Does the Combination of Quantitative Ultrasound and Dual-Energy X-Ray Absorptiometry Improve Fracture Discrimination?

The widespread availability of quantitative ultrasound (QUS) and X-ray absorptiometry densitometers raises the question of whether a combination of QUS and bone mineral density (BMD) measurements could provide a clinically useful method of enhancing the prediction of fracture risk. The aim of this study was to examine whether a combination of axial BMD and calcaneal QUS measurements can enhance fracture discrimination compared with either method alone. The study population consisted of 154 postmenopausal women with a history of atraumatic fracture at the spine, hip or forearm and 221 healthy postmenopausal women with no clinical risk factors for osteoporosis. Subjects had dual-energy X-ray absorptiometry (DXA) measurements of the lumbar spine (LS), femoral neck (FN) and total hip (THIP) and calcaneal broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements on the Hologic Sahara (SAH) and Osteometer DTUone (DTU). Z-scores were calculated using the mean and SD obtained from the healthy postmenopausal group. Logistic regression analysis yielded odds ratios for BMD measurements at the LS, FN and THIP of 2.2, 2.2 and 2.3, respectively. The odds ratios obtained for QUS measurements ranged from 2.5 for DTU BUA to 3.3 for SAH SOS. While these odds ratios for QUS measurements were higher than those obtained for BMD measurements, the differences were not statistically significant. When the odds ratios for QUS were adjusted for BMD at the spine and hip, the odds ratios remained significant in all cases indicating that QUS and BMD variables contribute independently to fracture discrimination. When the BMD-adjusted odds ratios were compared with those for QUS alone, they were slightly lower but not significantly so. When the QUS measurements were adjusted for THIP BMD, the odds ratios for QUS tended to be lower than when adjusted for LS and FN BMD. The Z-scores for each of the QUS measurement variables were combined with spine or hip Z-scores. Logistic regression analysis of the QUS and BMD combined Z-scores yielded slightly higher odds ratios of approximately 3.1 (compared with 2.9 obtained for QUS alone) and increases in the area under the curve of approximately 2%. However, these increases were not clinically significant. In conclusion, the combination of axial BMD and calcaneal QUS measurements did not significantly improve fracture discrimination compared with either method alone. Received: 29 June 2000 / Accepted: 18 December 2000     

A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual X-ray absorptiometry in women with a history of fracture at sites other than the spine and hip

The aim of this study was to determine whether calcaneal quantitative ultrasound can discriminate between women with and those without fragility fracture at (1) the wrist or (2) at sites other than the spine, hip, or forearm, as well as axial DXA measurements of BMD can. The study population consisted of 342 postmenopausal Caucasian women who were placed into one of three groups: (1) healthy women with no clinical risk factors for osteoporosis (n = 240); (2) women with a history of atraumatic fracture at the wrist (n = 50); (3) women with a history of atraumatic fracture at a skeletal site other than the spine, hip, or wrist (n = 52). Subjects had DXA measurements of the lumbar spine (LS), femoral neck (FN), and total hip (THIP), and calcaneal broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements on the Hologic Sahara (s) and Osteometer DTUone (d). Z-scores were calculated using the mean and SD obtained from the healthy postmenopausal group. All the BMD and QUS variables were significantly reduced in women reporting a fracture of the wrist or at a site other than the spine, hip, or forearm. When the group of women with a history of wrist fracture were compared with the postmenopausal controls, age-adjusted logistic regression yielded odds ratios associated with a 1 SD decrease, that were significant for both BMD and QUS, averaging 2.2. The AUC values ranged from 0.65 for FN BMD to 0.75 for BUAd. BMD and QUS measurements were also significantly reduced in women reporting a skeletal fracture at a site other than the spine, hip, or wrist, and odds ratios for BMD and QUS were significant, averaging 1.7. BMD and QUS showed similar fracture discriminatory abilities that were not significantly different from one another. In conclusion, calcaneal QUS can discriminate between women with and those without fracture at the wrist or at sites other than the spine, hip, or forearm as well as axial DXA measurements of BMD can.     

Imaging Ultrasonometry of the Calcaneus: Optimum T-Score Thresholds for the Identification of Osteoporotic Subjects

The purpose of the present study was to (1) examine the age dependence of T-score results for calcaneal imaging ultrasonometry and dual X-ray absorptiometry of the axial skeleton and (2) determine the optimum T-score thresholds appropriate for broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements. A total of 453 healthy women aged 20-9 years were included in the study. All study participants underwent bone mineral density (BMD) measurements of the lumbar spine, femoral neck, total hip and calcaneal measurements of the BUA and SOS. An imaging ultrasound device (UBIS, DMS, France) was used for the ultrasound measurements. T-scores were calculated using a subgroup of 71 healthy women aged 20-35 years to estimate the mean value of young normals and SD for BUA, SOS, and BMD. The age-related decline in both BUA and SOS T-scores was slower than that in the equivalent figures obtained by BMD measurements. The optimum T-score thresholds estimated by receiver operating characteristic (ROC) analysis were 1.3 for BUA and 1.5 for SOS. Using the optimum threshold, the sensitivity and specificity for BUA was 68% and 83%, respectively. Corresponding values for SOS were 63% and 79%. Utilizing calculated optimum T score thresholds for BUA and SOS, the agreement among BUA, SOS, and BMD at the femoral neck was improved compared with that found using the T-score of < or = -2.5 criterion. In conclusion, the definition of osteoporosis by a T-score of , or = -2.5 was not applicable to imaging ultrasonometry of the calcaneus. Optimum T-score thresholds were determined for both BUA and SOS suitable to Ubis QUS device.     

