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Instant Vertebral Assessment
Journal of Clinical Densitometry, vol. 4, no. 4, 373–380, Winter 2001 © Copyright 2001 by Humana Press Inc. All rights of any nature whatsoever reserved. 1094-6950/01/4:373–380/$12.00
Original Article
Instant Vertebral Assessment A Noninvasive Dual X-ray Absorptiometry Technique to Avoid Misclassification and Clinical Mismanagement of Osteoporosis
Susan L. Greenspan, MD,1,2 Eric von Stetten, PHD,3 Sarah K. Emond, BA,4 Lisa Jones, BS, CNMT,3 and Robert A. Parker, ScD2,5 1University
of Pittsburgh Medical Center, Pittsburgh, PA; 2Charles A. Dana Research Institute, Harvard-Thorndike General Clinical Research Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; 3Hologic, Bedford, MA; 4Feinstein Kean Healthcare, Cambridge, MA; and 5Biometrics Center, Beth Israel Deaconess Medical Center, Boston, MA
Abstract The presence of a vertebral fracture significantly increases the risk of future fracture, classifies a patient with “clinical” osteoporosis, and usually results in treatment for osteoporosis. However, the majority of vertebral fractures are silent, and lateral X-rays (the standard method for identification) are not routinely obtained. Instant vertebral assessment (IVA), a technology that utilizes dual X-ray absorptiometry (DXA), provides rapid assessment of vertebral fractures and is highly correlated with vertebral fractures, as assessed on standard lateral spine X-rays. To assess the role of IVA in patient management, we examined standard bone mineral density, (BMD) of the spine, total hip, and femoral neck and spine IVA by DXA in 482 participants screened for an osteoporosis study, who had no previous knowledge of vertebral fractures. Using World Health Organization (WHO) guidelines, subjects were classified using BMD at the spine, total hip, femoral neck, or any combination of these central sites. In addition, we considered subjects as osteoporotic if they had vertebral fractures independent of low bone density. We found that vertebral fractures assessed by IVA were present in 18.3% of asymptomatic postmenopausal women recruited for this study. The sensitivity of BMD alone to diagnose osteoporosis based on either a vertebral fracture or low BMD using WHO criteria ranged from 40 to 74%. This means that between 26 and 60% of osteoporotic individuals could have potentially been missed. Furthermore, 11.0–18.7% of clinically osteoporotic individuals would have been classified as normal by BMD criteria alone. We conclude that IVA is a useful adjunct in the clinical identification of osteoporosis and may prevent mismanagement of osteoporotic patients. Key Words: Instant vertebral assessment; osteoporosis; vertebral fractures.
Introduction
Received 03/01/00; Revised 04/19/00; Accepted 04/24/01. Address correspondence to Dr. Susan L. Greenspan, Professor of Medicine, University of Pittsburgh Medical Center, Osteoporosis Prevention and Treatment Center, Lilliane S. Kaufmann Medical Building, Suite 1110, 3471 Fifth Avenue, Pittsburgh, PA 15213. [email protected].
Although osteoporosis is a common and costly problem (1–3), there are noninvasive, accurate techniques for the assessment of low bone mass—the risk factor that has one of the strongest associations with
373
374 fracture risk (4–8). However, in addition to bone mass, the combination of other risk factors, including a previous vertebral fracture, significantly increases the risk of developing a future fracture (5,9,10). Specifically, a vertebral fracture increases the risk of a new fracture up to fourfold (10–13), thereby changing the patient’s therapeutic management. Moreover, the presence of a vertebral fracture is associated with increased back pain (14–16), decreased mobility, increased days of bed rest, decreased time at work (16), depression (17,18), and higher rates of hospitalization and mortality (19,20). Therefore, a vertebral fracture has a significant clinical impact. Approximately two-thirds to three-quarters of vertebral fractures are asymptomatic (21,22). Diagnosis of an asymptomatic vertebral fracture is rare in clinical practice. Making such a diagnosis would require ordering lateral vertebral X-rays, which would increase the expense and radiation exposure for the patient and often requires measurement at a different facility (23–25). Recently, instant vertebral assessment (IVA) has become available (Hologic, Bedford, MA) (25). This technology utilizes dual X-ray absorptiometry (DXA) (25–30) to provide rapid assessment of vertebral fractures. Rea et al. (31) have previously reported a strong agreement between the visual interpretation of these IVA images and standard vertebral X-rays in classifying a vertebra as normal or deformed (96.3% agreement, kappa score = 0.79). When quantitative assessment is used with the DXA image (also known as morphometric X-ray absorptiometry), the agreement with standard radiologic assessment may be better in an osteoporotic population (32,33). We postulated that performing IVA immediately following bone mineral density (BMD) examination would increase the prevalence of a diagnosis of osteoporosis in patients being screened for the disease, thereby decreasing the misclassification and potential mismanagement of patients with unknown baseline vertebral deformities. To examine this, we assessed BMD of the spine and hip by DXA and vertebral fractures using IVA of T4–L4 in postmenopausal women.
