Biomedical subjects

H Weinans

Publications and source records attributed to H Weinans.

At least 19 recordsLinked to original sources

PubMed2007

Long-term fluoxetine administration does not result in major changes in bone architecture and strength in growing rats.

Many studies have indicated that serotonin and its transporter play a role in bone metabolism. In this study we investigated the effect of selective serotonin re-uptake inhibitor (SSRI), fluoxetine (Prozac) on bone architecture and quality in growing female rats. We therefore administrated rats with clinically relevant doses of fluoxetine for a period of 6 months. DXA scans were performed during the treatment period in order to follow parameters as body weight, fat percentage and BMD. After 6 months of treatment, femurs were used to analyze bone architecture and bone strength, by means of microCT scans and three-point bending assays, respectively. We found a slightly diminished bone quality, reflected in a lower bone tissue strength, which was compensated by changes in bone geometry. As leptin and adiponectin could be possible factors in the serotonergic regulation of bone metabolism, we also determined the levels of these factors in plasma samples of all animals. Leptin and adiponectin levels were not different between the control group and fluoxetine-treated group, indicating that these factors were not involved in the observed changes in bone geometry and quality.

Adiponectin↗

PubMed2006

Interrelationships between electrical properties and microstructure of human trabecular bone.

Microstructural changes, such as reduction of trabecular thickness and number, are characteristic signs of osteoporosis leading to diminished bone strength. Electrical and dielectric parameters might provide diagnostically valuable information on trabecular bone microstructure not extractable from bone mineral density measurements. In this study, structural properties of human trabecular bone samples (n=26) harvested from the distal femur and proximal tibia were investigated using the computed microtomography (microCT) technique. Quantitative parameters, e.g. structural model index (SMI) or trabecular bone volume fraction (BV/TV), were calculated. In addition, the samples were examined electrically over a wide frequency range (50 Hz-5 MHz) using a two-electrode impedance spectroscopy set-up. Relative permittivity, loss factor, conductivity, phase angle, specific impedance and dissipation factor were determined. Significant linear correlations were obtained between the dissipation factor and BV/TV or SMI (|r| 0.70, p<0.01, n=26). Principal component analyses, conducted on electrical and structural parameters, revealed that the high frequency principal component of the dissipation factor was significantly related to SMI (r=0.72, p<0.01, n=26). The linear combination of high and low frequency relative permittivity predicted 73% of the variation in BV/TV. To conclude, electrical and dielectric parameters of trabecular bone, especially relative permittivity and dissipation factor, were significantly and specifically related to a trabecular microstructure as characterized with microCT. The data gathered in this study constitute a useful basis for theoretical and experimental work towards the development of impedance spectroscopy techniques for detection of bone quality in vitro or in special cases of open surgery.

Bone Density↗

PubMed2006

Biochemical and functional modulation of the cartilage collagen network by IGF1, TGFbeta2 and FGF2.

OBJECTIVE: Examine effects of insulin-like growth factor 1 (IGF1), transforming growth factor beta2 (TGFbeta2) and fibroblast growth factor 2 (FGF2) on proteoglycan and collagen network and biomechanical properties of the newly formed cartilage matrix. METHODS: Bovine articular chondrocytes were cultured in alginate beads for 3 weeks with or without FGF2, TGFbeta2 or IGF1 in the presence of 10% FCS. Proteoglycan content, collagen content, hydroxylysylpyridinoline cross-links and overall matrix metalloproteinase (MMP) activity in the culture medium were measured. Alginate disks cultured for 5 weeks were used to evaluate the effect of growth factors on mechanical properties of the construct by determining the equilibrium aggregate modulus and secant modulus. RESULTS: IGF1 increased collagen and proteoglycan deposition. FGF2 mainly decreased collagen deposition and TGFbeta2 proteoglycan deposition. A decrease in cross-links was observed in matrix produced by chondrocytes cultured in the presence of TGFbeta2. IGF1 and FGF2 had no influence on the number of cross-links per collagen molecule. Overall MMP activity was significantly higher in culture medium of cells cultured with FGF2. TGFbeta2 and IGF1 had no effect on MMP activity. After 35 days of culture, the matrix produced under influence of IGF1 had a lower permeability and a trend to increase stiffness. FGF2 showed a trend to lower both properties. TGFbeta2 had no effect on these parameters. CONCLUSION: IGF1, TGFbeta2 and FGF2 had differential effects on collagen network formation. Of the three growth factors tested, IGF1 seems to be best in promoting the formation of a functional collagen network since it increased proteoglycan and collagen deposition and improved the mechanical properties.

