The value of drug and metabolite concentration in blood as a biomarker of psychopharmacological therapy.

Desirable and undesirable effects of a drug are related to its concentration at various sites of actions. For many psychotropic drugs, it has been shown that drug concentration in brain correlates with concentration in blood. The latter is also an available estimate of clearance and bioavailability. Its monitoring enables identification of multiple factors that have an impact on clinical outcomes, especially uncertain compliance and pharmacokinetic peculiarities. For this review we analysed for antidepressants if drug concentration in blood can be used as biomarker for psychopharmacological treatment. Systematic review of the literature revealed for new and old antidepressant drugs that drug and metabolite concentrations in blood are measures of the pharmacokinetic phenotype and related differentially to occupancy of primary target structures, therapeutic effects and unwanted anticholinergic, cardiac and other side effects. Drug concentration in blood can therefore be used as biomarker in clinical practice to guide psychopharmacological treatment with established antidepressant drugs. Monitoring of drug concentration is suitable to improve efficacy and safety of the pharmacotherapy, especially in elderly patients who require complex pharmacological therapies.

Effects of strontium ranelate and alendronate on bone microstructure in women with osteoporosis. Results of a 2-year study.

UNLABELLED: Strontium ranelate appears to influence more than alendronate distal tibia bone microstructure as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), and biomechanically relevant parameters as assessed by micro-finite element analysis (µFEA), over 2 years, in postmenopausal osteoporotic women. INTRODUCTION: Bone microstructure changes are a target in osteoporosis treatment to increase bone strength and reduce fracture risk. METHODS: Using HR-pQCT, we investigated the effects on distal tibia and radius microstructure of strontium ranelate (SrRan; 2 g/day) or alendronate (70 mg/week) for 2 years in postmenopausal osteoporotic women. This exploratory randomized, double-blind trial evaluated HR-pQCT and FEA parameters, areal bone mineral density (BMD), and bone turnover markers. RESULTS: In the intention-to-treat population (n = 83, age: 64 ± 8 years; lumbar T-score: -2.8 ± 0.8 [DXA]), distal tibia Cortical Thickness (CTh) and Density (DCort), and cancellous BV/TV increased by 6.3%, 1.4%, and 2.5%, respectively (all P < 0.005), with SrRan, but not with alendronate (0.9%, 0.4%, and 0.8%, NS) (P < 0.05 for all above between-group differences). Difference for CTh evaluated with a distance transformation method was close to significance (P = 0.06). The estimated failure load increased with SrRan (+2.1%, P < 0.005), not with alendronate (-0.6%, NS) (between-group difference, P < 0.01). Cortical stress was lower with SrRan (P < 0.05); both treatments decreased trabecular stress. At distal radius, there was no between-group difference other than DCort (P < 0.05). Bone turnover markers decreased with alendronate; bALP increased (+21%) and serum-CTX-I decreased (-1%) after 2 years of SrRan (between-group difference at each time point for both markers, P < 0.0001). Both treatments were well tolerated. CONCLUSIONS: Within the constraints of HR-pQCT method, and while a possible artefactual contribution of strontium cannot be quantified, SrRan appeared to influence distal tibia bone microstructure and FEA-determined biomechanical parameters more than alendronate. However, the magnitude of the differences is unclear and requires confirmation with another method.

Effect of age on bone mineral density and micro architecture in the radius and tibia of horses: an Xtreme computed tomographic study.

BACKGROUND: The effect of age on the bone mineral density and microarchitecture of the equine radius and tibia was investigated. Fifty-six bones from 15 horses aged four to 21 years were used. There were nine geldings and six mares, and none of the horses had any disease influencing bone properties. Xtreme computed tomography was used to evaluate a 9-mm segment of the diaphysis and metaphysis of each bone. The following variables were determined: length of the bone, circumference and diameter in the frontal and sagittal planes in the middle of the bone.Diaphysis: total volume, bone volume, bone volume ratio, slice area, bone area, marrow area, cortical and marrow thickness, bone mineral density, polar moment of inertia of the cortex.Metaphysis: total area, bone area, cortical bone area, cortical thickness, bone mineral density, bone mineral density in the cortex, bone mineral density in the trabecular region, trabecular number, trabecular thickness, trabecular separation, polar moment of inertia of the metaphysis, polar moment of inertia of the cortex of the metaphysis. RESULTS: Bone density and microarchitecture were not affected by breed or gender. However, the microarchitecture varied with the age of the horse; the number of trabeculae decreased significantly and the distance between trabeculae increased significantly with increasing age. There were no significant differences between bones of the left and right limbs or between the radius and tibia. CONCLUSION: The variables investigated did not differ between geldings and mares. However, there were age-related changes in the microstructure of the bones. Further experimental studies are necessary to determine whether these changes reduce bone strength. Age-related changes in the bones were seen and may explain the higher incidence of fractures and fissures in older horses.

