Is short vertebral height always an osteoporotic fracture? The Osteoporosis and Ultrasound Study (OPUS)

INTRODUCTION AND HYPOTHESIS: Diagnosis of prevalent osteoporotic vertebral fracture is complicated by normal or developmental variation in vertebral shape or size and non-osteoporotic deformities that appear to have 'reduced' height. Using our visual approach, the algorithm-based qualitative method (ABQ) a vertebra with apparent "reduced" height without evidence of osteoporotic endplate depression is classified as non-osteoporotic short vertebral height (SVH). We aimed to determine whether ABQ classification of SVH represents true or false negative diagnosis of osteoporotic vertebral fracture, by testing the associations with clinical outcomes of osteoporosis or vertebral fracture. METHODS: The ABQ method was used to assess spinal radiographs acquired at baseline for a subset of 904 postmenopausal women participating in the Osteoporosis and Ultrasound Study (OPUS). The sample was enriched with vertebral fracture cases. Subjects were categorized by ABQ diagnosis as (i) normal, (ii) non-osteoporotic short vertebral height (SVH) or (iii) osteoporotic vertebral fracture. RESULTS: Women were classified by ABQ as follows: osteoporotic vertebral fracture, n=231; SVH, n=376 and normal, n=297. Women with vertebral fracture were older, with lower height, weight and height loss than those classified as SVH or normal. Women with SVH were heavier and older, with greater historical height loss than normal women. Age-adjusted SD units (z-scores) for BMD were lower than expected among women with osteoporotic vertebral fracture, but not among those with SVH. There was a significant association between diagnosis of osteoporotic vertebral fracture and history of low-trauma non-vertebral and vertebral fracture (p<0.001, odds ratios=3.2 and 20.6, respectively). There was also an association between diagnosis of SVH and previous low-trauma non-vertebral fracture (p<0.05, odds ratio=1.7). CONCLUSIONS: Short vertebral height without evidence of central endplate fracture in postmenopausal women is largely unrelated to osteoporosis. Quantitative morphometry should not be used alone for the assessment of vertebral fracture in clinical decision making: we recommend differential diagnosis of morphometric vertebral deformities by an expert reader to rule out non-osteoporotic deformities with short vertebral height.     

Mild morphometric vertebral fractures predict vertebral fractures but not non-vertebral fractures

Summary

In this meta-analysis of the control arms of four phase 3 trials, mild vertebral fractures were a significant risk factor for future vertebral fractures but not for non-vertebral fracture.

Introduction

A prior vertebral fracture is a risk factor for future fracture that is commonly used as an eligibility criterion for treatment and in the assessment of fracture probability. The aim of this study was to determine the prognostic significance of a morphometric fracture according to the severity of fracture.

Methods

We examined the control (placebo) treated arms of four phase 3 trials. Vertebral fracture status was graded at baseline in 7,623 women, and fracture outcomes were documented over the subsequent 20,000 patient-years. Fracture outcomes were characterised as a further vertebral fracture, a non-vertebral fracture or a clinical fracture (non-vertebral plus clinical vertebral fracture). The relative risk of fracture was computed from the merged β coefficients of each trial weighted according to the variance.

Results

Mild vertebral fractures were a significant risk factor for vertebral fractures [risk ratio (RR)?=?2.17; 95 % CI?=?1.70–2.76] but were not associated with an increased risk of non-vertebral fractures (RR?=?1.08; 95 % CI?=?0.86–1.36). Moderate/severe vertebral fractures were associated with a high risk of vertebral fractures (RR?=?4.23; 95 % CI?=?3.58–5.00) and a moderate though significant increase in non-vertebral fracture risk (RR?=?1.64; 95 % CI?=?1.38–1.94).

Conclusions

Prior moderate/severe morphometric vertebral fractures are a strong and significant risk factor for future fracture. The presence of a mild vertebral fracture is of no significant prognostic value for non-vertebral fractures. These findings should temper the use of morphometric fractures in the assessment of risk and the design of phase 3 studies.     