Aggrecans↗

PubMed2006

Strength of cancellous bone trabecular tissue from normal, ovariectomized and drug-treated rats over the course of ageing.

Hormone therapy (HT) drugs and bisphosphonates prevent osteoporosis by inhibiting osteoclastic bone resorption. However, the effects of osteoporosis and anti-resorptive drugs on the mechanical behavior of the bone tissue constituting individual trabeculae have not yet been quantified. In this study, we test the hypothesis that the mechanical properties of bone trabecular tissue will differ for normal, ovariectomized and drug-treated rat bones over the course of ageing. Microtensile testing is carried on individual trabeculae from tibial bone of ovariectomized (OVX) rats, OVX rats treated with tibolone and placebo-treated controls. The method developed minimizes errors due to misalignment and stress concentrations at the grips. The local mineralization of single trabeculae is compared using micro-CT images calibrated for bone mineral content assessment. Our results indicate that ovariectomy in rats increases the stiffness, yield strength, yield strain and ultimate stress of the mineralized tissue constituting trabecular bone relative to normal; we found significant differences (P < 0.05) at 14, 34 and 54 weeks of treatment. These increases are complemented by a significant increase in the mineral content at the tissue level, although overall bone mineral density and mass are reduced. With drug treatment, the properties remain at, or slightly below, the placebo-treated controls levels for 54 weeks. The higher bone strength in the OVX group may cause the trabecular architecture to adapt as seen during osteopenia/osteoporosis, or alternately it may compensate for loss of trabecular architecture. These findings suggest that, in addition to the effects of osteoporosis and subsequent treatment on bone architecture, there are also more subtle processes ongoing to alter bone strength at the tissue level.

Aging↗

PubMed2006

Stress-concentrating effect of resorption lacunae in trabecular bone.

Analyses of the distributions of stress and strain within individual bone trabeculae have not yet been reported. In this study, four trabeculae were imaged and finite elements models were generated in an attempt to quantify the variability of stress/strain in real trabeculae. In three of these trabeculae, cavities were identified with depths comparable to values reported for resorption lacunae ( approximately 50 microm)-although we cannot be certain, it is most probable that they are indeed resorption lacunae. A tensile load was applied to each trabeculum to simulate physiological loading and to ensure that bending was minimized. The force carried by each trabecula was calculated from this value using the average cross sectional area of each trabecula. The analyses predict that very high stresses (>100 MPa) existed within bone trabecular tissue. Stress and strain distributions were highly heterogeneous in all cases, more so in trabeculae with the presumptive resorption lacunae where at least 30% of the tissue had a strain greater than 4000 micoepsilon in all cases. Stresses were elevated at the pit of the lacunae, and peak stress concentrations were located in the longitudinal direction ahead of the lacunae. Given these high strains, we suggest that microdamage is inevitable around resorption lacunae in trabecular bone, and may cause the bone multicellular unit to proceed to resorb a packet of bone in the trabeculum rather than just resorb whatever localized area was initially targeted.

Animals↗

PubMed2005

Glucosamine decreases expression of anabolic and catabolic genes in human osteoarthritic cartilage explants.

