Karen M. Knapp

Multisite Quantitative Ultrasound: Precision, Age- and Menopause-Related Changes, Fracture Discrimination, and T-score Equivalence with Dual-Energy X-ray Absorptiometry

Abstract: This study evaluated the clinical utility of a new multisite ultrasound device capable of measuring speed of sound (SOS) at the phalanx, radius, tibia and metatarsal. The in vitro and in vivo short- and long-term precision were evaluated, reference data were collected for 409 healthy white women (236 premenopausal and 173 postmenopausal), and age and menopause related changes were calculated using linear regression. Fracture discrimination was evaluated using 109 women with vertebral fractures and the age-adjusted odds ratios calculated for each standard deviation decrease in SOS measurement. Correlations between SOS measurements and spine and femur bone mineral density (BMD) were calculated. T-score equivalence with BMD was also investigated together with the prevalence of osteoporosis as defined by the WHO criteria. The in vivo short-term precision standardized in T-score units ranged from 0.14 to 0.33 and long-term standardized precision was 0.35–0.65. Postmenopausal age-related bone loss expressed as the annual change in T-score ranged from 0.040 to 0.089 for SOS and 0.053 to 0.066 for BMD, whilst menopause-related annual loss ranged from 0.036 to 0.094 for SOS and 0.050 to 0.074 for BMD. Correlations between the different SOS sites ranged from r= 0.24 to 0.55, and between SOS and BMD from r= 0.12 to 0.47. The odds ratio (and 95% confidence intervals) for fracture per 1 SD decrease in SOS were 2.0 (1.22 to 3.23) for the phalanx; 1.5 (1.01 to 2.24) for the metatarsal; 1.4 (1.03 to 1.99) for the radius and 1.2 (0.87 to 1.66) for the tibia. Odds ratios for BMD in the same population ranged from 2.6 to 4.8 (1.70 to 8.29). The prevalence of osteoporosis as defined by T= <–2.5 in the age range 60–69 ranged from 7.1% to 20.6% for SOS and 6.4% to 12.1% for BMD. In conclusion, this study demonstrated that multisite ultrasound has adequate precision for investigating skeletal status, is capable of differentiating between pre- and postmenopausal women and women with vertebral fractures, has a T-score equivalence similar to that of dual-energy X-ray absorptiometry (DXA), and appears to be a promising new technique for evaluating skeletal status at clinically relevant sites.

Can the WHO definition of osteoporosis be applied to multi-site axial transmission quantitative ultrasound?

Osteoporosis is a highly prevalent but preventable disease and, as such, it is important that there are appropriate diagnostic criteria to identify those at risk of low trauma fracture. In 1994 the World Health Organization (WHO) introduced definitions of osteoporosis and osteopenia using T-scores, which identified 30% of all Caucasian post-menopausal women as having osteoporosis. However, the use of the WHO T-score thresholds of −2.5 for osteoporosis and −1.0 for osteopenia may be inappropriate at skeletal sites other than the spine, hip and forearm or when other modalities, such as quantitative ultrasound (QUS) are used. The aim of this study was to evaluate the age-dependence of T-scores for speed of sound (SOS) measurements at the radius, tibia, phalanx and metatarsal by use of the Sunlight Omnisense, to evaluate the prevalence of osteoporosis and osteopenia at these sites by use of the WHO criteria, and calculate appropriate equivalent T-score thresholds. The study population consisted of 278 healthy pre-menopausal women, 194 healthy post-menopausal women and 115 women with atraumatic vertebral fractures. All women had SOS measurements at the radius, tibia, phalanx and metatarsal and bone mineral density (BMD) measurements at the lumbar spine and hip. A group of healthy pre-menopausal women aged 20–40 years from the pre-menopausal group were used to estimate the population mean and SD for each of the SOS and BMD measurement sites. Healthy post-menopausal women were classified into normal, osteopenic or osteoporotic, based upon the standard WHO definition of osteoporosis and expressed as a percentage. We investigated the age-related decline in T-scores from 20–79 by stratifying the healthy subjects into 10-year age groups and calculating the mean T-score for each of these groups. Finally, we estimated appropriate T-score thresholds, using five different approaches. The prevalence of osteoporosis in the post-menopausal women aged 50 years and over ranged from 1.4 to 12.7% for SOS and 1.3 to 5.2% for BMD. The age-related decline in T-scores ranged from −0.92 to −1.80 for SOS measurements in the 60 to 69-year age group and −0.60 to −1.19 for BMD measurements in the same age group. The WHO definition was not suitable for use with SOS measurements, and revised T-score thresholds for the diagnosis of osteoporosis of −2.6, −3.0, −3.0 and −2.2 and for osteopenia of −1.4, −1.6, −2.3, and −1.4, for the radius, tibia, phalanx and metatarsal, respectively, were recommended.

