Home About us Contact
|
Home About us Contact | ||
|
|
||
Trabecular Bone (trabecular + bone)
Terms modified by Trabecular Bone Selected AbstractsHip Fractures and the Contribution of Cortical Versus Trabecular Bone to Femoral Neck Strength,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2009Gerold Holzer Abstract Osteoporotic fractures are caused by both cortical thinning and trabecular bone loss. Both are seen to be important for bone fragility. The relative contributions of cortical versus trabecular bone have not been established. The aim of this study was to test the contribution of cortical versus trabecular bone to femoral neck stability in bone strength. In one femur from each pair of 18 human cadaver femurs (5 female; 4 male), trabecular bone was completely removed from the femoral neck, providing one bone with intact and the other without any trabecular structure in the femoral neck. Geometrical, X-ray, and DXA measurements were carried out before biomechanical testing (forces to fracture). Femoral necks were osteotomized, slices were analyzed for cross-sectional area (CSA) and cross-sectional moment of inertia (CSMI), and results were compared with biomechanical testing data. Differences between forces needed to fracture excavated and intact femurs (,F/F mean) was 7.0% on the average (range, 4.6,17.3%). CSA of removed spongiosa did not correlate with difference of fracture load (,F/F mean), nor did BMD. The relative contribution of trabecular versus cortical bone in respect to bone strength in the femoral neck seems to be marginal and seems to explain the subordinate role of trabecular bone and its changes in fracture risk and the effects of treatment options in preventing fractures. [source] Microarchitecture Influences Microdamage Accumulation in Human Vertebral Trabecular Bone,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2008Monique E Arlot Abstract It has been suggested that accumulation of microdamage with age contributes to skeletal fragility. However, data on the age-related increase in microdamage and the association between microdamage and trabecular microarchitecture in human vertebral cancellous bone are limited. We quantified microdamage in cancellous bone from human lumbar (L2) vertebral bodies obtained from 23 donors 54,93 yr of age (8 men and 15 women). Damage was measured using histologic techniques of sequential labeling with chelating agents and was related to 3D microarchitecture, as assessed by high-resolution ,CT. There were no significant differences between sexes, although women tended to have a higher microcrack density (Cr.Dn) than men. Cr.Dn increased exponentially with age (r = 0.65, p < 0.001) and was correlated with bone volume fraction (BV/TV; r = ,0.55; p < 0.01), trabecular number (Tb.N; r = ,0.56 p = 0.008), structure model index (SMI; r = 0.59; p = 0.005), and trabecular separation (Tb.Sp; r = 0.59; p < 0.009). All architecture parameters were strongly correlated with each other and with BV/TV. Stepwise regression showed that SMI was the best predictor of microdamage, explaining 35% of the variance in Cr.Dn and 20% of the variance in diffuse damage accumulation. In addition, microcrack length was significantly greater in the highest versus lowest tertiles of SMI. In conclusion, in human vertebral cancellous bone, microdamage increases with age and is associated with low BV/TV and a rod-like trabecular architecture. [source] Bone Material Properties in Trabecular Bone From Human Iliac Crest Biopsies After 3- and 5-Year Treatment With Risedronate,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2006Erich Durchschlag Abstract Long-term effects of risedronate on bone mineral maturity/crystallinity and collagen cross-link ratio in triple iliac crest biopsies of osteoporotic women were evaluated. In this double-blinded study, 3- and 5-year treatment with risedronate arrested the tissue aging encountered in untreated osteoporosis and in osteoporosis treated with other antiresorptives. This effect may be contributing to risedronate's antifracture efficacy. Introduction: Risedronate is widely used in the treatment of osteoporosis. It reduces bone turnover, increases BMD, and decreases fracture risk. To date, there are no data available on the long-term effects of risedronate on bone material properties in humans. Materials and Methods: Osteoporotic women enrolled in the VERT-NA trial received either risedronate (5 mg/day, orally) or placebo for up to 5 years. All subjects received calcium. They also received vitamin D supplementation if deficient at baseline. Triple iliac crest biopsies were collected from a subset of these subjects at baseline, 3 years, and 5 years. Mineral maturity/crystallinity and collagen cross-link ratio was measured in these biopsies using Fourier transform infrared imaging. Results: Patients that received placebo exhibited increased mineral maturity/crystallinity and collagen cross-link ratio after 3 and 5 years compared with baseline values. On the contrary, patients that received risedronate retained baseline values in both bone material indices throughout. A more spatially detailed analysis revealed that this was achieved mainly through beneficial effects on active bone-forming areas. Surprisingly, patients that received risedronate achieved premenopausal values at bone-forming areas in both indices after 5 years of treatment. Conclusion: Long-term treatment with risedronate affects bone material properties (mineral maturity/crystallinity and collagen cross-link ratio) and arrests the tissue aging apparent in untreated osteoporosis. These changes at the material level of the bone matrix may contribute to risedronate's rapid and sustained antifracture efficacy in osteoporotic patients. [source] QTL Analysis of Trabecular Bone in BXD F2 and RI Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2006Abbey L Bower Abstract A sample of 693 mice was used to identify regions of the mouse genome associated with trabecular bone architecture as measured using ,CT. QTLs for bone in the proximal tibial metaphysis were identified on several chromosomes indicating regions containing genes that regulate properties of trabecular bone. Introduction: Age-related osteoporosis is a condition of major concern because of the morbidity and mortality associated with osteoporotic fractures in humans. Osteoporosis is characterized by reduced bone density, strength, and altered trabecular architecture, all of which are quantitative traits resulting from the actions of many genes working in concert with each other and the environment over the lifespan. ,CT gives accurate measures of trabecular bone architecture providing phenotypic data related to bone volume and trabecular morphology. The primary objective of this research was to identify chromosomal regions called quantitative trait loci (QTLs) that contain genes influencing trabecular architecture as measured by ,CT. Materials and Methods: The study used crosses between C57BL/6J (B6) and DBA/2J (D2) as progenitor strains of a second filial (F2) generation (n = 141 males and 148 females) and 23 BXD recombinant inbred (RI) strains (n , 9 of each sex per strain). The proximal tibial metaphyses of the 200-day-old mice were analyzed by ,CT to assess phenotypic traits characterizing trabecular bone, including bone volume fraction, trabecular connectivity, and quantitative measures of trabecular orientation and anisotropy. Heritabilities were calculated and QTLs were identified using composite interval mapping. Results: A number of phenotypes were found to be highly heritable. Heritability values for measured phenotypes using RI strains ranged from 0.15 for degree of anisotropy in females to 0.51 for connectivity density in females and total volume in males. Significant and confirmed QTLs, with LOD scores ,4.3 in the F2 cohort and ,1.5 in the corresponding RI cohort were found on chromosomes 1 (43 cM), 5 (44 cM), 6 (20 cM), and 8 (49 cM). Other QTLs with LOD scores ranging from 2.8 to 6.9 in the F2 analyses were found on chromosomes 1, 5, 6, 8, 9, and 12. QTLs were identified using data sets comprised of both male and female quantitative traits, suggesting similar genetic action in both sexes, whereas others seemed to be associated exclusively with one sex or the other, suggesting the possibility of sex-dependent effects. Conclusions: Identification of the genes underlying these QTLs may lead to improvements in recognizing individuals most at risk for developing osteoporosis and in the design of new therapeutic interventions. [source] ,-Arrestin2 Regulates the Differential Response of Cortical and Trabecular Bone to Intermittent PTH in Female Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2005Mary L Bouxsein PhD Abstract Cytoplasmic arrestins regulate PTH signaling in vitro. We show that female ,-arrestin2,/, mice have decreased bone mass and altered bone architecture. The effects of intermittent PTH administration on bone microarchitecture differed in ,-arrestin2,/, and wildtype mice. These data indicate that arrestin-mediated regulation of intracellular signaling contributes to the differential effects of PTH at endosteal and periosteal bone surfaces. Introduction: The effects of PTH differ at endosteal and periosteal