Materials and Methods Subjects Ambulatory, community-dwelling, postmenopausal women age 65 and older were recruited for an Journal of Clinical Densitometry
Greenspan et al. osteoporosis prevention and treatment trial. Women were ineligible for the study if they had any history of illness or medication use known to affect bone mineral metabolism. Other exclusion criteria included a contraindication for hormone replacement therapy or alendronate (the medications used in the trial) and a baseline hip BMD of 0.900 g/cm2 or higher. The study was approved by the Committee on Clinical Investigations, New Devices, and New Forms of Therapy at Beth Israel Deaconess Medical Center in Boston, MA. All potential participants were advised of the nature of the study and written informed consent was obtained. Five hundred seventy-two women signed informed consent and were screened for participation in this trial between January 1996 and December 1997. In this cross-sectional study, 482 women stated that they had no prior knowledge of vertebral fractures, and they were included in the analysis.
Outcome Variables BMD of the nondominant hip (total hip, femoral neck) and PA spine (L1–L4) was measured by DXA using a QDR-4500A bone densitometer (Hologic) located in the General Clinical Research Center at the Beth Israel Deaconess Medical Center in Boston, MA. Measurements were obtained and analyzed using standard protocols as provided by the manufacturer. We have previously reported that the coefficient of variation in postmenopausal women at our center is 1.5% for the PA spine, 1.2% for the total hip, and 1.9% for the femoral neck (34). If the subject had a previous hip fracture, that site was not included in the analysis. A diagnosis of osteoporosis was based on the World Health Organization (WHO) criteria: normal (T-score of –1.0 SD and above young adult peak bone mass), osteopenia (T-score between –1.0 and –2.5 SDs), and osteoporosis (T-score of –2.5 and below) (35,36) using the National Health and Nutrition Examination Survey (NHANES) III database for the hip (37). The skeletal sites of the PA spine, femoral neck, and total hip were utilized as suggested by the clinical practice recommendations of the International Society for Clinical Densitometry (ISCD) (38). IVA was performed through lateral spine imaging of T4–L4 on the Hologic QDR-4500A. Using the IVA technique, a single image of the full spine Volume 4, 2001
IVA for Osteoporosis Classification (L4–T4) is acquired with the patient in a supine position. The resulting electronic image is reviewed on the monitor, where brightness and contrast can be adjusted to maximize visibility of vertebral bodies. Previous studies have shown that visualization of vertebral bodies is excellent using this technique, with 93% of patients visualized up to T6 (29). Visual assessment of vertebral fractures was performed by an investigator blinded to subject data. Fractures were classified if visual inspection indicated a reduction in vertebral height (anterior, posterior, or middle) of 20–25% or more (23,31).
375 Table 1 Clinical Characteristics Clinical characteristic (mean ± SD) n Age (yr) Height (m) Weight (kg) BMI (kg/m2) Calcium intake (mg/d) Vitamin D intake (IU/d)
482 72 ± 5 159 ± 6.5 70 ± 16 27.6 ± 5.6 890 ± 446 257 ± 225
Clinical Characteristics Height was measured to the nearest millimeter using a Harpenden Stadiometer (Holtain, Crymych, Dyfed, UK), and weight was measured by an ACME Digital In-bed Scale (Model 0501; ACME Medical Scale, San Liandro, CA). Body mass index (BMI) was calculated as kilograms/square meter. We assessed calcium and vitamin D intake with a food frequency questionnaire and medication history.
Statistical Analyses Data are summarized as mean ± SD. The “gold standard” for osteoporosis is defined as either low BMD or vertebral fracture. As such, the specificity is 100% for each criterion separately. Comparison of BMD in subjects with and without fractures was done using a Wilcoxon rank sum test. The MantelHaenszel test for trend was used to assess the trend in fracture rates by BMD classification.
