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Osteoporotic vertebral fracture (OVF) is a risk factor for morbidity and mortality in elderly population, and accurate diagnosis is important for improving treatment outcomes. OVF diagnosis suffers from high misdiagnosis and underdiagnosis rates, as well as high workload. Deep learning methods applied to plain radiographs, a simple, fast, and inexpensive examination, might solve this problem. We developed and validated a deep-learning-based vertebral fracture diagnostic system using area loss ratio, which assisted a multitasking network to perform skeletal position detection and segmentation and identify and grade vertebral fractures. As the training set and internal validation set, we used 11,397 plain radiographs from six community centers in Shanghai. For the external validation set, 1276 participants were recruited from the outpatient clinic of the Shanghai Sixth People's Hospital (1276 plain radiographs). Radiologists performed all X-ray images and used the Genant semiquantitative tool for fracture diagnosis and grading as the ground truth data. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were used to evaluate diagnostic performance. The AI_OVF_SH system demonstrated high accuracy and computational speed in skeletal position detection and segmentation. In the internal validation set, the accuracy, sensitivity, and specificity with the AI_OVF_SH model were 97.41%, 84.08%, and 97.25%, respectively, for all fractures. The sensitivity and specificity for moderate fractures were 88.55% and 99.74%, respectively, and for severe fractures, they were 92.30% and 99.92%. In the external validation set, the accuracy, sensitivity, and specificity for all fractures were 96.85%, 83.35%, and 94.70%, respectively. For moderate fractures, the sensitivity and specificity were 85.61% and 99.85%, respectively, and 93.46% and 99.92% for severe fractures. Therefore, the AI_OVF_SH system is an efficient tool to assist radiologists and clinicians to improve the diagnosing of vertebral fractures. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Vertebral fractures are associated with height loss, reduced quality of life, and increased mortality and are an important endpoint for osteoporosis trials. However, height loss is associated with quality of life and mortality independent of associations with fracture. We have used data from a recent 6-year trial of zoledronate in 2000 osteopenic women aged >65 years to assess the impact of the semiquantitative and quantitative components of the definition of vertebral fracture on the outcome of that trial, to determine what factors impacted on height loss and to test whether height loss can be used as a surrogate for vertebral fracture incidence. In the trial protocol, an incident vertebral fracture was defined as a change in Genant grade plus both a 20% and 4 mm decrease in a vertebral height. The addition of the quantitative criteria reduced the number of fractures detected but did not change the size of the anti-fracture effect (odds ratios of 0.49 versus 0.45) nor the width of the confidence intervals for the odds ratios. Multivariate analysis of baseline predictors of height change showed that age accelerated height loss (p < 0.0001) and zoledronate reduced it (p = 0.0001). Incident vertebral fracture increased height loss (p = 0.0005) but accounted for only 0.7% of the variance in height change, so fracture could not be reliably inferred from height loss. In women without incident vertebral fractures, height loss was still reduced by zoledronate (height change: zoledronate, -1.23; placebo -1.51 mm/yr, p < 0.0001). This likely indicates that zoledronate prevents a subtle but widespread loss of vertebral body heights not detected by vertebral morphometry. Because height loss is associated with quality of life and mortality independent of associations with fracture, it is possible that zoledronate impacts on these endpoints via its effects on vertebral body integrity. © 2022 American Society for Bone and Mineral Research (ASBMR)., (© 2022 American Society for Bone and Mineral Research (ASBMR).)

Accumulation of advanced glycation end-products (AGE) in bone alters collagen structure and function. Fluorescent AGEs are associated with fractures but less is known regarding non-fluorescent AGEs. We examined associations of carboxy-methyl-lysine (CML), with incident clinical and prevalent vertebral fractures by type 2 diabetes (T2D) status, in the Health, Aging, and Body Composition cohort of older adults. Incident clinical fractures and baseline vertebral fractures were assessed. Cox regression was used to analyze the associations between serum CML and clinical fracture incidence, and logistic regression for vertebral fracture prevalence. At baseline, mean ± standard deviation (SD) age was 73.7 ± 2.8 and 73.6 ± 2.9 years in T2D (n = 712) and non-diabetes (n = 2332), respectively. Baseline CML levels were higher in T2D than non-diabetes (893 ± 332 versus 771 ± 270 ng/mL, p < 0.0001). In multivariate models, greater CML was associated with higher risk of incident clinical fracture in T2D (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.24-1.79 per 1-SD increase in log CML) but not in non-diabetes (HR 1.03; 95% CI, 0.94-1.13; p for interaction = 0.001). This association was independent of bone mineral density (BMD), glycated hemoglobin (hemoglobin A1c), weight, weight loss, smoking, cystatin-C, and medication use. CML was not significantly associated with the odds of prevalent vertebral fractures in either group. In conclusion, higher CML levels are associated with increased risk of incident clinical fractures in T2D, independent of BMD. These results implicate CML in the pathogenesis of bone fragility in diabetes. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Greater kyphosis angles lead to increased loading on vertebral bodies in computational models. However, results about the relationship between severity of kyphosis and incident vertebral fracture (VF) risk have been conflicting. Therefore, the aim of this study was to evaluate associations between 1) prevalent VFs and severity of kyphosis, and 2) severity of kyphosis and incident VF risk in smokers with or without chronic obstructive pulmonary disease (COPD). Former and current smokers with or without COPD were included. CT scans were made at baseline, 1-year, and 3-year follow-up. VFs were evaluated on superposed sagittal CT reconstructions. Kyphosis was measured as the angle between the lines above T 4 and below T 9 or T 12 . We included 1239 subjects (mean age 61.3 ± 8.0 years, 61.1% male, 80.6% with COPD), of whom 253 (20.4%) had a prevalent VF and 294 (23.7%) an incident VF within 3 years. Presence, number, and severity of prevalent VFs were associated with a greater kyphosis angle. The mean increase in kyphosis angle within 3 years was small but significantly greater in subjects with incident VFs compared with those without (2.2 ± 4.1 versus 1.2 ± 3.9 degrees, respectively, for T 4 to T 12 angle, p < 0.001). After adjustment for bone attenuation (BA) and prevalent VFs, baseline kyphosis angle was associated with incident VFs within 1 and 3 years (angle T 4 to T 12 per +1 SD, hazard ratio [HR] = 1.34 [1.12-1.61] and HR 1.29 [1.15-1.45], respectively). Our data showed that a greater kyphosis angle at baseline was independently associated with increased risk of incident VFs within 1 and 3 years, supporting the theory that greater kyphosis angle contributes to higher biomechanical loads in the spine. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

