Osteoporosis: Augat P

Engelke K, Adams JE, Armbrecht G, Augat P, Bogado CE, Bouxsein ML, Felsenberg D, Ito M, Prevrhal S, Hans DB, Lewiecki EM. · Institute of Medical Physics, University of Erlangen, Germany; Synarc, Hamburg, Germany. <> · J Clin Densitom. · Pubmed #18442757 No free full text.

Abstract: The International Society for Clinical Densitometry (ISCD) has developed Official Positions for the clinical use of dual-energy X-ray absorptiometry (DXA) and non-DXA technologies. While only DXA can be used for diagnostic classification according to criteria established by the World Health Organization, DXA and some other technologies may predict fracture risk and be used to monitor skeletal changes over time. ISCD task forces reviewed the evidence for clinical applications of non-DXA techniques and presented reports with recommendations at the 2007 ISCD Position Development Conference. Here we present the ISCD Official Positions for quantitative computed tomography (QCT) and peripheral QCT (pQCT), with supporting medical evidence, rationale, controversy, and suggestions for further study. QCT is available for bone mineral density measurements at the spine, hip, forearm, and tibia. The ISCD Official Positions presented here focus on QCT of the spine and pQCT of the forearm. Measurements at the hip may have clinical relevance, as this is an important fracture site; however, due to limited medical evidence, definitive advice on its use in clinical practice cannot be provided until more data emerge.

Goldhahn J, Scheele WH, Mitlak BH, Abadie E, Aspenberg P, Augat P, Brandi ML, Burlet N, Chines A, Delmas PD, Dupin-Roger I, Ethgen D, Hanson B, Hartl F, Kanis JA, Kewalramani R, Laslop A, Marsh D, Ormarsdottir S, Rizzoli R, Santora A, Schmidmaier G, Wagener M, Reginster JY. · Schulthess Clinic Zurich and Clinical Priority Program Fracture Fixation in Osteoporotic, Bone of AO Foundation, Davos, Switzerland. · Bone. · Pubmed #18544475 No free full text.

Abstract: Pre-clinical studies indicate that pharmacologic agents can augment fracture union. If these pharmacologic approaches could be translated into clinical benefit and offered to patients with osteoporosis or patients with other risks for impaired fracture union (e.g. in subjects with large defects or open fractures with high complication rate), they could provide an important adjunct to the treatment of fractures. However, widely accepted guidelines are important to encourage the conduct of studies to evaluate bioactive substances, drugs, and new agents that may promote fracture union and subsequent return to normal function. A consensus process was initiated to provide recommendations for the clinical evaluation of potential therapies to augment fracture repair in patients with meta- and diaphyseal fractures. Based on the characteristics of fracture healing and fixation, the following study objectives of a clinical study may be appropriate: a) acceleration of fracture union, b) acceleration of return to normal function and c) reduction of fracture healing complications. The intended goal(s) should determine subsequent study methodology. While an acceleration of return to normal function or a reduction of fracture healing complications in and of themselves may be sufficient primary study endpoints for a phase 3 pivotal study, acceleration of fracture union alone is not. Radiographic evaluation may either occur at multiple time points during the healing process with the aim of measuring the time taken to reach a defined status (e.g. cortical bridging of three cortices or disappearance of fracture lines), or could be obtained at a single pre-determined timepoint, were patients are expected to reach a common clinical milestone (i.e. pain free full weight-bearing in weight-bearing fracture cases). Validated Patient Reported Outcomes (PRO's) measures will need to support the return to normal function co-primary endpoints. If reduction of complication rate (e.g. non-union) is the primary objective, the anticipated complications must be defined in the study protocol, along with their possible associations with the specified fracture type and fixation device. The study design should be randomized, parallel, double-blind, and placebo-controlled, and all fracture subjects should receive a standardized method of fracture fixation, defined as Standard of Care.

Augat P, Eckstein F. · Biomechanics Laboratory, Trauma Center Murnau, 82418 Murnau, Germany. · Annu Rev Biomed Eng. · Pubmed #18466110 No free full text.