surfaces, suggesting that PTH activity in these compartments may depend on some yet unidentified mechanism(s) of regulation. The action of PTH in bone is mediated primarily by intracellular cAMP, and the cytoplasmic molecule ,-arrestin2 plays a central role in this signaling regulation. Thus, we hypothesized that arrestins would modulate the effects of PTH on bone in vivo. Materials and Methods: We used pDXA, ,CT, histomorphometry, and serum markers of bone turnover to assess the skeletal response to intermittent PTH (0, 20, 40, or 80 ,g/kg/day) in adult female mice null for ,-arrestin2 (,-arr2,/,) and wildtype (WT) littermates (7-11/group). Results and Conclusions: ,-arr2,/, mice had significantly lower total body BMD, trabecular bone volume fraction (BV/TV), and femoral cross-sectional area compared with WT. In WT females, PTH increased total body BMD, trabecular bone parameters, and cortical thickness, with a trend toward decreased midfemoral medullary area. In ,-arr2,/, mice, PTH not only improved total body BMD, trabecular bone architecture, and cortical thickness, but also dose-dependently increased femoral cross-sectional area and medullary area. Histomorphometry showed that PTH-stimulated periosteal bone formation was 2-fold higher in ,-arr2,/, compared with WT. Osteocalcin levels were significantly lower in ,-arr2,/, mice, but increased dose-dependently with PTH in both ,-arr2,/, and WT. In contrast, whereas the resorption marker TRACP5B increased dose-dependently in WT, 20-80 ,g/kg/day of PTH was equipotent with regard to stimulation of TRACP5B in ,-arr2,/,. In summary, ,-arrestin2 plays an important role in bone mass acquisition and remodeling. In estrogen-replete female mice, the ability of intermittent PTH to stimulate periosteal bone apposition and endosteal resorption is inhibited by arrestins. We therefore infer that arrestin-mediated regulation of intracellular signaling contributes to the differential effects of PTH on cancellous and cortical bone. [source] Loss of Chaotic Trabecular Structure in OPG-Deficient Juvenile Paget's Disease Patients Indicates a Chaogenic Role for OPG in Nonlinear Pattern Formation of Trabecular BoneJOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2004Phil Salmon PhD Abstract The RANK-RANKL-OPG system of osteoclast regulation may play a key role in determining chaotic structure in trabecular bone. Iliac trabecular bone from juvenile Paget's disease patients deficient in functional OPG shows parallel, anisotropic structure instead of normal chaotic structure. Evidence from experimental systems suggests that RANK-RANKL-OPG controls key nonlinear "chaogenic" parameters, such as friction, forcing frequency, feedback, and boundary forcing. The RANK-RANKL-osteoprotegerin (OPG) system of osteoclast regulation may play a key role in determining chaotic structure in trabecular bone. Iliac trabecular bone from juvenile Paget's disease (JPD) patients deficient in functional OPG shows parallel, anisotropic structure instead of normal chaotic structure. Evidence from experimental systems suggests that RANK-RANKL-OPG controls key nonlinear "chaogenic" parameters, such as friction, forcing frequency, feedback, and boundary forcing. The Belousov-Zhabotinsky reaction-diffusion system, the catalytic oxidation of CO on platinum surfaces, and thermal diffusion in liquid helium allow visualization of nonlinear emergent patterns such as labyrinthine structures, turbulence, and cellular structures, all of which bear some resemblance to trabecular bone. In JPD, the gene for OPG (TNFRSF11B) is subject to an inactivating mutation, leading to increased resorption and accelerated remodeling. Histomorphometric images of iliac crest trabecular bone from teenagers suffering from JPD show a highly unusual array of parallel, regular trabecular plates, instead of the typical chaotic, fractal patterns of normal trabecular bone. Loss of OPG function is associated with a change from chaotic to regular structure, suggesting that the RANK-RANKL-OPG system is controlling key nonlinear "chaogenic" parameters. Looking at trabecular bone from the perspective of nonlinear pattern formation may help understand other phenomena, such as the marked dependence of trabecular bone's architectural and mechanical quality on remodeling rate independent of the trabecular bone mass. [source] A Three-Dimensional Simulation of Age-Related Remodeling in Trabecular Bone,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2001J. C. Van Der Linden Abstract After peak bone mass has been reached, the bone remodeling process results in a decrease in bone mass and strength. The formation deficit, the deficit of bone formation compared with previous resorption, results in bone loss. Moreover, trabeculae disconnected by resorption cavities probably are not repaired. The contributions of these mechanisms to the total bone loss are unclear. To investigate these contributions and the concomitant changes in trabecular architecture and mechanical properties, we made a computer simulation model of bone remodeling using microcomputed tomography (micro-CT) scans of human vertebral trabecular bone specimens. Up to 50 years of physiological remodeling were simulated. Resorption cavities were created and refilled 3 months later. These cavities were not refilled completely, to simulate the formation deficit. Disconnected trabeculae were not repaired; loose fragments generated during the simulation were removed. Resorption depth, formation deficit, and remodeling space were based on biological data. The rate of bone loss varied between 0.3% and 1.1% per year. Stiffness anisotropy increased, and morphological anisotropy (mean intercept length [MIL]) was almost unaffected. Connectivity density increased or decreased, depending on the remodeling parameters. The formation deficit accounted for 69,95%, disconnected trabeculae for 1,21%, and loose fragments for 1,17% of the bone loss. Increasing formation deficit from 1.8% to 5.4% tripled bone loss but only doubled the decrease in stiffness. Increasing resorption depth from 28 to 56 ,m slightly increased bone loss but drastically decreased stiffness. Decreasing the formation deficit helps to prevent bone loss, but reducing resorption depth is more effective in preventing loss of mechanical stiffness. [source] Influence of preimplant surgical intervention and implant placement on bone wound healingCLINICAL ORAL IMPLANTS RESEARCH, Issue 5 2003Christer Slotte Abstract: The aims of the present investigation were to study (1) the influence of preimplant (4 weeks) surgical intervention and (2) the influence of the implant placement per se on bone density and mineralized bone,implant contact (BIC) at implant sites in the rabbit jawbone. The experiment was performed in the edentulous area of the maxillas of 16 adult rabbits. In eight rabbits, the alveolar bone on the left side (test) was surgically exposed and a groove was prepared in the bone crest. Trabecular bone and marrow tissue were removed, and a bioabsorbable barrier membrane was placed to cover the groove. The right side underwent no treatment and served as the control. Four weeks later, a screw-shaped titanium implant was placed transversally through the maxilla, penetrating both the test and the control areas. After another 4 weeks of healing, the animals were killed to obtain ground sections for histomorphometry. Untreated jaws from eight rabbits served as reference specimens. In the rabbits subjected to surgery, the areas (mm2) of both mineralized bone and marrow tissue were similar for test and control (4.9 ± 1.7 vs. 5.1 ± 2.2 and 6.3 ± 5.7 vs. 6.8 ± 5.7 for bone and marrow, respectively). The BIC (%) for all threads was significantly lower on the test side than on the control side (32.1 ± 27.7 vs. 47.7 ± 20.3). The bone density (%) of the total experimental area was similar for test and control (48.5 ± 12.1 vs. 46.5 ± 9.3), as was the bone density in the area within the implant thread valleys and their mirror areas (43.0 ± 13.9 vs. 41.3 ± 13.5, and 40.2 ± 11.0 vs. 40.3 ± 7.2 for thread area and mirror area, respectively). The bone density of the total experimental area in the untreated rabbits was 35.9 ± 5.2%. This value was significantly lower than the values in the total experimental areas (test and control) of the surgically treated rabbits. Similarly, the density of the reference area in the untreated rabbits was 25.4 ± 5.3%, which was also significantly lower than the bone density of the periimplant area of the surgically treated rabbits. We conclude that the surgical trauma caused by the placement of implants in the maxilla of rabbits significantly enhanced the bone density of the implant sites. Surgical intervention in the implant sites 4 weeks prior to the implant placements, however, did not further enhance bone density or BIC. Résumé Les buts de cette étude ont été d'étudier 1) l'influence d'une intervention chirurgicale préimplantaire (4 semaines) et 2) l'influence du placement de l'implant per se sur la densité osseuse et le contact implant-os minéralisé (BIC). Cette expérience a été effectuée dans la région édentée du maxillaire de seize lapins adultes. Chez huit lapins, l'os alvéolaire du côté gauche (test) était chirurgicalement exposé