The current diagnosis of osteoporosis is limited to a T-score ≤-2.5. However, asymptomatic vertebral fractures (VF) are known to predict a high risk of subsequent fractures and pharmaceutical intervention is known to reduce future fracture risk in these individuals. In a prospective, population-based cohort of ambulant older women, we sought to evaluate the role of VF detection by screening densitometric lateral spine imaging (LSI) for VF at time of bone density testing to the effect on the magnitude of fracture risk. A total of 1084 women (mean age 75 years ± SD 3 years) had baseline LSI that identified 100 (9%) women with VFs and 89 (8%) with femoral neck (FN) T-score osteoporosis ≤-2.5. Follow-up identified incident clinical spine fracture in 73 (7%), 305 (28%) with any fracture-related hospitalization, and 121 (11%) with a hip fracture-related hospitalization. Compared with those without baseline VF, in those with baseline VF, relative risk (RR) for incident clinical spine, hip, and any fracture were 3.46 (95% confidence interval [CI] 2.14-5.60, p < 0.001); 1.72 (95% CI 1.09-2.71, p = 0.02), and 1.4 (95% CI 1.07-1.84, p = 0.02), respectively. In 675 (62%) of women with femoral neck osteopenia (T-score <-1 to >-2.5), 61 (9%) also had a VF. Compared with those without baseline VF, RR for any incident fragility fractures and fractures at spine and hip in those with baseline VF were 1.6 (95% CI 1.2-2.1, p < 0.01), 3.9 (95% CI 2.2-6.9, p < 0.01), and 1.6 (95% CI 0.9-2.8, p = 0.10), respectively. On basis of the prognosis, older women with LSI VF with osteopenia should be diagnosed with osteoporosis and should be considered for pharmaceutical intervention. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

We sought to determine if vertebral trabecular attenuation values measured on routine body computed tomography (CT) scans obtained for a variety of unrelated indications can predict future osteoporotic fractures at multiple skeletal sites. For this Health Insurance Portability and Accountability Act (HIPAA)-compliant and Institutional Review Board (IRB)-approved retrospective cohort study, trabecular attenuation of the first lumbar vertebra was measured in 1966 consecutive older adults who underwent chest and/or abdominal CT at a single institution over the course of 1 year. New pathologic fragility fractures that occurred after a patient's CT study date were identified through an electronic health record database query using International Classification of Diseases (ICD)-9 codes for vertebral, hip, and extremity fractures. Univariate and multivariate Cox proportional hazards regression were performed to determine the effect of L 1 trabecular attenuation on fracture-free survival. Age at CT, sex, and presence of a prior fragility fracture were included as confounders in multivariate survival analysis. Model discriminative capability was assessed through calculation of an optimism-corrected concordance index. A total of 507 patients (mean age 73.4 ± 6.3 years; 277 women, 230 men) were included in the final analysis. The median post-CT follow-up interval was 5.8 years (interquartile range 2.1-11.0 years). Univariate analysis showed that L 1 attenuation values ≤90 Hounsfield units (HU) are significantly associated with decreased fracture-free survival (p < 0.001 by log-rank test). After adjusting for age, sex, prior fracture, glucocorticoid use, bisphosphonate use, chronic kidney disease, tobacco use, ethanol abuse, cancer history, and rheumatoid arthritis history, multivariate analysis demonstrated a persistent modest effect of L 1 attenuation on fracture-free survival (hazard ratio [HR] = 0.63 per 10-unit increase; 95% confidence interval [CI] 0.47-0.85). The model concordance index was 0.700. Ten-year probabilities for major osteoporosis-related fractures straddled the treatment threshold for most subcohorts over the observed L 1 HU range. In conclusion, for patients undergoing body CT scanning for any indication, L 1 vertebral trabecular attenuation is a simple measure that, when ≤90 HU, identifies patients with a significant decrease in fracture-free survival. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Trabecular bone score (TBS) is a gray-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual-level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow-up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. © 2015 American Society for Bone and Mineral Research., (© 2015 American Society for Bone and Mineral Research.)

Somewhat paradoxically, fracture risk, which depends on applied loads and bone strength, is elevated in both anorexia nervosa and obesity at certain skeletal sites. Factor-of-risk (Φ), the ratio of applied load to bone strength, is a biomechanically based method to estimate fracture risk; theoretically, higher Φ reflects increased fracture risk. We estimated vertebral strength (linear combination of integral volumetric bone mineral density [Int.vBMD] and cross-sectional area from quantitative computed tomography [QCT]), vertebral compressive loads, and Φ at L4 in 176 women (65 anorexia nervosa, 45 lean controls, and 66 obese). Using biomechanical models, applied loads were estimated for: 1) standing; 2) arms flexed 90°, holding 5 kg in each hand (holding); 3) 45° trunk flexion, 5 kg in each hand (lifting); 4) 20° trunk right lateral bend, 10 kg in right hand (bending). We also investigated associations of Int.vBMD and vertebral strength with lean mass (from dual-energy X-ray absorptiometry [DXA]) and visceral adipose tissue (VAT, from QCT). Women with anorexia nervosa had lower, whereas obese women had similar, Int.vBMD and estimated vertebral strength compared with controls. Vertebral loads were highest in obesity and lowest in anorexia nervosa for standing, holding, and lifting (p < 0.0001) but were highest in anorexia nervosa for bending (p < 0.02). Obese women had highest Φ for standing and lifting, whereas women with anorexia nervosa had highest Φ for bending (p < 0.0001). Obese and anorexia nervosa subjects had higher Φ for holding than controls (p < 0.03). Int.vBMD and estimated vertebral strength were associated positively with lean mass (R = 0.28 to 0.45, p ≤ 0.0001) in all groups combined and negatively with VAT (R = -[0.36 to 0.38], p < 0.003) within the obese group. Therefore, women with anorexia nervosa had higher estimated vertebral fracture risk (Φ) for holding and bending because of inferior vertebral strength. Despite similar vertebral strength as controls, obese women had higher vertebral fracture risk for standing, holding, and lifting because of higher applied loads from higher body weight. Examining the load-to-strength ratio helps explain increased fracture risk in both low-weight and obese women., (© 2015 American Society for Bone and Mineral Research.)

Hyponatremia may be a risk factor for fracture. To determine the relationship between hyponatremia and fracture we conducted cross-sectional and longitudinal analyses using data from the Osteoporotic Fractures in Men (MrOS) study. The MrOS study enrolled 5122 community dwelling men aged ≥65 years from six centers across the United States. We excluded men taking bisphosphonates, those with unknown medication history, those without serum sodium measures, or those with out of range assays for serum sodium. Serum sodium was measured at study entry. Subjects were followed for fractures (nonspine [including hip], hip, incident morphometric, and prevalent morphometric) for up to 9 years. We used Cox proportional hazards models to analyze the association between serum sodium levels (<135 mmol/L versus ≥135 mmol/L) and risk of nonspine and hip fractures, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). We examined the association between morphometric vertebral fractures and serum sodium using logistic regression models, presented as odds ratios (ORs) and 95% CI. Hyponatremia was observed in 64 men (1.2% of the cohort). After adjusting for age, BMI, study center, and other covariates, we found that, compared to men with serum sodium ≥135 mmol/L, those with serum sodium <135 mmol/L, had an increased risk of hip fracture (HR = 3.04; 95% CI, 1.37 to 6.75), prevalent morphometric spine fracture (OR = 2.46; 95% CI, 1.22 to 4.95), and incident morphometric spine fracture (OR = 3.53; 95% CI, 1.35 to 9.19), but not nonspine fracture (OR = 1.44; 95% CI, 0.85 to 2.44). Adjusting for bone mineral density (BMD) did not change our findings. Our data show that hyponatremia is associated with up to a doubling in the risk of hip and morphometric spine fractures, independent of BMD. Further studies, to determine how hyponatremia causes fractures and if correction of hyponatremia decreases fractures, are needed., (© 2015 American Society for Bone and Mineral Research.)

