Dual-Layer Spectral-Computed Tomography Enhances the Separability of Calcium-Based Implant Material from Bone: An Ex Vivo Quantitative Imaging Study.

Local treatment of bone loss with an injection of a resorbable, calcium-based implant material to replace bone has a long history of clinical use. The in vivo discrimination of changes in bone versus implant is challenging with standard computed tomography (CT). However, spectral-CT techniques enable the separation between tissues of similar densities but different chemical compositions. Dual-layer spectral-CT imaging and postprocessing analysis methods were applied to investigate the separability of AGN1 (a triphasic calcium-based implant) and bone after AGN1 injection in n = 10 male cadaveric femurs ex vivo. Using the area under the curve (AUC) from receiver-operating characteristic (ROC) analyses, the separability of AGN1 from bone was assessed for AGN1 (postoperatively) versus compact and versus femoral neck cancellous bone (both preoperatively). CT techniques included conventional Hounsfield (HU) and density-equivalent units (BMD, mg hydroxyapatite [HA]/cm3 ) and spectral-CT measures of effective atomic number (Zeff) and electron density (ED). The samples had a wide range of femoral neck BMD (55.66 to 241.71 mg HA/cm3 ). At the injection site average BMD, HU, Zeff, and ED increased from 69.5 mg HA/cm3 , 109 HU, 104.38 EDW, and 8.30 Zeff in the preoperative to 1233 mg HA/cm3 , 1741 HU, 181.27 EDW, and 13.55 Zeff in the postoperative CT scan, respectively. For compact bone at the femoral shaft the preoperative values were 1124.15 mg HA/cm3 , 1648 HU, 177 EDW, and 13.06 Zeff and were maintained postoperatively. Zeff showed substantially sharper distributions and significantly greater separability compared to ED, BMD, and HU (all p < 0.002, for both regions) with average AUCs for BMD, HU, ED, and Zeff of 0.670, 0.640, 0.645, and 0.753 for AGN1 versus compact and 0.996, 0.995, 0.994, and 0.998 for AGN1 versus femoral neck cancellous sites, respectively. Spectral-CT permits better discrimination of calcium-based implants like AGN1 from bone ex vivo. Our results warrant application of spectral-CT in patients undergoing procedures with similar implants. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Lipid-Iron Nanoparticle with a Cell Stress Release Mechanism Combined with a Local Alternating Magnetic Field Enables Site-Activated Drug Release.

Most available cancer chemotherapies are based on systemically administered small organic molecules, and only a tiny fraction of the drug reaches the disease site. The approach causes significant side effects and limits the outcome of the therapy. Targeted drug delivery provides an alternative to improve the situation. However, due to the poor release characteristics of the delivery systems, limitations remain. This report presents a new approach to address the challenges using two fundamentally different mechanisms to trigger the release from the liposomal carrier. We use an endogenous disease marker, an enzyme, combined with an externally applied magnetic field, to open the delivery system at the correct time only in the disease site. This site-activated release system is a novel two-switch nanomachine that can be regulated by a cell stress-induced enzyme at the cellular level and be remotely controlled using an applied magnetic field. We tested the concept using sphingomyelin-containing liposomes encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin. We engineered the liposomes by adding paramagnetic beads to act as a receiver of outside magnetic energy. The developed multifunctional liposomes were characterized in vitro in leakage studies and cell internalization studies. The release system was further studied in vivo in imaging and therapy trials using a squamous cell carcinoma tumor in the mouse as a disease model. In vitro studies showed an increased release of loaded material when stress-related enzyme and magnetic field was applied to the carrier liposomes. The theranostic liposomes were found in tumors, and the improved therapeutic effect was shown in the survival studies.

Correction: Large cortical bone pores in the tibia are associated with proximal femur strength.

[This corrects the article DOI: 10.1371/journal.pone.0215405.].

Large cortical bone pores in the tibia are associated with proximal femur strength.