OBJECTIVE: To investigate the effect of glucosamine (GlcN) in a human osteoarthritic explant model on expression of genes involved in anabolic and catabolic activities of chondrocytes. METHODS: Human osteoarthritic explants, obtained during knee arthroplasty surgery, were pre-cultured (3 days) and treated with glucosamine-hydrochloride (GlcN-HCl) or glucosamine-3-sulphate (GlcN-S) at 0.5mM and 5mM (4 days). RNA was isolated from the explants and real time RT-PCR was performed. Additionally, total matrix metalloproteinase (MMP) activity was measured in culture medium. RESULTS: Addition of 5mM GlcN led to significant down-regulation of aggrecan (2.65-7.73-fold) and collagen type II (7.75-22.17-fold) gene expression, indicating inhibited anabolic activity. Considering catabolic activities, 5mM GlcN significantly down-regulated aggrecanase-1 and MMP3 and 5mM GlcN-S additionally down-regulated aggrecanase-2 and tissue inhibitor of MMP gene expression significantly. Gene expression was not significantly altered by 0.5mM GlcN. Total MMP activity in culture medium was only significantly reduced after addition of 5mM GlcN-HCl. CONCLUSION: The effects of GlcN on gene expression in a human osteoarthritic explant model suggest that enzymatic breakdown of the extra-cellular matrix might be reduced by the addition of 5mM GlcN. Additionally, restoration of already damaged cartilage is not to be expected, because gene expression of anabolic genes is also down-regulated. We suggest that chondroprotective properties of GlcN in vivo may be based on inhibiting further degradation due to catabolic activities, rather than on the ability to rebuild cartilage.

Aged↗

PubMed2005

Prediction of mechanical properties of human trabecular bone by electrical measurements.

In trabecular bone, the interrelationships of electrical and dielectric properties with mechanical characteristics are poorly known. Information on these relations is crucial for evaluation of the diagnostic potential of impedance techniques. In this study, electrical and dielectric properties, i.e. permittivity, conductivity, phase angle, loss factor, specific impedance and dissipation factor of human trabecular bone samples (n=26, harvested from the distal femur and proximal tibia) were characterized in a wide frequency range (50 Hz-5 MHz). Mechanical properties, i.e. Young's modulus, ultimate strength, yield stress, yield strain and resilience of the samples (n=20) were determined by using destructive compressive testing. Subsequently, measurements of electrical and dielectric properties were repeated after mechanical testing. The measurements were also repeated for the control samples (n=6) that were not mechanically tested. Electrical, dielectric or mechanical properties showed no significant differences between the intact femoral and tibial samples. The electrical and dielectric parameters as well as the linear correlations between the dielectric and electrical parameters with mechanical parameters were strongly frequency dependent. At the frequency of 1.2 MHz, the relative permittivity showed the strongest linear correlations with the Young's modulus (r=0.71, p<0.01, n=20) and ultimate strength (r=0.73, p<0.01, n=20). Permittivity and dissipation factor showed statistically significant changes after mechanical testing. Our results suggest that the measurements of low frequency electrical and dielectric properties may provide information on the mechanical status of trabecular bone and, possibly, may even help to diagnose bone microdamage. In the future, these measurement techniques may be further developed for use during open surgery, such as bone grafting or total hip replacement surgery.

Algorithms↗

PubMed2004

Stretch-induced phosphorylation of ERK1/2 depends on differentiation stage of osteoblasts.