Contact Quantitative Ultrasound: An Evaluation of Precision, Fracture Discrimination, Age-Related Bone Loss and Applicability of the WHO Criteria

The aim of this study was to assess a dry calcaneal quantitative ultrasound (QUS) device by examining: (i) short- and long-term precision; (ii) the ability of the ultrasound parameters to identify women with vertebral fractures; (iii) age- and menopause-related bone loss; (iv) applicability of the WHO criteria in scan interpretation. The study group consisted of 422 healthy women with no risk factors associated with osteoporosis (227 premenopausal and 195 postmenopausal) and 93 women with one or more vertebral fractures. All women had calcaneal QUS and bone mineral density (BMD) measurements of the lumbar spine and hip performed. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements in the heel were combined and expressed as estimated heel BMD. Short-term precision studies yielded coefficient of variations of 0.3% for SOS, 4% for BUA and 3.3% for estimated heel BMD. Standardized short-term precision values were approximately 0.2 SD. Long-term standardized precision errors ranged from 0.17 to 0.38 SD. All the QUS and BMD measurement parameters showed significant negative relationships with age in the postmenopausal group. Annual losses were 0.35 dB/MHz per year for BUA, 0.56 m/s per year for SOS and 0.002 g/cm² per year for estimated heel BMD. All the QUS and BMD parameters were able to discriminate between healthy postmenopausal women and women with vertebral fracture. Age-adjusted odds ratios for each SD decline in QUS measurements were 3.63, 5.25 and 4.79 for BUA, SOS and estimated heel BMD respectively. Corresponding odds ratios for BMD at the lumbar spine, femoral neck and total hip were 2.39, 2.51 and 2.95 respectively. When the QUS and BMD parameters were expressed as T-scores, estimated heel BMD showed the least age-related decline, while femoral neck BMD displayed the greatest decrease with age. The mean T-score and prevalence of osteoporosis (T<−2.5) for a Caucasian woman aged 60–65 years were −1.35 and 21% respectively for the lumbar spine compared with −0.59 and 2% for estimated heel BMD. In conclusion, this study revealed that contact ultrasound can detect age- and menopause-related influences on bone status and was able to discriminate between healthy individuals and women with vertebral fracture. However, the widely accepted threshold of a T-score of less than −2.5 for the definition of osteoporosis may need modifying for the interpretation of QUS scans. Received: 8 February 1999 / Accepted: 5 May 1999     

Differential Effects of Primary Hyperparathyroidism on Ultrasound Properties of Bone

Primary hyperparathyroidism (PHPT) may result in greater cortical than trabecular bone loss. Ultrasound is able to predict osteoporotic fracture risk independent of densitometric measurements, but little is known about the changes in ultrasound variables with PHPT. The aim of our study was to examine the effect of PHPT on ultrasound variables and bone density measurements at cortical (hand) and trabecular (lumbar spine and heel) sites, and to evaluate their reversibility following surgical treatment. We recruited 25 postmenopausal women diagnosed with PHPT ages 51–76 years (mean 62 years) and 95 postmenopausal controls ages 57–80 years (mean 67 years). Measurements were made at baseline and 1 year. Speed of sound (SOS) and broadband ultrasound attenuation (BUA) of the heel were measured using the Lunar Achilles (LA+) and McCue CUBA Clinical (CC). Amplitude-dependent speed of sound (AD-SoS) and ultrasound bone profile index (UBPI) of the fingers were measured using the IGEA DBM Sonic. Bone mineral density (BMD) of the hand and lumbar spine (LS) were measured by dual-energy X-ray absorptiometry (DXA). At baseline, hand BMD, LS BMD and heel BUA were significantly lower and finger UBPI significantly higher in the PHPT patients compared with controls (p<0.001). There were no differences in Stiffness Index, heel SOS or finger AD-SoS between control and PHPT subjects. At 1 year postoperatively, there was a mean (±SD) increase in LS and hand BMD of 3 ± 1% (p<0.01). BUA at the heel increased (11 ± 5%, p<0.001), and UBPI of the fingers decreased (17 ± 7%, p<0.001) probably reflecting different modes of attenuation in trabecular (scattering) and cortical (absorption) bone. Stiffness Index, SOS of the heel and AD-SoS of the fingers did not change. BUA, UBPI and BMD returned towards normal postmenopausal values following surgery. There were no changes in BMD or QUS variables at 1 year in the control group. Quantitative ultrasound (QUS) measurements provide different information about bone structure than densitometric measurements and cannot be regarded as simply reflecting bone density. With further research the combined use of BMD and QUS could improve the assessment of skeletal status in patients with PHPT before and after surgery. Received: 10 September 2001 / Accepted: 31 January 2002     

Heritability of calcaneal quantitative ultrasound measures in healthy adults from the Fels Longitudinal Study