Results Clinical Characteristics The mean age of the 482 participants was 72 ± 5 yr. Average dietary intake of calcium and vitamin D was 890 mg/d and 257 IU/d, respectively (Table 1). Of these asymptomatic patients, 18.3% had vertebral fractures as determined by IVA. The percentage of subjects with vertebral fractures in each BMD classification category is given in Table 2. Depending on the number of sites used for classification of osteoporosis (spine only, total hip only, femoral neck only, or any combination of these central sites), the proportion of osteoporotic subjects with vertebral fractures ranged from 19.0 to 25.5%. Between 11.0 and 18.7% of subjects classified as Journal of Clinical Densitometry
normal based on their BMD classification (depending on the number of sites chosen) had asymptomatic vertebral fractures. There was a significant trend in the proportion of patients with a vertebral fracture when subjects were classified by BMD at the femoral neck (p = 0.03), with fracture rate higher in osteoporotic patients. Although similar trends were observed when subjects were classified by BMD at the total hip or at any central sites, these trends were not significant (Table 2). The prevalence of osteoporosis varied considerably when BMD alone was used to make the classification vs when vertebral fracture was added to the BMD classification (i.e., true classification). For example, 10.6% of women were classified as osteoporotic based on total hip BMD; however, when vertebral fracture was taken into account, the diagnosis increased to 26.1% (Table 3). When spine BMD was examined, 25.1% of women were classified as having osteoporosis. This increased to 38.6% when vertebral fractures and BMD were used for the classification (Table 3). Overall, the sensitivity of BMD alone to diagnose osteoporosis based on either a vertebral fracture or low BMD ranged from 40 to 74%, so that between 26 and 60% of osteoporotic patients could potentially be missed (Table 3). There was no significant difference in BMD at the spine or femoral neck in subjects with and without vertebral fractures (Fig. 1). However, BMD was significantly lower (p < 0.05) at the total hip in subjects with a vertebral fracture.
Discussion We found that vertebral fractures assessed by IVA were present in 18.3% of asymptomatic, postVolume 4, 2001
376
Greenspan et al. Table 2 Percentage of Patients with Vertebral Fractures by WHO BMD Classification Criteria
BMD classification Osteoporosis Osteopenia Normala Test for trend (p values) a
Spine only 19.0 17.3 18.7 >0.50
Total Hip only
Femoral neck only
Any central site BMD
25.5 18.4 16.2 >0.10
22.5 19.7 11.0 0.03
21.6 17.9 12.8 >0.10
These patients would be classified as normal when they should be managed as if they had osteoporosis.
Table 3 Prevalence of Osteoporosis by WHO BMD Classification and Sensitivity of BMD Alone Spine only BMD with vertebral fracture (true classification) Osteoporosis 38.6 Osteopenia 30.7 Normal 30.7 BMD alone Osteoporosis 25.1 Osteopenia 37.1 Normal 37.8 Sensitivity of BMD alone 65.1
Fig. 1.
Total hip only
Femoral neck only
Any central site BMD
26.1 39.6 34.2
32.7 47.3 20.1
43.2 42.7 14.1
10.6 48.5 40.9 40.5
18.5 58.9 22.6 56.7
31.7 52.1 16.2 73.6
BMD (g/cm2) of spine, total hip, and femoral neck in women with and without vertebral fractures; *p < 0.05.
Journal of Clinical Densitometry
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IVA for Osteoporosis Classification menopausal women who were recruited for this study. The sensitivity of BMD alone to diagnose osteoporosis based on either a vertebral fracture or low BMD using WHO criteria ranged from 40 to 74%. This means that between 26 and 60% of osteoporotic patients could potentially be missed. Furthermore, 11.0–18.7% of clinically osteoporotic patients would have been classified as normal by BMD alone. This study agrees with the study by Jones et al. (39), who performed standard spinal radiographs and DXA of the spine and hip in a sample of 187 elderly women age 60 and older participating in the Dubbo Osteoporosis Epidemiology study. The investigators found that vertebral deformities were present in 12–25% of women depending on the criteria used for vertebral deformity. In addition, they found that femoral neck BMD was superior to spine BMD in its association with vertebral deformity owing to the presence of false positive increases in spine BMD from degenerative joint disease of the spine. There are several advantages to our study. First, both DXA and IVA were performed by the same technologist during the same visit to eliminate the potential of a fracture occurring after the DXA was performed. Second, we used the diagnosis of osteoporosis classification based on WHO cutoff points (35,36) and used a single central skeletal site or multiple central skeletal sites for analysis as suggested by the ISCD (38). This organization suggests that the lowest BMD be used to classify and manage the patient’s disease. Finally, the study focused on women age 65 and older—the group with the highest fracture potential. The National Osteoporosis Foundation recommends that women age 65 and older have a BMD assessment regardless of risk factors (40). This is a clinically and economically relevant group to evaluate, since DXA for women in this age bracket is currently covered by the Health Care Finance Agency (41). Our study also has several limitations. First, our results could be biased because the subjects were volunteers for an osteoporosis prevention and treatment clinical trial, and this may not be representative of the community at large. In addition, the results may not be applicable to premenopausal or minority women (the study population was primarily Caucasian). Second, the low spatial resolution and