The risk and burden of vertebral fractures in Sweden

The aim of this study was to determine the risk and burden of vertebral fractures judged as those coming to clinical attention and as morphometric fractures. Incidence and utility loss were computed from data from Malmo, Sweden. Clinical fractures accounted for 23% of all vertebral deformities in women and for 42% in men. The average 10-year fracture probability for morphometric fractures increased with age in men from 2.9% at the age of 50 years (7.2% in women) to 8.4 at the age of 85 years (26.7% in women). As expected, probabilities increased with decreasing T-score for hip BMD. Cumulative utility loss from a clinical vertebral fracture was substantial and was 50–62% of that due to a hip fracture depending on age. When incidence of fractures in the population was weighted by disutility, all spine fractures accounted for more morbidity than hip fracture up to the age of 75 years. We conclude that vertebral fractures have a major personal and societal impact that needs to be recognised in algorithms for assessment of risk and in health economic strategies for osteoporosis.     

Instant Vertebral Assessment: A Noninvasive Dual X-ray Absorptiometry Technique to Avoid Misclassification and Clinical Mismanagement of Osteoporosis

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.     

Comparison of morphometric assessment of prevalent vertebral deformities in women using different reference data

The semiquantitative assessment of vertebral deformities is based on visual evaluation. The quantitative approach is based on different morphometric criteria. This study is aimed at comparing the impact of different reference groups to define normal vertebral shape on the diagnosis of verterbral deformities. Reference normal values were obtained in three groups of women: French, mixed European, and Argentinian. All these women had normal lumbar spine bone mineral density and no vertebral deformities according to the semiquantitative assessment. In a group of 135 women having vertebral deformities according to Genant’s semiquantitative assessment, three different morphometric criteria were applied. Morphometric diagnosis disclosed a good agreement with semiquantitative assessment. Agreement of diagnosis was higher for a given cutoff using thresholds obtained in different reference groups (κ = 0.84–0.96) and lower when different criteria were compared using thresholds obtained in the same reference group (κ = 0.75–0.85). When fracture thresholds obtained in three different cohorts were compared separately for the three morphometric criteria, agreement was the highest when the cutoff was based only on the arithmetical mean of vertebral heights and was independent of its standard deviation (SD). Average vertebral height ratios did not differ between the three reference cohorts, whereas SDs of vertebral height ratios were the highest in the mixed European cohort and the lowest in the French cohort (F = 7.41, p < 0.001). In the three groups of women of different nationality, SDs of vertebral height ratios, but not the arithmetical means, were significantly higher in the radiographs of poor quality compared with those of good quality. Thus, the main source of difference of diagnosis was related to different SDs whereas average height ratios were not different. Differences in SDs between the three groups were found to be related, at least partly, to poor quality of radiographs. The impact of the differences between populations seems less important, however, only three countries were compared. These findings suggest that those techniques that take into account the SD of vertebral height ratios will provide different reference values for vertebral morphometry. Because differences in SDs depend mainly on the quality of radiographs, they can be reduced by improving the X-ray technique and by the use of standardized protocols. This variability will result in the identification of a variable number of vertebral deformities in osteoporotic women. These results may be of importance especially for multicentric studies.     

