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Jürg A Gasser

Publications and source records attributed to Jürg A Gasser.

9 recordsLinked to original sources
PubMed2006

Evaluation of three-dimensional image registration methodologies for in vivo micro-computed tomography.

The advent of in vivo micro-computed tomography (micro-CT) provides a novel approach to measure the temporal adaptation of bone micro-architecture within an individual. Spatial alignment in the scanner between serial scans is challenging, but three-dimensional image registration can be used to superimpose the resulting image data, thus ensuring consistent regions of interest (ROI) for analysis. There have been several approaches to image registration developed, yet little is known about their application to high resolution micro-CT data. The purpose of this study was to explore combinations of three image registration similarity measures and three image interpolators, in addition to multi-resolution registration configurations, for assessment of computational efficiency and accuracy on both in vitro and in vivo micro-CT data. Accuracy measures were assessed by comparison with a gold-standard reference transform based on attached fiducial markers. It was concluded that a mutual information registration similarity measure with a linear image interpolator, applied at steps of increasing image resolution, provided the best compromise between accurate and efficient results. In vivo registration of tibial bone microstructure measured in an ovariectomized rat model provided consistent ROI thus demonstrating the usefulness of three-dimensional image registration for in vivo experimental and clinical micro-CT research. It is a technique that is poised to become commonly utilized for analysis of micro-CT data to diagnose and monitor efficacy of therapy in bone diseases.

Animals↗
PubMed2006

A single intravenous administration of zoledronic acid prevents the bone loss and mechanical compromise induced by aromatase inhibition in rats.

Recent evidence has demonstrated that long-term estrogen deprivation using aromatase inhibitor therapy in postmenopausal women with breast cancer results in bone loss and increased fracture risk. Bisphosphonates are potent inhibitors of bone resorption and have demonstrated efficacy in preventing bone loss in postmenopausal women with low bone mineral density (BMD) and in patients with breast cancer receiving estrogen deprivation therapy. Therefore, this study investigated the effects of the bisphosphonate zoledronic acid on BMD and bone strength in rats treated with the aromatase inhibitor, letrozole. Peripheral quantitative computed tomography demonstrated that treatment of rats with daily oral letrozole (1 mg/kg) induced significant bone loss and cortical thinning compared with control animals (P < 0.01). A single prior intravenous dose of zoledronic acid dose dependently protected against letrozole-induced bone loss and cortical thinning, with the highest evaluated dose (20 microg/kg) resulting in BMD values that were not significantly different from controls over the 24 weeks of letrozole treatment. Furthermore, biomechanical testing of the distal femoral metaphysis demonstrated that zoledronic acid (20 microg/kg) significantly prevented the decrease in stiffness and elastic modulus induced by letrozole treatment. Taken together, these data support the use of zoledronic acid for the prevention of bone loss in women with breast cancer receiving aromatase inhibitor therapy.

Animals↗
PubMed2006

Monitoring individual morphological changes over time in ovariectomized rats by in vivo micro-computed tomography.

The ovariectomized (OVX) rat is a well established model for osteoporosis research. The recent development of in vivo micro-computed tomography (micro-CT) provides new possibilities to monitor individual bone changes over time. The purpose of this study was to establish the normal time course of bone loss in the OVX rat model, and to determine the ability to detect morphological changes in vivo compared to cross-sectional study designs where animals are sacrificed at each time point. Eight-month-old female Wistar rats were randomly assigned to one of two groups: OVX (N = 10) or sham-operated (N = 10). In vivo micro-CT scanning of the right proximal tibial metaphyses occurred at 1-month intervals for 6 months. Morphological analyses were performed at each time step for every animal, and a two-way ANOVA with repeated measures was used to analyze the data. A second statistical analysis was performed without repeated measures for analysis as a cross-sectional study design. The repeated measures analysis was more sensitive to early changes than the cross-sectional study analysis. Changes were detected by longitudinal analysis in the sham-operated and OVX animals over time (P < 0.001) with the exception of trabecular separation in the sham animals. The OVX animals had decreases of bone volume ratio of 33% after 1 month, and 72% after 3 months relative to baseline measurements. Significant changes in bone volume ratio, trabecular number and separation were detected early using a longitudinal analysis, thus in vivo assessment is well poised to enable the study of early treatment protocols on the effects of bone architecture. The in vivo analysis found significant changes in the sham animals which were not detected by the cross-sectional analysis, and the changes to the OVX animal morphology was detected sooner. A substantial variation of baseline morphometry within the homogenous group of rats and response to OVX was observed, thus emphasizing the advantage of performing in vivo analysis where each animal acts as its own control. These data provide new insight into individual bone changes following OVX, and can be used as baseline information upon which future in vivo studies can be designed.