Journal of Clinical Densitometry
377 high noise level of IVA limit visualization compared with the high resolution of standard lateral vertebral X-rays. Third, it is possible that using a 20% reduction in vertebral height to diagnose a vertebral fracture may not be appropriate for IVA (31). However, these criteria were previously utilized by Rea (31), who found high correlation between readings from IVA and radiographs performed on the same patients, using the same semiquantitative criteria. Although we have included “asymptomatic” vertebral fractures, nonclinical vertebral fractures may be associated with mild back disability or back pain, both of which are common in this population. Finally, we used the WHO classification based on the reference database provided by the densitometer’s manufacturer. The results could be different if we had enrolled our own young normal subjects and established our own normative database to determine the true T-scores of these older women. However, our primary objective was to determine the number of fractures that could be missed in clinical practice. Therefore, we wanted to utilize the manufacturer’s database available in clinical practice so that our findings would be more relevant to physicians practicing in the community. Although there is no “gold standard” for identification of a vertebral fracture using IVA, there is controversy about the most appropriate analysis for vertebral fractures, for which standard lateral radiographs are used (42–44). For the present study, we used a semiquantitative approach with a visual reduction in height of 20–25%. This would identify mild to severe prevalent fractures (23,31). This semiquantitative approach, often used in clinical practice (31), classifies grades of deformities (grade 1 is mild with 20–25% height reduction, grade 2 is moderate with 25–40% reduction, and grade 3 is severe with ≥40% reduction) and describes the deformities (crush, wedge, end plate). There are additional benefits to the use of radiographs. An expert radiologist can identify discontinuities of end plates as evidence of a vertebral deformity, which would be missed by IVA. Furthermore, radiographs can distinguish processes other than osteoporosis, which IVA would label as a deformity. Finally, IVA visualization of vertebrae above T7 is more difficult, whereas a lateral thoracic X-ray examines the entire thoracic spine.
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378 Our study revealed that 11.0–18.7% of normal subjects diagnosed by WHO criteria had vertebral fractures assessed by IVA. Patients with a classification of “normal” BMD often would be counseled with preventive measures, such as calcium and vitamin D supplementation, exercise, and elimination of smoking and excess alcohol (40). However, patients with normal BMD and a vertebral fracture deserve a work-up to determine the etiology of the fracture. Ross et al. (a) showed that patients with high BMD and a fracture are actually at higher risk for subsequent fracture than those with low BMD and no fracture. Such patients may also have a high rate of bone resorption, subclinical vitamin D deficiency, a secondary cause increasing bone turnover that could lead to skeletal fragility and fractures, or perhaps may represent a genetic subset with an increased fracture risk. Furthermore, patients with vertebral fractures have clinical osteoporosis and deserve therapy directed at treatment rather than general preventive measures. In summary, IVA is a quick, noninvasive, lowradiation technique that identifies women with vertebral fractures during BMD examinations. Such techniques provide important information that could alter physicians’ work-ups and clinical management, for the up to 19% of women who could potentially be misclassified owing to normal BMD results. Overall, even if we classified patients with osteoporosis using the most restrictive clinical guidelines of a T-score < –2.5 SDs below mean at any one of three clinical sites, 26% of patients with “clinical osteoporosis” would have been missed without vertebral assessment. Since therapies are available to successfully treat patients with vertebral fractures (45–47) and several bisphosphonates have been shown to reduce vertebral fractures significantly in 1 yr (47,48), this type of clinical information is valuable. Future studies are needed to investigate skeletal fragility and pathophysiology in women with normal BMD and silent vertebral fractures.
Acknowledgments We gratefully acknowledge the nursing and nutrition support of the Harvard-thorndike General Clinical Research Center at Beth Israel Deaconess Journal of Clinical Densitometry
Greenspan et al. Medical Center in Boston, the bone mineral densitometry technical support from Judith Oakley, and assistance with preparation of the manuscript from Dawn Griffiths. This study was supported in part by grant no. M01-RR01032 from the National Institutes of Health to the Beth Israel Deaconess Medical Center General Clinical Research Center.