et une marque a été faite dans la crête osseuse. L'os trabéculaire et le tissu spongieux ont été enlevés et une membrane biorésorbable a été placée pour couvrir ce trou. Le côté droit ne subissait aucun traitement et a servi de contrôle. Quatre semaines après, un implant en titane vis a été placé transversalement à travers le maxillaire pénétrant tant la zone test que contrôle. Après quatre semaines de guérison les animaux ont été tués pour obtenir des coupes pour l'histomorphométrie. Les mâchoires non-traitées de huit lapins ont servi de spécimens de référence. Chez les lapins soumis à la chirugie les zones d'os minéralisé et de tissu spongieux étaient semblables pour le test et le contrôle (respectivement 4,9±1,7 mm2 vs 5,1±2,2 mm2 et 6,3±5,7 mm2 vs 6,8±5,7mm2). Les BIC pour tous les filetages étaient significativement moins importants au niveau des tests que des contrôles (32,1±27,7% vs 47,7±20,3%). La densité osseuse du total de l'aire expérimentale était semblable pour les tests et les contrôles (48,5±12,1%vs 46,3±9,3%) comme l'était la densité osseuse dans la zone à l'intérieur du filetage de l'implant et de leurs aires mineures (43,0±13,9%vs 41,3±13,5% pour les filetages et 40,2±11,0% vs40,3±7,2% pour les aires mineures). La densité osseuse de l'aire expérimentale totale chez les lapins nont-traités était de 35,9 ±5,2%. Cette valeur était significativement inférieure à celles dans les aires expérimentales totales (tests et contrôles) des lapins traités chirurgicalement. Parallèlement, la densité de l'aire de référence des lapins non-traités était de 25,4±5,3% c.-à-d. inférieure à la densité osseuse de la zone paroïmplantaire des lapins traités chirurgicalement. Le trauma chirurgical causé par le placement d'implants dans le maxillaire de lapins augmente significativement la densité osseuse au niveau des sites implantaires. L'intervention chirurgicale des sites à implanter quatre semaines avant le placement des implants n'avait cependant augmenté ni la densité osseuse ni le BIC. Zussammenfassung Der Einfluss eines praeimplantären chirurgischen Eingriffes und der Implantation per se auf die Heilung der Knochenwunde. Eine Studie am Kieferknochen des Kaninchens. Ziel: Das Ziel dieser Studie war es 1) den Einfluss eines praeimplantären chirurgischen Eingriffes (4 Wochen vorher) und 2) den Einfluss der Implantation per se auf die Knochendichte und den mineralisierten Knochen-Implantatkontakt (BIC) an einer Implantationsstelle im Kieferknochen des Kaninchens zu untersuchen. Material und Methode: Die Testregion war der zahnlose Oberkieferabschnitt von 16 ausgewachsenen Kaninchen. Bei 8 Kaninchen wurde der Alveolarknochen der linken Seite (Test) chirurgisch freigelegt und eine Vertiefungen in den Knochenkortex präpariert. Dann entfernte man den trabekulären Knochen und das Knochenmark und deckte die Vertiefung mit einer bioresorbierbaren Membran ab. Die rechte Seite wurde unbehandelt belassen und diente als Kontrolle. Vier Wochen später implantierte man ein schraubenförmiges Titanimplantat transversal durch die Maxilla, so dass es Test- oder Kontrollregion durchdrang. Nach einer Heilphase von weiteren vier Wochen wurden die Tiere geopfert und von der zu untersuchenden Region Grundschnitte für die Histologie hergestellt. Als Referenz dienten unbehandelte (jungfräuliche) Kiefer von weiteren 8 Kaninchen. Resultate: Bei den Kaninchen, welche die oben beschriebenen chirurgischen Schritte durchlaufen haben, waren sowohl bei der Test- wie auch bei der Kontrollgruppe die Fläche von mineralisiertem Knochen und Knochenmark (in mm2) ähnlich gross (4.9+1.7 gegenüber 5.1+2.2 beim Knochen und 6.3+5.7 gegenüber 6.8+5.7 beim Knochenmark). Der BIC (%) war in allen Schraubenwindungen auf der Testseite signifikant tiefer als auf der Kontrollseite (32.1+27.7 gegenüber 47.7+20.3). Die Knochendichte (%) war in der untersuchten Region bei der Test- und Kontrollseite etwa gleich gross (48.5+12.1 gegenüber 46.5+9.3) wie die Knochendichte in den Vertiefungen der Schraubenwindungen und ihrer spiegelbildlichen Regionen (43.0+13.9 gegenüber 41.3+13.5 in den Schraubenwindungen und 40.2+11.0 gegenüber 40.3+7.2 in den spiegelbildlichen Regionen). Die Knochendichte in der gesamten Region der unbehandelten (jungfräulichen) Kaninchen betrug 35.9+5.2%. Dieser Wert war signifikant tiefer als die Werte der gesamten untersuchten Region der chirurgisch behandelten Kaninchen (Test- und Kontrollseite). Ganz ähnlich war die Dichte in der Referenzregion der unbehandelten Kaninchen 25.4+5.3%, ein Wert der auch signifikant tiefer war als die Knochendichte in der periimplantären Region von chirurgisch behandelten Kaninchen. Zusammenfassung: Das chirurgische Trauma, das beim Setzen eines Implantates im Oberkiefer von Kaninchen entsteht, begünstigt die Knochendichte an den Stellen der Implantate signifikant. Der chirurgischen Eingriff vier Wochen vor der Implantation jedoch, förderte an den zur Implantation vorgesehenen Stellen weder Knochendichte noch BIC. Resumen Objetivos: La intención de la presente investigación fue estudiar 1) la influencia de la intervención quirúrgica (4 semanas) periimplantaria y 2) la influencia de la colocación de implantes per se en la densidad ósea y el contacto del hueso mineralizado al implante (BIC) en los lugares de implante en el hueso mandibular del conejo. Material y métodos: El experimento se realizó en el área edéntula del maxilar de 16 conejos adultos. Se expuso quirúrgicamente el hueso alveolar en el lado izquierdo (test) de 8 conejos y se preparó un hueco en la cresta ósea. Se retiró el hueso trabecular y el tejido de médula ósea, colocándose una membrana de barrera biorreabsorbible para cubrir el hueco. El lado derecho no sufrió ningún tratamiento y sirvió de control. Cuatro semanas mas tarde, se colocó un implante de forma roscada transversalmente a través del maxilar, penetrando las áreas de prueba y de control. Tras otras 4 semanas de cicatrización, los animales se sacrificaron para obtener cortes histológicos para histomorfometría. Las mandíbulas sin tratar de los 8 conejos sirvieron como especímenes de referencia. Resultados: En los conejos sometidos a cirugía las áreas (mm2) del hueso mineralizado y del tejido medular fueron similares para la prueba y el control (4.9 ± 1.7 vs. 5.1 ± 2.2 y 6.3 ± 5.7 vs. 6.8 ± 5.7, hueso y médula respectivamente). El BIC (%) para todas las roscas fue significativamente mas bajo en el lado de prueba que en el de control (32.1 ± 27.7 vs. 47.7 ± 20.3). La densidad de ósea (%) de toda el área experimental fue similar para la prueba y el control (48.5 ± 12.1 vs. 46.5 ± 9.3) así como la densidad ósea en el área en los valles entre las roscas y en su área espejo (43.0 ± 13.9 vs. 41.3 ± 13.5, y 40.2 ± 11.0 vs. 40.3 ± 7.2, área de roscas y área espejo respectivamente). La densidad ósea en el área total experimental en los conejos no tratados (vírgenes) fue del 35.9 ± 5.2%. Este valor fue significativamente mas bajo que los valores en el total de las áreas experimentales (test y control) de los conejos tratados quirúrgicamente. Del mismo modo, la densidad del área de referencia de los conejos no tratados fue de 25.4 ± 5.3%, que también fue significativamente mas baja que la densidad ósea del área periimplantaria de los conejos tratados quirúrgicamente. Conclusión: El trauma quirúrgico causado por la colocación de implantes en el maxilar de conejos estimuló significativamente la densidad ósea de los lugares de implantes. Sin embargo, la intervención quirúrgica de los lugares de implantes 4 semanas antes de la colocación de los implantes no estimuló mas la densidad ósea o el BIC. [source] Functional behaviour of bone around dental implants,GERODONTOLOGY, Issue 2 2004Clark M. Stanford Achieving a long-term stable implant interface is a significant clinical issue when there is insufficient cortical bone stabilisation at implant placement. Clinical outcomes studies suggest that the higher risk implants are those placed in compromised cortical bone (thin, porous, etc.) in anatomical sites with minimal existing trabecular bone (characterised as type IV bone). In establishing and maintaining an implant interface in such an environment, one needs to consider the impact of masticatory forces, the response of bone to these forces and the impact of age on the adaptive capacity of bone. These forces, in turn, have the potential to create localised changes in interfacial stiffness through viscoelastic changes at the interface. Changes in bone as a function of age (e.g. localised hypermineralised osteopetrosis and localised areas of osteopenia) will alter the communication between osteocytes and osteoblasts creating the potential for differences in response of osteoblastic cells in the older population. A key to understanding the biomechanical and functional behaviour of implants in the older population is to control the anticipated modelling and remodelling behaviour through implant design that takes into account how tissues respond to the mechanically active environment. [source] Relevance of a new rat model of osteoblastic metastases from prostate carcinoma for preclinical studies using zoledronic acidINTERNATIONAL JOURNAL OF CANCER, Issue 4 2008François Lamoureux Abstract Animal models that mimic osteoblastic