Age Factors↗
PubMed2006

The relative merits of anabolics versus anti-resorptive compounds: where our targets should be, and whether we are addressing them.

Currently available results from fracture trials provide evidence that the most potent anti-resorptive agents reduce vertebral and non-vertebral fractures maximally by 61% and 51%, respectively. Results from the Phase III trial with denosumab, the human monoclonal antibody, are eagerly awaited. Denosumab leads to sustained 80-90% reduction of bone resorption markers, which is below the level commonly achieved with bisphosphonates, and it will be interesting to see whether this leads to an improvement in its anti-fracture efficacy over bisphosphonates. If the majority of the anti-fracture efficacy of anti-resorptive agents results from the reduction of the remodelling space (removal of stress raisers) and the conservation of structural integrity of cancellous bone, a further decrease in bone resorption might not be desirable, especially as suppression of the residual remodelling capacity could lead to an increased risk for accumulation of microdamage. In contrast to anti-resorptive agents, the bone anabolic parathyroid hormone activates modelling drifts, which act to increase trabecular thickness and add bone predominantly on the endocortical, and to a lesser degree the periosteal, surface. Despite its anabolic nature, reduction of vertebral and non-vertebral fractures is only marginally better than those achieved with anti-resorptive agents. Ageing compromises locomotor capacity and is associated with an increased risk of falls. Perhaps it is time to shift our attendance to the age-related deterioration of muscle or neuromuscular function as a target and add this 'adjuvant therapy' to the potent anti-remodelling and bone anabolic agents available for the treatment of osteoporosis if we truly want to reduce fracture incidence beyond what is possible today.

Accidental Falls↗
PubMed2005

Noninvasive monitoring of changes in structural cancellous bone parameters with a novel prototype micro-CT.

Characterization of trabecular bone structures requires necropsy of animals followed by a labor-intense histomorphometric or ex vivo micro-CT analysis. We tested the novel vivaCT40 from Scanco Medical AG (Bassersdorf, Switzerland), which allows monitoring such changes repeatedly in anesthetized rats and mice. Postmenopausal osteoporosis: in 8-month-old ovariectomized (OVX) rats, the vivaCT40 was capable of picking up the decrease in trabecular bone volume and trabecular thinning as well as the decrease in the number of trabecular elements as a function of time. The bone anabolic effects of parathyroid hormone [hPTH(1-34)], which resulted in an increase in trabecular thickness but not their number, as well as the bone protective effect of the two antiresorptive agents zoledronic acid (ZA) and 17-alpha ethinylestradiol (aEE), were detected correctly with the vivaCT40. Adjuvans arthritis: the vivaCT40 allowed measuring trabecular bone loss caused by periarticular inflammation in a rat model of adjuvans arthritis and demonstrated the bone protective effect of dexamethasone (DM). In addition, it was possible to image the subtle erosive lesions in subchondral bone caused by the inflammatory processes. Tumor osteolysis: the vivaCT40 allowed monitoring of the progressive osteolytic response following the local administration of 4T1luc2000 tumor cells into the tibia metaphysis of nude mice. The potent protective effect of ZA on tumor osteolysis was demonstrated. In summary, the new vivaCT40 can monitor the effects of known agents and diseases such as osteoporosis, inflammatory arthritis, and tumor invasion on 3-D trabecular microarchitecture accurately, repeatedly, reliably, and quickly in anesthetized rats and mice. The scanner represents a breakthrough for noninvasive imaging and structural measurements in small rodents.

Animals↗
PubMed2003

Proton-sensing G-protein-coupled receptors.

Blood pH is maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. The molecular mechanisms involved in pH homeostasis are not completely understood. Here we show that ovarian cancer G-protein-coupled receptor 1 (OGR1), previously described as a receptor for sphingosylphosphorylcholine, acts as a proton-sensing receptor stimulating inositol phosphate formation. The receptor is inactive at pH 7.8, and fully activated at pH 6.8-site-directed mutagenesis shows that histidines at the extracellular surface are involved in pH sensing. We find that GPR4, a close relative of OGR1, also responds to pH changes, but elicits cyclic AMP formation. It is known that the skeleton participates in pH homeostasis as a buffering organ, and that osteoblasts respond to pH changes in the physiological range, but the pH-sensing mechanism operating in these cells was hitherto not known. We detect expression of OGR1 in osteosarcoma cells and primary human osteoblast precursors, and show that these cells exhibit strong pH-dependent inositol phosphate formation. Immunohistochemistry on rat tissue sections confirms the presence of OGR1 in osteoblasts and osteocytes. We propose that OGR1 and GPR4 are proton-sensing receptors involved in pH homeostasis.

Amino Acid Sequence↗