Michael Jergas

Accurate assessment of precision errors: how to measure the reproducibility of bone densitometry techniques.

Assessment of precision errors in bone mineral densitometry is important for characterization of a techniques ability to detect logitudinal skeletal changes. Short-term and long-term precision errors should be calculated as root-mean-square (RMS) averages of standard deviations of repeated measurements (SD) and standard errors of the estimate of changes in bone density with time (SEE), respectively. Inadequate adjustment for degrees of freedom and use of arithmetic means instead of RMS averages may cause underestimation of true imprecision by up to 41% and 25% (for duplicate measurements), respectively. Calculation of confidence intervals of precision errors based on the number of repeated measurements and the number of subjects assessed serves to characterize limitations of precision error assessments. Provided that precision error are comparable across subjects, examinations with a total of 27 degrees of freedom result in an upper 90% confidence limit of +30% of the mean precision error, a level considered sufficient for characterizing technique imprecision. We recommend three (or four) repeated measurements per individual in a subject group of at least 14 individuals to characterize short-term (or long-term) precision of a technique.

Three Quantitative Ultrasound Parameters Reflect Bone Structure

We investigated whether quantitative ultrasound (QUS) parameters are associated with bone structure. In an in vitro study on 20 cubes of trabecular bone, we measured broadband ultrasound attenuation (BUA) and two newly defined parameters—ultrasound velocity through bone (UVB) and ultrasound attenuation in bone (UAB). Bone mineral density (BMD) was measured by dual X-ray absorptiometry (DXA) and bone structure was assessed by microcomputed tomography (μCT) with approximately 80 μm spatial resolution. We found all three QUS parameters to be significantly associated with bone structure independently of BMD. UVB was largely influenced by trabecular separation, UAB by connectivity, and BUA by a combination of both. For a one standard deviation (SD) increase in UVB, a decrease in trabecular separation of 1.2 SD was required compared with a 1.4 SD increase in BMD for the same effect. A 1.0 SD increase in UAB required a reduction in connectivity of 1.4 SD. Multivariate models of QUS versus BMD combined with bone structure parameters showed squared correlation coefficients of r2=0.70–0.85 for UVB, r2=0.27–0.56 for UAB, and r2=0.30–0.68 for BUA compared with r2=0.18–0.58 for UVB, r2<0.26 for UAB and r2<0.13 for BUA for models including BMD alone. QUS thus reflects bone structure, and a combined analysis of QUS and BMD will allow for a more comprehensive assessment of skeletal status than either method alone.

Comparisons of Noninvasive Bone Mineral Measurements in Assessing Age‐Related Loss, Fracture Discrimination, and Diagnostic Classification