Quantitative ultrasound (QUS) measurements of bone have been reported to predict osteoporotic fracture risk in postmenopausal women and older men. Although many studies have examined the heritability of bone mineral density (BMD), few studies have estimated the heritability of calcaneal QUS phenotypes. In the present study, we examined the genetic regulation of calcaneal QUS parameters in individuals from nuclear and extended families. The study population includes 260 men and 295 women aged 18-91 years (mean+/-SD: 46+/-16 years) who belong to 111 pedigrees in the Fels Longitudinal Study. Three measures of calcaneal structure were collected from both the right and left heel using the Sahara bone sonometer. These measures included broadband ultrasound attenuation (BUA), speed of sound (SOS), and the quantitative ultrasound index (QUI). We used a variance components based maximum likelihood method to estimate the heritability of QUS parameters while simultaneously adjusting for covariate effects. Additionally, we used bivariate extensions of these methods to calculate additive genetic and random environmental correlations among QUS measures. All phenotypes demonstrated statistically significant heritabilities (P<0.0000001). Heritabilities in the right heel (h2+/-SE) were h2=0.59+/-0.10 for BUA, h2=0.73+/-0.09 for SOS, and h2=0.72+/-0.09 for QUI. Similarly, heritabilities for the left heel were h2=0.52+/-0.10, h2=0.75+/-0.10, and h2=0.70+/0.10, respectively. There was evidence for significant genetic and environmental correlations among these six QUS measures. Combinations of QUS measures in the right and left heel demonstrated genetic correlations of 0.94-0.99 and all were significantly different from one indicating at least a partially unique genetic architecture for each of these measures. This study demonstrates that QUS measures of the calcaneus among healthy men and women are heritable, and there are large shared additive genetic effects among all of the traits examined.     

Heel Ultrasonography in Monitoring Alendronate Therapy: A Four-Year Longitudinal Study

The possibility of using quantitative ultrasound (QUS) in monitoring the response to antiresorptive drugs has yet to be defined. The aim of the present study was to evaluate whether heel ultrasonography, considering its characteristics of long-term precision, is able to monitor osteoporotic patients treated with alendronate. We studied 150 postmenopausal osteoporotic women (age 59.6 ± 5.3 years) treated with alendronate and calcium (n= 74) or with calcium alone (n= 76) for 4 years. At baseline and after 12, 24, 36 and 48 months, we measured bone mineral density (BMD) at the lumbar spine by dual-energy X-ray absorptiometry (DXA, Hologic 4500), and speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness at the calcaneus by Achilles plus. Moreover, the longitudinal precision of QUS parameters was assessed by measuring 10 subjects once a month for 1 year and, on the basis of the coefficients of variation we obtained, we calculated the Least Significant Change between two measurements. In the alendronate-treated patients, at year 1, BMD increased by 4.2%, SOS by 0.4%, BUA by 1.1% and Stiffness by 3.2%; at year 2, BMD increased by 5.0%, SOS by 0.7%, BUA by 1.4% and Stiffness by 5.7%. At year 3, BMD increased by 6.2%, SOS by 0.9%, BUA by 1.8% and Stiffness by 7.6%. At the end of the study period, BMD increased by 7.6%, SOS by 1.2%, BUA by 1.9% and Stiffness by 9.0%. The minimal significant difference between two measurements was 0.8% for SOS, 5.6% for BUA and 5.0% for Stiffness. Among the QUS parameters, Stiffness showed the greatest total treatment effect and a longitudinal sensitivity which was only slightly lower than BMD. The MTI, which represents the period between scans required to show that a ‘true’ change has occurred, was 1.8, 2.7, 11.9 and 2.2 years for BMD, SOS, BUA and Stiffness respectively. Therefore, although the spinal BMD remains the optimal method, QUS at the heel, and in particular Stiffness, seems to be a sensitive tool for monitoring the response to alendronate. Received: 30 August 2001 / Accepted: 29 November 2001     

Assessment of a New Quantitative Ultrasound Calcaneus Measurement: Precision and Discrimination of Hip Fractures in Elderly Women Compared with Dual X-ray Absorptiometry

The incidence of osteoporotic hip fracture increases in postmenopausal women with low hip bone mineral density (BMD). Dual X-ray absorptiometry (DXA) is the most commonly used technique for the assessment of bone status and provides good measurement precision. However, DXA affords little information about bone architecture. Quantitative ultrasound (QUS) systems have been developed to evaluate bone status for assessment of fracture risk. Our study was designed to assess a new QUS system from Hologic, the Sahara; to compare it with a previous model, the Walker-Sonix UBA 575+; and to investigate whether it is able to discriminate between women with and without fracture. Using both ultrasound devices, the measurements were performed at the heels of 33 postmenopausal women who had recently sustained hip fracture. A control group of 35 age-matched postmenopausal women was recruited for comparison. The total, neck and trochanter femoral BMD values were assessed using DXA for both groups. QUS and DXA measurements were significantly lower in fractured patients (p<0.005) than in the control group. The short-term, mid-term and standardized short-term precisions were used to evaluate the reproducibility of the two QUS systems. The Sahara showed a better standardized coefficient of variation for broadband ultrasound attenuation (BUA) than did the UBA 575+ (p<0.001). The correlation of BUA and speed of sound (SOS) between the two QUS devices was highly significant, with an r value of 0.92 for BUA and 0.91 for SOS. However, the correlation between DXA and ultrasound parameters ranged from 0.28 to 0.44. We found that ultrasound measurements at the heel were significant discriminators of hip fractures with odds ratios (OR) ranging from 2.7 to 3.2. Even after adjusting the logistic regressions for total, neck or trochanter femoral BMD, QUS variables were still significant independent discriminators of hip fracture. The areas under the ROC curves of each ultrasound parameter ranged from 0.75 to 0.78, and compared very well with femoral neck BMD (p>0.05). In conclusion, our study indicated that the calcaneal QUS variables, as measured by the Sahara system can discriminate hip fracture patients equally as well as hip DXA. Received: 29 October 1999 / Accepted: 7 September 1999     

