Journal of Clinical Densitometry, vol. 6, no. 3, 237–245, 2003 © Copyright 2003 by Humana Press Inc. All rights of any nature whatsoever reserved. 1094-6950/03/6:237–245/$25.00
Original Article
Evaluation of Calcaneal Quantitative Ultrasound in a Primary Care Setting as a Screening Tool for Osteoporosis in Postmenopausal Women Adolfo Díez-Pérez, MD, PhD,*,1,3 Fernando Marín, MD, PhD,2 Joan Vila, BSc,3 Mercedes Abizanda, MD,4 Artur Cervera, MD,4 Cristina Carbonell, MD,5 Rosa M a Alcolea, MD,6 Adoración Cama, MD,5 Teresa Rama, MD,6 Elena Galindo, MD,6 and Carmen Olmos MD5 1Unidad
de Investigación de Fisiopatología Ósea y Articular, Hospital Universitario del Mar, Universitat Autonoma, Barcelona, Spain; 2Department of Medical Research, Eli Lilly and Company, Madrid, Spain; 3Institut Municipal d’Investigació Mèdica (IMIM), Barcelona, Spain; 4Centro de Atención Primaria Gran Vía, Barcelona, Spain; 5Area Básica de Salud Vía Roma, Barcelona, Spain; 6Area Básica de Salud Llefiá, Badalona, Barcelona, Spain
Abstract Screening of osteoporosis by quantitative ultrasound (QUS) has become widely available in Europe, but no clear strategies for its clinical use have been established. The aim of this study was to validate the use of QUS in a cross-sectional study carried out in three primary care centers. Measurements of calcaneal QUS and bone mineral density (BMD) at proximal femur were obtained by dual-energy X-ray absorptiometry (DXA). Osteoporosis was diagnosed by DXA T-score ≤ –2.5 at the femoral neck. Sensitivity, specificity, kappa index, and receives operator characteristics (ROC) curve QUS values were calculated with respect to the standard reference. Both positive and negative likelihood ratios (LR) were used to calculate the optimum cut-off levels. Two hundred and sixty-seven women aged 65 or older were included. Fifty-five percent had osteoporotic femoral neck BMD values (T-score ≤ –2.5). The same threshold for QUS yielded a lower prevalence of osteoporosis (10%). Women with BMD diagnosis of osteoporosis were older and showed lower age-adjusted values for all QUS parameters (p < 0.001). Area under the curve (AUC) ranged from 0.662–0.678 for the different QUS parameters; correlation and concordance of all parameters with femoral neck BMD were statistically significant (p < 0.001). Cut-off values calculated from the AUC yielded 61.1% sensitivity and 65.3% specificity for the best QUS parameter (i.e., Estimated Heel T-score ≤ –1.55). Estimated Heel T-score values of +0.05 or above ruled out osteoporosis (LR 0.18), whereas those –2.50 or below supported the diagnosis (LR 5.98). The application of these cutoff points allowed classification of 22.1% of cases. In conclusion, in postmenopausal women, QUS screening conclusively confirms or rules out osteoporosis in approximately one-fifth of cases, thereby avoiding the need for a DXA measurement. Key Words: Bone; diagnosis; osteoporosis; menopause; screening; ultrasound.
