Dietrich von Stechow

TRANCE/RANKL Knockout Mice Are Protected from Bone Erosion in a Serum Transfer Model of Arthritis

There is considerable evidence that osteoclasts are involved in the pathogenesis of focal bone erosion in rheumatoid arthritis. Tumor necrosis factor-related activation-induced cytokine, also known as receptor activator of nuclear factor-kappaB ligand (TRANCE/RANKL) is an essential factor for osteoclast differentiation. In addition to its role in osteoclast differentiation and activation, TRANCE/RANKL also functions to augment T-cell dendritic cell cooperative interactions. To further evaluate the role of osteoclasts in focal bone erosion in arthritis, we generated inflammatory arthritis in the TRANCE/RANKL knockout mouse using a serum transfer model that bypasses the requirement for T-cell activation. These animals exhibit an osteopetrotic phenotype characterized by the absence of osteoclasts. Inflammation, measured by clinical signs of arthritis and histopathological scoring, was comparable in wild-type and TRANCE/RANKL knockout mice. Microcomputed tomography and histopathological analysis demonstrated that the degree of bone erosion in TRANCE/RANKL knockout mice was dramatically reduced compared to that seen in control littermate mice. In contrast, cartilage erosion was present in both control littermate and TRANCE/RANKL knockout mice. These results confirm the central role of osteoclasts in the pathogenesis of bone erosion in arthritis and demonstrate distinct mechanisms of cartilage destruction and bone erosion in this animal model of arthritis.

Trabecular Bone Response to Mechanical and Parathyroid Hormone Stimulation: The Role of Mechanical Microenvironment

Bone response under combined mechanical and PTH stimuli is important in osteoporosis. A rat tail animal model with computer modeling was used to examine bone response to loading and PTH. PTH enhances and sustains increased bone formation rate, which directly correlates to mechanical microenvironment, suggesting beneficial effects of combined PTH treatment and exercise in preventing osteoporosis.

Bone Volume Fraction Explains the Variation in Strength and Stiffness of Cancellous Bone Affected by Metastatic Cancer and Osteoporosis

Preventing nontraumatic fractures in millions of patients with osteoporosis or metastatic cancer may significantly reduce the associated morbidity and reduce health-care expenditures incurred by these fractures. Predicting fracture occurrence requires an accurate understanding of the relationship between bone structure and the mechanical properties governing bone fracture that can be readily measured. The aim of this study was to test the hypothesis that a single analytic relationship with either bone tissue mineral density or bone volume fraction (BV/TV) as independent variables could predict the strength and stiffness of normal and pathologic cancellous bone affected by osteoporosis or metastatic cancer. After obtaining institutional review board approval and informed consent, 15 patients underwent excisional biopsy of metastatic prostate, breast, lung, ovarian, or colon cancer from the spine and/or femur to obtain 41 metastatic cancer specimens. In addition, 96 noncancer specimens were excised from 43 age- and site-matched cadavers. All specimens were imaged using micro-computed tomography (micro-CT) and backscatter emission imaging and tested mechanically by uniaxial compression and nanoindentation. The minimum BV/TV, measured using quantitative micro-CT, accounted for 84% of the variation in bone stiffness and strength for all cancellous bone specimens. While relationships relating bone density to strength and stiffness have been derived empirically for normal and osteoporotic bone, these relationships have not been applied to skeletal metastases. This simple analytic relationship will facilitate large-scale screening and prediction of fracture risk for normal and pathologic cancellous bone using clinical CT systems to determine the load capacity of bones altered by metastatic cancer, osteoporosis, or both.

Three-Dimensional Quantitation of Periradicular Bone Destruction by Micro-Computed Tomography

We have previously shown that two-dimensional, high-resolution, micro-computed tomography is a rapid, reproducible, and noninvasive method for measuring periradicular bone resorption in mice, giving results virtually identical to histology. In this study, we determined whether a three-dimensional volumetric quantitation of bone resorption could be achieved and whether this correlates with two-dimensional measurements. Periradicular lesions were induced in the lower first molars of mice by pulp exposure and infection; unexposed teeth served as controls. Mandibles were harvested on day 21 and subjected to: (a) three-dimensional micro-computed tomography imaging; and (b) conventional histology. Using a three-dimensional model and a semiautomatic contouring algorithm, we determined three-dimensional void volume, void surface, void thickness, and the standard deviation of the thickness distribution. The results showed a significant correlation between lesion void volume and two-dimensional lesion area by histology (r2 = 0.73), as well as high correlations between void volume and void thickness (r2 = 0.86) and standard deviation of the void thickness (r2 = 0.87), but no relationship with void surface. These results show that three-dimensional analysis of micro-computed tomography images is highly correlated with two-dimensional cross-sectional measures of periradicular lesions. Nevertheless, micro-computed tomography allows assessment of additional microstructural features as well as sub-regional analysis of lesion development.