The objective of this work was to study the associations between ankylosing spondylitis (AS) and clinical vertebral and nonvertebral fractures. Data from a large population-based public health database in Spain, Sistema d'Informació per al Desenvolupament de l'Investigació en Atenció Primària (SIDIAP), were used in this parallel cohort study. All participants registered in SIDIAP on January 1, 2006, were screened to identify those with a diagnosis of AS. Five age-matched, gender-matched, and general practice surgery-matched controls were selected for each patient with AS. All participants were followed until December 31, 2011, transfer out date, or death date. Fractures during this time were classified as vertebral or nonvertebral. Adjustment was made for potential confounders (tobacco smoking, alcohol consumption, body mass index, and use of oral steroids). Of 4,920,353 eligible patients in SIDIAP, 6474 AS patients with matched controls (n = 32,346) were available. A higher proportion of patients with AS versus controls had clinical vertebral (0.86% versus 0.41%) and nonvertebral (3.4% versus 2.7%) fractures. Adjusted Cox regression models showed an increased risk of clinical vertebral (hazard ratio [HR] 1.93; 95% confidence interval [CI], 1.39 to 2.68; p < 0.001) and nonvertebral (HR 1.19; 95% CI, 1.02 to 1.39; p = 0.03) fractures among patients with AS. However, the observed increased risks were apparent only in those not on regular nonsteroidal anti-inflammatory drugs (NSAIDs). There were no interactions with inflammatory bowel disease, psoriasis, or previous back pain. Patients with AS are at increased risk of vertebral and nonvertebral clinical fractures, independently of various risk factors. Regular use of NSAIDs appears to eliminate the excess fracture risk related to AS, but the mechanisms involved are unknown., (© 2014 American Society for Bone and Mineral Research.)

Prospective studies that have examined the association between physical activity and fracture risks have reported conflicting findings. We performed a meta-analysis to evaluate this association. We searched MEDLINE (1966 to February 1, 2013), EMBASE (1980 to February 1, 2013), and OVID (1950 to February 1, 2013) for prospective cohort studies with no restrictions. Categorical, heterogeneity, publication bias, and subgroup analyses were performed. There were 22 cohort studies with 1,235,768 participants and 14,843 fractures, including 8874 hip, 690 wrist, and 927 vertebral fractures. The pooled relative risk (RR) of total fractures for the highest versus lowest category of physical activity was 0.71 (95% confidence interval [CI], 0.63-0.80). The analysis of fracture subtypes showed a statistically significant inverse relationship between a higher category of physical activity and risk of hip and wrist fracture. The risk of hip or wrist fracture was 39% and 28% lower, respectively, among individuals with the highest category of physical activity than among those with the lowest category (95% CI, 0.54-0.69 and 0.49-0.96, respectively). The association between physical activity and vertebral fracture risk was not statistically related (RR, 0.87; 95% CI, 0.72-1.03). There was no evidence of publication bias. There was a statistically significant inverse association between physical activity and total fracture risk, especially for hip and wrist fractures. Additional subject-level meta-analyses are required for a more reliable assessment of subgroups and types of physical activity., (© 2014 American Society for Bone and Mineral Research.)

We have recently observed an increased risk for vertebral fractures (VF) in a randomized controlled trial comparing the analgesic effect of vertebroplasty (VP) versus conservative treatment in symptomatic VF. The aim of the present study was to evaluate the risk factors related to the development of VF after VP in these patients. We evaluated risk factors including age, gender, bone mineral density, the number, type, and severity of vertebral deformities at baseline, the number of vertebral bodies treated, the presence and location of disk cement leakage, bone remodeling (determining bone turnover markers) and 25 hydroxyvitamin D [25(OH)D] levels at baseline in all patients. Twenty-nine radiologically new VF were observed in 17 of 57 patients undergoing VP, 72% adjacent to the VP. Patients developing VF after VP showed an increased prevalence of 25(OH)D deficiency (<20 ng/mL) and higher P1NP values. The principal factor related to the development of VF after VP in multivariate analysis was 25(OH)D levels < 20 ng/mL (RR, 15.47; 95% CI, 2.99-79.86, p < 0.0001), whereas age >80 years (RR, 3.20; 95% CI, 1.70-6.03, p = 0.0007) and glucocorticoid therapy (RR, 3.64; 95% CI, 1.61-8.26, p = 0.0055) constituted the principal factors in the overall study population. Increased risk of VF after VP was also associated with cement leakage into the inferior disk (RR, 6.14; 95% CI, 1.65-22.78, p = 0.044) and more than one vertebral body treated during VP (RR, 4.19; 95% CI, 1.03-34.3, p = 0.044). In conclusion, nearly 30% of patients with osteoporotic VF treated with VP had a new VF after the procedure. Age, especially >80 years, the presence of inferior disk cement leakage after the procedure, the number of cemented vertebrae, and low 25(OH)D serum levels were related to the development of new VF in these patients, with the latter indicating the need to correct vitamin D deficiency prior to performing VP., (Copyright © 2013 American Society for Bone and Mineral Research.)

Approximately 12% of postmenopausal women have osteoporotic vertebral fractures (VFs); these are associated with excess morbidity and mortality and a high risk of future osteoporotic fractures. Despite this, less than one-third come to clinical attention, partly due to lack of clear clinical triggers for referral for spinal radiographs. The aim of this study was to investigate whether a novel primary care-based screening tool could be used to identify postmenopausal women with osteoporotic VFs and increase appropriate management of osteoporosis. A randomized controlled trial was undertaken in 15 general practices within the Bristol area of the UK. A total of 3200 women aged 65 to 80 years were enrolled, with no exclusion criteria. A simple screening tool was carried out by a nurse in primary care to identify women at high risk of osteoporotic VFs. All identified high-risk women were offered a diagnostic thoracolumbar radiograph. Radiographs were reported using standard National Health Service (NHS) reporting, with results sent back to each participant's general practitioner (GP). Participants in the control arm did not receive the screening tool or radiographs. The main outcome measure was self-reported prescription of medication for osteoporosis at 6 months with a random 5% subsample verified against electronic GP records. Secondary outcome was self-reported incidence of new fractures. Results showed that allocation to screening increased prescription of osteoporosis medications by 124% (odds ratio [OR] for prescription 2.24 at 6 months; 95% confidence interval [CI], 1.16 to 4.33). Allocation to screening also reduced fracture incidence at 12-month follow-up (OR for new fracture 0.60; 95% CI, 0.35-1.03; p = 0.063), although this did not reach statistical significance. This study supports the use of a simple screening tool administered in primary care to increase appropriate prescription of medications for osteoporosis in postmenopausal women in the UK., (© 2012 American Society for Bone and Mineral Research)

We examined if height loss in older women predicts risk of hip fractures, other nonspine fractures, and mortality, and whether this risk is independent of both vertebral fractures (VFx) and bone mineral density (BMD) by dual-energy X-ray absorptiometry. Among 3124 women age 65 and older in the Study of Osteoporotic Fractures, we assessed the association with measured height change between year 0 (1986-1988) and year 15 (2002-2004) and subsequent risk of radiologically confirmed hip fractures, other nonspine fractures, and mortality assessed via death certificates. Follow-up occurred every 4 months for fractures and vital status (>95% contacts complete). Cox proportional hazards models assessed risk of hip fracture, nonspine fracture, and mortality over a mean of 5 years after height change was assessed (ie, after final height measurement). After adjustment for VFx, BMD, and other potential covariates, height loss >5 cm was associated with a marked increased risk of hip fracture [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.06, 2.12], nonspine fracture (HR 1.48; 95% CI 1.20, 1.83), and mortality (1.45; 95% CI 1.21, 1.73). Although primary analyses were a subset of 3124 survivors healthy enough to return for a year 15 height measurement, a sensitivity analysis in the entire cohort (n = 9677) using initial height in earlier adulthood [self-reported height at age 25 (-40 years) to measured height age >65 years (Year 0)] demonstrated consistent results. Height loss >5 cm (2″) in older women was associated with a nearly 50% increased risk of hip fracture, nonspine fracture, and mortality-independent of incident VFx and BMD., (Copyright © 2012 American Society for Bone and Mineral Research.)