Introduction The currently accepted gold standard diagnostic method for osteoporosis is based on evaluation of bone mineral density (BMD) and/or bone mineral content (BMC) by dual X-ray absorptiometry (DXA)
Received September 18, 2002; Accepted January 24, 2003 *Address correspondence to Dr. Adolfo Díez-Pérez. Lilly Corporate Center. DC 6134, Indianapolis, IN 46285. E-mail:
[email protected]
237
238 techniques (1). However, DXA equipment is expensive, nonportable, involves exposure to ionizing radiation, and in many geographical areas, including ours, are usually restricted to tertiary-care hospitals, because specialized, trained personnel are required. Given the considerable health problem posed by postmenopausal osteoporosis (2), a need exists for low-cost screening methods able to identify women at risk for the disease. Quantitative bone ultrasound (QUS) is a relatively inexpensive screening technique, which may be used by general practitioners in primary care and in ambulatory settings (3). QUS parameters permit analysis of some mechanical properties of bone tissue that, in turn, are important determinants of bone stiffness, failure load, and fracture risk (3,4). Moreover, several large prospective studies have shown that QUS results can be used to predict future fracture risk as well as BMD in older women (5–13). In addition to the value of DXA as the reference standard for diagnosis, most currently available clinical decision-making guidelines, efficacy evaluation of therapeutic interventions, or reliability for followup are based on BMD measured by this technique. However, neither clear diagnostic algorithms nor screening strategies for clinical decisions can be derived from the currently available QUS technique, and the inferred calculations of BMD. In addition, the reference scores offered by the different manufacturers lack sufficient methodological consistency and may be potentially misleading. The aim of this study was to evaluate the performance of a QUS device as a screening tool for postmenopausal osteoporosis in a primary care clinical setting, and assess cut-off values for a reliable clinical decision-making process to avoid the maximum percentage of DXA measurements. Correlations between QUS measurements and proximal femur BMD were also analyzed as a secondary endpoint.
Patients and Methods Participants Two hundred and ninety-one postmenopausal Caucasian women, consecutively seen in the context of a routine clinical visit at three primary care centers in the metropolitan area of Barcelona between March and October 2000, were invited to participate in this study. Two hundred and sixty-seven agreed to participate. Journal of Clinical Densitometry
Díez-Pérez et al. Women were considered eligible if they were at least 65 yr old, were not hospitalized, and had no language barrier, and excluded if they had any of the following: Paget’s disease of the bone; multiple myeloma; metastatic bone disease; chronic renal failure (serum creatinine > 265 µmol/dL); hypercalcemia (serum calcium > 2.75 µmol/dL); any anatomical abnormality of the right foot that would interfere with a calcaneal bone ultrasound, including moderate-severe edema; had had a period of immobilization of more than 3 mo within the previous year; had received therapeutic doses of fluoride (>20 mg/d) for more than 3 mo within the last 2 yr or for more than 2 yr at any time in their lives; had a life expectancy of less than 3 yr in the opinion of their physicians; or were participating in any clinical research program involving investigational drugs. Previous or current therapy with antiresorptive drugs, calcium, or vitamin D was not considered noneligibility criteria.
Sample Size To obtain a 95% confidence interval (precision) of ± 5 percent units in concordance analysis between QUS and DXA for an estimated specificity of approx 80%, the sample size had to be at least 246 women. A total of 267 women agreed to participate and were included in the study. The study was approved by the Ethics Review Board of the Fundació Jordi Gol i Gurina, Barcelona.
