed method could ultimately improve the determination of bone fracture risk.     

Fracture risk in the femoral hip region: A finite element analysis supported experimental approach

The decrease of bone mineral density (BMD) is a multifactorial bone pathology, commonly referred to as osteoporosis. The subsequent decline of the bone's micro-structural characteristics renders the human skeletal system, and especially the hip, susceptible to fragility fractures. This study represents a systematic attempt to correlate BMD spectrums to the mechanical strength characteristics of the femoral neck and determine a fracture risk indicator based on non-invasive imaging techniques. The BMD of 30 patients' femurs was measured in vivo by Dual-energy X-ray absorptiometry (DXA). As these patients were subjected to total hip replacement, the mechanical strength properties of their femurs' were determined ex-vivo using uniaxial compression experiments. FEA simulations facilitated the correlation of the DXA measurements to the apparent fracture risk, indicating critical strain values during complex loading scenarios.     

Prediction of femoral strength using 3D finite element models reconstructed from DXA images: validation against experiments

Computed tomography (CT)-based finite element (FE) models may improve the current osteoporosis diagnostics and prediction of fracture risk by providing an estimate for femoral strength. However, the need for a CT scan, as opposed to the conventional use of dual-energy X-ray absorptiometry (DXA) for osteoporosis diagnostics, is considered a major obstacle. The 3D shape and bone mineral density (BMD) distribution of a femur can be reconstructed using a statistical shape and appearance model (SSAM) and the DXA image of the femur. Then, the reconstructed shape and BMD could be used to build FE models to predict bone strength. Since high accuracy is needed in all steps of the analysis, this study aimed at evaluating the ability of a 3D FE model built from one 2D DXA image to predict the strains and fracture load of human femora. Three cadaver femora were retrieved, for which experimental measurements from ex vivo mechanical tests were available. FE models were built using the SSAM-based reconstructions: using only the SSAM-reconstructed shape, only the SSAM-reconstructed BMD distribution, and the full SSAM-based reconstruction (including both shape and BMD distribution). When compared with experimental data, the SSAM-based models predicted accurately principal strains (coefficient of determination >0.83, normalized root-mean-square error <16%) and femoral strength (standard error of the estimate 1215 N). These results were only slightly inferior to those obtained with CT-based FE models, but with the considerable advantage of the models being built from DXA images. In summary, the results support the feasibility of SSAM-based models as a practical tool to introduce FE-based bone strength estimation in the current fracture risk diagnostics.     

Application of homogenization theory to the study of trabecular bone mechanics.

It is generally accepted that the strength and stiffness of trabecular bone is strongly affected by trabecular microstructure. It has also been hypothesized that stress induced adaptation of trabecular bone is affected by trabecular tissue level stress and/or strain. At this time, however, there is no generally accepted (or easily accomplished) technique for predicting the effect of microstructure on trabecular bone apparent stiffness and strength or estimating tissue level stress or strain. In this paper, a recently developed mechanics theory specifically designed to analyze microstructured materials, called the homogenization theory, is presented and applied to analyze trabecular bone mechanics. Using the homogenization theory it is possible to perform microstructural and continuum analyses separately and then combine them in a systematic manner. Stiffness predictions from two different microstructural models of trabecular bone show reasonable agreement with experimental results, depending on metaphyseal region, (R2 greater than 0.5 for proximal humerus specimens, R2 less than 0.5 for distal femur and proximal tibia specimens). Estimates of both microstructural strain energy density (SED) and apparent SED show that there are large differences (up to 30 times) between apparent SED (as calculated by standard continuum finite element analyses) and the maximum microstructural or tissue SED. Furthermore, a strut and spherical void microstructure gave very different estimates of maximum tissue SED for the same bone volume fraction (BV/TV). The estimates from the spherical void microstructure are between 2 and 20 times greater than the strut microstructure at 10-20% BV/TV.     

Dependence of mechanical properties of trabecular bone on plate–rod microstructure determined by individual trabecula segmentation (ITS)