Alterations of structure and density of cortical bone are associated with fragility fractures and can be assessed in vivo in humans at the tibia. Bone remodeling deficits in aging women have been recently linked to an increase in size of cortical pores. In this ex vivo study, we characterized the cortical microarchitecture of 19 tibiae from human donors (aged 69 to 94 years) to address, whether this can reflect impairments of the mechanical competence of the proximal femur, i.e., a major fracture site in osteoporosis. Scanning acoustic microscopy (12 µm pixel size) provided reference microstructural measurements at the left tibia, while the bone vBMD at this site was obtained using microcomputed tomography (microCT). The areal bone mineral density of both left and right femoral necks (aBMDneck) was measured by dual-energy X-ray absorptiometry (DXA), while homogenized nonlinear finite element models based on high-resolution peripheral quantitative computed tomography provided hip stiffness and strength for one-legged standing and sideways falling loads. Hip strength was associated with aBMDneck (r = 0.74 to 0.78), with tibial cortical thickness (r = 0.81) and with measurements of the tibial cross-sectional geometry (r = 0.48 to 0.73) of the same leg. Tibial vBMD was associated with hip strength only for standing loads (r = 0.59 to 0.65). Cortical porosity (Ct.Po) of the tibia was not associated with any of the femoral parameters. However, the proportion of Ct.Po attributable to large pores (diameter > 100 µm) was associated with hip strength in both standing (r = -0.61) and falling (r = 0.48) conditions. When added to aBMDneck, the prevalence of large pores could explain up to 17% of the femur ultimate force. In conclusion, microstructural characteristics of the tibia reflect hip strength as well as femoral DXA, but it remains to be tested whether such properties can be measured in vivo.

Ex vivo cortical porosity and thickness predictions at the tibia using full-spectrum ultrasonic guided-wave analysis.

The estimation of cortical thickness (Ct.Th) and porosity (Ct.Po) at the tibia using axial transmission ultrasound was successfully validated ex vivo against site-matched micro-computed tomography. The assessment of cortical parameters based on full-spectrum guided-wave analysis might improve the prediction of bone fractures in a cost-effective and radiation-free manner. PURPOSE: Cortical thickness (Ct.Th) and porosity (Ct.Po) are key parameters for the identification of patients with fragile bones. The main objective of this ex vivo study was to validate the measurement of Ct.Po and Ct.Th at the tibia using a non-ionizing, low-cost, and portable 500-kHz ultrasound axial transmission system. Additional ultrasonic velocities and site-matched reference parameters were included in the study to broaden the analysis. METHODS: Guided waves were successfully measured ex vivo in 17 human tibiae using a novel 500-kHz bi-directional axial transmission probe. Theoretical dispersion curves of a transverse isotropic free plate model with invariant matrix stiffness were fitted to the experimental dispersion curves in order to estimate Ct.Th and Ct.Po. In addition, the velocities of the first arriving signal (υFAS) and A0 mode (υA0) were measured. Reference Ct.Po, Ct.Th, and vBMD were obtained from site-matched micro-computed tomography. Scanning acoustic microscopy (SAM) provided the acoustic impedance of the axial cortical bone matrix. RESULTS: The best predictions of Ct.Po (R2 = 0.83, RMSE = 2.2%) and Ct.Th (R2 = 0.92, RMSE = 0.2 mm, one outlier excluded) were obtained from the plate model. The second best predictors of Ct.Po and Ct.Th were vBMD (R2 = 0.77, RMSE = 2.6%) and υA0 (R2 = 0.28, RMSE = 0.67 mm), respectively. CONCLUSIONS: Ct.Th and Ct.Po were accurately predicted at the human tibia ex vivo using a transverse isotropic free plate model with invariant matrix stiffness. The model-based predictions were not further enhanced when we accounted for variations in axial tissue stiffness as reflected by the acoustic impedance from SAM.

Improved accuracy in the assessment of vertebral cortical thickness by quantitative computed tomography using the Iterative Convolution OptimizatioN (ICON) method.