In patients with adrenal incidentalomas (AIs), cross-sectional studies suggested the presence of an association between subclinical hypercortisolism (SH) and an increased prevalence of vertebral fractures (VFx) and spinal deformity index (SDI), which is a clinical index of bone quality. No longitudinal studies investigated the incidence of VFx and SDI changes over time in SH. The aim of this study was to evaluate VFx risk and SDI changes in SH over time. One-hundred-three consecutive AI patients were studied at baseline and after 12 and 24 months. Patients were divided into SH(+) (n = 27) and SH(-) (n = 76) groups on the basis of the presence of two or more among urinary free cortisol greater than 70 µg/24 hours, serum cortisol after 1-mg dexamethasone suppression test greater than 3.0 µg/dL, and adrenocorticotropic hormone (ACTH) less than 10 pg/mL in 2 or more of the 3 evaluations. At baseline and after 24 months, bone mineral density (BMD) by dual-energy X-ray absorptiometry and the presence of VFx and SDI by summing the grade of deformity for each vertebra were evaluated. At the end of follow-up, the SH(+) group showed a higher prevalence of VFx (81.5%) as compared with baseline (55.6%, p = .04) and a worsening of SDI (2.11 ± 1.85 versus 1.11 ± 1.47, p = .032) associated with SH regardless of age, gender, body mass index , BMD, baseline SDI, menopause duration [odds ratio (OR) = 12.3, 95% confidence interval (CI) 4.1-36.5, p = .001]. The incidence of new vertebral fractures was higher in the SH(+) group (48%) than in the SH(-) group (13%; p = .001). It is concluded that subclinical hypercortisolism is associated with an increased risk of VFx and a possible deterioration of bone quality., (Copyright © 2011 American Society for Bone and Mineral Research.)

The aim of this study was to investigate the association between smoking and bone mineral density (BMD) and radiographically verified prevalent vertebral fractures and incident fractures in elderly men. At baseline 3003 men aged 69 to 80 years of age from the Swedish Mr Os Study completed a standard questionnaire concerning smoking habits and had BMD of the hip and spine measured using dual-energy X-ray absorptiometry (DXA); 1412 men had an X-ray of the thoracic- and lumbar spine. Radiologic registers were used to confirm reported new fractures after the baseline visit. At baseline, 8.4% were current smokers. Current smokers had a 6.2% lower BMD at the total hip and a 5.4% lower BMD at the lumbar spine (p < .001). Current smoking remained independently inversely associated with BMD at the hip and lumbar spine after adjusting for age, height, weight, calcium intake, physical activity, and centers as covariates. Prevalent vertebral fractures among current smokers were increased in unadjusted analyses [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.26-2.87] and after adjustment for lumbar BMD (OR = 1.67, 95% CI 1.09-2.55). Smokers had a high risk for two or more prevalent vertebral fractures (OR = 3.18, 95% CI 1.88-5.36). During the average follow-up of 3.3 years, 209 men sustained an X-ray-verified fracture. Incident fracture risk among smokers was calculated with Cox proportional hazard models. Current smokers had an increased risk of all new fractures [hazard ratio (HR) = 1.76, 95% CI 1.19-2.61]; nonvertebral osteoporotic fractures, defined as humerus, radius, pelvis, and hip fractures (HR = 2.14, 95% CI 1.18-3.88); clinical and X-ray-verified vertebral fractures (HR = 2.53, 95% CI 1.37-4.65); and hip fractures (HR = 3.16, 95% CI 1.44-6.95). After adjustment for BMD, including other covariates, no significant association between smoking and incident fractures was found. Current tobacco smoking in elderly men is associated with low BMD, prevalent vertebral fractures, and incident fractures, especially vertebral and hip fractures., ((c) 2010 American Society for Bone and Mineral Research.)

Bone morbidity remains a major problem even after successful renal transplantation. We investigated the role of calcium-sensing receptor (CaSR) polymorphisms and 25-hydroxyvitamin D levels on the persistence of secondary hyperparathyroidism (SHPT) and their relationships with vertebral fractures (VFx) in 125 renal allograft recipients transplanted 44 +/- 23 months before. All patients underwent evaluation of the main biochemical parameters of calcium metabolism as well as vertebral and femoral bone density. In 87 patients, CaSR polymorphisms (A986S, R990G, and Q1011E) also were assessed. X-ray images of the lateral spine were obtained in 102 subjects to perform vertebral morphometry. High parathyroid hormone (PTH) and 25-hydroxyvitamin D lower than 80 nmol/L were found in 54% and 97% of patients, respectively, with 40% of these showing vitamin D levels lower than 30 nmol/L. VFx were detected in 57% of the subjects. After multiple adjustments, 25-hydroxyvitamin D, age, and hemodialysis duration, but not CaSR polymorphisms, were found to be significant predictors of high PTH, whereas age and time since transplant were positively related with lower 25-hydroxyvitamin D values. PTH and time since transplant were significantly associated with VFx. Patients with two or more VFx showed serum PTH levels 50% higher than patients without fractures. We therefore conclude that persistent SHPT is a very common feature after renal transplantation and that, unlike CaSR polymorphisms, low 25-hydroxyvitamin D is involved in its pathogenesis. High PTH levels, in turn, are associated with an increased VFx risk, which confirms the need for strategies aimed at lowering serum PTH in this setting as well., (Copyright 2010 American Society for Bone and Mineral Research.)