The goal of this study was to investigate the effect of mechanical loading on osteoblasts and extracellular signal-regulated kinase (ERK1/2) signaling in relation to osteoblast differentiation and mineralization. A human osteoblast cell line (SV-HFO) was triggered to differentiate to the advanced state of mineralization by addition of the osteogenic factors dexamethasone and beta-glycerophosphate. Osteoblasts were subjected to cyclic, equibiaxial stretch for 5, 15, or 60 min at different stages of differentiation (days 7, 14, and 21). Baseline (static) phosphorylated ERK1/2 and total ERK1/2 levels gradually increased during osteoblast differentiation. Cyclic stretch induced a rapid increase in ERK1/2 phosphorylation with a maximum between 5 and 15 min. Prolonged stretching for 60 min resulted in a decrease of phosphorylated ERK1/2 towards baseline level, suggesting a desensitization mechanism. The effect of stretch on ERK1/2 phosphorylation was strongest at later stages of differentiation (days 14 and 21). At day 21, the increase of ERK1/2 phosphorylation in response to stretch was significantly lower in non-differentiating than in differentiating osteoblasts. This could not be explained by differences in cell density, but did correlate with the formation of extracellular matrix, collagen fibrils. Mineralization of the extracellular matrix did not lead to a further increase of ERK1/2 phosphorylation. In conclusion, the current study demonstrates that the extent of activation of the ERK1/2 pathway is dependent on the differentiation or functional stage of the osteoblast. The presence of an extracellular matrix, but not per se mineralization, seems to be the predominant determinant of osteoblastic response to strain.

Calcification, Physiologic↗

PubMed2004

Detecting and tracking local changes in the tibiae of individual rats: a novel method to analyse longitudinal in vivo micro-CT data.

In this study we present the analysis of in vivo micro-CT scans using a new method based on image registration that accurately evaluates longitudinal micro-CT studies. We tested if detailed changes in the bone architecture could be detected and tracked in individual animals. A prototype in vivo micro-CT scanner (Skyscan 1076) was developed in which tibiae of rats that are lying on a bed under gas anaesthesia were scanned. For this study, three female Wistar rats were used: a sham-operated rat, an ovariectomised (OVX) rat and one rat that served as a reproducibility control. The reproducibility control rat was scanned twice in 1 day. The other animals were scanned at week 0, just before surgery, at week 4 and at week 14 after surgery. Architectural changes over time were detected by overlaying two data sets made at different time points using an algorithm that uses mutual information for optimal registration. The scans were segmented into binary data sets using a local thresholding algorithm. The reproducibility test showed small errors of less than 3% in bone volume measurements and errors less than 0.5% in measurements of trabecular thickness. The sham-operated rat showed no changes in total bone volume, though thinning and eventual loss of some small trabeculae could be detected, which could be related to the age of the animal. The OVX rat lost much trabecular bone volume, especially in the metaphysis (60% at week 4, 75% at week 14). The remaining trabeculae slowly increased in thickness. Following the different scans in time showed the forming of new trabecular structures. Additionally, small longitudinal growth at the growth plate could be detected after the first 4 weeks. Further, the OVX rat showed extensive modelling at the proximal endosteal lateral cortex. We have shown a new method that can detect and track changes in the local bone architecture and individual trabeculae in time, in an individual living animal. This method enables longitudinal in vivo micro-CT studies and has the potential to greatly contribute to experimental rat or mouse studies on pharmacological intervention and transgenic models.

Animals↗

PubMed2004

The osteoporotic vertebral structure is well adapted to the loads of daily life, but not to infrequent "error" loads.

Osteoporotic vertebral fractures typically have a gradual onset, frequently remain clinically undetected, and do not seem to be related to traumatic events. The osteoporotic vertebrae may therefore be expected to display a less "optimal" bone architecture, leading to an uneven load distribution over the bone material. We evaluated the trabecular load distribution in an osteoporotic and a healthy vertebra under normal daily loading by combining three recent innovations: high resolution computed tomography (microCT) of entire bones, microfinite element analyses (microFEA), and parallel supercomputers. Much to our surprise, the number of highly loaded trabeculae was not higher in the osteoporotic vertebra than in the healthy one under normal daily loads (8% and 9%, respectively). The osteoporotic trabeculae were more oriented in the longitudinal direction, compensating for effects of bone loss and ensuring adequate stiffness for normal daily loading. The increased orientation did, however, make the osteoporotic structure less resistant against collateral "error" loads. In this case, the number of overloaded trabeculae in the osteoporotic vertebra was higher than in the healthy one (13% and 4%, respectively). These results strengthen the paradigm of a strong relationship between bone morphology and external loads applied during normal daily life. They also indicate that vertebral fractures result from actions like forward flexion or lifting, loads that may not be "daily" but are normally not traumatic either. If future clinical imaging techniques would enable such high-resolution images to be obtained in vivo, the combination of microCT and microFEA would produce a powerful tool to diagnose osteoporosis.