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380 from a 3-year randomized clinical trial. JAMA 282: 637–645. 47. Harris ST, Watts NB, Genant HK, et al., for the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. 1999 Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteo-
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Volume 4, 2001
Original Article
Instant Vertebral Assessment A Noninvasive Dual X-ray Absorptiometry Technique to Avoid Misclassification and Clinical Mismanagement of Osteoporosis
Susan L. Greenspan, MD,1,2 Eric von Stetten, PHD,3 Sarah K. Emond, BA,4 Lisa Jones, BS, CNMT,3 and Robert A. Parker, ScD2,5 1University
of Pittsburgh Medical Center, Pittsburgh, PA; 2Charles A. Dana Research Institute, Harvard-Thorndike General Clinical Research Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; 3Hologic, Bedford, MA; 4Feinstein Kean Healthcare, Cambridge, MA; and 5Biometrics Center, Beth Israel Deaconess Medical Center, Boston, MA
Abstract The presence of a vertebral fracture significantly increases the risk of future fracture, classifies a patient with “clinical” osteoporosis, and usually results in treatment for osteoporosis. However, the majority of vertebral fractures are silent, and lateral X-rays (the standard method for identification) are not routinely obtained. Instant vertebral assessment (IVA), a technology that utilizes dual X-ray absorptiometry (DXA), provides rapid assessment of vertebral fractures and is highly correlated with vertebral fractures, as assessed on standard lateral spine X-rays. To assess the role of IVA in patient management, we examined standard bone mineral density, (BMD) of the spine, total hip, and femoral neck and spine IVA by DXA in 482 participants screened for an osteoporosis study, who had no previous knowledge of vertebral fractures. Using World Health Organization (WHO) guidelines, subjects were classified using BMD at the spine, total hip, femoral neck, or any combination of these central sites. In addition, we considered subjects as osteoporotic if they had vertebral fractures independent of low bone density. We found that vertebral fractures assessed by IVA were present in 18.3% of asymptomatic postmenopausal women recruited for this study. The sensitivity of BMD alone to diagnose osteoporosis based on either a vertebral fracture or low BMD using WHO criteria ranged from 40 to 74%. This means that between 26 and 60% of osteoporotic individuals could have potentially been missed. Furthermore, 11.0–18.7% of clinically osteoporotic individuals would have been classified as normal by BMD criteria alone. We conclude that IVA is a useful adjunct in the clinical identification of osteoporosis and may prevent mismanagement of osteoporotic patients. Key Words: Instant vertebral assessment; osteoporosis; vertebral fractures.
Introduction
Received 03/01/00; Revised 04/19/00; Accepted 04/24/01. Address correspondence to Dr. Susan L. Greenspan, Professor of Medicine, University of Pittsburgh Medical Center, Osteoporosis Prevention and Treatment Center, Lilliane S. Kaufmann Medical Building, Suite 1110, 3471 Fifth Avenue, Pittsburgh, PA 15213. [email protected].
Although osteoporosis is a common and costly problem (1–3), there are noninvasive, accurate techniques for the assessment of low bone mass—the risk factor that has one of the strongest associations with
373
374 fracture risk (4–8). However, in addition to bone mass, the combination of other risk factors, including a previous vertebral fracture, significantly increases the risk of developing a future fracture (5,9,10). Specifically, a vertebral fracture increases the risk of a new fracture up to fourfold (10–13), thereby changing the patient’s therapeutic management. Moreover, the presence of a vertebral fracture is associated with increased back pain (14–16), decreased mobility, increased days of bed rest, decreased time at work (16), depression (17,18), and higher rates of hospitalization and mortality (19,20). Therefore, a vertebral fracture has a significant clinical impact. Approximately two-thirds to three-quarters of vertebral fractures are asymptomatic (21,22). Diagnosis of an asymptomatic vertebral fracture is rare in clinical practice. Making such a diagnosis would require ordering lateral vertebral X-rays, which would increase the expense and radiation exposure for the patient and often requires measurement at a different facility (23–25). Recently, instant vertebral assessment (IVA) has become available (Hologic, Bedford, MA) (25). This technology utilizes dual X-ray absorptiometry (DXA) (25–30) to provide rapid assessment of vertebral fractures. Rea et al. (31) have previously reported a strong agreement between the visual interpretation of these IVA images and standard vertebral X-rays in classifying a vertebra as normal or deformed (96.3% agreement, kappa score = 0.79). When quantitative assessment is used with the DXA image (also known as morphometric X-ray absorptiometry), the agreement with standard radiologic assessment may be better in an osteoporotic population (32,33). We postulated that performing IVA immediately following bone mineral density (BMD) examination would increase the prevalence of a diagnosis of osteoporosis in patients being screened for the disease, thereby decreasing the misclassification and potential mismanagement of patients with unknown baseline vertebral deformities. To examine this, we assessed BMD of the spine and hip by DXA and vertebral fractures using IVA of T4–L4 in postmenopausal women.