Abstract: Quantitative imaging of musculoskeletal tissue, including radiography, computed tomography (CT), and magnetic resonance imaging (MRI), has become the essential methodology in clinical practice for diagnosis and monitoring of various musculoskeletal conditions. Furthermore, quantitative imaging technologies have become indispensable for research and development in diseases of the human skeleton. Standardized methods of image analysis have been developed through the years to quantify measurements on bone and cartilage with high precision and accuracy. Key areas of musculoskeletal disease where quantitative imaging is currently employed are osteoporosis and arthritis.

Augat P, Schorlemmer S. · Trauma Centre Murnau, Prof. Kuentscher Strasse 8, 82418 Murnau, Germany. <> · Age Ageing. · Pubmed #16926200 links to  free full text

Abstract: Bone's mechanical competence and its fragility in particular depend to a certain extent on the structure and microstructure of the cortical bone compartment. Beyond bone mineral density (BMD) and bone mineral content, a variety of other features of cortical bone contribute to whole bone's resistance to fracture. Structural properties of cortical bone most commonly employed as surrogate for its mechanical competence include thickness of the cortex, cortical cross-sectional area and area moment of inertia. But microstructural properties such as cortical porosity, crystallinity or the presence of microcracks also contribute to bone's mechanical competence. Microcracks in particular not only weaken the cortical bone tissue but also provide an effective mechanism for energy dissipation. Bone is a damageable, viscoelastic composite and most of all a living material capable of self-repair and thus exhibits a complex repertoire of mechanical properties. This review provides an overview of a variety of features of cortical bone known to provide mechanical competence and how these features may be applied for fracture risk prediction.

Augat P, Simon U, Liedert A, Claes L. · Institute for Orthopaedic Research and Biomechanics, University of Ulm, Germany. · Osteoporos Int. · Pubmed #15372141 No free full text.

Abstract: Fracture repair, which aims at regaining the functional competence of a bone, is a complex and multifactorial process. For the success of fracture repair biology and mechanics are of immense importance. The biological and mechanical environments must be compatible with the processes of cell and tissue proliferation and differentiation. The biological environment is characterized by the vascular supply and by many biochemical components, the biochemical milieu. A good vascular supply is a prerequisite for the initiation of the fracture repair process. The biochemical milieu involves complex interactions among local and systemic regulatory factors such as growth factors or cytokines. The mechanical environment is determined by the local stress and strain within the fracture. However, the local stress and strain is not accessible, and the mechanical environment, therefore, is described by global mechanical factors, e.g., gap size or interfragmentary movement. The relationship between local stress and strain and the global mechanical factors can be obtained by numerical models (Finite Element Model). Moreover, there is considerable interaction between biological factors and mechanical factors, creating a biomechanical environment for the fracture healing process. The biomechanical environment is characterized by osteoblasts and osteocytes that sense the mechanical signal and express biological markers, which effect the repair process. This review will focus on the effects of biomechanical factors on fracture repair as well as the effects of age and osteoporosis.

Schorlemmer S, Gohl C, Iwabu S, Ignatius A, Claes L, Augat P. · Institute of Orthopaedic Research and Biomechanics, University of Ulm, Ulm, Germany. · J Bone Miner Res. · Pubmed #14606514 No free full text.