We attempt to assess quantitatively thoracic kyphosis and its influence on incident fractures and quality of life over three years in postmenopausal women with osteoporosis and the effect of strontium ranelate on thoracic kyphosis progression. This study was performed on women with postmenopausal osteoporosis from the Spinal Osteoporosis Therapeutic Intervention (SOTI) and Treatment of Peripheral Osteoporosis (TROPOS) studies. Vertebral fractures were assessed on lateral thoracic radiographs performed at baseline and at three years according to standardized procedure. Kyphosis index (KI, %), was defined as the percentage ratio between the maximum depth of thoracic curvature and the height measured from the T4 to the T12 vertebrae. Baseline characteristics of the 3218 patients (1594 strontium ranelate, 1624 placebo) were mean age 73.3 years, spine bone mineral density (BMD) T-score (L2-4) -3.1, femoral neck T-score -3.0, and KI 25.4%. In the placebo group, patients with the highest baseline KI experienced significantly more vertebral fractures than those with medium KIs [relative risk (RR) = 1.53; 95% confidence interval (CI) 1.19-1.96, p < .001) or the lowest KIs (RR = 1.70, 95%CI 1.32-2.21, p < .001), even after adjusting for the presence of prevalent fractures, age, body mass index (BMI), and BMD. There was no difference in the risk of nonvertebral fractures according to baseline KI. Three-year changes in quality-of-life physical scores reflected significantly better status for patients in the lowest tertile of KI compared with those in the highest at baseline. Over three years, the KI increased for all patients, indicating worsening of thoracic kyphosis, whatever the presence of prevalent or incident vertebral fractures. This KI progression was lower in the strontium ranelate group than in the placebo group. Thoracic kyphosis is a risk factor for vertebral fractures over three years and influences physical capacity changes in postmenopausal women with osteoporosis. Thoracic kyphosis progression over three years is lower in a subgroup of strontium ranelate-treated patients compared with placebo-treated patients., (Copyright 2010 American Society for Bone and Mineral Research.)

Low radiation dose imaging of the lateral spine acquired with a bone densitometer for vertebral fracture assessment (VFA) has great potential for clinical use. We have undertaken an evaluation of VFA in a prospective population cohort of elderly women to examine the prevalence of vertebral fractures, their ability to predict incident fractures, and their use in targeting therapy. Women (n = 5157) >or=75 yr of age living in the general community in the United Kingdom underwent posteroanterior and lateral imaging of the spine (T(4)-L(4)) with a densitometer (Hologic QDR4500A) at entry to a randomized, double-blind, controlled trial of 800 mg oral clodronate (Bonefos) or matching placebo daily over 3 yr. The women were identified from general practice registers and recruited by letter of invitation regardless of skeletal status. The proportion of vertebrae interpretable varied from 98.2% at T(12) to 57.1% at T(4), with >92% interpretable at levels between T(8) and L(3). As judged by BMD at the total hip, 19.6% of the women had osteoporosis, and the prevalence of vertebral fracture was 14.5%. Women with one or more vertebral fractures had a relative risk (RR) for incident osteoporotic fractures of 2.01 (95% CI, 1.64-2.47). The RR for hip fractures was 2.29 (95% CI, 1.63-3.21). After adjustment for age, femoral neck BMD, weight, and treatment, the RR was 1.50 (95% CI, 1.21-1.86) for osteoporotic fractures, with similar results for hip fractures (RR, 1.41; 95% CI, 0.99-2.02). For women with two or more vertebral fractures, the adjusted RRs were 1.97 (95% CI, 1.24-2.72) and 1.86 (95% CI, 1.14-3.03) for osteoporotic and hip fractures, respectively. We conclude that VFA can frequently detect vertebral fractures in a population cohort of elderly women. These fractures, like radiographic fractures, predict future clinical fractures independent of age, weight, and BMD. Having multiple vertebral fractures was associated with greater risk of incident osteoporotic fractures and hip fractures.

Unlabelled: We compared SQ and ABQ diagnosis of VF imaged by radiography and X-ray absorptiometry. Mild ABQ VF had stronger associations with osteoporosis than mild SQ VF. Interobserver agreement (radiographic diagnosis) was better for ABQ., Introduction: Vertebral fracture (VF) assessment from images acquired by X-ray absorptiometry (VFA) is often based on a semiquantitative approach (SQ); prevalent VF is identified if vertebral height appears reduced by >20%. Algorithm-based qualitative definition of osteoporotic VF (ABQ) requires evidence of endplate depression, and there is no threshold for reduction in vertebral height. The aims of this study were to (1) compare the prevalence of VFs; (2) compare the characteristics of women with and without VFs; (3) compare interobserver agreement; and (4) compare agreement between methods and imaging modalities for ABQ and SQ definitions of VFs., Materials and Methods: Spine radiographs and absorptiometry images for 203 elderly women were assessed using ABQ (readers ABQ-1 and ABQ-2). These readings were compared with SQ assessments (readers SQ-1 and SQ-2) of the same images performed in a previous study. Agreement between readers and methods was assessed by kappa (kappa) statistics., Results: The prevalence of VF was 15-18% (radiography) and 12-24% (VFA) for ABQ and SQ, respectively. Women with ABQ or SQ fractures were older and had lower BMD than those without fracture (p < 0.01). Mild ABQ (but not SQ) VF was associated with low BMD. Kappa scores for interobserver agreement for radiography and VFA, respectively, were as follows: ABQ, kappa = 0.74 (95% CI, 0.60, 0.87) and 0.65 (95% CI, 0.48, 0.81); SQ, kappa = 0.53 (95% CI, 0.46, 0.60) and 0.51 (95% CI, 0.44, 0.58). For agreement between ABQ-1 and SQ-1, kappa = 0.55 (95% CI, 0.39, 0.72) for radiography and 0.41 (95% CI, 0.25, 0.58 for VFA., Conclusions: The prevalence of radiographic VF identified by ABQ and SQ was similar, but on VFA was 50% higher for SQ. Mild ABQ VF was associated with low BMD. Interobserver agreement for radiographic diagnosis was significantly better for ABQ than for SQ. Agreement between ABQ and SQ was moderate.

Unlabelled: Many fractures occur in women with moderate fracture risk caused by osteopenia. Strontium ranelate was studied in 1431 postmenopausal women with osteopenia. Vertebral fracture risk reduction of 41-59% was shown depending on the site and fracture status at baseline. This is the first report of antivertebral fracture efficacy in women with vertebral osteopenia., Introduction: Women with osteoporosis are at high risk for fracture. However, more than one half of all fractures in the community originate from the larger population at more moderate risk of fracture caused by osteopenia. Despite this, evidence for antifracture efficacy in these persons is limited. The aim of this study was to determine whether strontium ranelate, a new drug that reduces fracture risk in women with osteoporosis, is also effective in women with osteopenia., Materials and Methods: Data from the Spinal Osteoporosis Therapeutic Intervention study (SOTI; n = 1649) and the TReatment Of Peripheral OSteoporosis (TROPOS; n = 5091) were pooled to evaluate the antivertebral fracture efficacy of strontium ranelate in women with lumbar spine (LS) osteopenia with any BMD value at the femoral neck (FN; N = 1166) and in 265 women with osteopenia at both sites (intention-to-treat analysis). The women were randomized to strontium ranelate 2 g/d orally or placebo for 3 yr., Results: No group differences were present in baseline characteristics that may influence fracture outcome independent of therapy. In women with LS osteopenia, treatment reduced the risk of vertebral fracture by 41% (RR = 0.59; 95% CI, 0.43-0.82), by 59% (RR = 0.41; 95% CI, 0.17-0.99) in the 447 patients with no prevalent fractures, and by 38% (RR = 0.62; 95% CI, 0.44-0.88) in the 719 patients with prevalent fractures. In women with osteopenia at both sites, treatment reduced the risk of fracture by 52% (RR = 0.48; 95% CI, 0.24-0.96)., Conclusions: Strontium ranelate safely reduces the risk of vertebral fractures in women with osteopenia with or without a prevalent fracture.

