Diagnosis of Vertebral Fractures by Vertebral Fracture Assessment

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1 Journal of Clinical Densitometry, vol. 9, no. 1, 66 71, 2006 Ó Copyright 2006 by The International Society for Clinical Densitometry /06/9:66 71/$32.00 DOI: /j.jocd Original Article Diagnosis of Vertebral Fractures by Vertebral Fracture Assessment Jo el Damiano, 1 Sami Kolta, 1 Rapha el Porcher, 2 Caroline Tournoux, 2 Maxime Dougados, 1 and Christian Roux*,1 1 Service de Rhumatologie, Universite Paris-Descartes, Faculte demedecine, Assistance Publique-H^opitaux de Paris, H^opital Cochin, Paris, France; and 2 Departement de Biostatistiques, Universite Paris 7, Assistance Publique-H^opitaux de Paris, H^opital Saint-Louis, Paris, France Abstract Vertebral fractures are independent risk factors for both vertebral and peripheral fractures and only one-third of these fractures come to clinical attention. Vertebral fracture assessment (VFA) is a radiographic method using dual X-ray absorptiometry (DXA) to assess vertebral deformities during bone density measurement. We performed VFA of the spine from T4 to L5 on a Delphi W device (Hologic, Bedford, MA) in 136 postmenopausal patients ( yr). These patients also had X-rays of the thoracic and lumbar spine. VFA was independently compared with X-rays by two rheumatologists, for the diagnosis of vertebral fractures at both the patient and vertebral levels. Using X-rays, 61 patients (45%) had at least one vertebral fracture. The percentage of unreadable vertebrae was 1% and 12.4% on X-rays and VFA, respectively ( p! ). At the patient level, VFA allowed to diagnose if the patient had no fracture or had at least one fracture in 74% of patients. In 11.2% of cases, VFA misclassified the patients. At the vertebral level, diagnostic efficacy of VFA as compared with X-rays was 97%. Concordance between both observers was good (k-score ). We designed an algorithm for decision of performing X-rays in postmenopausal women: Using results of VFA would avoid X-rays in 32% of our patients. VFA is a reliable technique with low radiation, and is easily and rapidly applicable during bone density measurement by DXA, which could improve management of osteoporotic patients. Key Words: DXA; osteoporosis; vertebral fracture; VFA. Introduction Vertebral fractures are the hallmark manifestation of osteoporosis, associated with back pain, increased morbidity, and functional limitations (1). Postmenopausal women with vertebral fractures are at higher risk of both vertebral and peripheral fractures, including hip fractures (2). Risk of vertebral fractures in women with one prevalent fracture is twice that of women without a prevalent fracture (1). Prevalent vertebral fractures are associated with increased mortality (3), probably related to comorbidity; the association of clinical vertebral fractures with the increase in mortality is similar to the one Received 09/07/05; Revised 11/23/05; Accepted 11/27/05. *Address correspondence to: Christian Roux, MD, PhD, Rheumatology Department, Cochin Hospital, AP-HP, Rene Descartes University, 27 rue du faubourg Saint Jacques, Paris, France. christian.roux@cch.ap-hop-paris.fr observed after hip fracture among older women (4). Efficient treatments decreasing by 50%, on average, the risk of incident fracture in patients having prevalent vertebral fractures are available. Postmenopausal women with prevalent vertebral fractures should be recognized in order to prevent the debilitating consequences of subsequent fractures (5,6). However, only one-third of vertebral fractures come to clinical attention, even if they are present on X-rays (7). There is no single clinical sign, or combination of clinical risk factors, able to predict existing vertebral fracture (8). Performing systematic spine X-rays in asymptomatic osteoporotic patients exposes these patients to radiation and would increase the cost of diagnosis of vertebral fractures. A possible way to check for these asymptomatic vertebral fractures is available through dual energy X-ray absorptiometry (DXA) devices. This technique has several advantages: it delivers a lower dose of radiation to the patient (entrance dose 5 70 msv, constructor data) than spine X-rays (

