A.R.M.M. Hermus

Bone mineral density and quantitative ultrasound parameters in patients with Klinefelter's syndrome after long-term testosterone substitution.

Abstract: Klinefelter’s syndrome (KS) is a common sex chromosomal disorder associated with androgen deficiency and osteoporosis. Only few bone mineral density (BMD) and no quantitative ultrasound (QUS) data are available in these patients after long-term testosterone replacement therapy. We examined in a cross-sectional study 52 chromatin-positive KS patients aged 39.1 ± 12.4 years (mean ± SD). Patients had been treated with oral or parenteral androgens for 9.2 ± 8.2 years (range 1–32 years). Areal BMD and bone mineral apparent density (BMAD, i.e., estimated volumetric BMD) at the lumbar spine, total hip and femoral neck were determined by dual-energy X-ray absorptiometry. BMD T-scores in the patient group were calculated based on three different North American reference databases. The QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured at the calcaneus using an ultrasound imaging device (UBIS 3000) and were compared with QUS results in a sex-, age- and height-matched control group. QUS T-scores were calculated based on the results of QUS measurements in 50 normal Dutch men between the ages of 20 and 30 years. QUS and BMD results in the KS patient group were compared. Overall, based on the three reference databases, 46% and 63% of the KS patients had a T-score between −1 and −2.5 and a further 10% and 14% had a T-score ≤−2.5 at the total hip and/or lumbar spine, as measured by areal BMD or BMAD, respectively. Thirty-nine percent of the KS patients had a T-score between −2.5 and −1, while 2% had a T-score ≤−2.5 for BUA and/or SOS. BUA (77.7 ± 15.0 dB/MHz) and SOS (1518.8 ± 36.5 m/s) were significantly lower in the KS patients than in age- and height-matched controls (87.1 ± 17.8 dB/MHz, p<0.005, and 1536.5 ± 42.5 m/s, p<0.05). Correlation coefficients between the QUS parameters and areal BMD (0.28 to 0.37) or BMAD (0.27 to 0.46) were modest. ROC analysis showed that discrimination of a BMD or BMAD T-score ≤−2.5 with either BUA or SOS was not statistically significant. Although a limitation of our study is that direct comparison of BMD and QUS T-scores is not possible because in the control group in which QUS parameters were determined no BMD measurements were performed, we conclude that despite long-term testosterone replacement therapy, a considerable percentage of patients with KS had a BMD T-score <−1 or even ≤−2.5, based on different North American reference databases. This percentage was even higher for BMAD. QUS parameters were also low in the KS patient group when compared with Dutch control subjects. QUS parameters cannot be used to predict BMD or BMAD in KS patients.

Calcaneal ultrasound imaging in healthy children and adolescents: relation of the ultrasound parameters BUA and SOS to age, body weight, height, foot dimensions and pubertal stage.

Abstract: We investigated the quantitative ultrasound (QUS) parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) measured in the posterior part of the calcaneus at the region of interest (ROI) with the lowest attenuation, using an ultrasound imaging device (UBIS 3000) in 491 healthy Caucasian children and adolescents (262 girls, 229 boys) between 6 and 21 years old. The relation of age, body weight, height, foot dimensions and pubertal stage to BUA and SOS was assessed. BUA increased nonlinearly with age in boys and girls, r2 being 0.44 (p<0.001) and 0.57 (p<0.001), respectively. SOS increased linearly with age in girls (r2= 0.04, p<0.001). There was no significant increase in SOS in boys (r2= 0.01, p>0.05). Heel width was significantly correlated with BUA (r= 0.20, p<0.005 in boys; r= 0.27, p<0.05 in girls) and with SOS (r=−0.19, p<0.005 in boys; r=−0.08, p<0.05 in girls). After downward adjustment of the ROI size according to foot length quartiles, significantly lower BUA and SOS values were found compared with those with the standard ROI size of 14 mm. After correction for heel width and adjustment of the ROI size based on foot length, BUA and SOS were significantly associated with age in boys (r2= 0.36, p<0.001 and 0.06, p<0.05) and in girls (r2= 0.53 and 0.06, both p<0.001). Tanner stage was significantly correlated with BUA (r= 0.62, p<0.001 in boys; r= 0.73, p<0.001 in girls) but not with SOS. BUA but not SOS increased significantly with the number of years since menarche (p<0.001). In a multiple stepwise regression analysis in boys, age, weight and foot length were independent predictors for BUA, and age and foot length for SOS. In girls, age and weight were independent predictors for BUA and age was the only independent predictor for SOS. After correction for age, pubertal stages and heel width were no longer determinants for QUS parameters in either boys or girls. In conclusion, BUA increased significantly with age in both sexes. SOS increased with age in both boys and girls, but the increase was small and not statistically significant in boys. SOS, as measured with the UBIS 3000 device, may therefore not be appropriate to assess skeletal status in healthy children. Whether SOS and BUA are affected in children with skeletal disorders has yet to be determined. In boys, age, weight and foot length were independent predictors for BUA and age and foot length for SOS. In girls, age and weight were independent predictors for BUA and age was the only independent predictor for SOS. In our opinion, children with small feet should be measured with a smaller ROI diameter than those with larger feet.

Speed of sound reflects Young's modulus as assessed by microstructural finite element analysis.