Measurements All women completed an osteoporosis and fall risk-factors questionnaire administered by their physician. Height, weight, and body mass index [BMI = weight (Kg)/height2 (m)] were obtained for each individual. Subjects were considered to have a history of a fragility fracture only if the fracture had occurred after the age of 35 and resulted from a fall from standing height or lower, or a minor trauma. Pathologic fractures or those caused by severe trauma, as well as fractures of the skull, face, metacarpals, and phalanges were not considered osteoporotic fractures. QUS measurements were taken at the right calcaneus, and DXA measurements at the hip. BMD of the nondominant femoral neck and the total hip were taken using a Hologic QDR4500 SL™ (Hologic®, Waltham, MA, USA). BMD units were grams per Volume 6, 2003
Bone Ultrasound in Osteoporosis Screening square centimeter; the in vivo coefficient of variation (CV) of femoral neck measurements at our center was 1.65%. BMD measurements were expressed as T- and Z-scores based on the mean and Standard deviation (SD) of the manufacturer’s reference population (V.9.03 C., November 1999). QUS measurements were obtained by a Hologic Sahara Sonometer™ (Hologic®). This device is a portable ultrasound measurement system of the calcaneus using gel as a coupling agent. It has two 19-mm diameter broadband ultrasound transducers with silicone pads mounted coaxially on a motorized caliper. The device measures both broadband ultrasound attenuation (BUA) (dB/MHz) and speed of sound (SOS) (m/s) at the midcalcaneus and the results are combined to provide an estimate of heel BMD with units of grams per square centimeter using the following equation: Estimated Heel BMD = 0.002592*(BUA + SOS) – 3.687 (g/cm2). It is important to note that this parameter is inferred from a linear combination of BUA and SOS and is not an actual measurement of calcaneal BMD. Estimated Heel BMD data were also expressed as Tscore based on the mean and SD of 700 Caucasian females between 20 and 29 yr of age enrolled at 16 clinical centers located across western Europe (14), which constitutes the database provided by the manufacturer for equipment used in Europe. The ultrasound device used in our study also combines BUA and SOS values linearly, into a single parameter called the Quantitative Ultrasound Index (QUI), using the following equation: QUI = 0.41* (BUA + SOS) – 571. QUI has a young adult value of approx 100. Daily quality control was performed with acoustic phantoms provided by the manufacturers. The in vivo coefficients of variation of the instrument were 3, 0.22, 2.6, and 3.7% for Estimated Heel BMD, SOS, QUI, and BUA, respectively (manufacturer’s data).
Statistical Analyses Continuous variables were described with mean and SD, and categorical variables as frequency and percentage. Journal of Clinical Densitometry
239 Agreement between DXA BMD T-score values and the different QUS parameters was analyzed by intraclass correlation coefficients when taken as continuous variables, and by Kappa statistics when categorized. ROC analysis was performed to determine the optimum thresholds of the QUS parameters, taking the femoral neck BMD T-Score < –2.5 as the gold standard to discriminate between nonosteoporotic and osteoporotic women. Likelihood ratios of a positive (LR+) and a negative (LR–) ultrasound test were calculated according to Jaeschke et al. (15) as follows: LR (+) = sensitivity/1 – specificity LR (–) = 1 – sensitivity/specificity Likelihood ratios (LR) were used to determine the optimal threshold cut-off levels to confirm (the first value yielding a LR [+] ≥ 5 for a positive test) and to rule out the disease (first value yielding an LR [–] ≤ 0.2 for a negative test) for BUA, SOS, QUI, Estimated Heel BMD, and its corresponding T-score. This approach offers threshold values for these tests that firmly support a clinical decision to refer a patient for DXA scanning (15). All results for each measured QUS parameter were classified according to their sensitivity, specificity, LR (+), and LR (–).