The purpose of this study was to examine the commonly available methods of noninvasively assessing bone mineral status across three defined female populations to examine their interrelationships, compare their respective abilities to reflect age‐ and menopause‐related bone loss, discriminate osteoporotic fractures, and classify patients diagnostically. A total of 47 healthy premenopausal (age 33 ± 7 years), 41 healthy postmenopausal (age 64 ± 9 years), and 36 osteoporotic postmenopausal (age 70 ± 6 years) women were examined with the following techniques: (1) quantitative computed tomography of the L1–L4 lumbar spine for trabecular (QCT TRAB BMD) and integral (QCT INTG BMD) bone mineral density (BMD); (2) dual X‐ray absorptiometry of the L1–L4 posterior‐anterior (DXA PA BMD) and L2–L4 lateral (DXA LAT BMD) lumbar spine, of the femoral neck (DXA NECK BMD) and trochanter (DXA TROC BMD), and of the ultradistal radius (DXA UD BMD) for integral BMD; (3) peripheral QCT of the distal radius for trabecular BMD (pQCT TRAB BMD) and cortical bone mineral content (BMC) (pQCT CORT BMC); (4) two radiographic absorptiometric techniques of the metacarpal (RA METC BMD) and phalanges (RA PHAL BMD) for integral BMD; and (5) two quantitative ultrasound devices (QUS) of the calcaneus for speed of sound (SOS CALC) and broadband ultrasound attenuation (BUA CALC). In general, correlations ranged from (r = 0.10−0.93) among different sites and techniques. We found that pQCT TRAB BMD correlated poorly (r ≤ 0.46) with all other measurements except DXA UD BMD (r = 0.62, p ≤ 0.0001) and RA PHAL BMD (r = 0.52, p ≤ 0.0001). The strongest correlation across techniques was between QCT INT BMD and DXA LAT BMD (r = 0.87, p ≤ 0.0001), and the weakest correlation within a technique was between pQCT TRAB BMD and pQCT CORT BMC (r = 0.25, p ≤ 0.05). Techniques showing the highest correlations with age in the healthy groups also showed the greatest differences among groups. They also showed the best discrimination (as measured by the odds ratios) for the distinction between healthy postmenopausal and osteoporotic postmenopausal groups based on age‐adjusted logistic regression analysis. For each anatomic site, the techniques providing the best results were: (1) spine, QCT TRAB BMD (annual loss, −1.2% [healthy premenopausal and healthy postmenopausal]); Students t‐value [not the T score], 5.4 [healthy postmenopausal vs. osteoporotic postmenopausal]; odds ratio, 4.3 [age‐adjusted logistic regression for healthy postmenopausal vs. osteoporotic postmenopausal]); (2) hip, DXA TROC BMD (−0.46; 3.5; 2.2); (3) radius, DXA UD BMD (−0.44; 3.3; 1.9) and pQCT, CORT BMC (−0.72; 2.9; 1.7); (4) hand, RA PHAL (−0.51; 3.6; 2.0); and (5) calcaneus, SOS (−0.09; 3.4; 2.1) and BUA (−0.52; 2.6; 1.7). Despite these performance trends, the differences among sites and techniques were statistically insignificant (p > 0.05) using age‐adjusted receiver operating characteristic (ROC) curve analysis. Nevertheless, kappa score analysis (using −2.0 T score as the cut‐off value for osteopenia and −2.5 T score for osteoporosis) showed that in general the diagnostic agreement among these measurements in classifying women as osteopenic or osteoporotic was poor, with kappa scores averaging about 0.4 (exceptions were QCT TRAB/INTG BMD, DXA LAT BMD, and RA PHAL BMD, with kappa scores ranging from 0.63 to 0.89). Often different patients were estimated at risk by using different measurement sites or techniques.

Evaluation of technical factors affecting the quantification of trabecular bone structure using magnetic resonance imaging

High resolution magnetic resonance (MR) techniques combined with standard techniques of stereology and texture analysis have been used to quantify trabecular structure. Using dried excised specimens from the tibia (n = 10) and radius (n = 2) we evaluate the impact of using volumetric gradient-echo (GE) and spin-echo (SE) MR imaging sequences, the relative importance of echo time in gradient-echo MR imaging, and the impact of different threshold values to segment the bone and bone marrow on the estimation of trabecular bone structure. We also investigate the inter-relationships between the different structural parameters derived from MR images. Images were obtained using fast gradient-echo and spin-echo imaging sequences, with TE values ranging from 7 to 17 ms using 4.7 and 1.5 Tesla imaging systems. In-plane image resolution ranged from 128 to 156 microns, and slice thickness ranged from 128 to 1000 microns. We derived stereological measures such as the mean intercept length, trabecular width, fractional area of trabecular bone, trabecular number, and trabecular spacing, the fractal dimension as a texture-related parameter and the Euler number as a measure of connectivity from these images. We found that the mean intercept length as a function of angle traced an ellipse with the orientation of the principal axis of the ellipse, a measure of trabecular orientation, identical when measured from the spin-echo or gradient-echo MR images. Absolute measures such as the fractional area, trabecular width, trabecular number, and fractal dimension as measured from gradient echo images were 28%, 30%, 1.3%, and 0.6% greater, respectively, than those calculated from spin-echo images, while the trabecular spacing was 14% less when calculated from gradient-echo images compared to spin-echo images. The structural parameters also depended on the echo time used to obtain the MR image. The choice of the threshold used to segment the high resolution images also affected the estimated structural parameters significantly. Our results indicate that MR may be used to visualize and quantify trabecular bone architecture; however, the different technical factors that could affect the appearance of MR images must be understood and considered in the data analysis and interpretation.