2 Vertebral Fracture Assessment 67 msv effective dose) (9,10), and the X-ray source is in theory always orthogonal to the vertebral bodies, avoiding geometric distortion. The main limitation of the technique is lack of visualization of the upper thoracic spine (above T7) (11 18). Quantitative measurements of the vertebral bodies have been used. They are time-consuming and not applicable in clinical settings. They are, therefore, used only in clinical research studies. Qualitative or semi-quantitative evaluation of the vertebrae could easily be used in clinical practice. DXA devices of recent generations have better image quality, allowing both a semi-quantitative and a quantitative evaluation of the vertebrae using visual assessment (vertebral fracture assessment [VFA]). This technique seems promising and its indications remain to be standardized. The aim of our study was to evaluate the sensitivity and specificity of this technique (VFA) for diagnosis of vertebral fractures in postmenopausal women and to design an algorithm using this technique to avoid unnecessary X-rays in this population. Patients and Methods Postmenopausal women with indication for spine X-rays in our rheumatology department, (e.g., height loss, risk factors for postmenopausal osteoporosis and back pain, long-term corticosteroid therapy) were included in this study. Considering that it has been suggested to combine VFA to bone mineral density (BMD) assessment (19), patients gave only an oral consent. They were informed that the results have to be compared with those of X-rays. For each patient, age, height, weight, body mass index (BMI; calculated as kg/m 2 ) were collected. Patients were classified as normal if their BMI was!27, overweight if BMI 27 and 30, and obese if BMI O 30. Every patient had thoracic and lumbar spine X-rays, Lateral thoracic spine X-ray was centered on T7 in order to assess the spine from T4 to L1. Lateral lumbar X-ray was centered on L3 allowing assessment of T12 to L5. In most of the cases additional X-rays were done centered either on thoraco-lumbar junction and/or on different spinal segments because of legibility problems. Within a 3-d interval, patients had measurement of BMD of the lumbar spine (L2 L4) and hip using a DXA device (Delphi W; Hologic, Bedford, MA). They were classified as normal, osteopenic, or osteoporotic according to the World Health Organization classification (20) using local reference values. VFA scan was done using the same DXA device (software version 11.2), with patients in the supine position for the anteroposterior view and the right lateral position for the lateral view. The scan is done from L5 to above T4 and takes about 10 s. Diagnosis of Fracture All X-rays and VFA scans were independently evaluated by two investigators (rheumatologists). One of them was more experienced in the assessment of spine X-rays. A training session was done before the start of the study. Each investigator read the X-rays and VFA scans of the same patient with at least 1-mo interval. On both X-rays and VFA images the following were evaluated: legibility, deformities of vertebral bodies, and scoliosis. Legibility of each vertebra was evaluated in three grades: unreadable, readable without difficulty, and readable with difficulty (if the contours of the vertebral body were not easily identified or needed the use of a spotlight for X-rays, or were not perfectly seen even after changing the contrast for VFA). For each readable vertebra, the deformity was scored from 0 to 3 according to Genant s semi-quantitative classification (21). Scoliosis was absent (grade 0) or classified in 3 grades according to rotation of the vertebral body judged on the distance between the spinous process and the lateral border of the vertebral body. This distance was divided in two. If the spinous process was projected in the first half of this distance, scoliosis was considered as minor, if it was in the second half it was considered as moderate, and if it was lateral to the vertebral body, it was considered as severe (grades 1, 2, and 3, respectively). Statistical Analysis In a first step, we assessed performance of VFA in the diagnostic of vertebral fracture, as compared to X-rays (gold standard). In a second step, we designed an algorithm using VFA results first to discuss the need for X-rays. Evaluation of VFA as a Diagnostic Tool (Evaluation of the Technique Compared with X-Ray Considered as the Gold Standard) The number of unreadable vertebrae was compared between the two methods using a McNemar test. Factors affecting legibility were tested using Fisher s