Individual trabecula segmentation (ITS) technique can decompose the trabecular bone network into individual trabecular plates and rods and is capable of quantifying the plate/rod-related microstructural characteristics of trabecular bone. This novel technique has been shown to be able to provide in-depth insights into micromechanics and failure mechanisms of human trabecular bone, as well as to distinguish the fracture status independent of area bone mineral density in clinical applications. However, the plate/rod microstructural parameters from ITS have never been correlated to experimentally determined mechanical properties of human trabecular bone. In this study, on-axis cylindrical trabecular bone samples from human proximal tibia (n=22), vertebral body (n=10), and proximal femur (n=21) were harvested, prepared, scanned using micro computed-tomography (µCT), analyzed with ITS and mechanically tested. Regression analyses showed that the plate bone volume fraction (pBV/TV) and axial bone volume fraction (aBV/TV) calculated by ITS analysis correlated the best with elastic modulus (R²=0.96–0.97) and yield strength (R²=0.95–0.96). Trabecular plate-related microstructural parameters correlated highly with elastic modulus and yield strength, while most rod-related parameters were found inversely and only moderately correlated with the mechanical properties. In addition, ITS analysis also identified that trabecular bone at human femoral neck had the highest trabecular plate-related parameters while the other sites were similar with each other in terms of plate–rod microstructure.     

How drugs decrease fracture risk: lessons from trials

In women with osteoporosis, each 1% improvement in spine BMD (by DXA) is expected to reduce vertebral fracture risk by about 4%. However, randomized trials of antiresorptive agents show that 1 to 6% improvements in spine BMD reduce vertebral fracture risk by 35 to 50%. Less 20% of the decreased spine fracture risk produced by alendronate or raloxifene be explained by improvement in spine BMD. The discrepancy is even greater during the first year or two of treatment when 1 to 4% improvements in BMD are associated with 65-68% decreases in spine fracture risk. Bisphosphonates continue to increase BMD but the reduction in fracture risk wanes to 20 to 45%. DXA underestimates the change in bone density of spinal trabecular bone and this might explain part of the discrepancy between expected and observed reductions in spine fracture risk. Even more accurate measurement of BMD would not explain the rapid onset and later waning of effect despite gradually increasing BMD. The biomechanical effects inhibiting bone resorption could explain the early onset but not the waning effectiveness. The waning effectiveness of antiresorptives raises concerns that prolonged inhibition of remodeling may weaken bone by allowing microdamage to accumulate. The effect of drugs on nonspine fracture risk is more complex and cannot be predicted from changes in DXA BMD. For example, Beck showed that long-term users of estrogen increase section modulus vs. nonusers with a net increase in section modulus and predicted femoral neck strength despite losing about 0.4% per year in femoral neck BMD. PTH reduces spine fracture risk and this effect is more completely explained by improvement in spine BMD. This suggests that sustaining the increased BMD produced by PTH may maintain long-term reductions in fracture risk.     

In-Vivo Assessment of Femoral Bone Strength Using Finite Element Analysis (FEA) Based on Routine MDCT Imaging: A Preliminary Study on Patients with Vertebral Fractures

PurposeTo experimentally validate a non-linear finite element analysis (FEA) modeling approach assessing in-vitro fracture risk at the proximal femur and to transfer the method to standard in-vivo multi-detector computed tomography (MDCT) data of the hip aiming to predict additional hip fracture risk in subjects with and without osteoporosis associated vertebral fractures using bone mineral density (BMD) measurements as gold standard.MethodsOne fresh-frozen human femur specimen was mechanically tested and fractured simulating stance and clinically relevant fall loading configurations to the hip. After experimental in-vitro validation, the FEA simulation protocol was transferred to standard contrast-enhanced in-vivo MDCT images to calculate individual hip fracture risk each for 4 subjects with and without a history of osteoporotic vertebral fractures matched by age and gender. In addition, FEA based risk factor calculations were compared to manual femoral BMD measurements of all subjects.ResultsIn-vitro simulations showed good correlation with the experimentally measured strains both in stance (R² = 0.963) and fall configuration (R² = 0.976). The simulated maximum stress overestimated the experimental failure load (4743 N) by 14.7% (5440 N) while the simulated maximum strain overestimated by 4.7% (4968 N). The simulated failed elements coincided precisely with the experimentally determined fracture locations. BMD measurements in subjects with a history of osteoporotic vertebral fractures did not differ significantly from subjects without fragility fractures (femoral head: p = 0.989; femoral neck: p = 0.366), but showed higher FEA based risk factors for additional incident hip fractures (p = 0.028).ConclusionFEA simulations were successfully validated by elastic and destructive in-vitro experiments. In the subsequent in-vivo analyses, MDCT based FEA based risk factor differences for additional hip fractures were not mirrored by according BMD measurements. Our data suggests, that MDCT derived FEA models may assess bone strength more accurately than BMD measurements alone, providing a valuable in-vivo fracture risk assessment tool.     