Activities of Daily Living↗

PubMed2004

The mechanical consequences of mineralization in embryonic bone.

The purpose of this study was to examine the effect of mineralization on the mechanical properties of embryonic bone rudiments. For this purpose, four-point bending experiments were performed on unmineralized and mineralized embryonic mouse ribs at 16 and 17 days of gestational age. Young's modulus was calculated using force-displacement data from the experiment in combination with finite element analysis (FEA). For the unmineralized specimens, a calculated average for the Young's modulus of 1.11 (+/- 0.62) MPa was established after corrections for sticking to the four-point bending device and aspect ratio, which is the ratio between the length of the bone and its diameter. For the mineralized specimens, the value was 117 (+/- 62) MPa after corrections. Hence, Young's moduli of embryonic bone rudiments increase by two orders of magnitude within 1 day, during endochondral ossification. As an effect, the hypertrophic chondrocytes in the calcifying cartilage experience a significant change in their mechanical environment. The chondrocytes are effectively stress shielded, which means that they do not carry stresses since stresses are supported by the stiffest parts of the tissue, which are in this case the diaphyseal cortex and the calcified matrix. The deformability of the hypertrophic chondrocytes is, therefore, severely reduced. Since the transition is so sudden and enormous, it can be seen as a process of 'catastrophic' proportion for the hypertrophic chondrocytes. The subsequent resorption of calcified cartilage and the expansion of the marrow cavity could be consequential to stress shielding.

Animals↗

PubMed2004

Fibroblast growth factor-2 in serum-free medium is a potent mitogen and reduces dedifferentiation of human ear chondrocytes in monolayer culture.

The loss of the differentiated phenotype (dedifferentiation) during the expansion culture of donor chondrocytes remains a large problem in cartilage tissue engineering. Dedifferentiated chondrocytes produce other matrix components and therefore the tissue produced will be of less suitable quality. Previously, the addition of fibroblast growth factor-2 (FGF2) to a serum-containing medium (SCM) during expansion culture was shown to have positive effects on the phenotype of articular chondrocytes. In the present study, we focused on a more defined, serum-free medium (SFM), to expand chondrocytes in monolayer culture for the purpose of cartilage tissue engineering. Adult human ear chondrocytes were expanded in serum-free medium supplemented with 100 ng/ml FGF2. Expansion culture in a conventional serum-containing medium (10% FCS) served as control. The cell yield during expansion culture in serum-free medium with FGF2 was significantly higher compared to serum-containing medium. In addition, chondrocytes expanded in the serum-free medium with FGF2 expressed a more differentiated phenotype at the end of monolayer culture, as indicated by higher gene expression ratios of collagen type II to collagen type I and aggrecan to versican. Also, a higher gene expression of Sox9 was found. Next, suspension in alginate and subsequent culture in vitro or subcutaneous implantation in nude mice was used to evaluate the capacity of the chondrocytes, expanded in either medium, to re-express the differentiated phenotype (redifferentiation) and to form cartilage. The observed beneficial effects of the serum-free medium with FGF2 on the chondrocyte phenotype at the end of monolayer culture were sustained on both transcriptional and extracellular level throughout both redifferentiation methods.

Adult↗

PubMed2004

Bisphosphonate treatment affects trabecular bone apparent modulus through micro-architecture rather than matrix properties.