Correlates of Quantitative Ultrasound in the Women’s Healthy Lifestyle Project

Quantitative ultrasound (QUS) assessment of bone is a strong predictor of hip fractures and is currently an FDA-approved tool to identify women at risk of osteoporosis. However, few studies have investigated the lifestyle and genetic correlates of QUS in women. This study investigated the cross-sectional associates of several lifestyle, demographic and genetic factors with calcaneal QUS parameters (broadband ultrasound attenuation (BUA) and speed of sound (SOS)) in 393 women aged 45–53 years. Leisure-time and historical physical activity, dietary calcium and protein, body composition, vitamin D receptor genotypes, menopause status, other health behaviors, calcaneal QUS parameters and bone mineral density (BMD) were assessed at a single clinic visit. Lean mass, recent physical activity and African-American race were the strongest correlates of SOS whereas dietary protein, calcium and recent physical activity were the strongest correlates of BUA. These predictors explained 13% and 6% of the variance in SOS and BUA, respectively. Smoking, alcohol intake, education, hormone replacement therapy, calcium and vitamin D supplements, historical physical activity and vitamin D receptor genotypes were not significantly associated with BUA or SOS. Lean body mass and premenopausal status were the strongest correlates of lumbar BMD whereas lean body mass, physical activity, African-American race and body mass index were significantly related to femoral neck BMD. Physical activity remained predictive of SOS after controlling for lumbar BMD. The spectrum and magnitude of risk factors for SOS and BUA, including lean body mass, physical activity, race, protein and calcium intake, parallel previously observed predictors of BMD. Received: 25 November 1998 / Accepted: 1 April 1999     

Can the WHO Criteria for Diagnosing Osteoporosis be Applied to Calcaneal Quantitative Ultrasound?

With the increasing number of quantitative ultrasound (QUS) devices in use worldwide it is important to develop strategies for the clinical use of QUS. The aims of this study were to examine the age-dependence of T-scores and the prevalence of osteoporosis using the World Health Organization Study Group criteria for diagnosing osteoporosis and to examine the T-score threshold that would be appropriate to identify women at risk of osteoporosis using QUS. Two groups of women were studied: (i) 420 healthy women aged 20–79 years with no known risk factors associated with osteoporosis; (ii) 97 postmenopausal women with vertebral fractures. All subjects had dual-energy X-ray absorptiometry (DXA) measurements of the spine and hip and QUS measurements on three calcaneal ultrasound devices (Hologic Sahara, Hologic UBA575+, Osteometer DTUone). A subgroup of 102 (76 on the DTUone) healthy women aged 20–40 years was used to estimate the young adult mean and SD for each QUS and DXA measurement parameter to calculate T-scores. The age-related decline in T-scores for QUS measurement parameters was half the rate observed for the bone mineral density (BMD) measurements. The average T-score for a woman aged 65 years was –1.2 for QUS measurements and –1.75 for the BMD measurements. When osteoporosis was defined by a T-score ≤–2.5 the prevalence of osteoporosis in healthy postmenopausal women was 17%, 16% and 12% for lumbar spine, femoral neck and total hip BMD respectively. When the same definition was used for QUS measurements the prevalence of osteoporosis ranged from 2% to 8% depending on which ultrasound device and measurement parameter was used. Four different approaches, based on DXA-equivalent prevalence rates of osteoporosis, were utilized to examine which T-score threshold would be appropriate for identifying postmenopausal women at risk of osteoporosis using QUS measurements. These ranged from –1.05 to –2.12 depending upon the approach used to estimate the threshold and on which QUS device the measurements were performed, but all were significantly lower than the threshold of –2.5 used for BMD measurements. In conclusion, the WHO threshold of T=–2.5 for diagnosing osteoporosis requires modification when using QUS to assess skeletal status. For the three QUS devices used in this study, a T-score threshold of –1.80 would result in the same percentage of postmenopausal women classified as osteoporotic as the WHO threshold for BMD measurements. Corresponding T-score thresholds for individual measurement parameters on the two commercially available devices were –1.61, –1.94 and –1.90 for Sahara BUA, SOS and estimated heel BMD respectively and –1.45 and –2.10 for DTU BUA and SOS respectively Additional studies are needed to determine suitable T-score thresholds for other commercial QUS devices. Received: 25 June 1999 / Accepted: 29 September 1999     

Unique and common genetic effects between bone mineral density and calcaneal quantitative ultrasound measures: the Fels Longitudinal Study