Radiographic methods for evaluating osteoporotic vertebral fractures

Reproducible methods for the radiological assessment of osteoporotic vertebral fractures, defined based on accurate criteria, are needed in everyday practice and in therapeutic trials and epidemiological studies.ObjectivesTo describe and to evaluate methods for osteoporotic vertebral fracture assessment based on standard radiographs or dual-energy X-ray absorptiometry (DXA) and to determine the role for each method in clinical practice, therapeutic trials, and epidemiological studies.MethodsA review written by a rheumatologist based on his clinical experience and on a literature review was submitted to four experts. Studies in English or French published between 1975 and February 2008 were retrieved from Medline using the keywords vertebral fracture, osteoporosis, vertebral deformity, and vertebral fracture assessment.ResultsOne hundred forty-nine articles were selected and read in their full-text version. There was no consensus regarding the definition of osteoporotic vertebral fractures. The following methods were evaluated: visual assessment, Genant's semi-quantitative assessment, Jiang's algorithm-based qualitative method, morphometric radiography, and DXA of the spine. In everyday practice, Genant's semi-quantitative assessment on standard radiographs may provide useful information on the severity and prognosis of osteoporosis. DXA done for bone mineral density measurement may detect vertebral fractures in asymptomatic patients. Assessment of standard radiographs remains the reference standard for diagnosing vertebral fractures in patients with suggestive symptoms (e.g., pain in the thoracic or lumbar spine, height loss, or thoracic kyphosis). For therapeutic trials and epidemiological studies, Genant's semi-quantitative assessment used by a trained and experienced observer is the preferred method, based on its good reproducibility and ability to differentiate fractures from other deformities. However, thousands of radiographs may be needed, making routine interpretation by an expert impractical. A visual semi-quantitative method may be used to separate normal radiographs from radiographs showing possible or obvious fractures, which can then be read by an expert. Alternatively, radiomorphometric indices can be determined on digitized radiographs in combination with a semi-quantitative assessment, with discordant cases being reviewed by an expert. We do not recommend Jiang's method at present, as it is still undergoing validation.     

Comparing non-vertebral fracture risk reduction with osteoporosis therapies: looking beneath the surface

Summary  Data from pivotal trials of pharmacologic agents used to treat osteoporosis differ, suggesting that these agents vary in ability to reduce the risk of non-vertebral fractures (NVFs). However, variability among clinical trials in inclusion criteria, baseline characteristics, and definition of NVFs may account for many of these apparent differences. Introduction  Data from pivotal trials of individual pharmacologic agents for osteoporosis differ, and suggest that differences may exist between anti-resorptive agents in their ability to reduce the risk of NVFs. Careful examination of these trials’ inclusion criteria and patient characteristics indicates substantial differences between patient populations with respect to the baseline risk of NVFs. When baseline fracture risk is lower, the ability to produce a statistically significant reduction in fracture risk over the course of a clinical trial is reduced. Methods  Analysis of clinical trials reveals that the number and type of baseline vertebral fractures and also baseline bone mineral density, all associated with the risk of vertebral fracture, vary. Discussion and conclusion  The propensity to fall and patient frailty are additional factors associated with fracture risk that may influence study outcomes. One of the most significant variables, which also often differs considerably between trials, is the definition of an NVF. Variability between clinical trials in inclusion criteria, patients’ baseline characteristics, and how NVFs are defined may account for much of the apparent difference between agents in their ability to reduce NVF risk.     

Vertebral Fracture Diagnosis in the Multinational BONE Study of Oral Ibandronate: Quality Management in Radiology

A multicenter trial has established the antifracture efficacy of oral daily (2.5 mg) as well as intermittent (20 mg every other day for 12 doses every 3 mo) ibandronate in women with postmenopausal osteoporosis. As diagnostic spinal radiographs for this trial were read at 2 centers, the study protocol included rigorous procedures for diagnosis of morphometric vertebral fractures. These included standardized qualitative and morphometric assessment methods for diagnosing vertebral osteoporotic fractures and consensus cross-validation procedures for maximizing fracture diagnostic accuracy and consistency between the 2 radiographic reading centers. Using these stringent measures, the between-center discrepancy in the diagnosis of prevalent fractures was only 8%. Furthermore, after cross-validation, discrepancy in the final diagnosis of incident fractures between centers was found for only 4 patients, resulting in a net gain of only 2 fractures in the trial. This meticulous methodology provided a highly effective means of identifying vertebral fractures and recruiting the trial population in which to assess the efficacy of ibandronate in postmenopausal osteoporosis.     