Abstract: Thus far, orthopedic research lacks a suitable animal model of osteoporosis. In OVX sheep, 6 months of steroid exposure reduced bone density and mechanical competence. Bone properties and bone formation did not recover for another 6 months. Therefore, steroid-treated OVX sheep may serve as a large animal model for osteopenic bone. INTRODUCTION: The purpose of this study was to explore the effects of glucocorticoid treatment on cancellous bone density, microarchitecture, biomechanics, and formation of new bone. MATERIALS AND METHODS: Sixteen ovariectomized merino sheep received either a 6-month glucocorticoid treatment (GLU; 0.45 mg/kg methylprednisolone) or were left untreated (control). Cancellous bone biopsy specimens from the tibia were harvested 6 months after ovariectomy. After 12 months, the animals were killed, and biopsy specimens were obtained from the contralateral tibia and the lumbar spine. All biopsy specimens were scanned for apparent bone mineral density by peripheral quantitative computed tomography (pQCT) and tested mechanically in uniaxial compression. Three-dimensional bone reconstructions were obtained by microcomputed tomography. Formation of new bone was analyzed using histologies of the femoral condyles. RESULTS: After 6 months, mineral density (-19%) and mechanical competence (-45%) were reduced by glucocorticoid treatment (p < 0.1). BV/TV (-21%; p < 0.01) and trabecular thickness (-20%; p = 0.01) declined, whereas BS/BV increased (24%; p = 0.01). After 12 months, mineral density (-33%) and mechanical properties (-55%) were reduced even more profoundly (p < 0.05). Also, the structural parameters (BS/BV and Tb.Th.) still seemed to be affected by glucocorticoid treatment (p < 0.05). New bone formation, assessed by measurement of osteoid surface, was markedly reduced (-63%, p < 0.1) by glucocorticoid treatment. The differences between groups were generally more pronounced at the tibia and the femur than at the spine. CONCLUSION: The effects of short-term high-dose steroid administration on bone mineral in this animal model were comparable with those observed in humans after long-term corticoid treatment. Reduction in bone quality and bone formation rate persisted after the cessation of steroid administration. Glucocorticoid treatment of ovariectomized sheep may therefore serve as a large animal model for steroid-induced osteopenia.

Wachter NJ, Augat P, Krischak GD, Mentzel M, Kinzl L, Claes L. · Department of Traumatology, Hand- and Reconstructive Surgery, University of Ulm, Ulm, Germany. · Calcif Tissue Int. · Pubmed #12037622 No free full text.

Abstract: The high importance of intracortical porosity for mechanical strength of cortical bone has been established. The contribution of other parameters of microstructure such as osteon dimensions for strength is in discussion. The aim of this study was to evaluate the predictive value of microcomputed tomography (mCT) for porosity and other microstructural parameters of cortical bone in cortical bone biopsies. Femoral cortical bone specimens from the middiaphysis of 24 patients were harvested during the procedure of total hip replacement at the location where normally one hole (Ø 4.5 mm) for the relief of the intramedullary pressure is placed. In vitro intracortical porosity and bone mineral density (BMD) measurements by mCT were compared with structural parameters assessed in histological sections of the same specimens. A strong correlation was found between intracortical porosity measured by mCT and histological porosity (r = 0.95, P <0.0001). Porosity measured by mCT was also a strong predictor for other parameters describing dimensions of porous structures. BMD?1 was associated with osteonal area (r = -0.76, P <0.0001). We consider the measurement of porosity by mCT as a very potent procedure for assessing intracortical porosity and parameters related to porous structures of cortical bone nondestructively in vitro.

Augat P, Rapp S, Claes L. · Institute of Orthopaedic Research and Biomechanics, University of Ulm, Helmholtzstrasse 14, 89081 Ulm, Germany. · J Orthop Trauma. · Pubmed #11972073 No free full text.

Abstract: OBJECTIVE: To evaluate a modified sliding hip screw for the fixation of trochanteric fractures that provides increased fixation strength in osteoporotic bones and allows for the safe intraoperative application of bone cement. DESIGN: Biomechanical cadaver study. MATERIALS: Unstable trochanteric fractures were simulated by osteotomy in nine pairs of cadaveric femurs and stabilized by a standard sliding hip screw randomly assigned to the left or right femur. The contralateral femur was stabilized with a newly designed hip screw, which was augmented with low-viscosity bone cement. MAIN OUTCOME MEASUREMENTS: Femoral bone mineral density was measured by dual x-ray absorptiometry and quantitative computed tomography. Fixation stability of the hip was assessed after dynamic loading by displacement measurement of the femoral head in a simulated one-leg stance configuration. RESULTS: Modification of the hip screw together with cement augmentation significantly (p < 0.05) increased the initial stability of the fracture fixation technique. The total displacement of the femoral head was reduced by 39 percent on average using cement augmentation in the modified screw compared with the standard sliding hip screw. The largest improvement in initial fixation stability was found for the most osteoporotic bones. CONCLUSIONS: This modified hip screw augmented with bone cement can significantly enhance the initial fixation stability of trochanteric fractures in osteoporotic femurs.