Results The response rate among eligible women was 92%. Participant women’s age was 72.6 (5.3) yr (mean, SD) and the remaining characteristics are shown in Table 1; 149 women (55.8%) had a femoral neck T-score equal to or less than –2.5. Age-adjusted QUS parameters remained significantly higher (p < 0.001) in women with a femoral neck T-score over –2.5 than those below –2.5, BUA: 66.6 vs 57.9 dB/MHz, SOS: 1.532 vs 1.517 m/s, QUI: 84.1 vs 74.8%. Estimated Heel BMD: 0.456 vs 0.397 g/cm2, and Estimated Heel BMD T-score: –1.11 vs –1.66, respectively. The AUC for each QUS parameter and intraclass correlation coefficients are presented in Table 2. The intraclass correlation coefficient between T-score values of femoral neck BMD and Estimated Heel BMD evaluated by ultrasound was 0.47 (95% confidence interval [CI] 0.37–0.56). Mean femoral neck BMD and Estimated Heel BMD T-scores were –2.58 (SD: 0.99) and –1.42 (SD: 1.03), respectively, with Volume 6, 2003
240
Díez-Pérez et al. Table 1 Characteristics of the 267 Women Who Participated in the Evaluation of the Calcaneal Quantitative Ultrasound in Primary Care as a Tool for Osteoporosis in Postmenopausal Women Femoral Neck T-Score Variable Age (yr) Age at menarche (yr) Age at menopause (yr) Surgical menopause Years of fertility Parity Height (cm) Weight (Kg) Body Mass Index (Kg/m2) Fragility fracture after age ≥ 35 Femoral neck BMD* (g/cm2) Femoral neck T-Score* Femoral neck Z-Score* Total hip BMD (g/cm2)* Total hip T-Score* Total hip Z-Score* BUA (dB/MHz) SOS (m/s) QUI (%) Estimated Heel BMD (g/cm2) Estimated Heel BMD T-Score
Above –2.5 (n = 118)
–2.5 and below (n = 149)
p value
71.3 (4.93) 13.0 (1.80) 49.2 (5.69) 8 (7.3%) 36.0 (5.99) 2.6 (2.19) 154.8 (6.85) 69.4 (9.83) 29.1 (4.57) 19 (16.1%) 0.72 (0.07) –1.70 (0.68) 0.60 (0.73) 0.86 (0.09) –0.98 (080) 0.78 (0.76) 67.8 (16.21) 1534.0 (31.70) 85.3 (18.96) 0.464 (0.12) –1.04 (1.06)
73.6 (5.37) 13.3 (1.76) 47.8 (6.09) 21 (16.0%) 34.8 (6.23) 2.4 (1.90) 152.9 (6.99) 63.5 (10.03) 27.2 (4.14) 44 (29.5%) 0.57 (0.06) –3.30 (0.56) –0.70 (0.68) 0.70 (0.09) –2.30 (0.79) –0.37 (0.75) 56.9 (16.16) 1515.8 (26.79) 73.9 (16.96) 0.390 (0.11) –1.71 (0.94)
< 0.001 0.234 0.177 0.040 0.240 0.546 0.032 < 0.001 < 0.001 0.007
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
Values are the mean (SD). * Not tested for statistical significance (different by design).
Table 2 Areas Under the Curve for Osteoporosis Diagnosed at Femoral Neck According to the WHO Criteria (T-score ≤ –2.5), and Intraclass Correlation Coefficients Between QUS Parameters and Femoral Neck T-score QUS parameter BUA (db/MHZ) SOS (m/s) QUI (%) Estimated Heel BMD (g/cm2) Estimated Heel BMD T-score
Area under the curve
95% confidence interval
Intraclass correlation coefficient (r)
p value
0.678 0.662 0.671 0.672 0.675
0.614–0.743 0.597–0.728 0.606–0.736 0.607–0.737 0.612–0.739
0.45 0.46 0.46 0.46 0.47
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
the mean difference between them being –1.16 (95% CI –1.29 to –1.04). ROC analysis revealed that the best T-score threshold for Estimated Heel BMD measured with the ultrasound machine we used was –1.55. This cutoff value yielded sensitivity and specificity for the Journal of Clinical Densitometry