Vertebral whole bone strength is substantially affected by cortical bone properties. Disease and therapy may affect cancellous and cortical bone differently. Unlike Dual X-ray Absorptiometry (DXA), Quantitative Computed Tomography (QCT) permits selective assessment of cortical and cancellous bone, but image quality limits the accuracy. We present an image processing method specifically adopted to thin cortices that substantially improves accuracy. Ten human vertebrae embedded in epoxy resin were imaged using clinical QCT and High-Resolution QCT (HR-QCT) protocols, both acquired on a clinical whole body CT scanner, whereas high resolution peripheral QCT (HR-pQCT) was used as gold standard. Microstructural variables and BMD were calculated using in-house software StructuralInsight for QCT and HR-QCT and the manufacturer's µCT evaluation software for HR-pQCT. An adjusted measure, a deconvolved cortical thickness (dcCt.Th), corrected for partial volume effects, was derived applying the new Iterative Convolution OptimizatioN (ICON) method. Direct measurements of cortical thickness (Ct.Th) showed substantial overestimation with mean ±â€¯standard deviation of 1.8 ±â€¯0.5 mm for QCT and 1.5 ±â€¯0.3 mm for HR-QCT compared to 0.37 ±â€¯0.07 mm using HR-pQCT. Correlations of both QCT (r2 = 0.05, p > 0.5.) and HR-QCT (r2 = 0.38, p = 0.060) with the gold standard HR-pQCT were not significant. Also QCT-based BMD and BMC as well as HR-QCT-based BMD did not show a significant correlation with the gold standard approach. Only HR-QCT-based BMC showed a modest correlation (r2 = 0.59, p = 0.01) After applying ICON corrections, dcCt.Th resulted in 0.52 ±â€¯0.09 mm for QCT and 0.43 ±â€¯0.07 mm for HR-QCT, both significantly correlated to HR-pQCT (r2 = 0.75, p = 0.0012 and r2 = 0.93, p < 0.0001, respectively). The average overestimation bias of Ct.Th was reduced from (402 ±â€¯157)% to (45 ±â€¯17)% for QCT and from (330 ±â€¯69)% to (19 ±â€¯8)% for HR-QCT. Due to inaccurate segmentation uncorrected QCT-based Ct.Th measures as well as BMD and BMC showed no correlation to HR-pQCT and thus such bias cortical data can be misleading. The application of ICON reduced random overestimation bias to about 50 µm and 20 µm for QCT and HR-QCT, respectively, leading to a recovery of a significant correlation with the reference data of HR-pQCT. This reveals the potential for fairly accurate assessment of cortical thickness, allowing to better characterize cortical mechanical competence. These results warrant testing of the performance in vivo.

BMD-based assessment of local porosity in human femoral cortical bone.

Cortical pores are determinants of the elastic properties and of the ultimate strength of bone tissue. An increase of the overall cortical porosity (Ct.Po) as well as the local coalescence of large pores cause an impairment of the mechanical competence of bone. Therefore, Ct.Po represents a relevant target for identifying patients with high fracture risk. However, given their small size, the in vivo imaging of cortical pores remains challenging. The advent of modern high-resolution peripheral quantitative computed tomography (HR-pQCT) triggered new methods for the clinical assessment of Ct.Po at the peripheral skeleton, either by pore segmentation or by exploiting local bone mineral density (BMD). In this work, we compared BMD-based Ct.Po estimates with high-resolution reference values measured by scanning acoustic microscopy. A calibration rule to estimate local Ct.Po from BMD as assessed by HR-pQCT was derived experimentally. Within areas of interest smaller than 0.5 mm2, our model was able to estimate the local Ct.Po with an error of 3.4%. The incorporation of the BMD inhomogeneity and of one parameter from the BMD distribution of the entire scan volume led to a relative reduction of the estimate error of 30%, if compared to an estimate based on the average BMD. When applied to the assessment of Ct.Po within entire cortical bone cross-sections, the proposed BMD-based method had better accuracy than measurements performed with a conventional threshold-based approach.

Bone-marrow densitometry: Assessment of marrow space of human vertebrae by single energy high resolution-quantitative computed tomography.