Obesity Increases Precision Errors in Dual-Energy X-Ray Absorptiometry Measurements

The precision errors of dual-energy X-ray absorptiometry (DXA) measurements are important for monitoring osteoporosis. This study investigated the effect of body mass index (BMI) on precision errors for lumbar spine (LS), femoral neck (NOF), total hip (TH), and total body (TB) bone mineral density using the GE Lunar Prodigy. One hundred two women with BMIs ranging from 18.5 to 45.9 kg/m(2) were recruited. Participants had duplicate DXA scans of the LS, left hip, and TB with repositioning between scans. Participants were divided into 3 groups based on their BMI and the percentage coefficient of variation (%CV) calculated for each group. The %CVs for the normal (<25 kg/m(2)) (n=48), overweight (25-30 kg/m(2)) (n=26), and obese (>30 kg/m(2)) (n=28) BMI groups, respectively, were LS BMD: 0.99%, 1.30%, and 1.68%; NOF BMD: 1.32%, 1.37%, and 2.00%; TH BMD: 0.85%, 0.88%, and 1.06%; TB BMD: 0.66%, 0.73%, and 0.91%. Statistically significant differences in precision error between the normal and obese groups were found for LS (p=0.0006), NOF (p=0.005), and TB BMD (p=0.025). These results suggest that serial measurements in obese subjects should be treated with caution because the least significant change may be larger than anticipated.

An investigation of unique and shared gene effects on speed of sound and bone density using axial transmission quantitative ultrasound and DXA in twins

The genetic influences of speed of sound (SOS) and BMD were evaluated using 215 pairs of healthy female twins. Genetic influences were found for all SOS and BMD measurements. A combination of shared and unique genetic influences was found to control BMD and SOS at the radius.

Multisite Quantitative Ultrasound: Colles’ Fracture Discrimination in Postmenopausal Women

Abstract:Distal forearm fractures are the most common perimenopausal fracture and are generally associated with osteoporosis. The aim of this study was to evaluate the capability of speed of sound (SOS) measurements in cortical bone at the phalanx, radius, tibia and metatarsal to discriminate Colles’ fracture cases from controls in postmenopausal women and to compare this with bone mineral density (BMD) measurements obtained by dual-energy X-ray absorptiometry (DXA). Sixty-three postmenpausal Colles’ fracture cases and 191 postmenopausal controls had SOS measurements of the radius, tibia, phalanx and metatarsal using a semi-reflection ultrasound technique and BMD measurements of the lumbar spine and proximal femur using DXA. The age-adjusted odds ratios (ORs) for fracture for the SOS measurement sites were 1.50 [95% CI 1.07–2.10] for the radius, 1.23 [0.86-1.76] for the tibia, 1.85 [1.06–3.23] for the phalanx and 1.74 [1.12–2.71] for the metatarsal site. For the BMD measurements the ORs were 1.95 [1.34–2.85] for the lumbar spine, 2.21 [1.43–3.40] for the femoral neck and 2.62 [1.69–4.08] for the total hip. The benefits of combining sites either by taking their average Z-score or by using the manufacturer’s ORI algorithm were evaluated. The two methods yielded similar results and the ORs for the combination of the radius and phalanx were 2.00 [1.21–3.33], for the radius and metatarsal 1.67 [1.05–2.67], for the phalanx and metatarsal 1.86 [1.11–3.08] and for the radius, phalanx and metatarsal 1.81 [1.07–3.06]. Combinations of DXA sites gave 2.22 [1.44–3.41] for the lumbar spine and femoral neck and 2.41 [1.57–3.70] for the lumbar spine and total hip. In conclusion, semi-reflection ultrasound measurements at the radius, phalanx or metatarsal demonstrated an ability to discriminate fracture cases from controls in postmenopausal Colles’ fracture patients, although the odds ratios were lower than with spine and femur BMD.