Bisphosphonates are emerging as an important treatment for osteoporosis. But whether the reduced fracture risk associated with bisphosphonate treatment is due to increased bone mass, improved trabecular architecture and/or increased secondary mineralization of the calcified matrix remains unclear. We examined the effects of bisphosphonates on both the trabecular architecture and matrix properties of canine trabecular bone. Thirty-six beagles were divided into a control group and two treatment groups, one receiving risedronate and the other alendronate at 5-6 times the clinical dose for osteoporosis treatment. After one year, the dogs were killed, and samples from the first lumbar vertebrae were examined using a combination of micro-computed tomography, finite element modeling, and mechanical testing. By combining these methods, we examined the treatment effects on the calcified matrix and trabecular architecture independently. Conventional histomorphometry and microdamage data were obtained from the second and third lumbar vertebrae of the same dogs [Bone 28 (2001) 524]. Bisphosphonate treatment resulted in an increased apparent Young's modulus, decreased bone turnover, increased calcified matrix density, and increased microdamage. We could not detect any change in the effective Young's modulus of the calcified matrix in the bisphosphonate treated groups. The observed increase in apparent Young's modulus was due to increased bone mass and altered trabecular architecture rather than changes in the calcified matrix modulus. We hypothesize that the expected increase in the Young's modulus of the calcified matrix due to the increased calcified matrix density was counteracted by the accumulation of microdamage.

Alendronate↗

PubMed2004

Altered tissue properties induce changes in cancellous bone architecture in aging and diseases.

The mechanical properties of cancellous bone depend on its architecture and the tissue properties of the mineralized matrix. The architecture is continuously adapted to external loads. In this paper, it was assumed that changes in tissue properties leading to changes in tissue deformation can induce adaptation of the architecture. We asked whether changes in cancellous bone architecture with aging and in e.g. early osteoarthrosis can be explained from changes in tissue properties. This was investigated using computer models in which the cancellous architecture was adapted to external loads. Bone tissue with deformations below a certain threshold was resorbed, deformations above another threshold induced formation. Deformations between these two boundaries, in the 'lazy zone', did not induce bone adaptation. The effects of changes in bone tissue stiffness on bone mass, global stiffness and architecture were investigated. The bone gain (40-60%) resulting from a 50% decrease in tissue stiffness (simulating diseased tissue) was much larger than the bone loss (2-30%) resulting from a 50% increase in tissue stiffness (simulating highly mineralized, old tissue). The adaptation induced by a decrease in tissue stiffness resulted in an almost constant stiffness in the main load bearing direction, but the transversal stiffness decreased. An increased tissue stiffness resulted in a higher stiffness in the main direction and overcompensation in the transversal directions: the global stiffness could become even smaller than the stiffness of the original model. Concluding, we showed that changes in trabecular bone in aging and diseases can be partly explained from changes in tissue properties.

Adaptation, Physiological↗

PubMed2004

Adaptation of subchondral bone in osteoarthritis.

Osteoarthritis is a chronic joint disease with pathological changes in the articulating cartilage and all other tissues that occupy the joint. Radin and coworkers have suggested the involvement of subchondral bone in the disease process. However, evidence for an essential role in the etiology has never been proven. Recent studies showing reduced chemical and mechanical properties of subchondral bone in various stages of the disease have invigorated interest in the role of subchondral bone in the development and progression of the disease. The current study showed that the concept of bone adaptation might explain subchondral stiffening, a process where subchondral bone becomes typically sclerotic in osteoarthritis. In addition, we report reduced mechanical matrix tissue properties as well as an increase in denatured collagen content. In conclusion, although osteoarthritic bone tissue contains increased denatured collagen and has reduced matrix mechanical properties, the widely accepted concept of subchondral stiffening is compatible with the process of normal bone adaptation.

Biomechanical Phenomena↗

PubMed2003

A simulation model at trabecular level to predict effects of antiresorptive treatment after menopause.