Introduction Areal bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) measures are correlated, and both traits predict osteoporotic fracture risk independently. However, few studies have examined whether common genetic effects (i.e., pleiotropy) exist between these traits in extended families. In this study, we estimated the additive genetic correlation and random environmental correlation between BMD measured at various skeletal sites and calcaneal QUS measures. Methods Our sample included 537 adults (251 men and 286 women) from 110 families participating in the Fels Longitudinal Study. Total hip, femoral neck, lumbar spine, and total body BMD were measured using dual energy X-ray absorptiometry. Three measures of calcaneal structure – broadband ultrasound attenuation (BUA), speed of sound (SOS), and quantitative ultrasound index (QUI) – were collected from the non-dominant heel using the Sahara sonometer. Applying a variance components-based maximum likelihood method, we estimated the heritability of each trait and estimated the genetic and environmental correlations between the different BMD and QUS measures. Results Heritability estimates were significant for all measures of BMD and QUS ranging from 0.55 to 0.78. Significant non-zero genetic correlations were found between the different BMD and QUS measures. All genetic correlations were also significantly different from 1. Genetic correlations between total hip BMD and each of the QUS measures were 0.63 with BUA, 0.50 with SOS, and 0.56 with QUI. For femoral neck BMD, genetic correlations were similar to those between total hip BMD and QUS measures. Genetic correlations between BMD of the lumbar spine and QUS measures ranged from 0.34 to 0.38, and those between total body BMD and QUS measures, from 0.51 to 0.54. In contrast, all random environmental correlations were not significantly different from zero. Conclusion This study demonstrates that BMD and calcaneal QUS measures among healthy men and women are significantly heritable and are, in part, jointly influenced by a common set of underlying genes. Additionally, this study also provides evidence for a unique set of genes that independently influences each individual trait.     

Quantitative Ultrasound Measurements of the Tibia and Calcaneus in Comparison with DXA Measurements at Various Skeletal Sites

The performance of quantitative ultrasound (QUS) measurements of the tibia and calcaneus was studied in 109 elderly people (age range 65–87 years). Broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured at the calcaneus and SOS was assessed at the tibia. Short-term precision of tibial QUS was studied in 16 volunteers. The coefficient of variation (CV) was 0.4% and the standardized CV (sCV) was 4.4%. We compared the calcaneal and tibial QUS measurements with bone mineral density (BMD) measurements of the lumbar spine, femoral neck, trochanter and total body assessed by dual-energy X-ray absorptiometry (DXA). Calcaneal QUS correlated better with BMD at various skeletal sites than tibial QUS. Calcaneal BUA showed higher correlations with BMD values of the lumbar spine, femoral neck, trochanter and total body than calcaneal and tibial SOS (r= 0.48–0.64, r= 0.30–0.47, r= 0.35–0.47, respectively; p<0.001). Body weight modified the relationships between calcaneal and tibial QUS and BMD measurements of the hip. Higher body weight was associated with higher BMD values at the femoral neck and trochanter for the same calcaneal and tibial QUS values. After adjustments for body weight correlations of tibial and calcaneal QUS with BMD improved and were very similar. This suggests that correction for body weight is important and could add to the predictive value of QUS measurements. Received: 16 July 1997 / Accepted: 8 July 1998     

Does Quantitative Ultrasound Imaging Enhance Precision and Discrimination?

The aim of this study was to compare quantitative ultrasound (QUS) measurements obtained using a new calcaneal QUS imaging device with a conventional non-imaging device using fixed transducers. The study group consisted of 340 healthy women with no risk factors associated with osteoporosis (176 premenopausal and 164 postmenopausal) and 83 women with one or more vertebral fractures. All women had QUS measurements performed on the Osteometer DTU-one (imaging) and Walker-Sonix UBA575+ (non-imaging) devices and bone mineral density (BMD) measurements performed at the spine and hip. A subgroup of 81 women had additional dual-energy X-ray absorptiometry (DXA) scans at the calcaneus. Short-term standardized precision (SP = SD/young adult SD) based on duplicate measurements was significantly better on the DTU for broadband ultrasound attenuation (BUA) (SP: DTU 0.15 vs UBA 0.21, p= 0.01) and speed of sound (SOS) (SP: DTU 0.14 vs UBA 0.18, p= 0.01). However, long-term SP of the DTU was comparable to or significantly poorer than the SP of the UBA device. The BUA and SOS measurements obtained on the DTU and UBA were significantly correlated (r= 0.76 and 0.89 for BUA and SOS measurements respectively). The correlations between QUS and BMD measurements were all significant, ranging from 0.53 to 0.72. No significant improvements in the correlation with axial or peripheral BMD were observed using the imaging device. All the QUS measurement parameters showed a significant negative relationship between age and years since menopause in the postmenopausal group. Annual losses were lower for the DTU for BUA (DTU 0.22 dB/MHz per year vs UBA 0.44 dB/MHz per year) but comparable for SOS (DTU 0.29 m/s per year vs UBA 0.22 m/s per year). However, when these figures were standardized to take into account the clinical range, the annual losses were similar on the DTU and UBA. Age-adjusted odds ratios for each SD decline were similar on the DTU for BUA (DTU 3.2 vs UBA 3.3) and SOS (DTU 3.4 vs UBA 5.1). The corresponding odds ratios for BMD at the lumbar spine, femoral neck and total hip were 2.7, 2.9 and 3.3 respectively. Age-adjusted receiver-operating characteristics analysis yielded values for the area under the curve (AUC) ranging from 0.74 to 0.83. The DTU BUA AUC of 0.83 was significantly greater than the AUC obtained for UBA BUA and BMD measurements at the lumbar spine and femoral neck. Ultrasound imaging at the calcaneus was found to improve the standardized precision of BUA and SOS measurements in the short term but not in the long term. Neither the correlation with BMD nor the discriminatory ability of QUS was improved by utilizing QUS images at the calcaneus. The inconsistencies of the imaging system used for this study demonstrate that further development is required before it will be possible to show improvements in long-term precision. Received: 18 June 1999 / Accepted: 29 October 1999     