Bone loss in the ovariectomized baboon Papio ursinus: densitometry, histomorphometry and biochemistry

To develop a non-human primate model of systemic bone loss after ovariectomy, 24 ovariectomized (OVX) and eight control (non-OVX) female baboons Papio ursinus were investigated over a period of 48 months using bone mineral density (BMD), iliac crest bone histomorphometry, bone turnover markers, and variables of calcium metabolism. Lumbar spine (L1-L4) BMD measured by dual energy X-ray absorptiometry (DXA) decreased in OVX animals in the first 12 months (-7.6%) and showed a slow trend towards recovery after 24 months. Controls showed a slow increase in spinal BMD over 4 years (+9.7%). Total hip BMD decreased slowly up to 48 months in all animals (OVX -12.6%versus controls -10%); this indicated that OVX had a limited effect on total hip BMD. Forearm BMD did not change. The significant decrease in trabecular bone volume (TBV) of the iliac crest from baseline to 12 months was followed by some recovery. Microarchitectural deterioration of trabecular bone in OVX animals was demonstrated by a decline in trabecular number and an increase in trabecular spacing. These changes were also evident on sections of whole vertebrae, proximal femora and iliac crests. Changes in iliac TBV reflected spinal but not hip BMD changes in the OVX animals. Static and dynamic histomorphometric variables indicated that bone turnover was increased for 36 months following OVX. Controls showed no changes in histomorphometric variables. Bone specific alkaline phosphatase (ALPs) in OVX animals remained elevated throughout the study; osteocalcin (OC) was significantly elevated only at 6 and 12 months, and deoxypyridinoline (Pyr-D) was elevated at 12 months but declined after 24 months. ALPs was thus more sensitive to the long-term effects of OVX than were OC or Pyr-D. Controls showed no changes in bone turnover markers. This study showed consistent deleterious changes in lumbar BMD, bone histomorphometry with microarchitectural deterioration together with altered biochemical markers of bone turnover in the first 12 months after OVX. Since these changes resemble those in post-menopausal women, the non-human primate Papio ursinus is suitable for the study of bone loss in post-menopausal women.     

Numerical modeling of bone tissue adaptation—A hierarchical approach for bone apparent density and trabecular structure

In this work, a three-dimensional model for bone remodeling is presented, taking into account the hierarchical structure of bone. The process of bone tissue adaptation is mathematically described with respect to functional demands, both mechanical and biological, to obtain the bone apparent density distribution (at the macroscale) and the trabecular structure (at the microscale). At global scale bone is assumed as a continuum material characterized by equivalent (homogenized) mechanical properties. At local scale a periodic cellular material model approaches bone trabecular anisotropy as well as bone surface area density. For each scale there is a material distribution problem governed by density-based design variables which at the global level can be identified with bone relative density. In order to show the potential of the model, a three-dimensional example of the proximal femur illustrates the distribution of bone apparent density as well as microstructural designs characterizing both anisotropy and bone surface area density. The bone apparent density numerical results show a good agreement with Dual-energy X-ray Absorptiometry (DXA) exams. The material symmetry distributions obtained are comparable to real bone microstructures depending on the local stress field. Furthermore, the compact bone porosity is modeled giving a transversal isotropic behavior close to the experimental data. Since, some computed microstructures have no permeability one concludes that bone tissue arrangement is not a simple stiffness maximization issue but biological factors also play an important role.     

Laser-Supported Dual Energy X-Ray Absorptiometry (DXL) Compared to Conventional Absorptiometry (DXA) and to FRAX as Tools for Fracture Risk Assessments

Dual X-ray and Laser (DXL) adds a measure of the external thickness of the heel, measured by laser, to a conventional measurement of bone mineral density (BMD) of the calcaneus, using Dual energy X-ray Absorptiometry (DXA). The addition of heel thickness aims at a better separation of fatty tissue from bone than the standard method of DXA, which may mistake fatty tissue for bone and vice versa. The primary aim of this study was to evaluate whether DXL of the calcaneus can be used to assess the 10-year risk of fractures. Secondary aims were to compare the predictive ability of DXL with the two most established methods, Dual energy X-ray Absorptiometry (DXA) of the hip and spine and the WHO fracture risk assessment tool, FRAX. In 1999 a cohort of 388 elderly Swedish women (mean age 73.2 years) was examined with all three methods. Prospective fracture data was collected in 2010 from health care registers. One SD decrease in BMD of the heel resulted in an age-adjusted Hazard Ratio (HR) of 1.47 for a hip fracture (95% CI 1.09–1.98). Harrell’s C is the Cox regression counterpart of the Area Under Curve (AUC) of the Receiver Operating Characteristic (ROC) as a measure of predictive accuracy. Harrell’s C for BMD of the calcaneus was 0.65 for prediction of hip fractures. These results were not significantly different from those for BMD of the femoral neck or for FRAX. The HR for a hip fracture, for one SD decrease in BMD at the femoral neck, was 1.72 (95% CI 1.21–2.44. Harrell’s C was 0.67 for BMD at the femoral neck and 0.59 for FRAX. We conclude that DXL of the calcaneus could be a useful tool for fracture risk assessments.     