Stereological measures of trabecular bone structure: comparison of 3D micro computed tomography with 2D histological sections in human proximal tibial bone biopsies.

Stereology applied on histological sections is the 'gold standard' for obtaining quantitative information on cancellous bone structure. Recent advances in micro computed tomography (microCT) have made it possible to acquire three-dimensional (3D) data non-destructively. However, before the 3D methods can be used as a substitute for the current 'gold standard' they have to be verified against the existing standard. The aim of this study was to compare bone structural measures obtained from 3D microCT data sets with those obtained by stereology performed on conventional histological sections using human tibial bone biopsies. Furthermore, this study forms the first step in introducing the proximal tibia as a potential bone examination location by peripheral quantitative CT and CT. Twenty-nine trabecular bone biopsies were obtained from autopsy material at the medial side of the proximal tibial metaphysis. The biopsies were embedded in methylmetacrylate before microCT scanning in a Scanco microCT 40 scanner at a resolution of 20 x 20 x 20 microm3, and the 3D data sets were analysed with a computer program. After microCT scanning, 16 sections were cut from the central 2 mm of each biopsy and analysed with a computerized method. Trabecular bone volume (BV/TV) and connectivity density (CD) were estimated in both modalities, whereas trabecular bone pattern factor (TBPf) was estimated on the histological sections only. Trabecular thickness (Tb.Th), number (Tb.N) and separation (Tb.Sp), and structure model index (SMI) were estimated with the microCT method only. Excellent correlations were found between the two techniques for BV/TV (r = 0.95) and CD (r = 0.95). Additionally, an excellent relationship (r = 0.95) was ascertained between TBPf and SMI. The study revealed high correlations between measures of bone structure obtained from conventional 2D sections and 3D microCT data. This indicates that 3D microCT data sets can be used as a substitute for conventional histological sections for bone structural evaluations.

Morphological determinants of femoral strength in growth hormone-deficient transgenic growth-retarded (Tgr) rats.

UNLABELLED: The extent to which childhood GHD affects adult fracture risk is unclear. We measured femoral strength in adult transgenic growth-retarded rats as a model of GHD. Long-term, moderate GHD was accompanied by endocrine and morphometric changes consistent with a significant reduction in femoral strength. INTRODUCTION: Childhood growth hormone deficiency (GHD) is associated with osteopenia, but little is known about its effects on subsequent adult bone strength and fracture risk. MATERIALS AND METHODS: We have therefore measured femoral strength (failure load measured by three-point bending) in a new model of moderate GHD, the transgenic growth-retarded (Tgr) rat at 15, 22-23, and 52 weeks of age, and have quantified potential morphological and endocrine determinants of bone strength. RESULTS: Skeletal growth retardation in Tgr rats was accompanied by a sustained reduction in the anterior-posterior diameter of the femoral cortex, whereas mid-diaphyseal cortical wall thicknesses were largely unaltered. Total femoral strength was significantly impaired in Tgr rats (p < 0.01), and this impairment was more pronounced in males than females. Compromised bone strength in Tgr rats could not be accounted for by the reduction in mechanical load (body weight) and was not caused by impairment of the material properties of the calcified tissue (ultimate tensile stress), despite marked reductions in femoral mineral density (areal bone mineral density; p < 0.001). Microcomputerized tomographical analysis revealed significant modification of the architecture of trabecular bone in Tgr rats, with reductions in the number and thickness of trabeculae (p < 0.05) and in the degree of anisotropy (p < 0.01). The marked reduction in plasma insulin-like growth factor-1 in Tgr rats was accompanied by the development of high circulating leptin levels (p < 0.01). CONCLUSION: These results show that the changes in endocrinology and bone morphology associated with long-term moderate GHD in Tgr rats are accompanied by changes consistent with a significant reduction in the threshold for femoral fracture.