metastases associated with prostate carcinoma are required to improve the therapeutic options in humans. A new model was then developed and characterized in immunocompetent rats. The bisphosphonate zoledronic acid (ZOL) was tested to validate this model as a therapeutic application. Rat AT6-1 prostate tumor cells were characterized in vitro at the transcriptional (bone and epithelial markers) and functional (induction of mineralized nodules) levels. The bone lesions induced after their direct injection into the femur bone marrow were characterized by radiography, microscanner and histology analyses. ZOL effects were studied in vivo on bone lesion development and in vitro on AT6-1 cell proliferation, apoptosis and cell cycle analysis. Apart from epithelial markers, AT6-1 cells express an osteoblast phenotype as they express osteoblastic markers and are able to induce mineralized nodule formation in vitro. A disorganization of the trabecular bone at the growth zone level was observed in vivo after intraosseous AT6-1 cell injection as well as cortical erosion. The tumor itself is associated with bone formation as revealed by SEM analysis and polarized light microscopy. ZOL prevents the development of such osteoblastic lesions, related to a direct inhibitory effect on tumor cell proliferation independent of caspase 3 activation, but associated with cell cycle arrest. A new rat model of osteoblastic bone metastases was validated in immunocompetent rats and used to show the relevance of using ZOL in such lesions, as this compound shows bifunctional effects on both bone remodelling and tumor cell proliferation. © 2007 Wiley-Liss, Inc. [source] Anticipating bipedalism: trabecular organization in the newborn iliumJOURNAL OF ANATOMY, Issue 6 2009Craig A. Cunningham Abstract Trabecular bone structural organization is considered to be predominantly influenced by localized temporal forces which act to maintain and remodel the trabecular architecture into a biomechanically optimal configuration. In the adult pelvis, the most significant remodelling forces are believed to be those generated during bipedal locomotion. However, during the fetal and neonatal period the pelvic complex is non-weight bearing and, as such, structural organization of iliac trabecular bone cannot reflect direct stance-related forces. In this study, micro-computed tomography scans from 28 neonatal ilia were analysed, using a whole bone approach, to investigate the trabecular characteristics present within specific volumes of interest relevant to density gradients highlighted in a previous radiographic study. Analysis of the structural indices bone volume fraction, trabecular thickness, trabecular spacing and trabecular number was carried out to quantitatively investigate structural composition. Quantification of the neonatal trabecular structure reinforced radiographic observations by highlighting regions of significant architectural form which grossly parallel architectural differences in the adult pattern but which have previously been attributed to stance-related forces. It is suggested that the seemingly organized rudimentary scaffold observed in the neonatal ilium may be attributable to other non-weight bearing anatomical interactions or even to a predetermined genetic blueprint. It must also be postulated that whilst the observed patterning may be indicative of a predetermined inherent template, early non-weight bearing and late stance-related locomotive influences may subsequently be superimposed upon this scaffolding and perhaps reinforced and likely remodelled at a later age. Ultimately, the analysis of this fundamental primary pattern has core implications for understanding the earliest changes in pelvic trabecular architecture and provides a baseline insight into future ontogenetic development and bipedal capabilities. [source] Porosity of human mandibular condylar boneJOURNAL OF ANATOMY, Issue 3 2007G. A. P. Renders Abstract Quantification of porosity and degree of mineralization of bone facilitates a better understanding of the possible effects of adaptive bone remodelling and the possible consequences for its mechanical properties. The present study set out first to give a three-dimensional description of the cortical canalicular network in the human mandibular condyle, in order to obtain more information about the principal directions of stresses and strains during loading. Our second aim was to determine whether the amount of remodelling was larger in the trabecular bone than in cortical bone of the condyle and to establish whether the variation in the amount of remodelling was related to the surface area of the cortical canals and trabeculae. We hypothesized that there were differences in porosity and orientation of cortical canals between various cortical regions. In addition, as greater cortical and trabecular porosities are likely to coincide with a greater surface area of cortical canals and trabeculae available for osteoblastic and osteoclastic activity, we hypothesized that this surface area would be inversely proportional to the degree of mineralization of cortical and trabecular bone, respectively. Micro-computed tomography was used to quantify porosity and mineralization in cortical and trabecular bone of ten human mandibular condyles. The cortical canals in the subchondral cortex of the condyle were orientated in the mediolateral direction, and in the anterior and posterior cortex in the superoinferior direction. Cortical porosity (average 3.5%) did not differ significantly between the cortical regions. It correlated significantly with the diameter and number of cortical canals, but not with cortical degree of mineralization. In trabecular bone (average porosity 79.3%) there was a significant negative correlation between surface area of the trabeculae and degree of mineralization; such a correlation was not found between the surface area of the cortical canals and the degree of mineralization of cortical bone. No relationship between trabecular and cortical porosity, nor between trabecular degree of mineralization and cortical degree of mineralization was found, suggesting that adaptive remodelling is independent and different between trabecular and cortical bone. We conclude (1) that the principal directions of stresses and strains are presumably directed mediolaterally in the subchondral cortex and superoinferiorly in the anterior and posterior cortex, (2) that the amount of remodelling is larger in the trabecular than in the cortical bone of the mandibular condyle; in trabecular bone variation in the amount of remodelling is related to the available surface area of the trabeculae. [source] Effect of Zn deficiency and subsequent Zn repletion on bone mineral composition and markers of bone tissue metabolism in 65Zn-labelled, young-adult ratsJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 7-8 2002W. Windisch Summary The objective of the present study was to investigate the effect of changing skeletal Zn load (mobilization/restoring) on bone mineral composition and bone tissue metabolism. For this purpose, 36 65Zn-labelled, young-adult female rats were fed with either a purified diet with sufficient Zn (21 ,g/g, control) for 26 days, or deficient Zn (1.4 ,g/g) for 12 days followed by 14 days repletion with the control diet. The animals were killed at the onset of the study (reference: n=4), at the end of the Zn deficiency episode (control: n=4; Zn deficiency: n=4), subgroups (n=4) of Zn repleted animals at repletion days 2, 4, 7, 10 and 14, and at day 14 the remaining controls also (n=4). Zn deficiency reduced skeletal Zn concentration from 198 to 155 ,g/g of bone dry matter. About half of mobilized skeletal Zn was refilled within 2 days of repletion and was completely restored until the end of the study. Concentrations of bone ash, Ca, P and Mg remained constant (means in bone dry matter: 51% bone ash, 191 mg Ca/g, 95 mg P/g, 4.4 mg Mg/g). Blood plasma concentrations of osteocalcin and daily urinary excretions of pyridinoline PYD and dexoxypyridinoline DPD were unaffected by treatment (mean: 57 ng/ml, 222 nmol/day, 137 nmol/day). Also daily urinary excretions of Ca, P and Mg remained fairly constant (means: 0.26 mg/day, 16 mg/day, 1.5 mg/day). 