diagnosis of osteoporosis of 61.1 and 65.3%, respectively (Fig. 1). Positive and negative predictive values (PPV/NPV) were 69 and 57%, respectively. Forty-nine percent of the whole cohort of women was below this cut-off value of –1.55. Table 3 shows the sensitivity, specificity, and kappa values of sevVolume 6, 2003
Bone Ultrasound in Osteoporosis Screening
241
Fig. 1. ROC curve of the Estimated Heel BMD T-score obtained with the Sahara to predict a femoral neck T-score below –2.5. Table 3 Sensitivity, Specificity, and Kappa Values of Different Cut-Off Values of the Estimated Heel BMD T-Score Measured by QUS for the Diagnosis of Osteoporosis According to the WHO Criteria (Femoral Neck T-Score ≤ –2.5) Osteoporosis Cut-off valve ≤ –1.0 ≤ –1.3 ≤ –1.5 ≤ –1.9
Sensitivity
Specificity
Kappa
p value
79.9% 67.8% 63.8% 44.3%
39.8% 52.5% 57.6% 78.0%
0.204 0.205 0.213 0.212
< 0.001 0.001 < 0.001 < 0.001
eral Estimated Heel BMD T-score thresholds previously reported in the literature as the optimum cutoff values for some QUS apparatus, including the Sahara (16–18). The Estimated Heel BMD T-score cut-off point for 90% sensibility at the femoral neck was –0.55 (specificity: 29%). The performance for osteoporosis screening of the different QUS parameters when the positive and negative likelihood ratios are applied is summarized in Table 4. All the parameters provided excellent sensitivities (range: 97–99%) for values above the cut-off levels. On the other hand, specificity was Journal of Clinical Densitometry
very high (range: 94–97%) to confirm a diagnosis of osteoporosis for values below the cut-off levels of all QUS parameters (Table 4). However, the percentage of corroborating DXA measurements that could be avoided by each of these QUS parameters varies, with the Estimated Heel BMD T-score being the parameter that yields the highest percentage of patients excluded for DXA (22.1% of the cases) (Table 4 and Fig. 2). It should be noted that the proposed cut points of the Estimated Heel BMD T-score produce a percentage of false-positive and false-negative of 12.5 and 18.5%, respectively (Table 4). Volume 6, 2003
242
Díez-Pérez et al. Table 4 Performance of the Different QUS Parameters for Osteoporosis Screening
QUS parameter BUA (db/MHz) SOS (m/sec) QUI (%) Estimated Heel BMD (g/cm2) Estimated Heel BMD T-score
No osteoporosis Osteoporosis No osteoporosis Osteoporosis No osteoporosis Osteoporosis No osteoporosis Osteoporosis No osteoporosis Osteoporosis
Cut-off valuea
Sensitivity (%)
Specificity (%)
Likelihood ratiob
Cases CCC/TCCc
95.5 42.0 1579 1490 115.6 60.3 0.650 0.305 + 0.05 –2.5
99 18 98 16 99 21 98 21 97 22
5 97 12 97 9 96 10 97 18 94
0.13 5.28 0.17 5.99 0.14 5.02 0.14 6.34 0.18 5.48
6/7 27/31 14/17 23/26 11/13 32/37 11/13 32/36 22/27 28/32
% of cases excluded for DXA 14.2 16.1 18.7 18.4 22.1
First value yielding a LR (+) ≥ 5 for a positive test, and first value yielding a LR (–) ≤ 0.2 for a negative test. Values above 5 refer to a positive likelihood ratio; values below 0.2 refer to a negative likelihood ratio. c CCC, correctly classified cases; TCC, total classified cases. a b
Fig. 2. Osteoporosis screening workout in our study population using Estimated Heel BMD T-score values. Women are classified as nonosteoporotic (normal or osteopenic), osteoporotic, and uncertain, in whom a DXA measurement should be taken to make an accurate diagnosis. Numbers refer to women classified in each group.