A micro-computed tomography study of the trabecular bone structure in the femoral head.

The goal of this study was to characterize the trabecular microarchitecture of the femoral head using micro-computed tomography (ICT). Femoral head specimens were obtained from subjects following total hip replacement. Cylindrical cores from the specimens were scanned to obtain 3-D images with an isotropic resolution of 26 Im. Bone structural parameters were evaluated on a per millimeter basis: relative bone volume (BV/TV), trabecular number (Tb.N), thickness (Tb.Th) and separation (Tb.Sp), structure model index (SMI), and connectivity (Conn.D). The ICT data show that the first two millimeters, starting at the joint surface, are characterized by more plate-like trabeculae, and are significantly denser than the underlying trabecular bone. Regional differences in the trabecular architecture reveal that the superior pole has significantly higher BV/TV, Tb.N and Tb.Th values, with lower Tb.Sp compared to the inferior and side poles. Because subchondral bone is essential in the load attenuation of joints, the difference in bone structure between the subchondral and trabecular bone might arise from the different functions each have within joint-forming bones. The denser trabecular structure of the superior pole as compared to the inferior pole can be interpreted as a functional adaptation to higher loading in this area.

Dietary essential amino acid supplements increase bone strength by influencing bone mass and bone microarchitecture in ovariectomized adult rats fed an isocaloric low-protein diet.

This study was designed to investigate whether the administration of dietary essential amino acid supplements in adult rats made osteoporotic by estrogen deficiency and reduced protein intake could reverse the deleterious effects caused by these maneuvers. This animal model was selected to mimic the situation observed in elderly women in whom estrogen deficiency and/or low-protein intake (but also calcium and vitamin D deficiency) are known to contribute to the pathogenesis of osteoporosis. Six-month-old rats were ovariectomized (OVX) and fed an isocaloric 2.5% casein diet for 10 weeks or sham-operated (SHAM) and fed an isocaloric 15% casein diet. The animals fed the 2.5% casein diet were given isocaloric supplements of essential amino acids in similar relative proportion to that of casein at doses of 2.5% or 5% of total diet for an additional 16 weeks. Vertebrae, femur, and tibia bone mineral density (BMD); ultimate strength; and microtomographic histomorphometry were evaluated before and after dietary essential amino acid supplements. Essential amino acid supplements increased vertebrae, femur, and tibia bone strength in OVX rats fed a low-protein diet. The mechanical changes induced by this dietary isocaloric supplement were associated with the prevention of a further BMD decrease or even with some increases and changes in microarchitecture such as from a rod to a plate trabecular spacial configuration and increased cortical thickness. Higher insulin-like growth factor (IGF) I levels, as well as greater bone formation and reduced bone resorption as assessed by biochemical markers of bone remodeling, were found in rats receiving essential amino acid supplements. In conclusion, dietary essential amino acid supplements increased bone strength through modifications of BMD, trabecular architecture, and cortical thickness possibly by an IGF-I-mediated process.

Mutation of the ectodysplasin-A gene results in bone defects in mice.

Anhidrotic ectodermal dysplasia (EDA) is an X-linked, recessive genetic disease characterized by dysfunctional sweat glands, poorly developed teeth, and premature balding in human beings. This disorder results from mutations in the gene for ectodysplasin-A, a type II transmembrane protein with tumour necrosis factor-alpha domains. An animal model of EDA, the Tabby mouse, also has mutations in the ectodysplasin-A gene and defects similar to those of human beings with EDA. In addition to these defects, Tabby mice acquire deformities in the distal portion of their tails at 10-12 weeks of age. Whole-mount staining of the skeleton with Alizarin Red and Alcian Blue revealed that the tail defect resulted from vertebral fractures just distal to the epiphysis. Histological analysis demonstrated that the structure of both the epiphysis and the subepiphyseal zone of the tail vertebrae was dysplastic while the shaft of the diaphysis was relatively normal. The overall structure of the trabecular bone of these animals was examined through 3-dimensional microcomputed tomography of the tibia. This analysis indicated that Tabby mice had a mild increase in the interconnectivity of the intertwined trabecular bone network but that individual trabeculae were relatively normal. Since it has been determined recently that the ectodysplasin-A gene is expressed in the osteoblasts of developing human embryos, it appears likely that this gene plays a role in normal bone development.