65Zn autoradiography of femur sections revealed a pronounced Zn exchange in the area of the metaphysis and epiphysis. We conclude that transient mobilization and restoration of skeletal Zn occurs mainly in trabecular bone, and does not involve major changes in bone mass, macro mineral content, or bone tissue turnover in young-adult rats. [source] Scanning texture analysis of lamellar bone using microbeam synchrotron X-ray radiationJOURNAL OF APPLIED CRYSTALLOGRAPHY, Issue 1 2007Wolfgang Wagermaier Texture analysis with microbeam scanning diffraction enables the local mapping of three-dimensional crystallite orientation in heterogeneous natural and synthetic materials. Cortical (compact) bone is an example of a hierarchically structured biocomposite, which is built mainly of cylindrical osteons, having a lamellar texture at the micrometre level. In this work, a combination of microbeam synchrotron X-ray texture analysis with thin sections of osteonal bone is used to measure the three-dimensional distribution of the c -axis orientation of the mineral apatite in bone with positional resolution of 1,µm. The data reduction procedure needed to go from the stereographic projection of X-ray intensity to the determination of the local orientation of mineralized collagen fibrils is described. The procedure can be applied to other mineralized tissues (such as trabecular bone and chitin) with micrometre scale and biologically controlled fibrillar texture. [source] Behavior of dense and porous hydroxyapatite implants and tissue response in rat femoral defectsJOURNAL OF BIOMEDICAL MATERIALS RESEARCH, Issue 1 2002J.C.T. Andrade Abstract Porous and dense hydroxyapatite cylinders (PHA and DHA) were implanted into cavities produced in rat femora and the sites of implantation were examined at different times over a period of 24 weeks by microradiologic and histological techniques. Microradiographs showed the presence of a layer of trabecular bone around the implants, which became more radiopaque and thinner along the experimental time. The microradiologic methodology used was suitable for the evaluation of the interface between hydroxyapatite and newly formed bone in nondecalcified materials. Microscopic observations showed that young bone grew over the surface of both types of implants after 1 and 2 weeks of surgery and that bone also grew inside PHA implants. Progressive bone absorption was observed in both types of implants after the fourth week. A layer of fibrous tissue was formed in the interface between new bone and DHA. Mature bone with haversian systems surrounded DHA implants and filled the pores of PHA implants throughout the experimental period. The pores of PHA implants were smaller than those commonly reported, which should have been a disadvantage, although it was observed that the extra cellular fluid induced disintegration of the ceramic granules, allowing the gradual growth of bone tissue into the spaces among them, without the interposition of fibrous tissue. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res 62: 30,36, 2002 [source] Aged mice have enhanced endocortical response and normal periosteal response compared with young-adult mice following 1 week of axial tibial compressionJOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2010Michael D Brodt Abstract With aging, the skeleton may lose its ability to respond to positive mechanical stimuli. We hypothesized that aged mice are less responsive to loading than young-adult mice. We subjected aged (22 months) and young-adult (7 months) BALB/c male mice to daily bouts of axial tibial compression for 1 week and evaluated cortical and trabecular responses using micro,computed tomography (µCT) and dynamic histomorphometry. The right legs of 95 mice were loaded for 60 rest-inserted cycles per day to 8, 10, or 12,N peak force (generating mid-diaphyseal strains of 900 to 1900 µ, endocortically and 1400 to 3100 µ, periosteally). At the mid-diaphysis, mice from both age groups showed a strong anabolic response on the endocortex (Ec) and periosteum (Ps) [Ec.MS/BS and Ps. MS/BS: loaded (right) versus control (left), p,<,.05]. Generally, bone formation increased with increasing peak force. At the endocortical surface, contrary to our hypothesis, aged mice had a significantly greater response to loading than young-adult mice (Ec.MS/BS and Ec.BFR/BS: 22 months versus 7 months, p,<,.001). Responses at the periosteal surface did not differ between age groups (p,>,.05). The loading-induced increase in bone formation resulted in increased cortical area in both age groups (loaded versus control, p,<,.05). In contrast to the strong cortical response, loading only weakly stimulated trabecular bone formation. Serial (in vivo) µCT examinations at the proximal metaphysis revealed that loading caused a loss of trabecular bone in 7-month-old mice, whereas it appeared to prevent bone loss in 22-month-old mice. In summary, 1 week of daily tibial compression stimulated a robust endocortical and periosteal bone-formation response at the mid-diaphysis in both young-adult and aged male BALB/c mice. We conclude that aging does not limit the short-term anabolic response of cortical bone to mechanical stimulation in our animal model. © 2010 American Society for Bone and Mineral Research [source] Mechanical implications of estrogen supplementation in early postmenopausal womenJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2010Felix W Wehrli Abstract Whereas the structural implications of drug intervention are well established, there are few data on the possible mechanical consequences of treatment. In this work we examined the changes in elastic and shear moduli (EM and SM) in a region of trabecular bone in the distal radius and distal tibia of early postmenopausal women on the basis of MRI-based micro-finite-element (µFE) analysis. Whole-section axial stiffness (AS) encompassing both trabecular and cortical compartments was evaluated as well. The study was conducted on previously acquired high-resolution images at the two anatomic sites. Images were processed to yield a 3D voxel array of bone-volume fraction (BVF), which was converted to a µFE model of hexahedral elements in which tissue modulus was set proportional to voxel BVF. The study comprised 65 early postmenopausal women (age range 45 to 55 years), of whom 32 had chosen estrogen supplementation (estradiol group); the remainder had not (control group). Subjects had been scanned at baseline and 12 and 24 months thereafter. At the distal tibia, EM and SM were reduced by 2.9% to 5.5% in the control group (p,<,.05 to <.005), but there was no change in the estradiol subjects. AS decreased 3.9% (4.0%) in controls (p,<,.005) and increased by 5.8% (6.2%) in estradiol group subjects (p,<,.05) at 12 (24) months. At the distal radius, EM and SM changes from baseline were not significant, but at both time points AS was increased in estradiol group subjects and decreased in controls (p,<,.005 to <.05), albeit by a smaller margin than at the tibia. EM and SM were strongly correlated with BV/TV (r2,=,0.44 to 0.92) as well as with topologic parameters expressing the ratio of plates to rods (r2,=,0.45 to 0.82), jointly explaining up to 96% of the variation in the mechanical parameters. Finally, baseline AS was strongly correlated between the two anatomic sites (r2,=,0.58), suggesting that intersubject variations in the bone's mechanical competence follows similar mechanisms. In conclusion, the results demonstrate that micro-MRI-based µFE models are suited for the study of the mechanical implications of antiresorptive treatment. The data further highlight the anabolic effect of short-term estrogen supplementation. © 2010 American Society for Bone and Mineral Research [source] Genetic Hypercalciuric Stone-Forming Rats Have a Primary Decrease in BMD and Strength,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2009Marc Grynpas Abstract Kidney stone patients often have a decrease in BMD. It is unclear if reduced BMD is caused by a primary disorder of bone or dietary factors. To study the independent effects of hypercalciuria on bone, we used genetic hypercalciuric stone-forming (GHS) rats. GHS and control (Ctl) rats were fed a low Ca (0.02% Ca, LCD) or a high Ca (1.2% Ca, HCD) diet for 6 wk in metabolic cages. All comparisons are to Ctl rats. Urine Ca was greater in the GHS rats on both diets. GHS fed HCD had reduced cortical (humerus) and trabecular (L1,L5 vertebrae) BMD, whereas GHS rats fed LCD had a reduction in BMD similar to Ctl. GHS rats fed HCD had a decrease in trabecular volume and thickness, whereas LCD led to a ,20-fold increase in both osteoid surface and volume. GHS rats fed HCD had no change in vertebral strength (failure stress), ductibility (failure strain), stiffness (modulus), or toughness, whereas in the humerus, there was reduced ductibility and toughness and an increase in modulus, indicating that the defect in mechanical properties is mainly manifested in cortical, rather than trabecular, bone. GHS rat cortical bone is more mineralized than trabecular bone and LCD led to a decrease in the mineralization profile. Thus, the GHS rats, fed an ample Ca diet, have reduced BMD with reduced trabecular volume, mineralized volume, and thickness, and their bones are more brittle and fracture prone, indicating that GHS rats have an intrinsic disorder of bone that is not secondary to diet. [source] Hip Fractures and the Contribution of Cortical Versus Trabecular Bone to Femoral Neck Strength,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2009Gerold Holzer Abstract Osteoporotic fractures are caused by both cortical thinning and trabecular bone loss. Both are seen to be important for bone fragility. The relative contributions of cortical versus trabecular bone have not been established. The aim of this study was to test the contribution of cortical versus trabecular bone to femoral neck stability in bone strength. In one femur from each pair of 18 human cadaver femurs (5 female; 4 male), trabecular bone was completely removed from the femoral neck, providing one bone with intact and the other without any trabecular structure in the femoral neck. Geometrical, X-ray, and DXA measurements were carried out before biomechanical