Clinical Performance of a Highly Portable, Scanning Calcaneal Ultrasonometer

The aim of this study was to establish a normative database, assess precision, and evaluate the ability to identify women with low bone mass and to discriminate women with fracture from those without for a highly portable, scanning calcaneal ultrasonometer: the QUS-2. Fourteen hundred and one Caucasian women were recruited for the study. Among them were 794 healthy women 25–84 years of age evenly distributed per 10-year period to establish a normative database. Of these, 171 aged 25–34 years were defined as the young normal group for the purpose of T-score determination. Precision was assessed within 1 day (short-term) and over a 16-week period (long-term) in 79 women aged 25–84 years. Five hundred twenty-eight women ranging from 50 to 84 years of age with or without prevalent fractures of the spine, hip or forearm were measured to compare the QUS-2 with bone mineral density (BMD) of the hip and spine. Mean calcaneal broadband ultrasound attenuation (BUA) was constant in healthy women from 25 to 54 years of age and decreased with increasing age thereafter. Short-term precision, with and without repositioning of the heel, and long-term precision yielded comparable results (BUA SDs of 2.1–2.4 dB/MHz, coefficients of variations (CVs) of 2.5–2.9%). Calcaneal BUA was significantly correlated with BMD of the total hip (TH), femoral neck (FN) and lumbar spine (LS) in 698 women (r= 0.6–0.7, all p<0.0001). A similar relationship was observed for LS BMD compared with either TH or FN BMD (r= 0.7, p<0.0001). Prevalence of osteoporosis in our population (WHO criteria) was 20%, 17%, 21%, and 24% for BUA, BMD of the TH, FN and LS, respectively. Age-adjusted values for a 1 SD reduction in calcaneal BUA and TH and FN BMD predicted prevalent fractures of the spine, forearm, and hip with significant (p<0.05) odds ratios of 2.3, 2.0 and 2.1, respectively. Areas under the receiver operating characteristic curves for age-adjusted bone mass values predicting prevalent fracture were 0.62 for BUA, 0.59 for TH BMD, 0.60 for FN BMD, and 0.57 for LS BMD; all statistically equivalent. We conclude that the QUS-2 calcaneal ultrasonometer exhibits reproducible clinical performance that is similar to BMD of the spine and hip in identifying women with low bone mass and discriminating women with fracture from those without. Received: 19 July 2000 / Accepted: 6 December 2000     

Comparison of ultrasound and X-ray absorptiometry bone measurements in a case control study of female rheumatoid arthritis patients and randomly selected subjects in the population

To compare quantitative ultrasound (QUS) and dual-energy X-ray absorptiometry (DXA) bone measurements in female rheumatoid arthritis (RA) patients and controls were randomly selected from the population; secondly, to examine disease and demographic factors associated with these bone measurements. In a total of 115 RA patients (mean age 63.0 years) and 115 age- and gender-matched controls demographic and clinical variables were collected and heel QUS parameters [speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index (SI)] as well as DXA bone mineral density (BMD) at spine and hip were measured. The differences in QUS and DXA measurements between RA patients and controls were tested both on a group and on an individual level. Univariate and multivariate statistical tests were applied to explore for associations to the bone measurements. In the RA patients mean disease duration was 16.6 years, erythrocyte sedimentation rate 23.6 mm/h, M-HAQ 1.68, 28-swollen joint count 7.7, 18-deformed joint count 4.5, 50.0% were rheumatoid factor (RF) positive and 44.2% were current users of prednisolone. All bone measurements were reduced in RA patients compared with controls (SOS 1.9%, BUA 9.4%, SI 19.5%, femoral neck BMD 7.4%, total hip BMD 7.5%, spine L2-L4 BMD -3.0%). Only at spine was the BMD reduction not statistically significant ( P=0.21). In the subgroup of never users of prednisolone SOS was decreased by 1.4%, BUA by 3.7%, SI by 11.0, femoral neck BMD by 2.7%, and total hip BMD by 0.6%, whereas for spine L2-L4 BMD was increased by 4.3% and only for SOS and SI was the decrease statistically significant. The QUS discriminated better than DXA between patients and controls on a group level, but this difference in favor of QUS disappeared on an individual level when the measurement errors were taken into account. Age, BMI, RF and deformed joint count, but not corticosteroids, were independently associated with at least one of the QUS and one of the DXA measures; however, the association between disease-related variables was stronger with the QUS bone measures than with the DXA bone measures. The results for the quantitative QUS bone measures seem to mainly reflect bone mass. Disease-related variables in multivariate analysis remained independently associated with all QUS measures even when adjusting for DXA bone measures. Further studies are needed to examine if QUS may reflect other aspects than bone mass and be a potential better predictor for fracture risk in RA and corticosteroid-induced osteoporosis.     