Reporting of vertebral fractures on spine X-rays

Vertebral fractures are the hallmark of osteoporosis, responsible for increased morbidity and mortality in post-menopausal women. However, two-thirds of vertebral fractures do not come to clinical attention. The aim of this study was to compare the identification of vertebral fractures on spine X-rays among rheumatologists. Study subjects were women aged 60–80 years having potential signs of vertebral fracture and visiting a rheumatologist. X-rays were performed according to standardized procedures. In 629 patients (among 824 included) at least one vertebral fracture was diagnosed, and the X-rays were then sent to a central facility where a semi-quantitative assessment of vertebral fracture was performed by a single rheumatologist trained for this evaluation. According to the vertebral level, kappa scores were between 0.20 to 0.77, i.e., below 0.6 from T4 to T7, and between 0.6 and 0.77 from T8 to L4. The false-negative fractures rate was 25.8% (and 15.7% of them were related to a numbering discrepancy). The rate of false positive fractures was 6.3%. At the patient level 6.8% had actually no fracture. This study shows that 25% of overall vertebral fractures are not diagnosed among patients considered as having at least one fracture. As a consequence, patients who require treatment to reduce fracture risk are not being properly identified.     

A comparison of morphometric definitions of vertebral fracture

To compare the accuracy of several approaches for defining prevalent vertebral fractures from measurements of vertebral dimensions (morphometry), we measured the lateral dimensions of vertebral bodies of 115 normal premenopausal and 100 postmenopausal women. Of the postmenopausal women two observers agreed that 49 had definite vertebral fractures and 38 were definitely normal. Using these classifications as an independent reference, women were then classified as fractured or normal by several definitions based on vertebral morphometry. No morphometric definition of vertebral fracture agreed perfectly with the consensus classifications. In general, definitions that involved combinations of measurements of anterior (Ha), middle (Hm), and posterior (Hp) vertebral height classified women more accurately than did definitions based on a single measurement or ratio. The Ha/Hp ratio produced many false positives unless it was adjusted for normal variations in the shapes of different vertebral bodies. Definitions of fracture based on a greater than 15% reduction in heights or ratios had higher sensitivity but more false positives than definitions that used a more stringent (greater than 20%) criterion. All morphometric definitions of vertebral fracture separated the post-menopausal women into two groups (fractured and normal) that had significantly (P less than 0.001) different mean spine bone density by quantitative computed tomography. Definitions that had the lowest rates of false positives also produced the largest differences in bone density between those defined as fractured and those defined as normal.     

Comparison of Four Morphometric Definitions and a Semiquantitative Consensus Reading for Assessing Prevalent Vertebral Fractures

The assessment of vertebral fracture in patients with osteoporosis by conventional radiography has been improved over the past 10 years using either the semiquantitative (SQ) method devised by Genant et al. or quantitative morphometry. However, there is still no internationally agreed definition for vertebral fracture and there have been few comparative studies between these different approaches. Our study assessed the reproducibility of the SQ method and of four commonly used morphometric algorithms (Melton’s, Eastell’s, Minne’s and McCloskey’s methods) for assessing prevalent vertebral fractures, and examined the agreement of each morphometric algorithm with a SQ consensus reading performed by three experts. With this consensus reading in place of a gold standard, we determined relative measures of sensitivity, specificity and optimal cutoff threshold for each morphometric algorithm. The study was conducted in 39 postmenopausal women who had at least one osteoporotic vertebral fracture. Normal values were derived from 84 healthy postmenopausal women with apparently normal vertebral bodies. Our results indicate that the concordance of SQ method was excellent (intraobserver agreement on serial radiographs = 96.4%, κ= 0.91; agreement between individual readings and the consensus reading = 98%, κ= 0.95). Three morphometric approaches demonstrated good intra- and interobserver concordance (Melton: intraobserver agreement on serial radiographs = 92.7%, κ= 0.82, interobserver agreement = 91.1%, κ= 0.79; Eastell: intraobserver agreement on serial radiographs = 87.6%, κ= 0.66, interobserver agreement = 88.6%, κ= 0.68; McCloskey: intraobserver agreement on serial radiographs = 91.5%, κ= 0.72, interobserver agreement = 93.9%, κ= 0.78). Except for McCloskey’s method, the optimal cutoff thresholds defined in our study by highest κ score or Youden index in comparison with the SQ consensus reading were near the cutoff thresholds that were arbitrarily fixed. The four morphometric algorithms provided a good agreement with the results of the SQ consensus reading, but the more complex algorithm did not provide better results and even if we adjusted the cutoff threshold, no morphometric algorithm agreed perfectly with the SQ consensus reading. We conclude that morphometric approaches currently used should not be employed alone to detect prevalent vertebral fractures in studies on osteoporosis, but should rather be used in combination with a visual assessment. The SQ approach that allows differential diagnosis of vertebral deformities and has demonstrated a better reproducibility can be employed alone when it is performed by experienced and well-trained readers. Received: 3 July 2000 / Accepted: 26 March 2001     