Bone mineral density correlates with fracture load in experimental side impacts of the pelvis

Pelvic fractures resulting from automotive side impacts are associated with high mortality and morbidity, as well as substantial economic costs. Previous experimental studies have produced varying results regarding the tolerance of the pelvis to lateral force and compression. While bone mineral density (BMD) has been shown to correlate with fracture loads in the proximal femur, no such correlation has been established for the pelvis. Presently, we studied the relationships between total hip BMD and impact response parameters in lateral impacts of twelve isolated human pelves. The results indicated that total hip BMD significantly correlated with fracture force, Fmax, and maximum ring compression, Cmax, of the fractured pelves. These findings are evidence that BMD may be useful in assessing the risk of pelvic fracture in automotive side impacts. Poor correlation was observed between total hip BMD and maximum viscous response, (VC)max, energy at fracture, Epeak, and time to fracture, tpeak. Mean Fmax and calculated tolerances for Cmax and (VC)max were lower than those established in previous studies using full cadavers, likely a result of our removal of soft tissues from the pelves prior to impact.     

Fracture prediction for the proximal femur using finite element models: Part II--Nonlinear analysis.

In Part I we reported the results of linear finite element models of the proximal femur generated using geometric and constitutive data collected with quantitative computed tomography. These models demonstrated excellent agreement with in vitro studies when used to predict ultimate failure loads. In Part II, we report our extension of those finite element models to include nonlinear behavior of the trabecular and cortical bone. A highly nonlinear material law, originally designed for representing concrete, was used for trabecular bone, while a bilinear material law was used for cortical bone. We found excellent agreement between the model predictions and in vitro fracture data for both the onset of bone yielding and bone fracture. For bone yielding, the model predictions were within 2 percent for a load which simulated one-legged stance and 1 percent for a load which simulated a fall. For bone fracture, the model predictions were within 1 percent and 17 percent, respectively. The models also demonstrated different fracture mechanisms for the two different loading configurations. For one-legged stance, failure within the primary compressive trabeculae at the subcapital region occurred first, leading to load transfer and, ultimately, failure of the surrounding cortical shell. However, for a fall, failure of the cortical and trabecular bone occurred simultaneously within the intertrochanteric region. These results support our previous findings that the strength of the subcapital region is primarily due to trabecular bone whereas the strength of the intertrochanteric region is primarily due to cortical bone.     

Gender-related changes in three-dimensional microstructure of trabecular bone at the human proximal tibia with aging

Despite increasing interest in age- and gender-related bone alterations, data on trabecular microstructure at the proximal tibia are scarce. The aim of this study was to identify trabecular microstructural change at the human proximal tibia with age and gender, using micro-computed tomography (micro-CT) and scanning electron microscopy (SEM). Fifty-six proximal tibias from 28 Japanese men and women (57-98 years of age) were used in this study. The subjects were chosen to give an even age and gender distribution. Both women and men were divided into three age groups, middle (57-68 years), old (72-82 years) and elderly (87-98 years) groups. The trabecular bone specimens from the medial compartment of the proximal tibial metaphysis were examined. Trabecular bone mineral density (BMD), bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) decreased between the middle-aged and elderly groups similarly in women and men. However, trabecular number (Tb.N) decreased by 13% between the middle-aged and elderly groups in women and nearly double that in men. As compared with women, men had higher BV/TV and lower trabecular separation (Tb.Sp) in the old age and elderly groups, and higher Tb.N and connectivity density (Conn.D) in the elderly group. Increased trabecular resorbing surfaces, perforated or disconnected trabeculae and microcallus formations were observed with age. These findings indicate that both BMD and BV/TV decreased at the proximal tibia with age similarly for women and men, but significant differences between women and men were observed for some microstructural parameters. These findings illustrate potential mechanisms underlying osteoporotic proximal tibial fracture.     