LRP5 coding polymorphisms influence the variation of peak bone mass in a normal population of French-Canadian women

INTRODUCTION: Bone mineral density has a strong genetic component but it is also influenced by environmental factors making it a complex trait to study. LRP5 gene was previously shown to be involved in rare diseases affecting bone mass. Mutations associated with gain-of-function were described as well as loss-of-function mutations. Following this discovery, many frequent LRP5 polymorphisms were tested against the variation of BMD in the normal population. MATERIALS AND METHODS: Heel bone parameters (SOS, BUA) were measured by right calcaneal QUS in 5021 healthy French-Canadian women and for 2104 women, BMD evaluated by DXA at two sites was available (femoral neck (FN) and lumbar spine (LS)). Among women with QUS measures and those with DXA measures, 26.5% and 32.8% respectively were premenopausal, 9.2% and 10.7% were perimenopausal and 64.2% and 56.5% were postmenopausal. About a third of the peri- and postmenopausal women never received hormone therapy. Two single nucleotide coding polymorphisms (Val667Met and Ala1330Val) in LRP5 gene were genotyped by allele-specific PCR. All bone measures were tested individually for associations with each polymorphism by analysis of covariance with adjustment for non genetic risk factors. Furthermore, haplotype analysis was performed to take into account the strong linkage disequilibrium between the two polymorphisms. RESULTS AND CONCLUSION: The two LRP5 polymorphisms were found to be associated with all five bone measures (L2L4 and femoral neck DXA as well as heel SOS, BUA and stiffness index) in the whole sample. Premenopausal women drove the association as expected from the proposed role of LRP5 in peak bone mass. Our results suggest that the Val667Met polymorphism is the causative variant but this remains to be functionally proven.     

Age-Specific Values and Cutoff Levels for the Diagnosis of Osteoporosis in Quantitative Ultrasound Measurements at the Calcaneus with SAHARA in Healthy Japanese Women: Japanese Population-Based Osteoporosis (JPOS) Study

To establish the reference values of the quantitative ultrasound (QUS) indices in healthy Japanese women and to propose a diagnostic criterion for osteoporosis by means of the QUS indices, 659 healthy women aged 20-79 years recruited from a larger cohort study (JPOS study), were examined for bone mass measurements by QUS at the calcaneus (SAHARA, Hologic Inc., USA) and by dual-energy X-ray absorptiometry at the spine, hip, and distal forearm. We presented 10-year age-specific mean values and T-scores of the QUS indices. The pattern of decrease in the T-score appeared to be linear in the QUS indices and total hip BMD but not in BMD at the spine. The T-score of the QUS of indices of the subjects in their 70s were significantly higher than that of BMD at the spine. The prevalence rates of osteoporosis in the subjects aged 50 and older diagnosed by QUS (8.7% for SOS, 10.7% for BUA) were similar to that diagnosed by total hip BMD (11.5%) and significantly lower than that by the spine BMD (36.1%) when the WHO criteria were applied. We performed receiver-operating characteristic analysis to set a cutoff level of the QUS indices for the diagnosis of osteoporosis to accurately identify the subjects diagnosed by either the spine or total hip BMD. The highest likelihood ratios for SOS and BUA were obtained at the cutoff levels of 1,517.7 m/sec (T-score: -1.58) with the sensitivity of 0.65 and the specificity of 0.65 and 59.5 dB/MHz (T-score: -1.52) with 0.66 and 0.69, respectively. The diagnostic accuracy of QUS indices for osteoporosis was not superior to that of age. However, the QUS indices showed a significant contribution to forming the diagnosis of osteoporosis independently of age and body size in multivariate diagnostic models developed by the logistic regression analysis. Therefore, the cutoff values presented in this study may be used as a tentative criterion until the cutoff levels for the QUS indices are set according to the fracture risk.     

Comparison of Six Calcaneal Quantitative Ultrasound Devices: Precision and Hip Fracture Discrimination