The assessment of vertebral deformity: A method for use in population studies and clinical trials

The absence of specific criteria for the definition of vertebral fracture has major implications for assessing the apparent prevalence and incidence of vertebral deformity. Also, little is known of the effect of using different criteria for new vertebral fractures in clinical studies. We therefore developed radiological criteria for vertebral fracture in women for assessing both the prevalence and the incidence of vertebral osteoporosis in population and in prospective studies and compared these with several other published methods. Normal ranges for vertebral shape were obtained from radiographs in 100 women aged 45–50 years. These included ranges for the ratios of anterior/posterior, central/posterior and posterior/predicted posterior vertebral heights from T4 to L5. The predicted posterior height was calculated from adjacent vertebrae. In contrast to other methods, our definition of fracture required the fulfilment of two criteria at each vertebral site, and was associated with a lower apparent prevalence of fracture in the control women due to a lower false positive rate. The prevalence and incidence of vertebral deformity using different criteria were then compared in a series of women with skeletal metastases from breast cancer in whom radiographs were obtained 6 months apart. The prevalence of vertebral deformity and the specificity for deformity varied markedly with differing criteria. Using a cut-off of 3 standard deviations the prevalence of vertebral deformity in the women with breast cancer was 46%. Using other methods, the prevalences of deformity ranged from 33% to 74%. Over a 6-month interval 25% of patients with breast cancer sustained 61 deformities using our method, of which only 8% resulted from errors in reproducibility. The number of patients sustaining new deformities was increased twofold when assessed by other methods (45%–53%), but errors of reproducibility may have accounted for 21% of the new deformities. The magnitude and distribution of these errors have important implications for the apparent therapeutic efficacy of agents in clinical trials of osteoporosis. The rapid semi-automated technique for assessing vertebral deformities on lateral spine radiographs that we have developed has a high specificity, and reduces the impact of errors of reproducibility on estimates of prevalence and incidence. The method should prove a value in assessing vertebral deformity both in population studies and in prospective clinical trials.     

Sex Difference in the Validity of Vertebral Deformities as an Index of Prevalent Vertebral Osteoporotic Fractures: A Population Survey of Older Men and Women

Morphometric methods have been developed for standardized assessment of vertebral deformities in clinical and epidemiologic studies of spinal osteoporosis. However, vertebral deformity may be caused by a variety of other conditions. To examine the validity of morphometrically assessed vertebral deformities as an index of osteoporotic vertebral fractures, we developed an algorithm for radiological differential classification (RDC) based on a combination of quantitative and qualitative assessment of lateral spinal radiographs. Radiographs were obtained in a population of 50- to 80-year-old German women (n= 283) and men (n = 297) surveyed in the context of the European Vertebral Osteoporosis Study (EVOS). Morphometric methods (Eastell 3 SD and 4 SD criteria, McCloskey) were validated against RDC and against bone mineral density (BMD) at the femur and the lumbar spine. According to RDC 36 persons (6.2%) had at least one osteoporotic vertebral fracture; among 516 (88.9%) nonosteoporotics 154 had severe spondylosis, 132 had other spinal disease and 219 had normal findings; 14 persons (2.4%) could not be unequivocally classified. The prevalence of morphometrically assessed vertebral deformities ranged from 7.3% to 19.2% in women and from 3.5% to 16.6% in men, depending on the stringency of the morphometric criteria. The agreement between RDC and morphometric methods was poor. In men, 62–86% of cases with vertebral deformities were classified as nonosteoporotic (severe spondylosis or other spinal disease) by RDC, compared with 31–68% in women. Among these, most had wedge deformities of the thoracic spine. On the other hand, up to 80% of osteoporotic vertebral fractures in men and up to 48% in women were missed by morphometry, in particular endplate fractures at the lumbar spine. In the group with osteoporotic vertebral fractures by RDC the proportion of persons with osteoporosis according to the WHO criteria (T-score <−2.5 SD) was 90.0% in women and 86.6% in men, compared with 67.9–85.0% in women and 20.8–50.0% in men with vertebral deformities by various methods. Although vertebral deformities by most definitions were significantly and inversely related to BMD as a continuous variable in both sexes [OR; 95% CI ranged between (1.70; 1.07–2.70) and (3.69; 1.33–10.25)], a much stronger association existed between BMD and osteoporotic fractures defined by RDC [OR; 95% CI between (4.85; 2.30–10.24) and (15.40; 4.65–51.02)]. In the nonosteoporotic group individuals with severe spondylosis had significantly higher BMD values at the femoral neck (p <0.01) and lumbar spine (p <0.0004) compared with the normal group. On the basis of internal (RDC) and external (BMD) validation, we conclude that assessment of vertebral osteoporotic fracture by quantitative methods alone will result in considerable misclassification, especially in men. Criteria for differential diagnosis as used within RDC can be helpful for a standardized subclassification of vertebral deformities in studies of spinal osteoporosis. Received: 5 February 1999 / Accepted: 24 June 1999     