Peripheral measurement techniques for the assessment of osteoporosis

Peripheral measurement techniques have been the first to be developed for the assessment of osteoporosis, and they remain useful. Besides traditional approaches such as radiographic absorptiometry (RA), radiogrammetry, and single-photon absorptiometry (SPA), new peripheral approaches have been developed that offer powerful ways to assess skeletal status in osteoporosis. These include single x-ray absorptiometry (SXA), peripheral dual x-ray absorptiometry (pDXA), peripheral quantitative computed tomography (pQCT), quantitative ultrasound (QUS) techniques, and magnetic resonance imaging (MRI) approaches. This review describes the current role of peripheral imaging techniques vis-à-vis their central imaging counterparts. Peripheral measurement techniques are attractive because equipment cost is substantially lower, radiation exposure is small, and the devices require less space and sometimes are even portable. Additionally, QUS and MRI offer the potential to measure aspects of bone status beyond the limits of bone densitometry. Peripheral techniques represent important diagnostic methods for the assessment of osteoporosis.

Bone densitometry and osteoporosis

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Analysis of trabecular bone structure in the distal radius using high-resolution MRI

The objective of this study was to develop high-resolution in vivo Magnetic resonance techniques to resolve the structure of trabecular bone in conjunction with image processing techniques to quantify variations in trabecular bone structure. Such techniques could then potentially be applied to assess osteoporotic changes and predict the risk fractures. Axial and coronal volumetric MRI images of the distal radius were obtained using a modified gradient echo sequence on a MRI images, on a 1.5 T imager at a spatial resolution of 150 μm and a slice thickness of 0.7 mm. Image thresholding techniques were used to identify trabecular bone and bone marrow: thereafter the area occupied by trabecular bone, mean trabecular width and mean intercept length as a function of angle were computed. An automatic boundary tracking algorithm was used to identify the bone and marrow interface. Fractal analysis was used to quantify the convolutedness of the marrow-trabecular bone interface. It is well known that the trabecular bone density is the greater at distal sites of the radius and decreases proximally. These variations were reflected by the decreases in the trabecular width. fractional area and fractal dimension. Over a 28 mm range, starting at 7 mm proximal from the joint line and extending 35 mm proximal to the joint line, the mean trabecular width decreased from 444.6 μm to 341.0, μm the fractional area of trabecular bone decreased from 0.44 to 0.15. and the fractal dimension decreased from 1.67 to 1.10. The choice of the threshold affected the quantification of the mean trabecular width and fractional trabecular bone area measurements, but the fractal dimension was more robust. High-resolution MRI images combined with image analysis techniques can he used to quantify structural variations in trabecular bone in the distal radius.