New model-independent measures of trabecular bone structure applied to in vivo high-resolution MR images.

Complementing measurements of bone mass with measurements of the architectural status of trabecular bone is expected to improve predictions of fracture risk in osteoporotic patients and improve the assessment of response to drug therapy. With high-resolution MRI the trabecular network can be imaged with 156 x 156 x 500 microm3 voxels, sufficient to depict individual trabeculae, albeit with inaccurate thickness. In this work, distance transformation techniques were applied to the three-dimensional image of the distal radius of postmenopausal patients. Structural indices such as trabecular number (app.Tb.N), thickness (app.Tb.Th) and separation (app.Tb.Sp) were determined without model assumptions. A new metric index, the apparent intra-individual distribution of separations (app.Tb.Sp.SD), is introduced. The reproducibility of the MR procedure and structure assessment was determined on volunteers, and the coefficient of variation was found to be 2.7-4.6% for the mean values of structural indices and 7.7% for app.Tb.Sp.SD. The distance transformation methods were then applied to two groups of patients: one of postmenopausal women without vertebral fracture and one of postmenopausal women with at least one vertebral fracture. It was found that app.Tb.Sp.SD discriminates fracture subjects from non-fracture patients as well as dual-energy X-ray absorptiometry (DXA) measurements of the radius and the spine, but not as well as DXA of the hip. Using receiver operating characteristic analysis, the area under the curve (AUC) values were 0.67 for app.Tb.Sp.SD, 0.72 for DXA radius, 0.67 for DXA spine and 0.81 for DXA of the hip. A combination of MR indices reached an AUC of 0.75. Age-adjusted odds ratio ranged from 1.85 to 2.03 for app.Tb.N, app.Tb.Sp and app.Tb.Sp.SD (p<0.003). We conclude that in vivo high-resolution MRI not only has the potential of imaging trabecular bone, but in combination with novel metrics may offer new insight into the structural changes occurring in postmenopausal women.

Changes in root canal geometry after preparation assessed by high-resolution computed tomography.

Root canal morphology changes during canal preparation, and these changes may vary depending on the technique used. Such changes have been studied in vitro by measuring cross-sections of canals before and after preparation. This current study used nondestructive high-resolution scanning tomography to assess changes in the canals' paths after preparation. A microcomputed tomography scanner (cubic resolution 34 microm) was used to analyze 18 canals in 6 extracted maxillary molars. Canals were scanned before and after preparation using either K-Files, Lightspeed, or ProFile .04 rotary instruments. A special mounting device enabled precise repositioning and scanning of the specimens after preparation. Differences in surface area (deltaA in mm2) and volume (deltaV in mm3) of each canal before and after preparation were calculated using custom-made software. deltaV ranged from 0.64 to 2.86, with a mean of 1.61 +/- 0.7, whereas deltaA varied from 0.72 to 9.66, with a mean of 4.16 +/- 2.63. Mean deltaV and deltaA for the K-File, ProFile, and Lightspeed groups were 1.28 +/- 0.57 and 2.58 +/- 1.83; 1.79 +/- 0.66 and 4.86 +/- 2.53; and 1.81 +/- 0.57 and 5.31 +/- 2.98, respectively. Canal anatomy and the effects of preparation were further analyzed using the Structure Model Index and the Transportation of Centers of Mass. Under the conditions of this study variations in canal geometry before preparation had more influence on the changes during preparation than the techniques themselves. Consequently studies comparing the effects of root canal instruments on canal anatomy should also consider details of the preoperative canal geometry.

High-resolution three-dimensional-pQCT images can be an adequate basis for in-vivo microFE analysis of bone.