testing (forces to fracture). Femoral necks were osteotomized, slices were analyzed for cross-sectional area (CSA) and cross-sectional moment of inertia (CSMI), and results were compared with biomechanical testing data. Differences between forces needed to fracture excavated and intact femurs (,F/F mean) was 7.0% on the average (range, 4.6,17.3%). CSA of removed spongiosa did not correlate with difference of fracture load (,F/F mean), nor did BMD. The relative contribution of trabecular versus cortical bone in respect to bone strength in the femoral neck seems to be marginal and seems to explain the subordinate role of trabecular bone and its changes in fracture risk and the effects of treatment options in preventing fractures. [source] Site-Specific Deterioration of Trabecular Bone Architecture in Men and Women With Advancing AgeJOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2008Eva-Maria Lochmüller Abstract We tested the hypothesis that the age dependence of trabecular bone microstructure differs between men and women and is specific to skeletal site. Furthermore, we aimed to investigate the microstructural pattern of bone loss in aging. Microstructural properties of trabecular bone were measured in vitro in 75 men and 75 age-matched women (age, 52,99 yr) using ,CT. Trabecular bone samples were scanned at a 26-,m isotropic resolution at seven anatomical sites (i.e., distal radius, T10 and L2 vertebrae, iliac crest, femoral neck and trochanter, and calcaneus). DXA measurements were obtained at the distal radius and proximal femur and QCT was used at T12. No significant decrease in bone density or structure with age was found in men using ,CT, DXA, or QCT at any of the anatomical sites. In women, a significant age-dependent decrease in BV/TV was observed at most sites, which was strongest at the iliac crest and weakest at the distal radius. At most sites, the reduction in BV/TV was associated with an increase in structure model index, decrease in Tb.N, and an increase in Tb.Sp. Only in the calcaneus was it associated with a significant decrease in Tb.Th. In conclusion, a significant, site-specific correlation of trabecular bone microstructure with age was found in women but not in men of advanced age. The microstructural basis by which a loss of BV/TV occurs with age can vary between anatomical sites. [source] Targeted Deletion of the Sclerostin Gene in Mice Results in Increased Bone Formation and Bone Strength,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2008Xiaodong Li Abstract Introduction: Sclerosteosis is a rare high bone mass genetic disorder in humans caused by inactivating mutations in SOST, the gene encoding sclerostin. Based on these data, sclerostin has emerged as a key negative regulator of bone mass. We generated SOST knockout (KO) mice to gain a more detailed understanding of the effects of sclerostin deficiency on bone. Materials and Methods: Gene targeting was used to inactivate SOST and generate a line of SOST KO mice. Radiography, densitometry, ,CT, histomorphometry, and mechanical testing were used to characterize the impact of sclerostin deficiency on bone in male and female mice. Comparisons were made between same sex KO and wildtype (WT) mice. Results: The results for male and female SOST KO mice were similar, with differences only in the magnitude of some effects. SOST KO mice had increased radiodensity throughout the skeleton, with general skeletal morphology being normal in appearance. DXA analysis of lumbar vertebrae and whole leg showed that there was a significant increase in BMD (>50%) at both sites. ,CT analysis of femur showed that bone volume was significantly increased in both the trabecular and cortical compartments. Histomorphometry of trabecular bone revealed a significant increase in osteoblast surface and no significant change in osteoclast surface in SOST KO mice. The bone formation rate in SOST KO mice was significantly increased for trabecular bone (>9-fold) at the distal femur, as well as for the endocortical and periosteal surfaces of the femur midshaft. Mechanical testing of lumbar vertebrae and femur showed that bone strength was significantly increased at both sites in SOST KO mice. Conclusions:SOST KO mice have a high bone mass phenotype characterized by marked increases in BMD, bone volume, bone formation, and bone strength. These results show that sclerostin is a key negative regulator of a powerful, evolutionarily conserved bone formation pathway that acts on both trabecular and cortical bone. [source] Influence of Orthogonal Overload on Human Vertebral Trabecular Bone Mechanical Properties,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2007Arash Badiei Abstract The aim of this study was to investigate the effects of overload in orthogonal directions on longitudinal and transverse mechanical integrity in human vertebral trabecular bone. Results suggest that the trabecular structure has properties that act to minimize the decrease of apparent toughness transverse to the primary loading direction. Introduction: The maintenance of mechanical integrity and function of trabecular structure after overload remains largely unexplored. Whereas a number of studies have focused on addressing the question by testing the principal anatomical loading direction, the mechanical anisotropy has been overlooked. The aim of this study was to investigate the effects of overload in orthogonal directions on longitudinal and transverse mechanical integrity in human vertebral trabecular bone. Materials and Methods: T12/L1 vertebral bodies from five cases and L4/L5 vertebral bodies from seven cases were retrieved at autopsy. A cube of trabecular bone was cut from the centrum of each vertebral body and imaged by ,CT. Cubes from each T12/L1 and L4/L5 pairs were assigned to either superoinferior (SI) or anteroposterior (AP) mechanical testing groups. All samples were mechanically tested to 10% apparent strain by uniaxial compression according to their SI or AP allocation. To elucidate the extent to which overload in orthogonal directions affects the mechanical integrity of the trabecular structure, samples were retested (after initial uniaxial compression) in their orthogonal direction. After mechanical testing in each direction, apparent ultimate failure stresses (UFS), apparent elastic moduli (E), and apparent toughness moduli (u) were computed. Results: Significant differences in mechanical properties were found between SI and AP directions in both first and second overload tests. Mechanical anisotropy far exceeded differences resulting from overloading the structure in the orthogonal direction. No significant differences were found in mean UFS and mean u for the first or second overload tests. A significant decrease of 35% was identified in mean E for cubes overloaded in the SI direction and then overloaded in the AP direction. Conclusions: Observed differences in the mechanics of trabecular structure after overload suggests that the trabecular structure has properties that act to minimize loss of apparent toughness, perhaps through energy dissipating sacrificial structures transverse to the primary loading direction. [source] Strontium Ranelate Treatment Improves Trabecular and Cortical Intrinsic Bone Tissue Quality, a Determinant of Bone Strength,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2007Patrick Ammann MD Abstract Beside its influence on determinants of bone strength (geometry, microarchitecture), which is likely to be related to a cellular effect, strontium ranelate improves bone tissue quality as evaluated by nanoindentation, increasing elastic modulus, hardness, and dissipated energy in vertebrae of rats treated for 104 wk with daily dose from 0 to 900 mg/kg. Introduction: We previously showed that strontium ranelate treatment improves the mechanical properties of the vertebral body and long bone midshaft in intact rats. The increased energy to failure obtained with strontium ranelate is essentially caused by an increase in plastic energy, suggesting that bone formed during treatment can withstand greater deformation before fracture. In the bone mineral phase, strontium is mainly located in the hydrated shell and could thus potentially influence intrinsic bone tissue quality. Materials and Methods: To study whether strontium ranelate treatment could positively influence intrinsic bone tissue quality (elastic modulus, hardness, and dissipated energy), nanoindentation tests were performed at the level of trabecular nodes and cortex under physiological or dry conditions in vertebrae of rats treated for 104 wk with strontium ranelate at a daily dose of 0, 225, 450, or 900 mg/kg (n = 12 per group). Ex vivo ,CT measurements and axial compression tests of adjacent vertebral bodies were also performed. Significance of difference was evaluated using ANOVA. Results: In agreement with previous results, strontium ranelate (900 mg/kg/d) significantly increased versus controls in maximal load (+23%), total energy (+71%), and plastic energy (+143%). At the level of trabecular bone, strontium ranelate treatment resulted in a significant increase in elastic modulus (+15.1%, p < 0.01), hardness (+11.5%, p < 0.05), and dissipated energy (+16.2%, p < 0.001) versus controls in