Materials and Methods Subjects Ambulatory, community-dwelling, postmenopausal women age 65 and older were recruited for an Journal of Clinical Densitometry
Greenspan et al. osteoporosis prevention and treatment trial. Women were ineligible for the study if they had any history of illness or medication use known to affect bone mineral metabolism. Other exclusion criteria included a contraindication for hormone replacement therapy or alendronate (the medications used in the trial) and a baseline hip BMD of 0.900 g/cm2 or higher. The study was approved by the Committee on Clinical Investigations, New Devices, and New Forms of Therapy at Beth Israel Deaconess Medical Center in Boston, MA. All potential participants were advised of the nature of the study and written informed consent was obtained. Five hundred seventy-two women signed informed consent and were screened for participation in this trial between January 1996 and December 1997. In this cross-sectional study, 482 women stated that they had no prior knowledge of vertebral fractures, and they were included in the analysis.
Outcome Variables BMD of the nondominant hip (total hip, femoral neck) and PA spine (L1–L4) was measured by DXA using a QDR-4500A bone densitometer (Hologic) located in the General Clinical Research Center at the Beth Israel Deaconess Medical Center in Boston, MA. Measurements were obtained and analyzed using standard protocols as provided by the manufacturer. We have previously reported that the coefficient of variation in postmenopausal women at our center is 1.5% for the PA spine, 1.2% for the total hip, and 1.9% for the femoral neck (34). If the subject had a previous hip fracture, that site was not included in the analysis. A diagnosis of osteoporosis was based on the World Health Organization (WHO) criteria: normal (T-score of –1.0 SD and above young adult peak bone mass), osteopenia (T-score between –1.0 and –2.5 SDs), and osteoporosis (T-score of –2.5 and below) (35,36) using the National Health and Nutrition Examination Survey (NHANES) III database for the hip (37). The skeletal sites of the PA spine, femoral neck, and total hip were utilized as suggested by the clinical practice recommendations of the International Society for Clinical Densitometry (ISCD) (38). IVA was performed through lateral spine imaging of T4–L4 on the Hologic QDR-4500A. Using the IVA technique, a single image of the full spine Volume 4, 2001
IVA for Osteoporosis Classification (L4–T4) is acquired with the patient in a supine position. The resulting electronic image is reviewed on the monitor, where brightness and contrast can be adjusted to maximize visibility of vertebral bodies. Previous studies have shown that visualization of vertebral bodies is excellent using this technique, with 93% of patients visualized up to T6 (29). Visual assessment of vertebral fractures was performed by an investigator blinded to subject data. Fractures were classified if visual inspection indicated a reduction in vertebral height (anterior, posterior, or middle) of 20–25% or more (23,31).
375 Table 1 Clinical Characteristics Clinical characteristic (mean ± SD) n Age (yr) Height (m) Weight (kg) BMI (kg/m2) Calcium intake (mg/d) Vitamin D intake (IU/d)
482 72 ± 5 159 ± 6.5 70 ± 16 27.6 ± 5.6 890 ± 446 257 ± 225
Clinical Characteristics Height was measured to the nearest millimeter using a Harpenden Stadiometer (Holtain, Crymych, Dyfed, UK), and weight was measured by an ACME Digital In-bed Scale (Model 0501; ACME Medical Scale, San Liandro, CA). Body mass index (BMI) was calculated as kilograms/square meter. We assessed calcium and vitamin D intake with a food frequency questionnaire and medication history.
Statistical Analyses Data are summarized as mean ± SD. The “gold standard” for osteoporosis is defined as either low BMD or vertebral fracture. As such, the specificity is 100% for each criterion separately. Comparison of BMD in subjects with and without fractures was done using a Wilcoxon rank sum test. The MantelHaenszel test for trend was used to assess the trend in fracture rates by BMD classification.