The mechanical properties of trabecular bone: Dependence on anatomic location and function

In 1961, Evans and King documented the mechanical properties of trabecular bone from multiple locations in the proximal human femur. Since this time, many investigators have cataloged the distribution of trabecular bone material properties from multiple locations within the human skeleton to include femur, tibia, humerus, radius, vertebral bodies, and iliac crest. The results of these studies have revealed tremendous variations in material properties and anisotropy. These variations have been attributed to functional remodeling as dictated by Wolff's Law. Both linear and power functions have been found to explain the relationship between trabecular bone density and material properties. Recent studies have re-emphasized the need to accurately quantify trabecular bone architecture proposing several algorithms capable of determining the anisotropy, connectivity and morphology of the bone. These past studies, as well as continuing work, have significantly increased the accuracy of analytical and experimental models investigating bone, and bone/implant interfaces as well as enhanced our perspective towards understanding the factors which may influence bone formation or resorption.     

Beyond Dxa: Advances in Clinical Applications of New Bone Imaging Technology

Dual-energy X-ray absorptiometry (DXA) is generally a very useful tool for assessing bone mineral density (BMD) and fracture risk. However, observational studies have shown that in certain instances, BMD as measured by DXA systematically over- or underestimates fracture risk. We herein describe the clinical conundrums encountered when assessing fracture risk by DXA in patients with primary hyperparathyroidism or type 2 diabetes and those of Chinese ethnicity. Furthermore, we discuss how advanced imaging technology that examines skeletal microarchitecture is furthering our understanding of fracture risk in these clinical situations.Abbreviations:BMD = bone mineral densityBMI = body mass indexBMS = bone material strengthBMT = bone microindentation testing3D = 3-dimensionalDM2 = type 2 diabetes mellitusDXA = dual-energy X-ray absorptiometryμFEA = microstructural finite element analysisFRAX = fracture risk assessment toolHRpQCT = high-resolution peripheral quantitative computed tomographyID = indentation distanceIDI = indentation distance increaseITS = individual trabecular segmentationPHPT = primary hyperparathyroidismPTH = parathyroid hormoneTBS = trabecular bone score     

Effects of spirulina, a blue-green alga, on bone metabolism in ovariectomized rats and hindlimb-unloaded mice

The safety and effectiveness were examined of the spirulina alga on bone metabolism in ovariectomized estrogen-deficient rats and hindlimb-unloaded mice. The dosage range was from an amount equal to that recommended in so-called health foods for humans (0.08 g/kg BW/day) to a 100-fold higher dose. The bone mineral density (BMD) of the whole femur and tibia of ovariectomized rats in the any spirulina-treated groups was not significantly different from that of the ovariectomized group, although BMD of the distal femur and proximal tibia was significantly lower in the spirulina-treated groups than in the ovariectomized group after a 6 week-experimental period. BMD of the femur and tibia was not affected by treatment with any dose of spirulina in hindlimb-unloaded mice. These results suggest that the intake of spirulina decreased BMD in the trabecular bone of rodents under estrogen-deficient conditions.     

Bone Analysis Using Trabecular Bone Score and Dual-Energy X-Ray Absorptiometry-Based 3-Dimensional Modeling in Postmenopausal Women With Primary Hyperparathyroidism

ObjectivePredominance of bone loss in cortical sites with relative preservation of trabecular bone, even in postmenopausal women, has been described in primary hyperparathyroidism (PHPT). The aim of this study was to evaluate bone microarchitectural differences using dual-energy x-ray absorptiometry (DXA), trabecular bone score (TBS), and DXA-based 3-dimensional (3D) modeling (3D-DXA) between postmenopausal women diagnosed with PHPT (PM-PHPT) and healthy postmenopausal controls.MethodsThis retrospective study included 44 women with PM-PHPT (9 of whom had fractures) and 48 healthy women matched by age, body mass index, and years since menopause treated at Hospital Universitario Fundación Jiménez Díaz between 2008 and 2017. The bone mineral density (BMD) of the lumbar spine (LS), femoral neck, total hip (TH), and 1/3 radius was assessed using DXA, and trabecular volumetric BMD (vBMD), cortical vBMD, integral vBMD, cortical thickness, and cortical surface BMD at TH were assessed using a 3D-DXA software and TBS at LS.ResultsThe mean adjusted BMD values at LS, the femoral neck, and TH; TBS at LS; and TH 3D-DXA parameters (trabecular vBMD, integral vBMD, cortical thickness, and cortical surface BMD) were significantly reduced in women with PM-PHPT compared with those in the controls. However, differences in mean cortical vBMD were not statistically significant (P = .078). There were no significant differences in mean BMD, TBS, or the 3D-DXA parameters between patients with fractures and those without fractures. The 25-hydroxyvitamin D level appeared to be associated with TBS but not with DXA and 3D-DXA measurements.ConclusionPM-PHPT has significant involvement of the trabecular and cortical compartments of the bone, as determined by DXA, TBS, and 3D-DXA.