Ignatius AA, Augat P, Ohnmacht M, Pokinskyj P, Kock HJ, Claes LE. · Institute of Orthopaedic Research and Biomechanics, University of Ulm, Helmholtzstrasse 14, 89081 Ulm, Germany. · J Biomed Mater Res. · Pubmed #11319738 No free full text.

Abstract: The aim of the study was to assess the mechanical efficacy of a new resorbable polymer developed on the basis of alkylene bis(dilactoyl)-methacrylate to improve the anchorage of osteosynthesis material in cancellous bone. Cancellous bone screws were inserted in bovine as well as in human vertebrae and human femoral condyles and were augmented with the new polymer or polymethylmethacrylate (PMMA), respectively. Nonaugmented screws were used as controls. A removal torque test, a dynamic fatigue test, and a pullout test were performed. Augmentation with the new polymer increased the removal torque by 84% in human femoral bone. In the dynamic fatigue test of bovine vertebrae, the removal torque after cyclic loading was 115% higher for the new polymer compared to the nonaugmented controls. In the human vertebrae, the reinforcement with the new polymer increased the removal torque after dynamic loading by 114%. The augmentation with the new polymer increased the pullout force by 88% in bovine vertebrae and by 118% in human vertebrae in comparison to nonaugmented screws. It was concluded that augmentation by the new resorbable polymer significantly enhanced the anchorage of bone screws in cancellous bone. The mechanical efficiency of the new polymer was comparable to that of PMMA cement.

Wachter NJ, Augat P, Mentzel M, Sarkar MR, Krischak GD, Kinzl L, Claes LE. · Department of Traumatology, Hand and Reconstructive Surgery, University of Ulm, Ulm, Germany. · Bone. · Pubmed #11165955 No free full text.

Abstract: Peripheral quantitative computed tomography (pQCT) is an established diagnostic method for assessment of bone mineral density in the diagnosis of osteoporosis. However, the capacity of structural parameters of cancellous bone measured by high-resolution computed tomography remains to be explored. In 33 patients, bone mineral density (BMD) of the proximal femur was measured in vitro by pQCT using cylindrical biopsies from the intertrochanteric region harvested before the implantation of an artificial hip joint. By digital image analysis of CT scans, parameters derived from histomorphometry describing the microarchitecture of cancellous bone were measured. The biopsies were also loaded to failure by an uniaxial compression test to determine the biomechanical parameters, Young's modulus, strength, and maximum energy absorption (E(max)). Strong correlations were found for BMD vs. mechanical parameters (r = 0.73 for Young's modulus, r = 0.82 for strength, and r = 0.79 for E(max); p < 0.001, n = 29). The morphological parameters, bone volume per trabecular volume (BV/TV), apparent trabecular thickness (app.Tb.Th), apparent trabecular separation (app.Tb.Sp), and trabecular number (Tb.N), correlated significantly with all mechanical parameters. The combination of morphological parameters with BMD in a multivariate regression model led to an overall, but only moderate, increase in R(2) in all cases. Our data confirm the high predictive value of BMD for the mechanical competence of cancellous bone of the intertrochanteric region. However, quantification of cancellous bone structure by image analysis of CT scans may provide additional qualitative information for the analysis of bone strength.

Majumdar S, Link TM, Millard J, Lin JC, Augat P, Newitt D, Lane N, Genant HK. · Department of Radiology, University of California, San Francisco 94143-1290, USA. · Med Phys. · Pubmed #11128312 No free full text.