Results Clinical Characteristics The mean age of the 482 participants was 72 ± 5 yr. Average dietary intake of calcium and vitamin D was 890 mg/d and 257 IU/d, respectively (Table 1). Of these asymptomatic patients, 18.3% had vertebral fractures as determined by IVA. The percentage of subjects with vertebral fractures in each BMD classification category is given in Table 2. Depending on the number of sites used for classification of osteoporosis (spine only, total hip only, femoral neck only, or any combination of these central sites), the proportion of osteoporotic subjects with vertebral fractures ranged from 19.0 to 25.5%. Between 11.0 and 18.7% of subjects classified as Journal of Clinical Densitometry
normal based on their BMD classification (depending on the number of sites chosen) had asymptomatic vertebral fractures. There was a significant trend in the proportion of patients with a vertebral fracture when subjects were classified by BMD at the femoral neck (p = 0.03), with fracture rate higher in osteoporotic patients. Although similar trends were observed when subjects were classified by BMD at the total hip or at any central sites, these trends were not significant (Table 2). The prevalence of osteoporosis varied considerably when BMD alone was used to make the classification vs when vertebral fracture was added to the BMD classification (i.e., true classification). For example, 10.6% of women were classified as osteoporotic based on total hip BMD; however, when vertebral fracture was taken into account, the diagnosis increased to 26.1% (Table 3). When spine BMD was examined, 25.1% of women were classified as having osteoporosis. This increased to 38.6% when vertebral fractures and BMD were used for the classification (Table 3). Overall, the sensitivity of BMD alone to diagnose osteoporosis based on either a vertebral fracture or low BMD ranged from 40 to 74%, so that between 26 and 60% of osteoporotic patients could potentially be missed (Table 3). There was no significant difference in BMD at the spine or femoral neck in subjects with and without vertebral fractures (Fig. 1). However, BMD was significantly lower (p < 0.05) at the total hip in subjects with a vertebral fracture.
Discussion We found that vertebral fractures assessed by IVA were present in 18.3% of asymptomatic, postVolume 4, 2001
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Greenspan et al. Table 2 Percentage of Patients with Vertebral Fractures by WHO BMD Classification Criteria
BMD classification Osteoporosis Osteopenia Normala Test for trend (p values) a
Spine only 19.0 17.3 18.7 >0.50
Total Hip only
Femoral neck only
Any central site BMD
25.5 18.4 16.2 >0.10
22.5 19.7 11.0 0.03
21.6 17.9 12.8 >0.10
These patients would be classified as normal when they should be managed as if they had osteoporosis.
Table 3 Prevalence of Osteoporosis by WHO BMD Classification and Sensitivity of BMD Alone Spine only BMD with vertebral fracture (true classification) Osteoporosis 38.6 Osteopenia 30.7 Normal 30.7 BMD alone Osteoporosis 25.1 Osteopenia 37.1 Normal 37.8 Sensitivity of BMD alone 65.1
Fig. 1.
Total hip only
Femoral neck only
Any central site BMD
26.1 39.6 34.2
32.7 47.3 20.1
43.2 42.7 14.1
10.6 48.5 40.9 40.5
18.5 58.9 22.6 56.7
31.7 52.1 16.2 73.6
BMD (g/cm2) of spine, total hip, and femoral neck in women with and without vertebral fractures; *p < 0.05.
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IVA for Osteoporosis Classification menopausal women who were recruited for this study. The sensitivity of BMD alone to diagnose osteoporosis based on either a vertebral fracture or low BMD using WHO criteria ranged from 40 to 74%. This means that between 26 and 60% of osteoporotic patients could potentially be missed. Furthermore, 11.0–18.7% of clinically osteoporotic patients would have been classified as normal by BMD alone. This study agrees with the study by Jones et al. (39), who performed standard spinal radiographs and DXA of the spine and hip in a sample of 187 elderly women age 60 and older participating in the Dubbo Osteoporosis Epidemiology study. The investigators found that vertebral deformities were present in 12–25% of women depending on the criteria used for vertebral deformity. In addition, they found that femoral neck BMD was superior to spine BMD in its association with vertebral deformity owing to the presence of false positive increases in spine BMD from degenerative joint disease of the spine. There are several advantages to our study. First, both DXA and IVA were performed by the same technologist during the same visit to eliminate the potential of a fracture occurring after the DXA was performed. Second, we used the diagnosis of osteoporosis classification based on WHO cutoff points (35,36) and used a single central skeletal site or multiple central skeletal sites for analysis as suggested by the ISCD (38). This organization suggests that the lowest BMD be used to classify and manage the patient’s disease. Finally, the study focused on women age 65 and older—the group with the highest fracture potential. The National Osteoporosis Foundation recommends that women age 65 and older have a BMD assessment regardless of risk factors (40). This is a clinically and economically relevant group to evaluate, since DXA for women in this age bracket is currently covered by the Health Care Finance Agency (41). Our study also has several limitations. First, our results could be biased because the subjects were volunteers for an osteoporosis prevention and treatment clinical trial, and this may not be representative of the community at large. In addition, the results may not be applicable to premenopausal or minority women (the study population was primarily Caucasian). Second, the low spatial resolution and