Discussion As the evaluation of bone status by QUS increases, an emerging need exists for guidelines that may help the physician to interpret the results
Journal of Clinical Densitometry
obtained with these new devices. The current recommendations for clinical applications of QUS have been summarized in three areas: diagnosis of osteoporosis, fracture risk prediction, and monitoring of skeletal changes (3). Although it is unlikely that
Volume 6, 2003
Bone Ultrasound in Osteoporosis Screening there will be a place for ultrasound in the monitoring of response to therapy, given the modest effects of current antiresorptives on the appendicular skeleton and the relatively low precision of this technique (19), several prospective studies have clearly demonstrated that heel QUS systems can be used to predict the risk of osteoporotic fractures, with similar performance to that of DXA (5,7–12). The two largest of these studies, EPIDOS and SOF (7,8), reported similar associations between several QUS parameters and hip fracture (approximately a twofold increase in risk for each SD reduction in BUA, SOS, or stiffness). Clear recommendations for fracturerisk assessment will be derived from currently ongoing prospective validation projects such as OPUS (Osteoporosis & Ultrasound Study) (20), or the SEMOF (Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk) Study (13), among others. The usefulness of QUS for screening and diagnosis of osteoporosis has been extensively studied in recent years. It has become increasingly clear that the World Health Organization (WHO) criteria for the diagnosis of osteoporosis based on DXA technology cannot be applied to QUS measurements because both techniques evaluate different physical properties of bone tissue. In our study, if the T-score value of ≤ –2.5 SD were applied to the QUS measurements, only approx 10% of women would be considered osteoporotic. This figure is quite far from the observed osteoporotic prevalence of 55.8% when femoral neck DXA is applied. Thus, several T-score thresholds have been proposed for different QUS parameters and devices using DXA as the method for validation (16–18). In our study, we analyzed the diagnostic performance of five different QUS parameters provided by the Sahara using a ROC analysis approach. Using a T-score threshold of ≤ –1.55 in Estimated Heel BMD, the best diagnostic correlation was observed with the current gold standard diagnostic criteria based on the BMD evaluation at the proximal femur, yielding sensitivity of 61.1% and specificity of 65.3% for the diagnosis of osteoporosis. Moreover, this threshold would classify 49% of women as osteoporotic, a percentage similar to that observed with femoral neck BMD in our study population. This cut-off value lies in the middle of the range published in two different
Journal of Clinical Densitometry
243 studies using this same device: Frost et al. (18) proposed a T-score threshold –1.90 (18), while Ayers et al. (16) found that a T-score ≤ –1.0 has sensitivity of 62% and specificity of 72% for the diagnosis of osteoporosis in a single site study. On the other hand, our proposed threshold is similar to the values for other heel ultrasound devices (17,18). However, for daily practice decision-making and individual patient management, this approach yields too high false-positive and false-negative values (34.0 and 38.9%, respectively) compared with the diagnostic classification by DXA. Given that currently available evidence on therapeutic interventions is based mainly on clinical trials that use DXA values as a criterion, clinicians have not sufficient certainty to support a treatment decision. The linear correlations between hip BMD and heel QUS parameters observed by us (0.45–0.47) are similar to those reported in other studies (16,21), which suggests that these techniques might provide independent information regarding bone tissue characteristics (3,4). In fact, the correlations between heel QUS and hip BMD in our study are comparable to the correlations among different sites obtained by DXA (e.g., peripheral vs spine vs hip). The second aim of our study was to validate this ultrasound device for osteoporosis screening in primary care. A real-life setting in primary care was used to increase the external validity of the study. Standard thresholds for positive and negative likelihood ratios were also applied according to EvidenceBased Medicine (15). This approach follows experts’ recommendations to use bone ultrasounds as a prescreening tool for identifying subjects at highest risk who would undergo further risk assessment using bone densitometry (22) and, from the clinical practitioner perspective, is more informative for the evaluation of an individual patient than the pure mathematical analysis of the correlation of two different diagnostic techniques or classification based on ROC analysis. Calculation of likelihood ratios permits cut-off values to be obtained that are meaningful for the clinician and useful for supporting a decision in the individual case. According to our findings, when the result is above +0.05 SD from the Estimated Heel BMD T-score, there is no call for additional more complicated, expensive, and frequently nonreimbursed diagnostic techniques. If the