exact tests for categorical factors and Wilcoxon rank-sum tests for continuous variables. Tested factors were age, height, BMI, BMD, and scoliosis. Evaluation of the diagnostic value was performed using the results of the more-experienced investigator, both at the vertebral and patient levels. At the vertebral level, sensitivity and specificity of VFA with 95% exact confidence intervals were calculated. Positive and negative likelihood ratios (LR) were also calculated, taking into account the grade of fracture. These ratios compare the probabilities of a given test result among individuals with and without the disease (as measured by a gold standard). A positive test is obtained LR1 times in individuals that truly have the disease compared with individuals that truly do not have the disease. Values above 10 were considered to indicate a useful diagnostic test. At the patient level, patients were classified as fractured (at least one fracture visible), normal (all vertebrae from T4 to L5 were analyzable and no vertebral fracture visible), or without possible diagnosis (no vertebral fracture visible but some vertebrae were unreadable). Some factors related to the patient (osteoporotic or osteopenic, obesity, scoliosis, and vertebral levels) that may interfere with diagnostic performance were evaluated. We calculated sensitivity and specificity

3 68 Damiano et al. with exact 95% confidence intervals (CI) and positive and negative predictive values of VFA. In a next step, we used a conservative approach, considering patients without possible diagnosis (because of some nonlegible vertebrae) as nonfractured; and we calculated sensitivity and specificity of the technique in this population. Inter-observer agreement for the diagnosis of fracture was evaluated for X-rays and VFA at the vertebral and patient level using k and weighted-k statistics, for dichotomous and polytomous criteria, respectively. A homogeneity test was done by stratifying on possible confounding factors. In case of heterogeneity, weighted-k values adjusted for the confounding factors are given. Evaluation of VFA as Part of Diagnostic Protocol (VFA Followed, if Needed, by X-ray) Aiming to test clinical utility of VFA, we calculated sensitivity and specificity of the following approach: considering VFA results for all patients, X-rays were not performed if all vertebrae were legible and normal on VFA. Results Patient Characteristics One-hundred and thirty-six patients were included in this study: 48% were osteoporotic, 34% were osteopenic, and 18% had a normal BMD (Table 1). Sixteen percent were obese, 22% overweight, and 62% had normal BMI. In our population, 48% of the patients did not have any scoliosis, 41% had grade 1, 10% grade 2, and 1% grade 3 scoliosis. Legibility of the Spine At the vertebral level (1904 vertebrae), on X-ray films, 1694 vertebrae (89%) were considered as readable without difficulty, 186 (10%) were considered as readable with difficulty, and 24 (1%) were unreadable. Most of the unreadable vertebrae were located in T4 and T5 (n 5 6 [25%] and n 5 5 [21%], respectively). This means that 4.4% of T4 vertebrae and 3.7% of T5 vertebrae were unreadable. Table 1 Patient Characteristics Variable n Mean SD Minimum Maximum Age (yr) Height (cm) Weight (kg) BMI (kg/m 2 ) BMD L2 L4 (g/cm 2 ) BMD total hip (g/cm 2 ) Abbr: BMD, bone mineral density; BMI, body mass index; SD, standard deviation. On the VFA scans, 1319 vertebrae (69.3%) were readable without difficulty, 348 (18.3%) were readable with difficulty and 237 (12.4%) were unreadable ( p! as compared with X-rays). Unreadable vertebrae were mostly located in T4 (40% unreadable), T5 (35% unreadable), and T6 (24% unreadable). Among unreadable vertebrae, 23% were in T4, 20% in T5, and 14% in T6. Only 1654 among the 1904 vertebrae, i.e., 86.9%, were readable using both X-rays and VFA. At the patient level, thoraco-lumbar spine from T4 to L5 was readable in 128 patients (94%) on X-rays and in 69 patients (51%) on VFA scans. Factors affecting the legibility of the vertebrae were a high BMI for X-rays ( p ), small height ( p ), scoliosis ( p ), and low BMD of total hip ( p ) for VFA. VFA as Diagnostic Tool At the vertebral level, there were 1654 vertebrae assessable using both methods. On X-ray films, 1509 vertebrae (91%) were normal, 46 (3%) had grade 1, 69 (4%) grade 2, and 30 (2%) grade 3 fractures. Using VFA scans, 1509 vertebrae (91%) were