Effects of Thresholding Techniques on μCT-Based Finite Element Models of Trabecular Bone

Microimaging based finite element analysis is widely used to predict the mechanical properties of trabecular bone. The choice of thresholding technique, a necessary step in converting grayscale images to finite element models, can significantly influence the predicted bone volume fraction and mechanical properties. Therefore, we investigated the effects of thresholding techniques on microcomputed tomography (micro-CT) based finite element models of trabecular bone. Three types of thresholding techniques were applied to 16-bit micro-CT images of trabecular bone to create three different models per specimen. Bone volume fractions and apparent moduli were predicted and compared to experimental results. In addition, trabecular tissue mechanical parameters and morphological parameters were compared among different models. Our findings suggest that predictions of apparent mechanical properties and structural properties agree well with experimental measurements regardless of the choice of thresholding methods or the format of micro-CT images.

Present and Future Therapies of Articular Cartilage Defects

AbstractBackground: Until today, no universally successful therapy to treat substantial articular cartilage defects has been available. Numerous therapeutic approaches can only improve clinical symptoms of joint lesions, but cannot stimulate the regenerative and reactive capacity of the biological tissue in the defect, and, thus, cannot restore an articular surface capable of functional load bearing. Some other therapeutic options promised impressing results at the beginning, but did not withstand the process of a closer investigation. Even after laborious, invasive and expensive therapies, patients still complain about pain, joint effusions, restricted movement, or articular blockage. Established and Novel Therapies: The aim of all therapeutic procedures to treat patients with damaged articular cartilage is to reconstruct the integrity of the articular cartilage surface in order to enable them to live an unrestricted painless professional and private life. This article gives an overview of the clinically established procedures, their indications and the present long-term results, as well as a crucial look on the limitations of each approach. Novel therapies, which integrate molecular biology techniques and tissue engineering into transplantation surgery, are introduced and analyzed in terms of their capability and future potential.

The Effect of Cement Augmentation on the Geometry and Structural Response of Recovered Osteopenic Vertebrae : An Anterior-Wedge Fracture Model

Study Design. The efficacy of cement augmentation in restoring the geometry and structural competence of failed thoracic and lumbar human vertebrae under mechanical loads was studied. Objectives. To quantify whether cement augmentation restores and maintains the geometry and structural competence of failed osteopenic vertebrae and to assess the contribution of vertebral geometry to the achieved augmentation. Summary of Background Data. Cement augmentation of failed vertebrae was clinically shown to alleviate significant pain and functional impairments associated with vertebral fragility fractures. However, the procedure’s efficacy in restoring the structural response of the failed vertebrae and maintaining the achieved geometry under functional loads remains unclear. Methods. Nineteen thoracic and lumbar human vertebrae were tested to failure under compression-flexion loading. The vertebrae were allowed to recover, were retested to failure, augmented with Polymethylmethacrylate and again retested to failure. Repeated measures analysis was used to compare the change in vertebral geometry and structural response, defined as the multiplanar force and moment response of the vertebra to the imposed deformation, at each of the test stages. Linear regression was used to assess the role of the geometry of the failed vertebrae in affecting the outcome of augmentation. Results. Augmentation significantly increased the compressive (228%) and flexion (118%) strength of the failed vertebrae and achieved a significant, albeit partial, restoration of vertebral geometry. However, the structural response of the failed vertebrae was markedly altered, whereas under applied loads, the achieved height restoration was significantly diminished. Although the geometry of the fractured vertebral body was associated with the degree of restoration of the vertebral body afteraugmentation, it was not correlated with the change in the structural parameters. Conclusion. Augmentation increases the structural competence of failed vertebrae and to a degree, restores their geometry. However, the structural response of the augmented vertebrae was significantly modified. Furthermore, the augmented vertebrae were unable to maintain the degree of geometry restoration under load.

Augmentation of failed human vertebrae with critical un-contained lytic defect restores their structural competence under functional loading: An experimental study

BACKGROUND Lytic spinal lesions reduce vertebral strength and may result in their fracture. Vertebral augmentation is employed clinically to provide mechanical stability and pain relief for vertebrae with lytic lesions. However, little is known about its efficacy in strengthening fractured vertebrae containing lytic metastasis. METHODS Eighteen unembalmed human lumbar vertebrae, having simulated uncontained lytic defects and tested to failure in a prior study, were augmented using a transpedicular approach and re-tested to failure using a wedge fracture model. Axial and moment based strength and stiffness parameters were used to quantify the effect of augmentation on the structural response of the failed vertebrae. Effects of cement volume, bone mineral density and vertebral geometry on the change in structural response were investigated. FINDINGS Augmentation increased the failed lytic vertebral strength [compression: 85% (P<0.001), flexion: 80% (P<0.001), anterior-posterior shear: 95%, P<0.001)] and stiffness [(40% (P<0.05), 53% (P<0.05), 45% (P<0.05)]. Cement volume correlated with the compressive strength (r(2)=0.47, P<0.05) and anterior-posterior shear strength (r(2)=0.52, P<0.05) and stiffness (r(2)=0.45, P<0.05). Neither the geometry of the failed vertebrae nor its pre-fracture bone mineral density correlated with the volume of cement. INTERPRETATION Vertebral augmentation is effective in bolstering the failed lytic vertebrae compressive and axial structural competence, showing strength estimates up to 50-90% of historical values of osteoporotic vertebrae without lytic defects. This modest increase suggests that lytic vertebrae undergo a high degree of structural damage at failure, with strength only partially restored by vertebral augmentation. The positive effect of cement volume is self-limiting due to extravasation.