Volume 6, 2003
244 value is below –2.50, the high probability of osteoporosis is high and no further examinations are required. By using these cut-off points, 22.1% of DXA measurements might be avoided with enough confidence in the decision made by the general practitioner, using the Estimated Heel BMD T-score, which proved to be the most discriminating diagnostic parameter in our study. This relatively low value should be considered in the context of the female population included in the study, in which a mass screening strategy was adopted, i.e., asymptomatic individuals regardless of their risk of osteoporosis who agreed to participate instead of a case-finding approach for individuals at increased risk for the disease. It seems obvious that if QUS measurements are combined with clinical risk factors for osteoporosis and future fracture, the effectiveness of the technique as a screening tool will be substantially improved. Nevertheless, for public health care systems, to decrease the need for referral of patients for a DXA examination by one-fifth represents significant cost saving, at least with our national cost for these diagnostic techniques (23). It should be also taken into account that only one-fourth of the family physicians working for the National Health System in Spain could request a bone densitometry according to a recent national surveillance (24). Nevertheless, this approach may be not applicable in geographies and health systems where DXA equipments are widely and easily available both for screening and monitoring purposes. For instance, the screening strategy we propose would not be cost-effective if a baseline DXA for monitoring BMD changes will be indicated in those patients who are –2.5 or below with heel QUS. It could also be argued that the false-positive cases that we have observed with the proposed cutoff threshold (4 out of 32 cases) would make universal DXA screening a more cost-effective approach than to treat these false-positive patients. One limitation of our study is that it refers to a population in Spain, and its applicability to other geographical areas needs to be confirmed. The study evaluated older women with a high prevalence of osteoporosis, and the thresholds and cutoffs may not apply to younger women or those with less bone density. Women attending the physician’s office also constitute the study participants and this could rep-
Journal of Clinical Densitometry
Díez-Pérez et al. resent a bias towards cases with higher incidence of the disease. However, given that these are the reallife conditions in the everyday practice in a primarycare setting, this factor might improve the external validity of our results. On the other hand, our results support Estimated Heel BMD T-score as the best predictor of fracture risk of measurements obtained with this device, including BUA, SOS, and QUI. In summary, QUS can be used as a screening tool in elderly postmenopausal women. With this technique, 22% of the population screened can be safely excluded for DXA, thereby supporting a clinical decision and avoiding referrals for DXA measurements. Wider and more efficient management of osteoporosis might therefore be achieved by introducing QUS as a first-line screening tool.
Acknowledgments The authors thank Dr. Jaume Marrugat for the Institut Municipal d’Investigació Mèdica, and the Universitat Autónoma, Barcelona, for his valuable comments on the design of the study, suggestions on the statistical analysis, and extensive contributions to interpretation of the results and preparation of the manuscript. The authors are very grateful to the women who participated in this study. We also thank Angel Pérez-Romero and Elena Arriaza, Medical Research Department, Eli Lilly and Company, Spain, for coordinating the study. This research was supported by a Grant of the Medical Research Department, Eli Lilly and Company, Spain.
References 1. Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N. 1994 The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141. 2. Siris ES, Miller PD, Barrett-Connor E, et al. 2001 Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women. Results from the National Osteoporosis Risk Assessment. JAMA 286:2815–2822. 3. Glüer C.C. 1997 Quantitative ultrasound techniques for the assessment of osteoporosis: expert agreement on current status. J Bone Miner Res 12:1280–1288. 4. Bouxsein ML, Radloff SE. 1997. Quantitative ultrasound of the calcaneous reflects the mechanical properties of calcaneal trabecular bone. J Bone Miner Res 12: 839–846. 5. Porter RW, Miller CG, Grainger D, Palmer SB. 1990 Prediction of hip fracture in elderly women: a prospective study. Br Med J 310:638–641.