The relationship between sagittal curvature and extensor muscle volume in the lumbar spine

A previous modelling study predicted that the forces applied by the extensor muscles to stabilise the lumbar spine would be greater in spines that have a larger sagittal curvature (lordosis). Because the force‐generating capacity of a muscle is related to its size, it was hypothesised that the size of the extensor muscles in a subject would be related to the size of their lumbar lordosis. Magnetic resonance imaging (MRI) data were obtained, together with age, height, body mass and back pain status, from 42 female subjects. The volume of the extensor muscles (multifidus and erector spinae) caudal to the mid‐lumbar level was estimated from cross‐sectional area measurements in axial T1‐weighted MRIs spanning the lumbar spine. Lower lumbar curvature was determined from sagittal T1‐weighted images. A stepwise linear regression model was used to determine the best predictors of muscle volume. The mean lower lumbar extensor muscle volume was 281 cm3 (SD = 49 cm3). The mean lower lumbar curvature was 30 ° (SD = 7 °). Five subjects reported current back pain and were excluded from the regression analysis. Nearly half the variation in muscle volume was accounted for by the variables age (standardised coefficient, B = −3.2, P = 0.03) and lower lumbar curvature (B = 0.47, P = 0.002). The results support the hypothesis that extensor muscle volume in the lower lumbar spine is related to the magnitude of the sagittal curvature; this has implications for assessing muscle size as an indicator of muscle strength.

Obesity Increases Precision Errors in Total Body Dual-Energy X-Ray Absorptiometry Measurements

Total body (TB) dual-energy X-ray absorptiometry (DXA) is increasingly being used to measure body composition in research and clinical settings. This study investigated the effect of body mass index (BMI) and body fat on precision errors for total and regional TB DXA measurements of bone mineral density, fat tissue, and lean tissue using the GE Lunar Prodigy (GE Healthcare, Bedford, UK). One hundred forty-four women with BMIs ranging from 18.5 to 45.9 kg/m(2) were recruited. Participants had duplicate DXA scans of the TB with repositioning between examinations. Participants were divided into 3 groups based on their BMI, and the root mean square standard deviation and the percentage coefficient of variation were calculated for each group. The root mean square standard deviation (percentage coefficient of variation) for the normal (<25 kg/m²; n = 76), overweight (25-30 kg/m²; n = 36), and obese (>30 kg/m²; n = 32) BMI groups, respectively, were total BMD (g/cm(2)): 0.009 (0.77%), 0.009 (0.69%), 0.011 (0.91%); total fat (g): 545 (2.98%), 486 (1.72%), 677 (1.55%); total lean (g): 551 (1.42%), 540 (1.34%), and 781 (1.68%). These results suggest that serial measurements in obese subjects should be treated with caution because the least significant change may be larger than anticipated.

Predicting the Risk of Fracture at Any Site in the Skeleton: Are All Bone Mineral Density Measurement Sites Equally Effective?