PURPOSE: Accurate noninvasive assessment of vertebral bone marrow fat fraction is important for diagnostic assessment of a variety of disorders and therapies known to affect marrow composition. Moreover, it provides a means to correct fat-induced bias of single energy quantitative computed tomography (QCT) based bone mineral density (BMD) measurements. The authors developed new segmentation and calibration methods to obtain quantitative surrogate measures of marrow-fat density in the axial skeleton. METHODS: The authors developed and tested two high resolution-QCT (HR-QCT) based methods which permit segmentation of bone voids in between trabeculae hypothesizing that they are representative of bone marrow space. The methods permit calculation of marrow content in units of mineral equivalent marrow density (MeMD). The first method is based on global thresholding and peeling (GTP) to define a volume of interest away from the transition between trabecular bone and marrow. The second method, morphological filtering (MF), uses spherical elements of different radii (0.1-1.2 mm) and automatically places them in between trabeculae to identify regions with large trabecular interspace, the bone-void space. To determine their performance, data were compared ex vivo to high-resolution peripheral CT (HR-pQCT) images as the gold-standard. The performance of the methods was tested on a set of excised human vertebrae with intact bone marrow tissue representative of an elderly population with low BMD. RESULTS: 86% (GTP) and 87% (MF) of the voxels identified as true marrow space on HR-pQCT images were correctly identified on HR-QCT images and thus these volumes of interest can be considered to be representative of true marrow space. Within this volume, MeMD was estimated with residual errors of 4.8 mg/cm(3) corresponding to accuracy errors in fat fraction on the order of 5% both for GTP and MF methods. CONCLUSIONS: The GTP and MF methods on HR-QCT images permit noninvasive localization and densitometric assessment of marrow fat with residual accuracy errors sufficient to study disorders and therapies known to affect bone marrow composition. Additionally, the methods can be used to correct BMD for fat induced bias. Application and testing in vivo and in longitudinal studies are warranted to determine the clinical performance and value of these methods.

A Meta-Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX.

Trabecular bone score (TBS) is a gray-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual-level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow-up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. © 2015 American Society for Bone and Mineral Research.

The risk-stratified osteoporosis strategy evaluation study (ROSE): a randomized prospective population-based study. Design and baseline characteristics.

The risk-stratified osteoporosis strategy evaluation study (ROSE) is a randomized prospective population-based study investigating the effectiveness of a two-step screening program for osteoporosis in women. This paper reports the study design and baseline characteristics of the study population. 35,000 women aged 65-80 years were selected at random from the population in the Region of Southern Denmark and-before inclusion-randomized to either a screening group or a control group. As first step, a self-administered questionnaire regarding risk factors for osteoporosis based on FRAX(®) was issued to both groups. As second step, subjects in the screening group with a 10-year probability of major osteoporotic fractures ≥15% were offered a DXA scan. Patients diagnosed with osteoporosis from the DXA scan were advised to see their GP and discuss pharmaceutical treatment according to Danish National guidelines. The primary outcome is incident clinical fractures as evaluated through annual follow-up using the Danish National Patient Registry. The secondary outcomes are cost-effectiveness, participation rate, and patient preferences. 20,904 (60%) women participated and included in the baseline analyses (10,411 in screening and 10,949 in control group). The mean age was 71 years. As expected by randomization, the screening and control groups had similar baseline characteristics. Screening for osteoporosis is at present not evidence based according to the WHO screening criteria. The ROSE study is expected to provide knowledge of the effectiveness of a screening strategy that may be implemented in health care systems to prevent fractures.

Quantitative ultrasound measurements at the heel: improvement of short- and mid-term speed of sound precision.

Calcaneal quantitative ultrasound can be used to predict osteoporotic fracture risk, but its ability to monitor therapy is unclear possibly because of its limited precision. We developed a quantitative ultrasound device (foot ultrasound scanner) that measures the speed of sound at the heel with the aim of minimizing common error sources like the position and penetration angle of the ultrasound beam, as well as the soft tissue temperature. To achieve these objectives, we used a receiver array, mechanics to adjust the beam direction and a foot temperature sensor. In a group of 60 volunteers, short-term precision was evaluated for the foot ultrasound scanner and a commercial device (Achilles Insight, GE Medical, Fairfield, CT, USA ). In a subgroup of 20 subjects, mid-term precision (1-mo follow-up) was obtained. Compared with measurement of the speed of sound with the Achilles Insight, measurement with the foot ultrasound scanner reduced precision errors by half (p < 0.05). The study indicates that improvement of the precision of calcaneal quantitative ultrasound measurements is feasible.