Benefits and Limitations of Bone Mineral Density and Bone Turnover Markers to Monitor Patients Treated for Osteoporosis

Medications are approved by regulatory agencies for treating osteoporosis when at least one randomized placebo-controlled clinical trial shows a reduction in vertebral fracture risk and the benefit-risk ratio is determined to be acceptable. Subjects who participate in registration trials are a generally homogeneous group carefully screened with strict entry criteria. Individual patients who are treated for osteoporosis in clinical practice commonly differ from subjects enrolled in these clinical trials according to confounding factors that include age, sex, comorbidities, compliance, and persistence. Because the goal of therapy is reduction of fracture risk, and this cannot be directly assessed in an individual patient, biomarkers are commonly used as surrogate end points for effectiveness. This article reviews the clinical use and abuse of the two biomarkers most commonly used to assess the effectiveness of therapy in clinical practice: bone mineral density testing and measurement of markers of bone turnover.     

The sample size required for intervention studies on fracture prevention can be decreased by using a bone resorption marker in the inclusion criteria: prospective study of a subset of the Nagano Cohort, on behalf of the Adequate Treatment of Osteoporosis (A-TOP) Research Group

In drug developments for osteoporosis, large-scale and longterm fracture prevention studies have been required. We investigated whether or not it was possible to reduce the sample size and observation period under new selection criteria for an osteoporotic fracture-prevention study. A Poisson regression model was used to identify independent risks for incident vertebral fracture in 515 postmenopausal women who had had no intervention for osteoporosis; this group was a subset of Nagano Cohort participants. The total observation period for this group was 2577 person-years, and a total of 146 new vertebral fractures were observed. Risk assessment for incident vertebral fracture among numerical covariates revealed that the following items showed significant independent risks for incident fractures; namely, baseline age (hazard ratio [HR]; 1.84; 95% confidence interval (CI), 1.44–2.35; P < 0.001), number of preexisting vertebral fractures (HR, 1.28; 95% CI, 1.17–1.40; P < 0.001), baseline lumbar bone mineral density (LBMD) (HR, 0.79; 95% CI, 0.71–0.88; P < 0.001), and urinary excretion of deoxypyridinoline (DPD) (HR, 1.18; 95% CI, 1.03–1.35; P = 0.016). Because the initial urinary excretion of DPD was found to be a risk for incident vertebral fracture, in addition to the conventional risks, we assessed whether or not the sample size or observation period could be reduced by the incorporation of the urinary excretion of DPD into the selection criteria of a fracture-prevention study. The assessment of sample size was calculated, using the log rank test, at a two-tailed significance level of 5% and with a power of 80%. When osteoporotic patients with preexisting fracture were selected (conventional criteria), the 3-year probability of vertebral fracture was estimated as 14.3% in the present population. On the other hand, the new vertebral fracture rate during 3 years in the osteoporotic patients with preexisting fracture plus high urinary DPD (HR, above 1.0); (new selection criteria) was estimated as 23.2%. When the HR between test drug and placebo was changed from 0.4 to 0.8, the required sample size for any level of HR showed a 40% reduction for the new selection criteria compared to the conventional criteria. Therefore, the addition of urinary DPD level to the selection criteria is useful to reduce sample size in an osteoporosis fracture-prevention study.     