Micro-finite element (microFE) models based on high-resolution images have enabled the calculation of elastic properties of trabecular bone in vitro. Recently, techniques have been developed to image trabecular bone structure in vivo, albeit at a lesser resolution. The present work studies the usefulness of such in-vivo images for microFE analyses, by comparing their microFE results to those of models based on high-resolution micro-CT (microCT) images. Fifteen specimens obtained from human femoral heads were imaged first with a 3D-pQCT scanner at 165 microns resolution and a second time with a microCT scanner at 56 microns resolution. A third set of images with a resolution of 165 microns was created by downscaling the microCT measurements. The microFE models were created directly from these images. Orthotropic elastic properties and the average tissue von Mises stress of the specimens were calculated from six FE-analyses per specimen. The results of the 165 microns models were compared to those of the 56 microns model, which was taken as the reference model. The results calculated from the pQCT-based models, correlated excellent with those calculated from the reference model for both moduli (R2 > 0.95) and for the average tissue von Mises stress (R2 > 0.83). Results calculated from the downscaled micro-CT models correlated even better with those of the reference models (R2 > 0.99 for the moduli and R2 > 0.96 for the average von Mises stress). In the case of the 3D-pQCT based models, however, the slopes of the regression lines were less than one and had to be corrected. The prediction of the Poisson's ratios was less accurate (R2 > 0.45 and R2 > 0.67) for the models based on 3D-pQCT and downscaled microCT images respectively). The fact that the results from the downscaled and original microCT images were nearly identical indicates that the need for a correction in the case of the 3D-pQCT measurements was not due to the voxel size of the images but due to a higher noise level and a lower contrast in these images, in combination with the application of a filtering procedure at 165 micron images. In summary: the results of microFE models based on in-vivo images of the 3D-pQCT can closely resemble those obtained from microFE models based on higher resolution microCT system.

The temporal changes of trabecular architecture in ovariectomized rats assessed by MicroCT.

To study the short- and long-term effects of estrogen deficiency on trabecular bone, three-dimensional measurements of proximal tibiae of ovariectomized rats were performed by micro-computed tomography (MicroCT). New three-dimensional (3D) techniques were employed to characterize the trabecular architecture from 0 to 110 days post-ovariectomy (OVX). These new methods no longer assume a plate or rod model of bone, but calculate trabecular thickness, separation, and number and their distribution by placing maximal spheres into the 3D representation of the structure. The model type of bone was quantified with the Structure Model Index (SMI). Utilizing these methods we found a rapid loss of trabecular bone in the first week after OVX. After the first week bone mass declined further, although the rate of loss was lower. In addition there was a complete change in model type from plate-like to rod-like within 7 days post-OVX, and then a very constant SMI after 12 days. After an initial thinning of trabecular structure, further bone loss seems to occur through removal of trabeculae, while the trabecular plate thickness remains constant. The heterogeneity of the network could be quantified by intra-individual standard deviation of local separations, which showed a stair-like progression, with a plateau between 12 and 60 days post-OVX. This study provides new insights into ovariectomy-related changes in cancellous bone structure evaluated by 3D MicroCT. In addition, these data suggest that the rapid change of model from plate-like to rod-like post-OVX may potentially introduce biases in the parameters that are determined using model-based algorithms, and these biases may modify the impact of age-related or therapeutic changes.

The skeletal structure of insulin-like growth factor I-deficient mice.

The importance of insulin-like growth factor I (IGF-I) for growth is well established. However, the lack of IGF-I on the skeleton has not been examined thoroughly. Therefore, we analyzed the structural properties of bone from mice rendered IGF-I deficient by homologous recombination (knockout [k/o]) using histomorphometry, peripheral quantitative computerized tomography (pQCT), and microcomputerized tomography (muCT). The k/o mice were 24% the size of their wild-type littermates at the time of study (4 months). The k/o tibias were 28% and L1 vertebrae were 26% the size of wild-type bones. Bone formation rates (BFR) of k/o tibias were 27% that of the wild-type littermates. The k/o bones responded normally to growth hormone (GH; 1.7-fold increase) and supranormally to IGF-I (5.2-fold increase) with respect to BFR. Cortical thickness of the proximal tibia was reduced 17% in the k/o mouse. However, trabecular bone volume (bone volume/total volume [BV/TV]) was increased 23% (male mice) and 88% (female mice) in the k/o mice compared with wild-type controls as a result of increased connectivity, increased number, and decreased spacing of the trabeculae. These changes were either less or not found in L1. Thus, lack of IGF-I leads to the development of a bone structure, which, although smaller, appears more compact.

Effects of four Ni-Ti preparation techniques on root canal geometry assessed by micro computed tomography.