Women's perspectives and experiences on screening for osteoporosis (Risk-stratified Osteoporosis Strategy Evaluation, ROSE).

UNLABELLED: This study aimed to investigate women's perspectives and experiences with screening for osteoporosis. Focus groups and individual interviews were conducted. Three main themes emerged: knowledge about osteoporosis, psychological aspects of screening, and moral duty. Generally, screening was accepted due to life experiences, self-perceived risk, and the preventive nature of screening. PURPOSE: The risk-stratified osteoporosis strategy evaluation (ROSE) study is a randomized prospective population-based trial investigating the efficacy of a screening program to prevent fractures in women aged 65-80 years. It is recommended by the World Health Organization that a set of criteria are met before a screening program is implemented. This sub-study aims to investigate women's perspectives and experiences with the ROSE screening program in relation to the patient-related criteria recommended by the World Health Organization. METHODS: A qualitative study was carried out involving 31 women by way of 8 focus group interviews and 11 individual interviews. Principles from critical psychology guided the analysis. RESULTS: Women's perspectives and experiences with the screening program were described by three main themes: knowledge about osteoporosis, psychological aspects of screening, and moral duty. The women viewed the program in the context of their everyday life and life trajectories. Age, lifestyle, and knowledge about osteoporosis were important to how women ascribed meaning to the program, how they viewed the possibilities and limitations, and how they rationalized their actions and choices. The women displayed limited knowledge about osteoporosis and its risk factors. However, acceptance was based on prior experience, perceived risk, and evaluation of preventive measures. To be reassured or concerned by screening was described as important issues, as well as the responsibility for health-seeking behaviour. CONCLUSION: In general, the women accepted the screening program. No major ethical reservations or adverse psychological consequences were detected. Only a minority of women declined screening participation due to a low perceived risk of osteoporosis.

Ultrasound to assess bone quality.

Bone quality is determined by a variety of compositional, micro- and ultrastructural properties of the mineralized tissue matrix. In contrast to X-ray-based methods, the interaction of acoustic waves with bone tissue carries information about elastic and structural properties of the tissue. Quantitative ultrasound (QUS) methods represent powerful alternatives to ionizing x-ray based assessment of fracture risk. New in vivo applicable methods permit measurements of fracture-relevant properties, [eg, cortical thickness and stiffness at fragile anatomic regions (eg, the distal radius and the proximal femur)]. Experimentally, resonance ultrasound spectroscopy and acoustic microscopy can be used to assess the mesoscale stiffness tensor and elastic maps of the tissue matrix at microscale resolution, respectively. QUS methods, thus, currently represent the most promising approach for noninvasive assessment of components of fragility beyond bone mass and bone microstructure providing prospects for improved assessment of fracture risk.

Modeling of femoral neck cortical bone for the numerical simulation of ultrasound propagation.

Quantitative ultrasound assessment of the cortical compartment of the femur neck (FN) is investigated with the goal of achieving enhanced fracture risk prediction. Measurements at the FN are influenced by bone size, shape and material properties. The work described here was aimed at determining which FN material properties have a significant impact on ultrasound propagation around 0.5 MHz and assessing the relevancy of different models. A methodology for the modeling of ultrasound propagation in the FN, with a focus on the modeling of bone elastic properties based on scanning acoustic microscopy data, is introduced. It is found that the first-arriving ultrasound signal measured in through-transmission at the FN is not influenced by trabecular bone properties or by the heterogeneities of the cortical bone mineralized matrix. In contrast, the signal is sensitive to variations in cortical porosity, which can, to a certain extent, be accounted for by effective properties calculated with the Mori-Tanaka method.

Influence of porosity, pore size, and cortical thickness on the propagation of ultrasonic waves guided through the femoral neck cortex: a simulation study.