FDG-PET Findings of Vertebral Compression Fractures in Osteoporosis: Preliminary Results

The aim of this study was to evaluate FDG-PET findings in patients with osteoporosis or preclinical osteoporosis and acute vertebral compression fractures in order to determine whether FDG-PET has a value for distinction of pathological from osteoporotic vertebral fractures. 17 patients with a spontaneous compression fracture of the spine were evaluated by bone scanning with Tc-99m HDP, positron emission tomography with fluorine-18 deoxyglucose (FDG-PET) and magnetic resonance imaging (MRI). Osteoporosis had been established in all cases by X-ray and osteodensitometry. PET and bone scan images were scored independently from 0 (no pathological uptake) to 4 (definitive pathological uptake) by two blinded nuclear medicine physicians. The results of the blinded scoring were compared to MRI findings which served as gold standard. In 13 out of 17 patients, MRI demonstrated a vertebral fracture generating from osteoporosis. In 12 of these 13 cases, PET scans were scored with 0 or 1 and categorized as true negative. Standard uptake values (SUV) ranged between 1.1 and 2.4. In one of the 13 patients, PET was interpreted false positive with an uptake score of 3 (SUV = 2.9). Of the 17 patients, MRI revealed a pathological fracture caused by spondylodiscitis in three patients and by plasmacytoma in one patient. In these patients, all PET scans were highly positive with a score of 3 and 4 and SUV values between 3.8 to 9.8. The bone scans of all 17 patients were positive with scores of 3 or 4 but a differentiation between osteoporotic and pathological fractures was not possible. Our preliminary results indicate that acute vertebral fractures that originated from osteoporosis or preclinical osteoporosis tend to have no pathologically increased FDG uptake. Since a high FDG uptake is characteristic for malignant and inflammatory processes, use of FDG-PET may have potential value for differentiation between osteoporotic and pathological vertebral fractures. Received: 18 October 2001 / Accepted: 25 April 2002     

Health-related quality of life and treatment of postmenopausal osteoporosis: results from the HORIZON-PFT

Osteoporosis-related fractures are associated with reductions in health-related quality of life (HRQL). We examined the benefits of zoledronic acid (ZOL) on HRQL in patients sustaining vertebral and clinical fractures from HORIZON-Pivotal Fracture Trial using mini-Osteoporosis quality of life Questionnaire (OQLQ). In this multicenter, double-blind, placebo-controlled trial, 1434 patients from a cohort of postmenopausal women with osteoporosis (mean age 73years) were randomized to receive annual infusions of ZOL 5mg or placebo for 3years. Baseline HRQL scores were comparable between ZOL and placebo groups based on the presence or absence of fractures, with exception of prevalent vertebral fractures where patients (irrespective of the treatment group) had lower baseline HRQL scores than those without prevalent vertebral fractures. Greater number of prevalent vertebral fractures was associated with lower baseline HRQL (p<0.001). No significant difference between ZOL and placebo in the overall summary score was observed but a significant benefit was noted in certain domains with ZOL, especially in patients sustaining incident clinical fractures. Improvements in HRQL were marked at first assessment after a morphometric vertebral fracture with significant differences favouring ZOL in pain (p=0.0115), standing pain (p=0.0125)), physical (lifting, p=0.0333) and emotional function (fear of fractures, p=0.0243; fear of falls, p=0.0075) but not for activities of daily living or leisure domains. HRQL is reduced in patients with vertebral fractures. Treatment with ZOL over 3years was associated with improvements in specific domains of quality of life vs. placebo, particularly in patients sustaining incident fractures.     