considered as normal, 52 (3%) had grade 1, 68 (4%) grade 2, and 25 (2%) grade 3 fractures. Comparison between results of VFA and X-rays are presented in Table 2. Sensitivity of the diagnosis of fractures using VFA is 82.8% (95% CI: %) and the specificity is 98.3% (95% CI: %). This yielded a diagnostic efficacy of VFA compared to X-rays of 97.0% (95% CI: %). Positive and negative likelihood ratios are presented in Table 3. The concordance was higher in case of fractures grade 2 or 3, with a positive likelihood ratio of It was less for fractures grade 1, where 20 nonfractured vertebrae were considered as having grade 1 on the VFA and 18 grade 1 fractures were considered as normal using VFA (Table 2). At the patient level, according to the experienced investigator using X-rays, 61 patients (45%) had at least one vertebral fracture and 72 patients (53%) had no fracture (Table 4). In three patients (2%), diagnosis was not possible (one or more unreadable vertebrae with no fracture seen on the legible ones). Among patients with fracture, there were on average fractured vertebrae. Among the 61 patients having vertebral fractures, 2 patients had a single fracture in T4 or T5. X-ray Table 2 Comparison of Results of VFA and X-Rays (at the Vertebral Level) Grade 0 Grade 1 Grade 2 Grade 3 Grade Grade VFA Grade Grade Total 1509 (91%) 46 (3%) 69 (4%) 30 (2%) Abbr: VFA, vertebral fracture assessment.

4 Vertebral Fracture Assessment 69 Table 3 Positive and Negative Likelihood Ratios of Diagnosis of Vertebral Fracture by VFA VFA grade Fracture No fracture LR1 LR (17.2%) 1484 (98.3%) (22.1%) 20 (1.3%) (60.7%) 5 (0.33%) Total Abbr: LR, likelihood ratio; VFA, vertebral fracture assessment. Analysis of the ability of VFA to diagnose vertebral fracture has been evaluated on the 133 patients for whom a diagnosis was possible. Using VFA, 56 patients (42%) had at least one vertebral fracture, 42 patients (32%) were considered as having no fracture and in 35 patients (26%) diagnosis was not possible. VFA allowed diagnosis if the patient had no fracture (all vertebrae from to T4 to L5 were analyzable and no vertebral fracture visible) or had at least one fracture in 74% of patients (Table 4). Sensitivity of the diagnosis of fractures using VFA is 94.1% (95% CI: %) and the specificity is 83.0% (95% CI: %). This yielded a diagnostic efficacy of VFA compared with X-rays of 88.8%. If we consider that the 35 patients (26%) for whom VFA did not provide a diagnosis would be correctly diagnosed by X-rays, the method would have a sensitivity of 95.1% (95% CI: %) and a specificity of 88.9% (95% CI: %). According to the fracture prevalence in our population, the positive predictive value was 87.9% and the negative predictive value was 95.5%. Comparison of Readers At the patient level, inter-observer concordance was good, with a k-score of 0.79 for X-rays and 0.56 for VFA without any influence of the different variables. The weaker Table 4 Diagnosis of Vertebral Fracture by VFA Compared with X-rays (at the Patient Level) Without fracture (n 5 72) X-rays With fracture (n 5 61) Total (N 5 133) n % n % n % VFA Without fracture With fracture Impossible diagnosis Abbr: VFA, vertebral fracture assessment. concordance with VFA is partially due to discrepancy on the legibility of some vertebrae increasing the number of cases were the diagnosis is not possible. For the 85 patients for whom the two observers could reach a diagnosis, concordance was good, with a k-score of At the vertebral level, only vertebrae that could be analyzed by both observers were included in this analysis (n for X-rays and 1562 for VFA). For the X-rays, there was very good inter-observer agreement for the diagnosis of fracture (k-score ). Factors such as osteoporosis, obesity, and scoliosis did not cause significant change of the concordance. However, considering the grading of fracture (no fracture, fracture grade 1, and fracture grade 2), the weighted-k was Concordance was significantly different according to the osteoporosis status (homogeneity test p ); being weaker for normal patients (neither osteoporotic nor osteopenic), weighted k Concordance score adjusted for osteoporosis was weighted k For VFA, concordance between both observers was somewhat weaker than for X-rays. For diagnosis of fracture, k , with a significant heterogeneity according to the osteoporosis, p (k for osteoporotic patients). If we considered the grading of