Unlabelled: Risk factors may vary for different types of fracture, in particular for vertebral fractures. We followed 367 women >50 yr of age from a population-based cohort for up to 10 yr. Factors that predicted vertebral rather than nonvertebral fractures related to physical weakness, poor health, and weight loss. Similar factors were also associated with greater bone loss at the hip., Introduction: Many risk factors predict fractures overall, but it is less clear whether certain factors relate to vertebral fractures in particular. The aim of this study was to compare the risk factors for vertebral and nonvertebral fractures., Materials and Methods: We carried out a 10-yr prospective population-based study of 375 women who were 50-85 yr of age initially. At baseline, we measured BMD, blood and urine biochemistry, and anthropometric measurements. Medical and lifestyle data were obtained by questionnaire. Incident vertebral fractures were determined for 311 subjects from spinal radiographs at 0, 2, 5, 7, and 10 yr using an algorithm-based qualitative method, and nonvertebral fractures were confirmed radiographically. Relative risks were calculated by Cox regression analysis., Results: During follow-up, 70 subjects sustained one or more nonvertebral fractures and 29 sustained one or more vertebral fractures. Risk factors that predicted both types of fracture included increasing age, decreasing BMD at all sites, prevalent vertebral fracture, and shorter estrogen exposure. For nonvertebral fractures only, the risk factors included low urinary creatinine and less frequent use of stairs. The factors for vertebral fractures included lighter weight, reduced body fat, heavy smoking, lower serum calcium, albumin, and thyroid T(3), weak grip strength, and poor physical capability. In a multivariate model, weight, fat mass, serum calcium and T(3), prevalent vertebral fracture, and physical capability remained significant. Furthermore, grip strength, serum albumin, weight loss, and physical capability were associated with rate of bone loss at the femoral neck, and a fast rate of bone loss was also associated with vertebral fractures., Conclusions: We conclude that overall frailty, which may consist of general poor health, small or thin body size, and lack of strength and physical capability, predicts vertebral fractures but is not a significant predictor of nonvertebral fractures. Bone loss rates are associated with similar risk factors and also with the incidence of vertebral fractures.

Unlabelled: Vertebral fractures are more strongly associated with specific bone density, structure, and strength parameters than with areal BMD, but all of these variables are correlated., Introduction: It is unclear whether the association of areal BMD (aBMD) with vertebral fracture risk depends on bone density per se, bone macro- or microstructure, overall bone strength, or spine load/bone strength ratios., Materials and Methods: From an age-stratified sample of Rochester, MN, women, we identified 40 with a clinically diagnosed vertebral fracture (confirmed semiquantitatively) caused by moderate trauma (cases; mean age, 78.6 +/- 9.0 yr) and compared them with 40 controls with no osteoporotic fracture (mean age, 70.9 +/- 6.8 yr). Lumbar spine volumetric BMD (vBMD) and geometry were assessed by central QCT, whereas microstructure was evaluated by high-resolution pQCT at the ultradistal radius. Vertebral failure load ( approximately strength) was estimated from voxel-based finite element models, and the factor-of-risk (phi) was determined as the ratio of applied spine loads to failure load., Results: Spine loading (axial compressive force on L3) was similar in vertebral fracture cases and controls (e.g., for 90 degrees forward flexion, 2639 versus 2706 N; age-adjusted p = 0.173). However, fracture cases had inferior values for most bone density and structure variables. Bone strength measures were also reduced, and the factor-of-risk (phi) was 35-37% greater (worse) among women with a vertebral fracture. By age-adjusted logistic regression, relative risks for the strongest fracture predictor in each of the five main variable categories were bone density (total lumbar spine vBMD: OR per SD change, 2.2; 95% CI, 1.1-4.3), bone geometry (vertebral apparent cortical thickness: OR, 2.1; 95% CI, 1.1-4.1), bone microstructure (none significant); bone strength ("cortical" [outer 2 mm] compressive strength: OR, 2.5; 95% CI, 1.3-4.8), and factor-of-risk (phi for 90 degrees forward flexion/overall vertebral compressive strength: OR, 3.2; 95% CI, 1.4-7.5). These variables were correlated with spine aBMD (partial r, -0.32 to 0.75), but each was a stronger predictor of fracture in the logistic regression analyses., Conclusions: The association of aBMD with vertebral fracture risk is explained by its correlation with more specific bone density, structure, and strength parameters. These may allow deeper insights into fracture pathogenesis.

Unlabelled: In a sample of 1358 women and 858 men, > or = 60 yr of age who have been followed-up for up to 15 yr, it was estimated that the mortality-adjusted residual lifetime risk of fracture was 44% for women and 25% for men. Among those with BMD T-scores < or = -2.5, the risks increased to 65% in women and 42% in men., Introduction: Risk assessment of osteoporotic fracture is shifting from relative risk to an absolute risk approach. Whereas BMD is a primary predictor of fracture risk, there has been no estimate of mortality-adjusted lifetime risk of fracture by BMD level. The aim of the study was to estimate the residual lifetime risk of fracture (RLRF) in elderly men and women., Materials and Methods: Data from 1358 women and 858 men > or = 60 yr of age as of 1989 of white background from the Dubbo Osteoporosis Epidemiology Study were analyzed. The participants have been followed for up to 15 yr. During the follow-up period, incidence of low-trauma, nonpathological fractures, confirmed by X-ray and personal interview, were recorded. Incidence of mortality was also recorded. BMD at the femoral neck was measured by DXA (GE-LUNAR) at baseline. Residual lifetime risk of fracture from the age of 60 was estimated by the survival analysis taking into account the competing risk of death., Results: After adjusting for competing risk of death, the RLRF for women and men from age 60 was 44% (95% CI, 40-48) and 25% (95% CI, 19-31), respectively. For individuals with osteoporosis (BMD T-scores < or = -2.5), the mortality-adjusted lifetime risk of any fracture was 65% (95% CI, 58-73) for women and 42% (95% CI, 24-71) for men. For the entire cohort, the lifetime risk of hip fracture was 8.5% (95% CI, 6-11%) for women and 4% (95% CI, 1.3-5.4%) for men; risk of symptomatic vertebral fracture was 18% (95% CI, 15-21%) for women and 11% (95% CI, 7-14%) for men., Conclusions: These estimates provide a means to communicate the absolute risk of fracture to an individual patient and can help promote the identification and targeting of high-risk individuals for intervention.

Unlabelled: Expert physicians and automated methods for the exclusion of vertebral levels in DXA scans containing focal artifacts were compared. All methods of vertebral exclusion led to a small improvement in fracture prediction. Computer algorithms performed at least as well as physicians., Introduction: Lumbar spine DXA is often confounded by focal artifacts. Clinical rules and automated methods for vertebral exclusion have been proposed, but their concordance, effect on diagnosis, and fracture prediction is unknown., Materials and Methods: We analyzed clinical DXA scans of the lumbar spine (20,478 women and 1534 men) performed from 1998 to 2002 (Province of Manitoba, Canada). Longitudinal health service records were assessed for the presence of nontrauma fracture codes after BMD testing. The effect of vertebral exclusions by expert physicians and several automated methods on diagnosis and prediction of incident fractures was compared., Results: Vertebral exclusions were reported by physicians in over one quarter of the scans (31% of women and 29% of men). All methods of vertebral exclusion significantly decreased the mean spine T-score and increased the proportion of women designated as osteoporotic. kappa values and ROC area under the curve (AUC) for physician-computer agreement in the identification of abnormal scans indicated fair to moderate agreement in both women and men. Compared with no vertebral exclusions, a small increase in the hazard ratio and AUC for spine fracture and osteoporotic fracture prediction was seen after physician and computer exclusions. Compared with physician exclusions, AUC for prediction of osteoporotic fractures in men increased significantly with one computer algorithm (p = 0.004). The minimum vertebral T-score enhanced fracture prediction compared with no exclusions but approximately doubled the prevalence of osteoporotic categorization., Conclusions: We observed fair to moderate agreement between the physician and computer methods for vertebral level exclusion. All methods of vertebral exclusion led to a small improvement in fracture prediction using the lumbar spine measurement. The automated algorithms performed at least as well as physicians when fractures were used as the endpoint.