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377 high noise level of IVA limit visualization compared with the high resolution of standard lateral vertebral X-rays. Third, it is possible that using a 20% reduction in vertebral height to diagnose a vertebral fracture may not be appropriate for IVA (31). However, these criteria were previously utilized by Rea (31), who found high correlation between readings from IVA and radiographs performed on the same patients, using the same semiquantitative criteria. Although we have included “asymptomatic” vertebral fractures, nonclinical vertebral fractures may be associated with mild back disability or back pain, both of which are common in this population. Finally, we used the WHO classification based on the reference database provided by the densitometer’s manufacturer. The results could be different if we had enrolled our own young normal subjects and established our own normative database to determine the true T-scores of these older women. However, our primary objective was to determine the number of fractures that could be missed in clinical practice. Therefore, we wanted to utilize the manufacturer’s database available in clinical practice so that our findings would be more relevant to physicians practicing in the community. Although there is no “gold standard” for identification of a vertebral fracture using IVA, there is controversy about the most appropriate analysis for vertebral fractures, for which standard lateral radiographs are used (42–44). For the present study, we used a semiquantitative approach with a visual reduction in height of 20–25%. This would identify mild to severe prevalent fractures (23,31). This semiquantitative approach, often used in clinical practice (31), classifies grades of deformities (grade 1 is mild with 20–25% height reduction, grade 2 is moderate with 25–40% reduction, and grade 3 is severe with ≥40% reduction) and describes the deformities (crush, wedge, end plate). There are additional benefits to the use of radiographs. An expert radiologist can identify discontinuities of end plates as evidence of a vertebral deformity, which would be missed by IVA. Furthermore, radiographs can distinguish processes other than osteoporosis, which IVA would label as a deformity. Finally, IVA visualization of vertebrae above T7 is more difficult, whereas a lateral thoracic X-ray examines the entire thoracic spine.
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378 Our study revealed that 11.0–18.7% of normal subjects diagnosed by WHO criteria had vertebral fractures assessed by IVA. Patients with a classification of “normal” BMD often would be counseled with preventive measures, such as calcium and vitamin D supplementation, exercise, and elimination of smoking and excess alcohol (40). However, patients with normal BMD and a vertebral fracture deserve a work-up to determine the etiology of the fracture. Ross et al. (a) showed that patients with high BMD and a fracture are actually at higher risk for subsequent fracture than those with low BMD and no fracture. Such patients may also have a high rate of bone resorption, subclinical vitamin D deficiency, a secondary cause increasing bone turnover that could lead to skeletal fragility and fractures, or perhaps may represent a genetic subset with an increased fracture risk. Furthermore, patients with vertebral fractures have clinical osteoporosis and deserve therapy directed at treatment rather than general preventive measures. In summary, IVA is a quick, noninvasive, lowradiation technique that identifies women with vertebral fractures during BMD examinations. Such techniques provide important information that could alter physicians’ work-ups and clinical management, for the up to 19% of women who could potentially be misclassified owing to normal BMD results. Overall, even if we classified patients with osteoporosis using the most restrictive clinical guidelines of a T-score < –2.5 SDs below mean at any one of three clinical sites, 26% of patients with “clinical osteoporosis” would have been missed without vertebral assessment. Since therapies are available to successfully treat patients with vertebral fractures (45–47) and several bisphosphonates have been shown to reduce vertebral fractures significantly in 1 yr (47,48), this type of clinical information is valuable. Future studies are needed to investigate skeletal fragility and pathophysiology in women with normal BMD and silent vertebral fractures.
Acknowledgments We gratefully acknowledge the nursing and nutrition support of the Harvard-thorndike General Clinical Research Center at Beth Israel Deaconess Journal of Clinical Densitometry
Greenspan et al. Medical Center in Boston, the bone mineral densitometry technical support from Judith Oakley, and assistance with preparation of the manuscript from Dawn Griffiths. This study was supported in part by grant no. M01-RR01032 from the National Institutes of Health to the Beth Israel Deaconess Medical Center General Clinical Research Center.
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