AIM: The aim of this study was to compare the effects of four preparation techniques on canal volume and surface area using three-dimensionally reconstructed root canals in extracted human maxillary molars. In addition, micro CT data was used to describe morphometric parameters related to the four preparation techniques. METHODOLOGY: A micro computed tomography scanner was used to analyse root canals in extracted maxillary molars. Specimens were scanned before and after canals were prepared using Ni-Ti - K-Files, Lightspeed instruments, ProFile.04 and GT rotary instruments. Differences in dentine volume removed, canal straightening, the proportion of unchanged area and canal transportation were calculated using specially developed software. RESULTS: Instrumentation of canals increased volume and surface area. Prepared canals were significantly more rounded, had greater diameters and were straighter than unprepared canals. However, all instrumentation techniques left 35% or more of the canals' surface area unchanged. Whilst there were significant differences between the three canal types investigated, very few differences were found with respect to instrument types. CONCLUSIONS: Within the limitations of the micro CT system, there were few differences between the four canal instrumentation techniques used. By contrast, a strong impact of variations of canal anatomy was demonstrated. Further studies with 3D-techniques are required to fully understand the biomechanical aspects of root canal preparation.

Three-dimensional analysis of root canal geometry by high-resolution computed tomography.

A detailed understanding of the complexity of root canal systems is imperative to ensure successful root canal preparation. The aim of this study was to evaluate the potential and accuracy of a three-dimensional, non-destructive technique for detailing root canal geometry by means of high-resolution tomography. The anatomy of root canals in 12 extracted human maxillary molars was analyzed by means of a micro-computed tomography scanner (microCT, cubic resolution 34 microm). A special mounting device facilitated repeated precise repositioning of the teeth in the microCT. Surface areas and volumes of each canal were calculated by triangulation, and means were determined. Model-independent methods were used to evaluate the canals' diameters and configuration. The calculated and measured volumes and the areas of artificial root canals, produced by the drilling of precision holes into dentin disks, were well-correlated. Semi-automated repositioning of specimens resulted in near-perfect matching (< 1 voxel) when outer canal contours were assessed. Root canal geometry was accurately assessed by this innovative technique; therefore, variables and indices presented may serve as a basis for further analyses of root canal anatomy in experimental endodontology.

3D micro-computed tomography of trabecular and cortical bone architecture with application to a rat model of immobilisation osteoporosis.

Bone mass and microarchitecture are the main determinants of bone strength. Three-dimensional micro-computed tomography has the potential to examine complete bones of small laboratory animals with very high resolution in a non-invasive way. In the presented work, the proximal part of the tibiae of hindlimb unloaded and control rats were measured with 3D MicroCT, and the secondary spongiosa of the scanned region was evaluated using direct evaluation techniques that do not require model assumptions. For determination of the complete bone status, the cortex of the tibiae was evaluated and characterised by its thickness. It is shown that with the proposed anatomically conforming volume of interest (VOI), up to an eight-fold volume increase can be evaluated compared to cubic or spherical VOIs. A pronounced trabecular bone loss of -50% is seen after 23 days of tail suspension. With the new evaluation techniques, it is shown that most of this bone loss is caused by the thinning of trabeculae, and to a lesser extent by a decrease in their number. What changes most radically is the structure type: the remaining bone is more rod-like than the control group's bone. Cortical bone decreases less than trabecular bone, with only -18% after 23 days.

Load transfer analysis of the distal radius from in-vivo high-resolution CT-imaging.