vertebral fracture, we obtained weighted-k , without any significant variation due to the different variables tested. VFA as Diagnostic Protocol Based on results of VFA as a diagnostic tool, we designed the following protocol: Case 1: All the vertebrae are legible and there is at least one vertebral fracture. X-rays are performed to eliminate nonosteoporotic causes of this fracture. Case 2: All vertebrae are legible and there is no vertebral fracture. X-rays are not performed. Case 3: Some vertebrae are not legible and there is no fracture on the others. X-rays are performed in order to check for these illegible vertebrae. This protocol has a specificity of 100% and a sensitivity of 95.1% ( %). In our study, this protocol would avoid unnecessary X-rays in 32% of patients. Discussion The VFA method can be easily used during BMD measurement by DXA in order to get information on the vertebral fracture status. In our study, VFA has a very high negative predictive value, indicating a good diagnostic value for the absence of vertebral fractures. Based on these results, we suggest a diagnostic procedure that was able to avoid 32% of spine X-rays in our population. The main limiting factor in utilizing VFA is the legibility of the vertebrae. The difficulty is mostly seen in the upper thoracic vertebrae as previously described (12 15). Newer generations of DXA devices did not totally resolve this problem, especially above T6. However, fractures above this level

5 70 Damiano et al. are less typical for primary postmenopausal osteoporosis (8) and, in our study, only two patients had fractures exclusively at T4 and/or T5. The legibility of the vertebrae using VFA was related to the degree of scoliosis and osteoporosis, as well as the height of the patients, with difficulty increasing in patients with low height or high BMI. The characteristics of our population with mostly older scoliotic and osteoporotic patients have contributed to the difficulty in analyzing vertebrae. If VFA is performed in younger postmenopausal women, the percentage of spines totally legible (from T4 to L5) would be better. In another study (22), in younger ( yr), and less-osteoporotic patients, VFA could analyze 94.9% of the vertebrae. It is worthy of note that when using X-rays, it is sometimes necessary to perform several views in order to visualize all vertebrae in such difficult cases, greatly increasing the radiation to the patients. In case of fracture, one should perform an X-ray in order to search for any signs of malignancy. The diagnostic performance of VFA is better to eliminate a vertebral fracture than to confirm its presence. In our study, VFA alone succeeded in diagnosing 74% of cases as having either no vertebral fracture or at least one vertebral fracture. However, in 11.2% of cases, VFA misclassified the patients, including three patients being false negative. Moreover, diagnosis was not possible in 26% of cases when some vertebrae were not legible and no fracture was seen on legible vertebrae. Our results show that there is a weaker concordance for VFA compared with X-rays between the readers, and the measurement error is greater using VFA. This means that training is necessary for use of VFA, before routine use. In order to get results that could be useful in clinical practice, we were interested in results at the patient level classifying her as either having vertebral fracture or not. VFA may be a screening method in order to avoid unnecessary radiation for X-rays. In our study, the negative predictive value of our diagnostic protocol based on VFA as a primary test reached 96%. This confirms results obtained by Rea et al. (22,23). In our study, our procedure would avoid X-ray in nearly one-third of the population. This proportion may be higher in a younger population with better legibility of the vertebrae. In conclusion, VFA is an interesting technique with low radiation, is easily and rapidly applicable during BMD measurement by DXA, and could improve management of osteoporotic patients. When the spine can be assessed from T4 to L5, VFA could help avoid unnecessary X-rays. The information obtained by VFA would improve management of osteoporotic patients diagnosed only on BMD results. The diagnosis of asymptomatic vertebral fractures in such patients would allow the proper indication of anti-osteoporotic treatments. References 1. 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