Quantitative ultrasound (QUS) is now accepted as a useful tool in the management of osteoporosis. There are a variety of QUS devices clinically available with a number of differences among them, including their coupling methods, parameter calculation algorithms and sites of measurement. This study evaluated the abilities of six calcaneal QUS devices to discriminate between normal and hip-fractured subjects compared with the established method of dual-energy X-ray absorptiometry (DXA). The short-term and mid-term precisions of these devices were also determined. Thirty-five women (mean age 74.5 ± 7.9 years) who had sustained a hip fracture within the past 3 years, and 35 age-matched controls (75.8 ± 5.6 years) were recruited. Ultrasound measurements were acquired using six ultrasound devices: three gel-coupled and three water-coupled devices. Bone mineral density was measured at the hip using DXA. Discrimination of fracture patients versus controls was assessed using logistic regression analysis (expressed as age- and BMI-adjusted odds ratios per standard deviation decrease with 95% confidence interval) and receiver operating characteristics (ROC) curve analysis. Measurement precision was standardized to the biological range (sCV). The sCV ranged from 3.14% to 5.5% for speed of sound (SOS) and from 2.45% to 6.01% for broadband ultrasound attenuation (BUA). The standardized medium-term precision ranged from 4.33% to 8.43% for SOS and from 2.77% to 6.91% for BUA. The pairwise Pearson correlation coefficients between different devices was highly significant (SOS, r= 0.79–0.93; BUA, r= 0.71–0.92). QUS variables correlated weakly, though significantly, with femoral BMD (SOS, r= 0.30–0.55; BUA, r= 0.35–0.61). The absolute BUA and SOS values varied among devices. The gel-coupled devices generally had a higher SOS than water-coupled devices. Bone mineral density (BMD) and BUA were weakly correlated with weight (r= 0.48–0.57 for BMD and r= 0.18–0.54 for BUA), whereas SOS was independent of weight. All the QUS devices gave similar, statistically significant hip fracture discrimination for both SOS and BUA measures. The odds ratios for SOS (2.1–2.8) and BUA (2.4–3.4) were comparable to those for femoral BMD (2.6–3.5), as were the area under the curve (SOS, 0.65–0.71; BUA, 0.62–0.71; BMD, 0.65–0.74) from ROC analysis. Within the limitation of the sample size all devices show similar diagnostic sensitivity. Received: 2 February 2000 / Accepted: 1 May 2000     

Calcaneal ultrasound predicts early postmenopausal fractures as well as axial BMD. A prospective study of 422 women

Low calcaneal ultrasound measurement (quantitative ultrasound, QUS) has been shown to predict fractures in elderly women. However, only a few studies have examined its ability to predict perimenopausal and early postmenopausal fractures. We conducted a prospective population-based cohort study to assess the capability of QUS as compared to axial BMD measurement to predict early postmenopausal fractures at that age. Four hundred and twenty-two women (mean age 59.6, range 53.7–65.3) from the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) were randomly chosen to undergo a calcaneal ultrasound measurement. In all, 9.4% of these women were premenopausal at the time of measurement. Thirty-two follow-up fractures were reported during the mean follow-up of 2.6 years (SD 0.7). These were validated with patient record perusal. Broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI) were significantly lower among women with than without fracture (P-values 0.028, 0.001 and 0.001, respectively). Mean T-score adapted from SI was –1.5 (95% CI –1.7 to –1.2) for fracture group and –1.0 (95% CI –1.1 to –0.9) for the non-fracture group. All QUS measurements predicted fractures even after adjusting for age, weight, height, previous fracture history, femoral neck BMD and use of hormone replacement therapy according to Cox regression. The adjusted hazard ratios (HR, 95% confidence interval) of a follow-up fracture for a 1 SD decrease were 1.80 (1.27–2.56), 1.72 (1.21–2.45) and 1.43 (1.01–2.03) for SOS, SI and BUA, respectively. Similarly, the adjusted HR for a 1 SD decrease of spinal BMD was 1.27 (0.85–1.94) and for that of femoral neck BMD 1.14 (0.78–1.70). In receiver operator analyses, the area under the curve (AUC) was greatest for QUS measurements: SOS (AUC=0.68), stiffness (AUC=0.67), BUA (AUC=0.62) and least for lumbar BMD (AUC=0.56), while and femoral neck BMD (AUC=0.59). The difference between AUCs was statistically significant between SI and lumbar BMD (P=0.02, Duncans P=0.07). We conclude that low calcaneal QUS predicts early postmenopausal fractures as well as or even better than axial BMD.     

Relationship between risk factors and QUS in a European Population: The OPUS study

There are many risk factors associated with low bone mineral density. Quantitative ultrasound (QUS) is a generally accepted method for measurement of bone and has been shown to be strongly associated with future fracture risk. The Osteoporosis and Ultrasound Study (OPUS) is a multi-centre European wide study examining 5 different QUS scanners (4 calcaneal, 1 finger device). The aim of this paper was to examine the relationship between risk factors (as assessed by questionnaire) and QUS measurements. 449 younger women (aged 20 to 39 years) and 2283 older women (aged 55 to 79 years) were included in this analysis. As expected, those with a self-reported previous fracture had lower QUS measurements than those without (P < 0.001). However, no significant difference was seen between those reporting a maternal hip fracture and those who did not report such an event. Differences were found for smokers vs. non-smokers for SOS but not for BUA measurements. Weight was positively correlated with all BUA variables but only with some SOS variables. We determined which risk factors were most strongly associated with QUS measurements by using step-wise multiple regression. Models for each QUS measurement were calculated, and the R2 values ranged from 0.18 to 0.28 for SOS, 0.27 to 0.32 for BUA and 0.31 to 0.42 for the finger QUS device. The most common risk factors across all models were age, use of hormone replacement therapy, self-reported previous fracture, self-reported diagnosis of osteoporosis, current weight, pulse rate and self-reported estimated height at age 20 years. We analysed relationships across the 5 centres and detected some geographical differences in the prevalence of the risk factors. In conclusion, similar relationships are seen with QUS measurements as are found for bone mineral density. However, the strength of the association is dependent on the type of QUS device and variable measured.