The femoral neck is a common fracture site in elderly people. The cortical shell is thought to be the major contributor to the mechanical competence of the femoral neck, but its microstructural parameters are not sufficiently accessible under in vivo conditions with current X-ray-based methods. To systematically investigate the influences of pore size, porosity, and thickness of the femoral neck cortex on the propagation of ultrasound, we developed 96 different bone models (combining 6 different pore sizes with 4 different porosities and 4 different thicknesses) and simulated the ultrasound propagation using a finite-difference time-domain algorithm. The simulated single-element emitter and receiver array consisting of 16 elements (8 inferior and 8 superior) were placed at anterior and posterior sides of the bone, respectively (transverse transmission). From each simulation, we analyzed the waveform collected by each of the inferior receiver elements for the one with the shortest time of flight. The first arriving signal of this waveform, which is associated with the wave traveling through the cortical shell, was then evaluated for its three different waveform characteristics (TOF: time point of the first point of inflection of the received signal, Δt: difference between the time point at which the signal first crosses the zero baseline and TOF, and A: amplitude of the first extreme of the first arriving signal). From the analyses of these waveform characteristics, we were able to develop multivariate models to predict pore size, porosity, and cortical thickness, corresponding to the 96 different bone models, with remaining errors in the range of 50 µm for pore size, 1.5% for porosity, and 0.17 mm for cortical thickness.

Comparison of different screening tools (FRAX®, OST, ORAI, OSIRIS, SCORE and age alone) to identify women with increased risk of fracture. A population-based prospective study.

PURPOSE: To compare the power of FRAX® without bone mineral density (BMD) and simpler screening tools (OST, ORAI, OSIRIS, SCORE and age alone) in predicting fractures. METHODS: This study was a prospective, population-based study performed in Denmark comprising 3614 women aged 40-90 years, who returned a questionnaire concerning items on risk factors for osteoporosis. Fracture risk was calculated using the different screening tools (FRAX®, OST, ORAI, OSIRIS and SCORE) for each woman. The women were followed using the Danish National Register registering new major osteoporotic fractures during 3 years, counting only the first fracture per person. Area under the receiver operating characteristic curve (ROC) and statistics and Harrell's index were calculated. Agreement between the tools was calculated by kappa statistics. RESULTS: A total of 4% of the women experienced a new major osteoporotic fracture during the follow-up period. There were no differences in the area under the curve (AUC) values between FRAX® and the simpler tools; AUC values between 0.703 and 0.722 (p = 0.86). Also, Harrell's C values were very similar between the tools. Agreement between the tools was modest. CONCLUSION: During 3 years follow-up FRAX® did not perform better in the fracture risk prediction compared with simpler tools such as OST, ORAI, OSIRIS, SCORE or age alone in a screening scenario where BMD was not measured. These findings suggest that simpler models based on fewer risk factors, which would be easier to use in clinical practice by the GP or the patient herself, could just as well as FRAX® be used to identify women with increased risk of fracture. SUMMARY: Comparison of FRAX® and simpler screening tools (OST, ORAI, OSIRIS, SCORE) in predicting fractures indicate that FRAX® did not perform better in fracture risk prediction compared with the simpler tools or even age alone in a screening scenario without bone mineral density assessment.

Quantitative ultrasound of cortical bone in the femoral neck predicts femur strength: results of a pilot study.

A significant risk of femoral neck (FN) fracture exists for men and women with an areal bone mineral density (aBMD) higher than the osteoporotic range, as measured with dual-energy X-ray absorptiometry (DXA). Separately measuring the cortical and trabecular FN compartments and combining the results would likely be a critical aspect of enhancing the diagnostic capabilities of a new technique. Because the cortical shell determines a large part of FN strength a novel quantitative ultrasound (QUS) technique that probes the FN cortical compartment was implemented. The sensitivity of the method to variations of FN cortical properties and FN strength was tested. Nine femurs (women, mean age 83 years) were subjected to QUS to measure the through transmission time-of-flight (TOF) at the FN and mechanical tests to assess strength. Quantitative computed tomography (QCT) scans were performed to enable analysis of the dependence of TOF on bone parameters. DXA was also performed for reference. An ultrasound wave propagating circumferentially in the cortical shell was measured in all specimens. Its TOF was not influenced by the properties of the trabecular compartment. Averaged TOF for nine FN measurement positions/orientations was significantly correlated to strength (R2 = 0.79) and FN cortical QCT variables: total BMD (R(2) = 0.54); regional BMD in the inferoanterior (R2 = 0.90) and superoanterior (R2 = 0.57) quadrants; and moment of inertia (R2 = 0.71). The results of this study demonstrate that QUS can perform a targeted measurement of the FN cortical compartment. Because the method involves mechanical guided waves, the QUS variable is related to the geometric and material properties of the cortical shell (cortical thickness, tissue elasticity, and porosity). This work opens the way to a multimodal QUS assessment of the proximal femur, combining our approach targeting the cortical shell with the existing modality sensitive to the trabecular compartment. In vivo feasibility of our approach has to be confirmed with experimental data in patients.