Abstract: Our purpose in this study was (i) to measure trabecular bone structure using fractal analysis of distal radius radiographs in subjects with and without osteoporotic hip fractures, and (ii) to compare these measures with bone mineral density (BMD) as well as with measures of trabecular bone structure derived from high resolution magnetic resonance (MR) images. Distal radius radiographs were obtained using semi-industrial films (55 kVp, 400 mAs) in 30 postmenopausal patients, who had suffered osteoporotic hip fractures (74.8+/-8.2 years) in the last 24 months and 27 postmenopausal age-matched (74.6+/-6.6 yr) normal volunteers. Radiographs were digitized at 50 microm. A Fourier power spectrum-based fractal dimension (FD) characterizing the trabecular pattern was measured in a region of interest proximal to the joint line. The fractal dimension was calculated over two spatial frequency (f) ranges: FD1 was calculated over 0.5<log(f)<l.0, FD2 over the higher range 1.0<log(f)<1.5. Trabecular BMD in the radius was obtained using peripheral quantitative computed tomography (pQCT) (Stratec GmbH, Germany). In addition BMD of the proximal femur was determined using dual x-ray absorptiometry (DXA) (QDR 2000, Hologic, MA). In a subset of patients (16 controls and 18 with hip fractures), high resolution MR imaging of the distal radius (spatial resolution of 156 x 156 x 500 microm) was used to obtain measures analogous to bone histomorphometry. There were significant differences (p<0.05) between the fracture and nonfracture groups in the total femur BMD (13%), trabecular BMD in the distal radius (4%), and the fractal dimension in the radiographs (FD2) (3%). The correlations between FD2 and the total femur BMD as well as trabecular bone BMD in the distal radius were -0.48 (p<0.006) and -0.22 (p<0.33); respectively; FD1 increased with BMD and showed lower correlations. FD2 showed good correlations with App. Tb.N (-0.71) and App. Tb.Sp (0.69) (p<0.01), moderate correlation with App BV/TV (-0.53) (p<0.05), and no significant correlation with App. Tb.Th. The correlations between structural measures and FD1 showed the inverse trend and were typically lower. The odds ratios for a hip fracture were 2.44 for total femur BMD, 1.5 for trabecular BMD (radius), and 1.5 for FD2, respectively. In summary, the fractal measures derived from radiographs of the radius show differences between subjects with and without hip fractures, the predictive power of measures in the distal radius are comparable to radial trabecular BMD but lower than that of total hip BMD.

Wu C, Hans D, He Y, Fan B, Njeh CF, Augat P, Richards J, Genant HK. · Osteoporosis and Arthritis Research Group, Department of Radiology, University of California, San Francisco, San Francisco, CA 94117-0784, USA. · Bone. · Pubmed #10773595 No free full text.

Abstract: This investigation compares quantitative ultrasound (QUS) measurement of the phalanges with peripheral quantitative computed tomography (pQCT) and dual X-ray absorptiometry (DXA) measurement of the forearm, to estimate the strength of the distal radius in 13 cadaveric forearms. The cadavers were scanned at the distal radius by pQCT and DXA for bone mineral density (BMD) and at the approximate phalanges by QUS for speed of sound (SOS). The distal radii were subjected to a simulated Colles fracture produced with a materials testing machine. The load at which the distal radius was fractured was considered as a representation of bone strength. The bone strength correlated significantly with SOS at different phalanges (r = 0.63-0.72), BMD at different regions of interest by DXA (r = 0.67-0.75), and cortical BMD at different sites by pQCT (r = 0.61-0.67). Standard stepwise regression analysis showed that adding phalangeal SOS into forearm densitometric variables significantly enhanced the statistical power for prediction of the strength of the distal radius. Our results suggest that, for assessment of site-specific distal forearm strength, QUS measurement of the phalanges is comparable to forearm densitometry. Phalangeal QUS may add clinical value if distal forearm strength has a high priority.

Majumdar S, Link TM, Augat P, Lin JC, Newitt D, Lane NE, Genant HK. · Department of Radiology, and Department of Internal Medicine, University of California, San Francisco, California, USA. · Osteoporos Int. · Pubmed #10525716 No free full text.