Spinal trabecular bone loss and fracture in American and Japanese women

Abstract. This study examined trabecular bone mineral density (BMD) in Japanese women with and without spinal fracture, and compared the results to American women with and without fracture. The quantitative computed tomography (QCT) systems used at the University of California, San Francisco (UCSF) and at Nagasaki University were cross-calibrated. Normative BMD was assessed with the K2HPO4 liquid phantom in 538 Americans aged 20–85 years, and with the B-MAS200 phantom in 577 Japanese aged 20–83 years. These BMD were adjusted for use with the Image Analysis solid phantom using the result of cross-calibration. The trabecular BMD in 111 postmenopausal American women (55 with fracture), and in 185 postmenopausal Japanese women (67 with fracture) were compared for investigation of the difference in BMD values relative to fracture status. The absolute BMD values in Japanese were lower than those in Americans, and the differences were greater with advancing age. The magnitude of the BMD difference was 8.6, 20.5, 38.1 mg/cm3 in women aged 20–24 years, 40–44 years, 60–64 years, respectively. In premenopausal women, BMD began to decrease at the age of 20 in Japanese, whereas the peak bone mass was maintained until the age of 35 in the American women. In immediate postmenopausal women, BMD significantly decreased in both populations. In later postmenopausal women, BMD significantly decreased with age in the Japanese women but decreased less rapidly in the American women. The aging decrease of BMD was 1.4% and 2.2% per year in the later postmenopausal American and Japanese women, respectively. The fracture threshold is considered to be lower in Japanese women. However, the BMD difference between American and Japanese women with fracture was similar to that without fracture. The Z-scores of fracture subjects versus controls were 2.9 in American and 1.8 in Japanese women. In conclusion, Japanese women were found to have a lower BMD and lower fracture threshold than American women. The significant decrease of spinal trabecular BMD in late postmenopause is potentially responsible for the higher prevalence of spinal fracture in Japanese women.

Relationships between Young modulus of elasticity, ash density, and MRI derived effective transverse relaxation T2 in tibial specimens

Objective It has been hypothesized that the MR relaxation time T2* of bone marrow present in the intertrabecular spaces may be related to the density of the trabecular network and may be a predictor of trabecular bone properties. Materials and Methods To derive a relationship between the marrow relaxation time T2* and biomechanical properties of trabecular bone, we studied two sets of trabecular bone specimens from human tibiae. The first set consisted of 12 specimens that were defatted and immersed in saline; the second set consisted of 18 specimens with marrow in the trabecular spaces. The MR studies were conducted on a 1.5 T imaging system. In the first set of specimens, a GE sequence (TR = 70 ms; TE = 5, 10, 15, 20, 23 ms) was used to obtain images in the axial plane. In the second set, a water suppression pulse was used prior to an asymmetric SE sequence (TR = 300 ms; TE = 4, 8, 12, 16, 20, 24 ms) to obtain images in the axial, coronal, and sagittal planes. The T2* of the intertrabecular saline of the marrow fat was calculated assuming a monoexponential decay. In both sets, the elastic moduli were measured in three orthogonal directions (superoinferior, anteroposterior, and mediolateral). The ash density was determined after the completion of the experiments. Results Our results indicate a moderate significant negative correlation between T2* and ash density or elastic modulus (E) in both sets of specimens. The correlation coefficients were slightly improved between the transverse relaxation rate 1/T2* and bone density or E. We found a good correlation between T2* and the reciprocal ash density (r = 0.88) and between T2* and the reciprocal elastic modulus 1/E (r = 0.87 to r = 0.95) in the first set, while in the second set the correlation remained moderate. With use of a multiple linear regression model (1/E = a x T2* + b x 1/T2* + n), the reciprocal elastic moduli 1/E were predicted to >90% by T2* and 1/T2* in the first set of specimens. This finding was not replicated with the second set of specimens. In the second set of specimens, we found poor to moderate correlation coefficients between the T2* times in the three orthogonal planes (r = 0.45 to r = 0.71). Conclusion Trabecular bone properties such as density and strength may potentially be assessed with quantitative MR techniques. However, especially for in vitro studies, specimen preparation, acquisition parameters, and specimen geometry may have a significant impact on the obtained results.

Advances in the noninvasive assessment of bone density, quality, and structure

Recent advances in the development of methods to assess the skeleton noninvasively have contributed to screening for risk of osteoporosis, early detection of the disease, and effective monitoring of its progression and response to therapy. The capability now exists to evaluate the peripheral, central, or entire skeleton as well as the trabecular bone or cortical bone envelopes accurately and precisely, with the capacity to determine bone strength and predict fracture risk. In this article we examine the current and future capabilities of quantitative computed tomography (QCT), quantitative ultrasound (QUS), and magnetic resonance microscopy (µMR) to assess architectural and densitometric properties of the skeleton to enhance the prediction of fracture risk.