Defining Incident Vertebral Deformities in Population Studies: A Comparison of Morphometric Criteria

Various morphometric criteria have been used to define incident vertebral deformity. The aim of this analysis was to compare the relative validity of two established criteria and a novel method in which these criteria were combined. Men and women aged 50 years and over were recruited from population registers across Europe and had lateral spinal radiographs performed using a standard protocol. A subsample of individuals had bone mineral density (BMD) at the spine or femoral neck. Subjects were followed prospectively and a subsample had repeat spinal radiographs a median of 3.8 years after the baseline survey. All radiographs were evaluated morphometrically in the radiology coordinating center in Berlin. Anterior, middle and posterior height were recorded in all vertebrae from T4 to L4. On the basis of these morphometric measurements incident vertebral deformity was defined using one of three methods: (i) the change method – a change in any vertebral height of 20% or more between films, plus the additional requirement that a vertebral body have changed in absolute vertebral height by 4 mm or more; (ii) the point prevalence method, where a vertebra satisfies criteria for a prevalent deformity (McCloskey–Kanis) on the follow-up, though not the baseline film; (iii) a combination of the height reduction and the point prevalence criteria. Paired films were also evaluated qualitatively by an experienced radiologist for the presence of incident vertebral deformity. Logistic regression was used to compare the three morphometric methods using known risk factors for vertebral deformity including age, baseline vertebral deformity and BMD, and the qualitative evaluation. Computer simulation was used to determine the potential degree of bias and loss of statistical efficiency due to misclassification for each of the three methods, using the radiologist’s assessment of incident deformity as the reference. Six thousand eight hundred subjects were included in this analysis. Of these 450 had sustained an incident vertebral deformity according to at least one of the three morphometric methods. The distribution of risk factors was similar in the subjects who satisfied only one morphometric criterion and those who satisfied neither. However, the subjects who satisfied both criteria had a very different distribution of risk factors: they were older, more likely to be female, more likely to have had a previous vertebral deformity and more likely to have an incident fracture in the opinion of an experienced radiologist. Using computer simulation, at low incidence levels, combining the criteria led to greater statistical efficiency and less bias in estimating associations with risk factors. Thus in this analysis the combination of the point prevalence and 20% change in height criterion for defining incident vertebral deformity showed a stronger relationship with clinical risk factors than either single criterion. Its application in population-based studies would increase the likelihood of detecting risk factors for incident vertebral deformity for a given sample size. Received: 6 November 2001 / Accepted: 7 May 2002     

Vertebral deformity in men.

Vertebral fracture is the most prevalent manifestation of osteoporosis in women, but there is very little information concerning vertebral fracture in men. These studies begin to determine the prevalence, radiographic character, and relationship to bone mineral density of vertebral deformity in men. A group of 144 white men aged 34-94 years (83% between 50 and 80 years) were studied. Thoracic and lumbar spine radiographs were obtained using standardized techniques, and morphometric measures of vertebrae (T6-L5) were obtained using a computerized digitization pad. Vertebral deformities (wedge, midbody, and crush) were identified using several criteria. In addition, a skeletal radiologist independently identified vertebral deformities, as well as vertebrae affected by epiphysitis (Scheuermann's disease), using classic radiographic criteria. Bone mineral density was measured at lumbar spine and proximal femoral sites using dual-photon absorptiometry. The prevalence of vertebral deformity was related to the criteria used for their identification. Utilizing vertebral-specific criteria (anterior/posterior or midbody/posterior vertebral height more than 3 SD below vertebral specific mean), 10% of subjects had vertebral deformity. Wedge deformity occurred primarily in thoracic vertebrae and were more common than midbody deformity, which occurred more commonly in lumbar vertebrae. Crush deformities were not observed. Evidence of vertebral epiphysitis was present in 9% of subjects but was not responsible for vertebral deformity sufficient to be falsely identified using the more than -3 SD criterion. Bone mineral density in subjects with vertebral deformity was clearly reduced at both vertebral (p = 0.003) and proximal femoral (p = 0.002) measurements sites. The number of vertebral deformities was negatively correlated with vertebral bone mineral density.(ABSTRACT TRUNCATED AT 250 WORDS)