We analyzed the ability of the quantitative ultrasound (QUS) parameter, speed of sound (SOS), and bone mineral density (BMD), as measured by dual-energy X-ray absorptiometry (DXA), to predict Youngs modulus, as assessed by microstructural finite element analysis (muFEA) from microcomputed tomography (muCT) reconstructions. With muFEA simulation, all bone elements in the model can be assigned the same isotropic Youngs modulus; therefore, in contrast to mechanical tests, only the trabecular structure plays a role in the determination of the elastic properties of the specimen. SOS, BMD, and microCT measurements were performed in 15 cubes of pure trabecular bovine bone in three orthogonal directions: anteroposterior (AP); mediolateral (ML); and craniocaudal (CC). The anisotropy of the architecture was determined using mean intercept length (MIL) measurements. SOS, MIL, and Youngs modulus (E) values were significantly different in all three directions (p < 0.001), with the highest values in the CC direction. There was a strong linear relationship between E and SOS in each of the three orthogonal directions, with r(2) being 0.88, 0.92, and 0.84 (all p < 0.0001) for the CC, ML, and AP directions, respectively. The relationship between E and BMD was less strong, with r(2) being between 0.66 and 0.85 (all p < 0.0001) in the different directions. There was also a significant, positive correlation between SOS and BMD in each of the three axes (r(2) being 0.81, 0.42, and 0.92 in the CC, ML, and AP directions, respectively; p < 0.0001). After correction for BMD, the correlations between SOS and E in each of the three directions remained highly significant (r(2) = 0.77, p < 0. 0001 for the AP direction; r(2) = 0.48, p < 0.001 for the CC direction; r(2) = 0.52, p < 0.005 for the ML direction). After correction for SOS, BMD remained significantly correlated with Youngs modulus in the AP and CC directions (r(2) = 0.52, p < 0.005; r(2) = 0.30, p < 0.05, respectively), but the correlation in the ML direction was no longer statistically significant. In a stepwise regression model, E was best predicted by SOS in each of the orthogonal directions. These observations illustrate the ability of the SOS technique to assess the architectural mechanical quality of trabecular bone.

The prospects of estimating trabecular bone tissue properties from the combination of ultrasound, dual-energy X-ray absorptiometry, microcomputed tomography, and microfinite element analysis

Osteoporosis commonly is assessed by bone quantity, using bone mineral density (BMD) measurements from dual‐energy X‐ray absorptiometry (DXA). However, such a measure gives neither information about the integrity of the trabecular architecture nor about the mechanical properties of the constituting trabeculae. We investigated the feasibility of deriving the elastic modulus of the trabeculae (the tissue modulus) from computer simulation of mechanical testing by microfinite element analysis (μFEA) in combination with measurements of ultrasound speed of sound (SOS) and BMD measurements. This approach was tested on 15 postmortem bovine bone cubes. The apparent elastic modulus of the specimens was estimated from SOS measurements in combination with BMD. Then the trabecular morphology was reconstructed using microcomputed tomography (μCT). From the reconstruction a mesh for μFEA was derived, used to simulate mechanical testing. The tissue modulus was found by correlating the apparent moduli of the specimens as assessed by ultrasound with the ones as determined with μFEA. A mean tissue modulus of 4.5 GPa (SD, 0.69) was found. When adjusting the μFEA‐determined elastic moduli of the entire specimens with their calculated tissue modulus, an overall correlation of R2 = 96% with ultrasound‐predicted values was obtained. We conclude that the apparent elastic stiffness characteristics as determined from ultrasound correlate linearly with those from μFEA. From both methods in combination, the elastic stiffness of the mineralized tissue can be determined as an estimator for mechanical tissue quality. This method can already be used for biopsy specimens, and potentially could be applicable in vivo as well, when clinical CT or magnetic resonance imaging (MRI) tools with adequate resolution reach the market. In this way, mechanical bone quality could be estimated more accurately in clinical practice.

Measuring Skeletal Changes with Calcaneal Ultrasound Imaging in Healthy Children and Adults: The Influence of Size and Location of the Region of Interest

Abstract: We measured the quantitative ultrasound (QUS) parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) at the calcaneus using an ultrasound imaging device (UBIS 3000) in 698 healthy Caucasian male and female subjects (110 prepubertal, 356 pubertal/adolescent and 210 adult) between 6 and 77 years of age. The influence of different region of interest (ROI) diameters (6–20 mm) and software techniques (automatic (ROIaut), copied (ROIcop) and fixed coordinate (ROIfix) measurements) on annual rate of change, trend assessment interval (TAI; an estimate of the follow-up time required for measuring a true change), percentage of positioning errors (positioning of the ROI partly at the cortical edge or even partly beyond the calcaneus) and short-term precision error was studied. When using ROI diameters increasing from 8 to 20 mm, the annual rate of change of BUA and SOS did not change in adults, but was higher in prepubertal subjects (when subjects with positioning errors were excluded) as well as in pubertal/adolescent subjects. TAIs for BUA were shortest when using ROIaut with ROI diameters between 8 and 14 mm (TAI between 1.2 and 1.5 years for prepubertal boys and pubertal/adolescent subjects, 2.4 years for prepubertal girls, 2.7 years for postmenopausal women, and 9 years in men and premenopausal women). TAIs for SOS were 4 years or more, except for postmenopausal women (2.1 years) and prepubertal boys (3.2 years). Measurements with large ROI diameters, especially with fixed region coordinates, resulted in a high percentage of positioning errors and mostly in longer TAIs. Analysis of the short-term precision errors did not reveal these important differences between the various ROI diameters. Our results indicate that calcaneal ultrasound imaging may be useful for measuring skeletal changes in healthy children, especially with BUA, and in postmenopausal women with BUA and SOS using an automatic measurement in the region of lowest attenuation. ROI diameters of 12 mm should be used in prepubertal subjects and of 14 mm in pubertal/adolescent and adult subjects.