physiological, but not in dry, conditions. The effect was less pronounced in cortex. Conclusions: These results show for the first time a direct action of strontium ranelate on bone tissue quality. Beside its shown influence on classical determinants of bone strength (geometry, microarchitecture), which is likely to be related to a cellular effect, strontium ranelate improves bone tissue quality. This could contribute to the increase in bone strength and thus be involved in the reduction of fracture risk in postmenopausal osteoporotic patients treated with strontium ranelate. [source] Monitoring Teriparatide-Associated Changes in Vertebral Microstructure by High-Resolution CT In Vivo: Results From the EUROFORS Study,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2007Christian Graeff Dipl-Ing Abstract We introduce a method for microstructural analysis of vertebral trabecular bone in vivo based on HRCT. When applied to monitor teriparatide treatment, changes in structural variables exceeded and were partially independent of changes in volumetric BMD. Introduction: Monitoring of osteoporosis therapy based solely on bone densitometry is insufficient to assess anti-fracture efficacy. Assessing bone microstructure in vivo is therefore of importance. We studied whether it is possible to monitor effects of teriparatide on vertebral trabecular microstructure independent of BMD by high-resolution CT (HRCT). Materials and Methods: In a subset of 65 postmenopausal women with established osteoporosis who participated in the EUROFORS study, HRCT scans of T12, quantitative CT of L1,L3, and DXA of L1,L4 were performed after 0, 6, and 12 mo of teriparatide treatment (20 ,g/d). We compared BMD and 3D microstructural variables in three groups of women, based on prior antiresorptive treatment: treatment-naïve; pretreated; and pretreated women showing inadequate response to treatment. Results: We found statistically highly significant increases in most microstructural variables and BMD 6 mo after starting teriparatide. After 12 mo, apparent bone volume fraction (app. BV/TV) increased by 30.6 ± 4.4% (SE), and apparent trabecular number (app. Tb.N.) increased by 19.0 ± 3.2% compared with 6.4 ± 0.7% for areal and 19.3 ± 2.6% for volumetric BMD. The structural changes were partially independent of BMD as shown by a significantly larger standardized increase and a standardized long-term precision at least as good as DXA. Patients who had shown inadequate response to prior osteoporosis treatment did show improvements in BMD and structural measures comparable to treatment-naïve patients. Conclusions: HRCT is a feasible method for longitudinal microstructural analysis of human vertebrae in vivo, offers information beyond BMD, and is sufficiently precise to show profound effects of teriparatide after 12 mo. [source] Osteoblast Deletion of Exon 3 of the Androgen Receptor Gene Results in Trabecular Bone Loss in Adult Male Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2007Amanda J Notini Abstract The mechanism of androgen action on bone was studied in male mice with the AR deleted in mature osteoblasts. These mice had decreased trabecular bone volume associated with a decrease in trabecular number, suggesting that androgens may act directly on osteoblasts to maintain trabecular bone. Introduction: Androgens modulate bone cell activity and are important for the maintenance of bone mass. However, the mechanisms by which they exert these actions on bone remain poorly defined. The aim of this study was to investigate the role of androgens acting through the classical androgen receptor (AR) signaling pathways (i.e., DNA-binding dependent pathways) in osteoblasts using male mice in which exon 3 of the AR gene was deleted specifically in mature osteoblasts. Materials and Methods: Mice with a floxed exon 3 of the AR gene were bred with Col 2.3-cre transgenic mice, in which Cre recombinase is expressed in mineralizing osteoblasts. The skeletal phenotype of mutant mice was assessed by histomorphometry and quantitative ,CT at 6, 12, and 32 weeks of age (n = 8 per group). Wildtype, hemizygous exon 3 floxed and hemizygous Col 2.3-cre male littermates were used as controls. Data were analyzed by one-way ANOVA and Tukey's posthoc test. Results: ,CT analysis of the fifth lumbar vertebral body showed that these mice had reduced trabecular bone volume (p < 0.05) at 32 weeks of age compared with controls. This was associated with a decrease in trabecular number (p < 0.01) at 12 and 32 weeks of age, suggesting increased bone resorption. These effects were accompanied by a reduction in connectivity density (p < 0.01) and an increase in trabecular separation (p < 0.01). A similar pattern of trabecular bone loss was observed in the distal femoral metaphysis at 32 weeks of age. Conclusions: These findings show that inactivation of the DNA binding,dependent functions of the AR, specifically in mature osteoblasts in male mice, results in increased bone resorption and decreased structural integrity of the bone, leading to a reduction in trabecular bone volume at 32 weeks of age. These data provide evidence of a role for androgens in the maintenance of trabecular bone volume directly through DNA binding,dependent actions of the AR in mature osteoblasts. [source] Remodeling and Vascular Spaces in BoneJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2007Erik Fink Eriksen Abstract In recent years, we have come to appreciate that the close association between bone and vasculature plays a pivotal role in the regulation of bone remodeling and fracture repair. In 2001, Hauge et al. characterized a specialized vascular structure, the bone remodeling compartment (BRC), and showed that the outer lining of this compartment was made up of flattened cells, displaying all the characteristics of lining cells in bone. A decrease in bone turnover leads to a decrease in surfaces covered with remodeling compartments, whereas increased turnover causes an increase. Immunoreactivity for all major osteotropic growth factors and cytokines including osteoprotegerin (OPG) and RANKL has been shown in the cells lining the BRC, which makes the BRC the structure of choice for coupling between resorption and formation. The secretion of these factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Reduction in BRC space brought about by antiresorptive therapies such as bisphosphonates reduce the number of skeletal events in advanced cancer, whereas an increase in BRC space induced by remodeling activators like PTH may increase the bone metastatic burden. The BRC has only been characterized in detail in trabecular bone; there is, however, evidence that a similar structure may exist in cortical bone, but further characterization is needed. [source] QTL Analysis of Trabecular Bone in BXD F2 and RI Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2006Abbey L Bower Abstract A sample of 693 mice was used to identify regions of the mouse genome associated with trabecular bone architecture as measured using ,CT. QTLs for bone in the proximal tibial metaphysis were identified on several chromosomes indicating regions containing genes that regulate properties of trabecular bone. Introduction: Age-related osteoporosis is a condition of major concern because of the morbidity and mortality associated with osteoporotic fractures in humans. Osteoporosis is characterized by reduced bone density, strength, and altered trabecular architecture, all of which are quantitative traits resulting from the actions of many genes working in concert with each other and the environment over the lifespan. ,CT gives accurate measures of trabecular bone architecture providing phenotypic data related to bone volume and trabecular morphology. The primary objective of this research was to identify chromosomal regions called quantitative trait loci (QTLs) that contain genes influencing trabecular architecture as measured by ,CT. Materials and Methods: The study used crosses between C57BL/6J (B6) and DBA/2J (D2) as progenitor strains of a second filial (F2) generation (n = 141 males and 148 females) and 23 BXD recombinant inbred (RI) strains (n , 9 of each sex per strain). The proximal tibial metaphyses of the 200-day-old mice were analyzed by ,CT to assess phenotypic traits characterizing trabecular bone, including bone volume fraction, trabecular connectivity, and quantitative measures of trabecular orientation and anisotropy. Heritabilities were calculated and QTLs were identified using composite interval mapping. Results: A number of phenotypes were found to be highly heritable. Heritability values for measured phenotypes using RI strains ranged from 0.15 for degree of anisotropy in females to 0.51 for connectivity density in females and total volume in males. Significant and confirmed QTLs, with LOD scores ,4.3 in the F2 cohort and ,1.5 in the corresponding RI cohort were found on chromosomes 1 (43 cM), 5 (44 cM), 6 (20 cM), and 8 (49 cM). Other QTLs with LOD scores ranging from 2.8 to 6.9 in the F2 analyses were found on chromosomes 1, 5, 6, 8, 9, and 12. QTLs were identified using data sets comprised of both male and female quantitative traits, suggesting similar genetic action in both sexes, whereas others seemed to be