Volume 6, 2003
Bone Ultrasound in Osteoporosis Screening 6. Heaney RP, Avioli LV, Chesnut CH III, Lappe J, Recker RR, Branderburger GH. 1995 Ultrasound velocity through bone predicts incident vertebral deformity. J Bone Miner Res 10:341–345. 7. Hans D, Dargent-Molina P, Schott AM, et al. 1996 Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study. Lancet 348:511–514. 8. Bauer DC, Glüer CC, Cauley JA, et al. 1997 Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Arch Inter Med 157:629–634. 9. Huang C, Ross PD, Yates AJ, et al. 1998 Prediction of fracture risk by radiographic absorptiometry and quantitative ultrasound: a prospective study. Calcif Tissue Inter 63:380–384. 10. Thompson PW, Taylor J, Oliver R, Fisher A. 1998 Quantitative ultrasound (QUS) of the heel predicts wrist and osteoporosis-related fractures in women age 45–75 years. J Clin Densitom 1:219–225. 11. Pluijm SMF, Graafmans WC, Bouter LM, Lips P. 1999 Ultrasound measurements for the prediction of osteoporotic fractures in elderly people. Osteoporos Int 9:550–556. 12. Gnudi S, Ripamonti C, Malavolta N. 2000 Quantitative ultrasound and bone densitometry to evaluate the risk of nonspine fractures: a prospective study. Osteoporos Int 11:518–523. 13. Cornuz J, Krieg MA, Burckhardt P. 2002 Comparison of 3 bone ultrasounds for determining hip fracture risk in 7494 elderly women: the SEMOF study. Osteoporos Int 13(Suppl 1):S9-S10. 14. von Stetten, Ouellet H, Wilson KE, Stein JA. 1998 European Caucasian female reference data values for the Sahara clinical bone sonometer. Bone 23(Suppl 5):S637. 15. Jaeschke R, Guyatt G, Lijmer J. 2002 Diagnostic tests. In: User’s Guide to the Medical Literature. A Manual for Evidence-Based Clinical Practice. Guyatt G, Rennie D,
Journal of Clinical Densitometry
245
16.
17.
18.
19.
20.
21.
22.
23.
24.
Hayward R, eds. JAMA & Archives Journals, AMA Press, Atlanta, GA, 187–217. Ayers M, Prince M, Ahmadi S, Baran DT. 2000 Reconciling quantitative ultrasound of the calcaneus with X-ray-based measurements of the central skeleton. J Bone Miner Res 15:1850–1855. Damilakis J, Pesinakis K, Gourtsoyiannis N. 2001 Imaging ultrasonometry of the calcaneus: optimum T-score thresholds for the identification of osteoporotic subjects. Calcif Tissue Int 68:219–224. Frost ML, Blake GM, Fogelman I. 2000 Can the WHO criteria for diagnosing osteoporosis be applied to calcaneal quantitative ultrasound? Osteoporos Int 11:321–330. Roux C, Giorgino R. 1999 Quantitative ultrasound for monitoring bone changes. In: Quantitative Ultrasound: Assessment of Osteoporosis and Bone Status. Njeh CF, Hans D, Fuerst T, Glüer CC, Genant HK, eds. Martin Dunitz Ltd; London, 299–307. Glüer CC, Eastell R, Reid DM, et al. 2001 Association of quantitative ultrasound parameters and bone density with osteoporotic vertebral deformities in a population based sample: The OPUS Study. J Bone Miner Res 16(Suppl 1):S196. He YQ, Hans D, Li J, et al. 2000 Assessment of a new quantitative ultrasound calcaneus measurement: precision and discrimination of hip fractures in elderly women compared with dual x-ray absorptiometry. Osteoporos Int 11:354–360. Glüer CC, Hans D. 1999 How to use ultrasound for risk assessment: a need for defining strategies. Osteoporos Int 9:193–195. Marín F, Sacristán JA, Díez-Pérez A, et al. 2002 Cost-effectiveness analysis of referral for DXA using QUS as a prescreen tool in posmenopausal women. Osteoporos Int 13(Suppl 3):S46. Aragonès R, Orozco P. 2002 Abordaje de la osteoporosis en la atención primaria en España (estudio ABOPAP-2000). Aten Primaria 30:350–356.
Volume 6, 2003