A device for in vivo measurements of quantitative ultrasound variables at the human proximal femur.

Quantitative ultrasound (QUS) at the calcaneus has similar power as a bone mineral density (BMD)- measurement using DXA for the prediction of osteoporotic fracture risk. Ultrasound equipment is less expensive than DXA and free of ionizing radiation. As a mechanical wave, QUS has the potential of measuring different bone properties than dual X-ray absorptiometry (DXA,) which depends on X-ray attenuation and might be developed into a tool of comprehensive assessment of bone strength. However, site-specific DXA at the proximal femur shows best performance in the prediction of hip fractures. To combine the potential of QUS with measurements directly at the femur, we developed a device for in vivo QUS measurements at this site. Methods comprise ultrasound transmission through the bone, reflection from the bone surface, and backscatter from the inner trabecular structure. The complete area of the proximal femur can be scanned except at the femoral head, which interferes with the ilium. To avoid edge artifacts, a subregion of the proximal femur in the trochanteric region was selected as measurement region. First, in vivo measurements demonstrate a good signal to noise ratio and proper depiction of the proximal femur on an attenuation image. Our results demonstrate the feasibility of in vivo measurements. Further improvements can be expected by refinement of the scanning technique and data evaluation method to enhance the potential of the new method for the estimation of bone strength.

Model-based estimation of quantitative ultrasound variables at the proximal femur.

To improve the prediction of the osteoporotic fracture risk at the proximal femur we are developing a scanner for quantitative ultrasound (QUS) measurements at this site. Due to multipath transmission in this complex shaped bone, conventional signal processing techniques developed for QUS measurements at peripheral sites frequently fail. Therefore, we propose a model-based estimation of the QUS variables and analyze the performance of the new algorithm. Applying the proposed method to QUS scans of excised proximal femurs increased the fraction of evaluable signals from approx. 60% (using conventional algorithms) to 97%. The correlation of the standard QUS variables broadband ultrasound attenuation (BUA) and speed of sound (SOS) with the established variable bone mineral density (BMD) reported in previous studies is maintained (BUA/BMD: r(2) = 0.69; SOS/BMD: r(2) = 0.71; SOS+BUA/BMD: r(2) = 0.88). Additionally, different wave types could be clearly detected and characterized in the trochanteric region. The ability to separate superimposed signals with this approach opens up further diagnostic potential for evaluating waves of different sound paths and wave types through bone tissue.

In vivo measurements of ultrasound transmission through the human proximal femur.

Quantitative ultrasound (QUS) measurements can be used to estimate osteoporotic fracture risk. The commonly used variables are the speed of sound (SOS) and the frequency dependent sound attenuation (broadband ultrasound attenuation, [BUA]) of a wave propagating through the bone, preferably the calcaneus. The technology, so far, is less suitable for direct measurement in vivo at the spine or the femur for prediction of bone mineral density (BMD) or fracture risk at the main osteoporotic fracture sites. To improve the clinical performance of QUS, we built a device for direct QUS measurements at the human femur in vivo. In vivo images of ultrasound transmission at one of the main fracture sites, the proximal femur, could be acquired. The estimated precision of SOS measurements of 0.5% achieved at the femur is comparable with the precision of peripheral QUS devices.