associated exclusively with one sex or the other, suggesting the possibility of sex-dependent effects. Conclusions: Identification of the genes underlying these QTLs may lead to improvements in recognizing individuals most at risk for developing osteoporosis and in the design of new therapeutic interventions. [source] Effect of Osteoblast-Targeted Expression of Bcl-2 in Bone: Differential Response in Male and Female Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2005Alexander G Pantschenko Abstract Transgenic mice (Col2.3Bcl-2) with osteoblast-targeted human Bcl-2 expression were established. Phenotypically, these mice were smaller than their wildtype littermates and showed differential effects of the transgene on bone parameters and osteoblast activity dependent on sex. The net effect was an abrogation of sex differences normally observed in wildtype mice and an inhibition of bone loss with age. Ex vivo osteoblast cultures showed that the transgene had no effect on osteoblast proliferation, but decreased bone formation. Estrogen was shown to stimulate endogenous Bcl-2 message levels. These studies suggest a link between Bcl-2 and sex regulation of bone development and age-related bone loss. Introduction: Whereas Bcl-2 has been shown to be an important regulator of apoptosis in development, differentiation, and disease, its role in bone homeostasis and development is not well understood. We have previously showed that the induction of glucocorticoid-induced apoptosis occurred through a dose-dependent decrease in Bcl-2. Estrogen prevented glucocorticoid-induced osteoblast apoptosis in vivo and in vitro by preventing the decrease in Bcl-2 in osteoblasts. Therefore, Bcl-2 may be an important regulator of bone growth through mechanisms that control osteoblast longevity and function. Materials and Methods: Col2.3Bcl-2 mice were developed carrying a 2.3-kb region of the type I collagen promoter driving 1.8 kb of human Bcl-2 (hBcl-2). Tissue specific expression of hBcl-2 in immunoassays validated the transgenic animal model. Histomorphometry and DXA were performed. Proliferation, mineralization, and glucocorticoid-induced apoptosis were examined in ex vivo cultures of osteoblasts. The effect of estrogen on mouse Bcl-2 in ex vivo osteoblast cultures was assayed by RT-PCR and Q-PCR. Results and Conclusions: Two Col2.3Bcl-2 (tg/+) founder lines were established and appeared normal except that they were smaller than their nontransgenic wildtype (+/+) littermates at 1, 2, and 6 months of age, with the greatest differences at 2 months. Immunohistochemistry showed hBcl-2 in osteoblasts at the growth plate and cortical surfaces. Nontransgenic littermates were negative. Western blots revealed hBcl-2 only in type I collagen-expressing tissues. Histomorphometry of 2-month-old mice showed a significant decrease in tg/+ calvaria width with no significant differences in femoral trabecular area or cortical width compared with +/+. However, tg/+ males had significantly more trabecular bone than tg/+ females. Female +/+ mice showed increased bone turnover with elevated osteoblast and osteoclast parameters compared with +/+ males. Col2.3Bcl-2 mice did not show such significant differences between sexes. Male tg/+ mice had a 76.5 ± 1.5% increase in ObS/BS with no significant differences in bone formation rate (BFR) or mineral apposition rate (MAR) compared with male +/+ mice. Transgenic females had a significant 48.4 ± 0.1% and 20.1 ± 5.8% decrease in BFR and MAR, respectively, compared with +/+ females. Osteoclast and osteocyte parameters were unchanged. By 6 months, femurs from female and male +/+ mice had lost a significant amount of their percent of trabecular bone compared with 2-month-old mice. There was little to no change in femoral bone in the tg/+ mice with age. Ex vivo cultures of osteoblasts from +/+ and Col2.3Bcl-2 mice showed a decrease in mineralization, no effect on proliferation, and an inhibition of glucocorticoid-induced apoptosis in Col2.3Bcl-2 cultures. Estrogen was shown to increase mouse Bcl-2 transcript levels in osteoblast cultures of wildtype mice, supporting a role for Bcl-2 in the sex-related differences in bone phenotype regulated by estrogen. Therefore, Bcl-2 differentially affected bone phenotype in male and female transgenic mice, altered bone cell activity associated with sex-related differences, and decreased bone formation, suggesting that apoptosis is necessary for mineralization. In addition, Bcl-2 targeted to mature osteoblasts seemed to delay bone development, producing a smaller transgenic mouse compared with wildtype littermates. These studies suggest that expression of Bcl-2 in osteoblasts is important in regulating bone mass in development and in the normal aging process of bone. [source] Ovariectomy-Induced Bone Loss Varies Among Inbred Strains of Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2005Mary L Bouxsein PhD Abstract There is a subset of women who experience particularly rapid bone loss during and after the menopause. However, the factors that lead to this enhanced bone loss remain obscure. We show that patterns of bone loss after ovariectomy vary among inbred strains of mice, providing evidence that there may be genetic regulation of bone loss induced by estrogen deficiency. Introduction: Both low BMD and increased rate of bone loss are risk factors for fracture. Bone loss during and after the menopause is influenced by multiple hormonal factors. However, specific determinants of the rate of bone loss are poorly understood, although it has been suggested that genetic factors may play a role. We tested whether genetic factors may modulate bone loss subsequent to estrogen deficiency by comparing the skeletal response to ovariectomy in inbred strains of mice. Materials and Methods: Four-month-old mice from five inbred mouse strains (C3H/HeJ, BALB/cByJ, CAST/EiJ, DBA2/J, and C57BL/6J) underwent ovariectomy (OVX) or sham-OVX surgery (n = 6-9/group). After 1 month, mice were killed, and ,CT was used to compare cortical and trabecular bone response to OVX. Results: The effect of OVX on trabecular bone varied with mouse strain and skeletal site. Vertebral trabecular bone volume (BV/TV) declined after OVX in all strains (,15 to ,24%), except for C3H/HeJ. In contrast, at the proximal tibia, C3H/HeJ mice had a greater decline in trabecular BV/TV (,39%) than C57BL/6J (,18%), DBA2/J (,23%), and CAST/EiJ mice (,21%). OVX induced declines in cortical bone properties, but in contrast to trabecular bone, the effect of OVX did not vary by mouse strain. The extent of trabecular bone loss was greatest in those mice with highest trabecular BV/TV at baseline, whereas cortical bone loss was lowest among those with high cortical bone parameters at baseline. Conclusions: We found that the skeletal response to OVX varies in a site- and compartment-specific fashion among inbred mouse strains, providing support for the hypothesis that bone loss during and after the menopause is partly genetically regulated. [source] Drugs Used to Treat Osteoporosis: The Critical Need for a Uniform Nomenclature Based on Their Action on Bone Remodeling,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2005B Lawrence Riggs MD Abstract There continues to be uncertainty about the classification of available drugs for treating osteoporosis. We find that grouping them into anti-catabolic and anabolic classes based on the mechanisms of their action on bone remodeling and fracture reduction removes ambiguities and provides a relatively straightforward classification. The recent introduction of teriparatide into clinical practice initiated the era of anabolic therapy for osteoporosis, but it is still unclear how to define an anabolic drug. All drugs that increase bone mass do so by affecting bone remodeling. When their mechanisms of action on bone remodeling and on fracture reduction are considered, we find that anti-osteoporotic drugs fall naturally into either anti-catabolic or anabolic classes. Anti-catabolic drugs increase bone strength and reduce fractures mainly by decreasing the number of bone multicellular units (BMUs). This reduces perforative resorption and preserves skeletal microarchitecture (by preventing further structural damage to trabecular bone and increased porosity in cortical bone induced by high bone remodeling). Reduction in bone remodeling by anti-catabolic drugs may increase bone mass moderately during the interval in which previously initiated BMUs are completing mineralization. Some anti-catabolic drugs may also enhance the formation phase of the remodeling cycle, but their major action is to reduce overall bone turnover (i.e., the number of BMUs in bone). In contrast, anabolic drugs increase bone strength and reduce fractures by substantially increasing bone mass as a result of an overall increase in the number of BMUs combined with a positive BMU balance (the magnitude of the formation phase is greater than that of the resorption phase). Some anabolic drugs also induce renewed modeling, increase periosteal apposition and repair of trabecular microstructure. We hope that this classification will serve as a starting point for continued discussion on the important issue of nomenclature. [source] | ||||||||||||||||