Abstract: To determine whether magnetic resonance (MR)-derived measures of trabecular bone architecture in the distal radius are predictive for prevalent hip fractures, 20 subjects with hip fractures and 19 age-matched postmenopausal controls were studied. Bone mineral density (BMD) measures at the hip (dual-energy X-ray absorptiometry, DXA) and the distal radius (peripheral quantitative computed tomography, pQCT) were also obtained. We compared the MR-based structural measures derived in the radius with those in the calcaneus of the same patients. In the radius, images were acquired at an in-plane resolution of 156 microm and a slice thickness of 0.5 mm. Stereologic measures such as the apparent trabecular thickness (app. Tb.Th), fractional trabecular bone volume (app. BV/TV), trabecular spacing (app. Tb.Sp) and trabecular number (app. Tb.N) were derived from the images. Measures of app. Tb.Sp and app. Tb.N in the distal radius showed significant (p<0.05) differences between the two groups, as did hip BMD measures. However, radial trabecular BMD measures showed only a marginal difference (p = 0.05). Receiver operating curve analysis was used to determine the diagnostic efficacy of BMD, structural measures and a combination of the two. The area under the curve (AUC) for total hip BMD was 0.73, and for radial trabecular BMD was 0.69. AUC for most of the measures of trabecular bone structure at the distal radius was lower than for hip BMD measures; however, AUC for app. Tb.N at the radius was 0.69, comparable to trabecular BMD using pQCT. The AUC for combined BMD (hip) and structure measures was higher (0.87) when radius and calcaneus structure was included. Measures of trabecular architecture derived from MR images combined with BMD measures improve the discrimination between subjects with hip fractures and normal age-matched controls.

Majumdar S, Lin J, Link T, Millard J, Augat P, Ouyang X, Newitt D, Gould R, Kothari M, Genant H. · Magnetic Resonance Science Center, Department of Radiology, University of California, San Francisco 94143, USA. · Med Phys. · Pubmed #10435535 No free full text.

Abstract: The purpose of this study was to determine whether fractal dimension of radiographs provide measures of trabecular bone structure which correlate with bone mineral density (BMD) and bone biomechanics, and whether these relationships depend on the technique used to calculate the fractal dimension. Eighty seven cubic specimen of human trabecular bone were obtained from the vertebrae and femur. The cubes were radiographed along all three orientations--superior-inferior (SI), medial-lateral (ML), and anterior-posterior (AP), digitized, corrected for background variations, and fractal based techniques were applied to quantify trabecular structure. Three different techniques namely, semivariance, surface area, and power spectral methods were used. The specimens were tested in compression along three orientations and the Young's modulus (YM) was determined. Compressive strength was measured along the SI direction. Quantitative computed tomography was used to measure trabecular BMD. High-resolution magnetic-resonance images were used to obtain three-dimensional measures of trabecular architecture such as the apparent bone volume fraction, trabecular thickness, spacing, and number. The measures of trabecular structure computed in the different directions showed significant differences (p<0.05). The correlation between BMD, YM, strength, and the fractal dimension were direction and technique dependent. The trends of variation of the fractal dimension with BMD and biomechanical properties also depended on the technique and the range of resolutions over which the data was analyzed. The fractal dimension showed varying trends with bone mineral density changes, and these trends also depended on the range of frequencies over which the fractal dimension was measured. For example, using the power spectral method the fractal dimension increased with BMD when computed over a lower range of spatial frequencies and decreased for higher ranges. However, for the surface area technique the fractal dimension increased with increasing BMD. Fractal measures showed better correlation with trabecular spacing and number, compared to trabecular thickness. In a multivariate regression model inclusion of some of the fractal measures in addition to BMD improved the prediction of strength and elastic modulus. Thus, fractal based texture analysis of radiographs are technique dependent, but may be used to quantify trabecular structure and have a potentially valuable impact in the study of osteoporosis.