Unlabelled: Using iliac bone histomorphometry on 78 patients with vertebral fracture and 66 healthy postmenopausal women, cortical thickness discriminated at least as well as any cancellous bone structural index between the two groups. Subjects with a deficit in both cortical and cancellous bone had much greater likelihood of fracture., Introduction: Vertebral fracture is often attributed to disproportional loss of cancellous bone, but fracture patients may have deficits in cortical and cancellous bone. Accordingly, we examined the contribution of cortical and cancellous bone deficits, separately and together, to the likelihood of vertebral fracture., Materials and Methods: Iliac bone histomorphometry was performed in 78 white woman with clinically apparent vertebral fracture, 66 healthy postmenopausal women, and 38 healthy premenopausal women. We measured cancellous bone volume (Cn.BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), cortical bone volume (Ct.BV/TV), and cortical thickness (Ct.Th). For each variable, a value of >1 SD below the mean in premenopausal women was treated as a putative risk factor, and its association with the presence or absence of fracture was determined by OR calculated by logistic regression and by receiver operating characteristic (ROC) curve analysis. Subsets of fracture and control subjects were separately matched for Cn.BV/TV and Ct.Th., Results: All structural indices differed between fracture patients and controls except Ct.BV/TV. There was a weak but highly significant correlation between Cn.BV/TV and Ct.Th in the entire group (r = 0.389, r(2) = 0.151 p < 0.001). Many control subjects had a high value for one of these variables and a low value for the other. Ct.Th., Cn.BV/TV, and Tb.N were all significantly associated with vertebral fracture (ORs, 4.4-5.8; ROC area under the curve [AUC], 0.74-0.85). In subjects matched for Cn.BV/TV, Ct.Th was reduced by 29% (OR, 5.0), and in subjects matched for Ct.Th, Cn.BV/TV was reduced by 27% (OR, 5.0). In patients with deficits in both cortical and cancellous bone, the ORs ( 28-35 ) were much higher., Conclusions: Deficits in cortical bone (reduced value for Ct.Th) and in cancellous bone (reduced values for Cn.BV/TV or Tb.N) were equally effective in discriminating between subjects with and without vertebral fracture. With a deficit in both cortical and cancellous bone, the association with vertebral fracture was much stronger. Vertebral fracture is not the result of disproportionate loss of cancellous bone in the patients as a whole, although individual patients may have relatively greater deficits in either cancellous or cortical bone.

Unlabelled: Mechanical experiments on cadaveric thoracolumbar spine specimens showed that intervertebral disc degeneration was associated with reduced loading of the anterior vertebral body in upright postures. Reduced load bearing corresponded to locally reduced BMD and inferior trabecular architecture as measured by histomorphometry. Flexed postures concentrated loading on the weakened anterior vertebral body, leading to compressive failure at reduced load., Introduction: Osteoporotic fractures are usually attributed to age-related hormonal changes and inactivity. However, why should the anterior vertebral body be affected so often? We hypothesized that degenerative changes in the adjacent intervertebral discs can alter load bearing by the anterior vertebral body in a manner that makes it vulnerable to fracture., Materials and Methods: Forty-one thoracolumbar spine "motion segments" (two vertebrae and the intervertebral disc) were obtained from cadavers 62-94 years of age. Specimens were loaded to simulate upright standing and flexed postures. A pressure transducer was used to measure the distribution of compressive "stress" inside the disc, and stress data were used to calculate how compressive loading was distributed between the anterior and posterior halves of the vertebral body and the neural arch. The compressive strength of each specimen was measured in flexed posture. Regional volumetric BMD and histomorphometric parameters were measured., Results: In the upright posture, compressive load bearing by the neural arch increased with disc degeneration, averaging 63 +/- 22% (SD) of applied load in specimens with severely degenerated discs. In these specimens, the anterior half of the vertebral body resisted only 10 +/- 8%. The anterior third of the vertebral body had a 20% lower trabecular volume fraction, 16% fewer trabeculae, and 28% greater intertrabecular spacing compared with the posterior third (p < 0.001). In the flexed posture, flexion transferred 53-59% of compressive load bearing to the anterior half of the vertebral body, regardless of disc degeneration. Compressive strength measured in this posture was proportional to BMD in the anterior vertebral body (r2 = 0.51, p < 0.001) and inversely proportional to neural arch load bearing in the upright posture (r2 = 0.28, p < 0.001)., Conclusions: Disc degeneration transfers compressive load bearing from the anterior vertebral body to the neural arch in upright postures, reducing BMD and trabecular architecture anteriorly. This predisposes to anterior fracture when the spine is flexed.

Unlabelled: Strontium ranelate produces an early and sustained reduction of both vertebral and nonvertebral fractures in patients > or = 80 years of age., Introduction: About 25-30% of the population burden of all fragility fractures in the community arise from women > or = 80 years of age, because this population is at high risk for all types of fracture, particularly nonvertebral fractures. Despite this, evidence that therapies reduce the risk of both vertebral and nonvertebral fractures in this group is lacking. The aim of this study was to determine whether strontium ranelate, an agent that reduces the risk of vertebral and nonvertebral fractures in postmenopausal women >50 years of age, also reduces fractures in the elderly., Materials and Methods: An analysis based on preplanned pooling of data from two international, phase III, randomized, placebo-controlled, double-blind studies (the Spinal Osteoporosis Therapeutic Intervention [SOTI] and TReatment Of Peripheral OSteoporosis [TROPOS]) included 1488 women between 80 and 100 years of age followed for 3 years. Yearly spinal X-rays were performed in 895 patients. Only radiographically confirmed nonvertebral fractures were included., Results: Baseline characteristics did not differ in placebo and treatment arms. In the intent-to-treat analysis, the risk of vertebral, nonvertebral, and clinical (symptomatic vertebral and nonvertebral) fractures was reduced within 1 year by 59% (p = 0.002), 41% (p = 0.027), and 37% (p = 0.012), respectively. At the end of 3 years, vertebral, nonvertebral, and clinical fracture risks were reduced by 32% (p = 0.013), 31% (p = 0.011), and 22% (p = 0.040), respectively. The medication was well tolerated, and the safety profile was similar to that in younger patients., Conclusions: Treatment with strontium ranelate safely reduces the risk of vertebral and nonvertebral fractures in women with osteoporosis > or = 80 years of age. Even in the oldest old, it is not too late to reduce fracture risk.