The ability to assess a patient’s risk of fracture is fundamental to the clinical role of bone densitometry. Fracture discrimination is quantified by the relative risk (RR), defined as the increased risk of fracture for a 1 standard deviation decrease in bone mineral density (BMD). The larger the value of RR, the more effective measurements are at identifying patients at risk of fracture. Epidemiological studies show that RR values for predicting the risk of any fracture are approximately the same for all BMD measurement sites. In this study, we show theoretically that this interesting observation is predictable and a consequence of two related observations: (1) that fracture prediction by BMD measurement sites distant from the fracture site is quantitatively explained by the correlation of BMD measurements and (2) that all correlation coefficients between distant BMD sites are comparable, with values in the range r = 0.55–0.65. The first of these conditions (referred to as the correlation hypothesis) is important because it sets a lower limit on the RR values at distant BMD sites on the assumption that measurements at these sites contain no independent information about fracture risk over and above that provided by their correlation with the fracture site BMD. If the correlation hypothesis is true, the present study points to the importance of the correlation coefficient between BMD sites as a key index that is indicative of the ability of different types of measurement to predict fracture risk. If, on the contrary, the correlation hypothesis is not valid, there is scope to improve bone densitometry by further studies to better identify those measurements that do provide independent information about fracture risk and how best to integrate this information with existing techniques to improve decision making.

Quantitative ultrasound and bone health

This review of quantitative ultrasound (QUS) and bone health uses the current literature to summarise the clinical and research effectiveness of QUS. QUS has been demonstrated to have the ability to predict fracture, particularly at the hip. However, the magnitude of prediction is fracture-site, measurement-site and device dependent. The correlations between dual X-ray absorptiometry (DXA) and bone mineral density (BMD) are weak to moderate, resulting in different subjects being identified as being at risk of fracture by the two different methods. QUS is sensitive to age and menopause-related changes and to clinical risk factors and lifestyle factors associated with osteoporosis. Whilst a limited ability of QUS to monitor therapeutic intervention has been demonstrated, this is still an area where its poorer precision, in comparison to DXA, results in limited applicability. Whilst DXA remains the gold standard for the diagnosis of osteoporosis, QUS may be of use for the prediction of those at risk of future fracture in areas where there is limited availability of DXA.

The Impact of Sport Participation on Bone Mass and Geometry in Male Adolescents.

Purpose Exercise is an effective approach for developing bone mass and adolescence is a key period to optimize bone health. However, sports-specific training may have different effects on bone outcomes. This study examined the differences on bone outcomes between osteogenic (football) and nonosteogenic (swimming and cycling) sports and a control group in male adolescents. Methods One hundred twenty one males (13.1 ± 0.1 yr) were measured: 41 swimmers, 37 footballers, 29 cyclists, and 14 controls. Dual energy X-ray absorptiometry measured bone mineral density (BMD) and bone mineral content at lumbar spine, right and left hip, and total body. Hip Structural Analysis evaluated bone geometry at the femoral neck. Quantitative ultrasound evaluated bone stiffness at both feet. Results Footballers had significantly higher BMD at total body less head (7%–9%), total hip (12%–21%), and legs (7%–11%) compared with all groups and significantly higher BMD at the femoral neck than controls (14%). Cyclists had higher BMD at the trochanter (10%) and bone mineral content at the arms (10%) compared with controls. Geometrical analysis showed that footballers had significantly higher cross-sectional area (8%–19%) compared with all groups, cross-sectional moment of inertia (17%) compared with controls and section modulus compared with cyclists (11%) and controls (21%). Footballers had significantly higher bone stiffness compared with all groups (10%–20%) at the dominant foot and (12%–13%) at the nondominant foot compared with swimmers and controls. Conclusions Adolescent male footballers exhibited higher bone density, geometry, and stiffness compared with swimmers, cyclists and controls. Although swimmers and cyclists had higher bone outcomes compared with controls, these differences were not significant.