Prevention of osteoporotic bone fractures requires accurate diagnostic methods to detect the increase in bone fragility at an early stage of osteoporosis. However, today's bone fracture risk prediction, primarily based on bone density measurement, is not sufficiently precise. There is increasing evidence that, in addition to bone density, also the bone microarchitecture and its mechanical loading conditions are important factors determining the fracture risk. Recently, it has been shown that new high-resolution imaging techniques in combination with new computer modeling techniques based on the finite-element (FE) method can account for these additional factors. These techniques might provide information that is more relevant for the prediction of bone fracture risk. So far, however, these new imaged-based FE techniques have not been feasible in-vivo. The objectives of this study were to quantify the load transfer through the trabecular network in a distal radius using a computer model based on in-vivo high-resolution images and to determine if common regions of fractures can be explained as a result of high tissue loading in these regions. The left distal radius and the two adjacent carpal bones of a healthy volunteer were imaged using a high-resolution three-dimensional CT system providing an isotropic resolution of 165 microm. The bone representation was converted into a FE-model that was used to calculate stresses and strains in the trabecular network. The two carpal bones were loaded using different load ratios (for each load case 1000 N in total) representing impact forces on the hand either in near-neutral position or ulnar/radial deviation. The load transfer through the trabecular network of the radius was characterized by the tissue strain energy density (SED) distribution for all load cases. It was found that the distribution of the tissue loading depends on the ratio of the forces acting on the carpal bones. For all load cases the higher SED values (on average: 0.02 +/- 0.08 (S.D.) N mm(-2)) are found in a 10 mm region adjacent to the articular surface which corresponds well with the region where Colles- or Chauffeur-fractures occur. We expect that, eventually, this new approach can lead to a better prediction of the fracture risk than methods based on bone density alone since it accounts for the bone microstructure as well as its loading conditions.

Direct three-dimensional morphometric analysis of human cancellous bone: microstructural data from spine, femur, iliac crest, and calcaneus.

The appearance of cancellous bone architecture is different for various skeletal sites and various disease states. During aging and disease, plates are perforated and connecting rods are dissolved. There is a continuous shift from one structural type to the other. So traditional histomorphometric procedures, which are based on a fixed model type, will lead to questionable results. The introduction of three-dimensional (3D) measuring techniques in bone research makes it possible to capture the actual architecture of cancellous bone without assumptions of the structure type. This requires, however, new methods that make direct use of the 3D information. Within the framework of a BIOMED I project of the European Union, we analyzed a total of 260 human bone biopsies taken from five different skeletal sites (femoral head, vertebral bodies L2 and L4, iliac crest, and calcaneus) from 52 donors. The samples were measured three-dimensionally with a microcomputed tomography scanner and subsequently evaluated with both traditional indirect histomorphometric methods and newly developed direct ones. The results show significant differences between the methods and in their relation to the bone volume fraction. Based on the direct 3D analysis of human bone biopsies, it appears that samples with a lower bone mass are primarily characterized by a smaller plate-to-rod ratio, and to a lesser extent by thinner trabecular elements.

The ability of three-dimensional structural indices to reflect mechanical aspects of trabecular bone.

Bone mineral density (BMD) and bone microarchitecture are important determinants for the mechanical properties of cancellous bone. Although BMD alone is a good predictor of average mechanical properties of cancellous bone, there remains unexplained variation in mechanical properties that might be due to missing information regarding bone microarchitecture. Recent developments in three-dimensional (3D) structural analysis have provided possibilities for measuring a variety of structural indices to characterize bone microarchitecture. The objectives of this study were to calculate structural indices and elastic constants of human cancellous bone from different skeletal sites and to investigate the predictive value of different 3D structural indices for the elastic properties of bone. A total of 237 cancellous bone samples taken from the iliac crest, lumbar spine, femoral head, and calcaneus were imaged with a 3D microcomputed tomography (microCT) system. The segmented 3D images were used to calculate BV/TV, BS/TV, Tb.Th, Tb.Sp, Tb.N, and MII ratio and for microstructural finite-element (microFE) analysis to calculate Young's moduli, shear moduli, and Poisson's ratios. A subgroup of "critical" specimens within each site was selected to represent specimens that could not be identified as osteoporotic or normal on the basis of BMD measurement alone. For these "critical" specimens, structural indices and elastic constants were correlated by means of linear multivariate regression analysis. It was found that the elastic constants clearly correlated better when one of the 3D structural indices was included as independent variable than when BV/TV was the only independent variable. Each of the examined structural indices could improve the correlation: the R2 values were maximally increased from 53% (BV/TV alone) to 82% (BV/TV and MIL ratio). The most effective indices, however, were not the same for the different skeletal sites. Even better correlations were found when more than one of the 3D structural indices were included as independent variables: the R2 values were maximally increased from 53% (BV/TV alone) to 92% (BV/TV, Tb.Sp, and MIL ratio). The prediction of elastic constants for cancellous bone samples is clearly improved when BV/TV is supplemented with 3D structural indices. These results suggest that the determination of mechanical properties of bone and the diagnosis of osteoporosis can be improved if, in addition to BMD, the 3D bone microarchitecture is assessed in vivo.