Antiresorptive drugs are widely used to prevent osteoporotic fractures in men and women. Large clinical trials have shown vertebral fracture risk reductions up to 50%, resulting from relatively small increases of 3-8% in bone mineral density (BMD). We developed a computer model that mimics bone turnover in human vertebral cancellous bone during menopause and antiresorptive treatment. This model links cell activity in trabeculae to changes in bone volume and mechanical properties. We asked whether treatment started shortly after menopause is better than treatment started late after menopause. In order to answer this question we used the model to simulate menopause and 5 years of anti-resorptive treatment with two different agents: one incorporated in the tissue, one not incorporated. We found that late treatment can result in almost the same bone mass as early treatment, but early treatment is much better in conserving the strength and stiffness of the cancellous bone. The effect of the incorporation of drugs in the tissue (giving the drugs a long half-life) was small. After discontinuation of treatment, bone was lost slower, but after 20 years the difference between the incorporated and the not incorporated drug in stiffness and bone volume was below 3%. This kind of simulation model may be used to preclinically test new pharmaceuticals and treatment protocols and to predict long-term effects of treatment before patient data become available.

Adult↗

PubMed2003

Mechanical control of human osteoblast apoptosis and proliferation in relation to differentiation.

Bone cells respond to mechanical stimulation. This is thought to be the mechanism by which bone adapts to mechanical loading. Reported responses of bone cells to mechanical stimuli vary widely and therefore there is no consensus on what mechanisms of mechanotransduction are physiologically relevant. We hypothesize that the differentiation stage of osteoblastic cells used to study responses to strain in vitro determines the outcome of applied loading. A human fetal osteoblast cell line was triggered to differentiate in culture to the advanced state of mineralization by addition of the osteogenic factors dexamethasone and b-glycerophosphate. Osteoblast cultures were subjected to increasing levels of cyclic, equibiaxial stretch at different stages of differentiation. We show that differentiation of human osteoblasts affects their responses to stretch in vitro. In 7-day osteoblast cultures, stretch results in decreased cell numbers as cells are triggered into apoptosis, independent of the stretch level (between 0.4-2.5%). In more mature cultures, apoptosis is not affected by the same treatment. Stretching differentiating cultures at day 14 actually increases proliferation. This is the first study reporting on differentiation-dependent mechanical control of osteoblast proliferation and apoptosis and is fundamental in understanding mechanotransduction processes in bone. The tight regulation of these responses by differentiation implies the significance of the differentiation stage of osteoblasts for the translation of mechanical signals and corroborates with the putative role of the osteoblastic lineage as mechanotransducer in bone.

Apoptosis↗

PubMed2003

Canine cancellous bone microarchitecture after one year of high-dose bisphosphonates.

We examined the effects of one-year high-dose bisphosphonates (risedronate 0.5 mg/kg/day or alendronate 1.0 mg/kg/day) on the three-dimensional (3-D) microstructural and mechanical properties of canine cancellous bone. A high-resolution micro-CT scanner was used to scan cubic specimens produced from the first lumbar vertebrae. Microstructural properties of the specimens were calculated directly from the 3-D datasets and the mechanical properties of the specimens were determined. Our data demonstrate significant microarchitectural changes in the bisphosphonate-treated cancellous bone that was typically plate-like, denser, with thicker and more trabeculae compared with those of the controls. Consistent with architectural changes, the Young's moduli of cancellous bone increased in all three directions with the greatest increase in primary axial loading (cephalo-caudal) direction after treatment. Our results suggest a bone remodeling-adaptation mechanism stimulated by bisphosphonates that increases bone volume fraction, thickens trabeculae, changes trabeculae towards more plate-like, and increases mechanical properties. The secondary degree of anisotropy contributed significantly to the explained variance in bone strength, and the primary or tertiary degree of anisotropy improved the explanation of variances for Young's moduli, i.e., 79% of strength variances or 74-83% of modulus variances could be explained by the combined anisotropy and bone volume fraction. These significant improvements of cancellous bone architecture provide a rationale for the clinical observation that fracture risk decreased by 50% in the first year of bisphosphonate therapy with only a 5% increase in bone mineral density. We conclude that bisphosphonates enhance mechanical properties and reduce fracture risk by improving architectural anisotropy of cancellous bone 3-D microarchitecture.

Alendronate↗