Unlabelled: It is unknown whether kyphosis of the thoracic spine is an independent risk factor for future osteoporotic fractures. In 596 community-dwelling women, we found that with increasing kyphosis, there was a significant trend of increasing fracture risk that was independent of previous history of fractures or BMD., Introduction: It is unknown whether kyphosis of the thoracic spine is an independent risk factor for future osteoporotic fractures., Materials and Methods: We conducted a prospective cohort study of 596 community-dwelling women, 47-92 years of age. Between 1988 and 1991, BMD of the hip and spine and kyphosis were measured. Kyphosis was measured by counting the number of 1.7-cm blocks necessary to place under the occiput so participants could lie flat without neck hyperextension. New fractures were reported over an average follow-up of 4 years., Results: Using a cut-off of at least one block, 18% of the participants had hyperkyphotic posture (range, one to nine blocks). There were 107 women who reported at least one new fracture (hip, spine, wrist, clavicle, shoulder, arm, hand, rib, pelvis, leg, or ankle). In logistic regression analyses, older women with hyperkyphotic posture (defined as at least one block) had a 1.7-fold increased risk of having a future fracture independent of age, prior fracture, and spine or hip BMD (95% CI: 1.00-2.97; p = 0.049). There was a significant trend of increasing fracture risk with increasing number of blocks, with ORs ranging from 1.5 to 2.6 as the number of blocks increased from one to at least three blocks compared with those with zero blocks (trend p = 0.03; models adjusted for age, baseline fracture, spine or hip BMD). Stratification by baseline fracture status and controlling for other possible confounders or past year falls did not change the results., Conclusions: Whereas hyperkyphosis may often result from vertebral fractures, our study findings suggest that hyperkyphotic posture itself may be an important risk factor for future fractures, independent of low BMD or fracture history.

Unlabelled: BMD is a major determinant of the risk of fragility fractures, but the role of the rate of postmenopausal bone loss is still unclear. In 671 postmenopausal women from the OFELY cohort, we found that the rate of bone loss was significantly associated with fracture risk independently of other well-known predictors including BMD and previous fractures., Introduction: The level of BMD is a major determinant of the risk of fragility fractures, but the role of the rate of postmenopausal bone loss is still unclear., Materials and Methods: In the OFELY study, we analyzed the risk of fracture in 671 postmenopausal women (mean age, 62.2 +/- 9 years), according to the rate of bone loss. BMD was measured annually by DXA at the forearm, with a mean number of measurements of 10.3 +/- 2.6. Peripheral fractures, all confirmed by radiographs, were prospectively registered, and vertebral fractures were evaluated with spine radiographs every 4 years., Results: During a median (interquartile range [IQ]) of 11.2 years (11-12.3 years) of follow-up, 183 incident fragility fractures including 53 vertebral and 130 nonvertebral fractures were recorded in 134 women. The annual median +/- IQ rate of bone loss, calculated from the slope, was -0.30 +/- 0.76% at the mid-radius, -0.55 +/- 0.79% at the distal radius, and -0.40 +/- 0.96% at the ultradistal radius. Women with incident fracture had a rate of bone loss (before fracture) higher by 38-53% than those without fracture (p = 0.0003-0.016). Using multivariate Cox regression models, we found that bone loss in the highest tertile at the mid-radius, distal radius, and ultradistal radius was associated with a significant increased risk of all fractures with an hazard ratio from 1.45 to 1.70 (p = 0.02 to p = 0.009 after adjusting for age, previous fractures, maternal history of fracture, physical activity, grip strength, falls, and baseline BMD)., Conclusions: The rate of bone loss in postmenopausal women is significantly associated with fracture risk independently of other well-known predictors such as BMD and history of fractures.

Unlabelled: Once-monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3-year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At least equivalent efficacy and similar safety and tolerability were shown after 1 year., Introduction: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose-free interval of >2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens., Materials and Methods: MOBILE is a 2-year, randomized, double-blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly., Results: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C-telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated., Conclusions: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis.

Unlabelled: We prospectively examined, in a large cohort of older women, the proportion of incident radiographic vertebral deformities diagnosed as incident clinical vertebral fractures in the same women at the same vertebral level. The proportion of deformities clinically diagnosed ranged from <15% for milder deformities to nearly 30% for more severe deformities., Introduction: The relationship between radiographic and clinical vertebral fractures is incompletely understood. No previous study has prospectively compared the agreement between incident radiographic vertebral deformities and incident community-recognized, radiographically confirmed vertebral fractures in the same women at the same vertebral level(s)., Materials and Methods: This analysis of data from the Fracture Intervention Trial included all participants who completed both baseline and at least one scheduled follow-up lateral spinal radiograph (n = 6084). Incident vertebral deformities were defined at a given vertebral level as a reduction between baseline and closeout radiographs of > or = 20% and 4 mm in any vertebral height and subdivided into two severity categories. Incident clinical vertebral fractures were those reported to clinical centers by participants and confirmed by the study radiologist, who compared the community spinal radiograph with the participant's baseline study radiograph using semiquantitative methods., Results: A total of 446 incident radiographic vertebral deformities were identified in 330 women, whereas 121 women experienced one or more confirmed incident clinical vertebral fracture. Of incident radiograpic vertebral deformities, 22.6% were also clinically diagnosed as incident vertebral fractures, with clinical diagnoses made for 28.4% of the deformities that exceeded 30% and 4 mm height loss (severe deformity) compared with 14.3% for deformities that involved > or = 20% and 4 mm but < 30% height loss (milder deformity). Of incident clinical vertebral fractures, 72.7% were morphometrically identified as incident deformities, most of them as severe deformities. More than 20% of incident clinical fractures were not identified as incident deformities by even the most liberal morphometric criterion used in this study., Conclusions: Approximately one-fourth of incident radiographic vertebral deformities were clinically diagnosed as new vertebral fractures, although the proportion clinically diagnosed was increased for more severe deformities. Whereas most incident clinical vertebral fractures were identified as severe morphometric deformities, approximately one-fourth did not meet even the most liberal study criterion for morphometric deformity. Further study of factors that may explain the discordance between incident vertebral deformities and incident clinical vertebral fractures is important.

Unlabelled: Accurate radiographic diagnosis of vertebral fractures is important. This multicenter, multinational study assessed radiographic diagnoses of vertebral fracture in 2451 postmenopausal women with osteoporosis. Comparison between local and central readings yielded a false-negative rate of 34%. Underdiagnosis of vertebral fracture is a worldwide problem., Introduction: Vertebral fractures are the most common complication of osteoporosis. Although they are associated with significant morbidity, they frequently do not come to clinical attention. Accurate radiographic diagnosis is important., Materials and Methods: In a multicenter, multinational prospective study (the IMPACT trial), the accuracy of radiographic diagnosis of vertebral fracture was evaluated in postmenopausal women 65-80 years of age newly diagnosed with osteoporosis (based on BMD measurement). Lateral radiographs of the thoracolumbar spine were evaluated for identification of vertebral fractures, first locally and subsequently at a central reading center, using a validated semiquantitative method. False-positive and false-negative rates were calculated based on adjudicated discrepancies between the initial interpretation at the local site and the subsequent central reading, considered the "reference standard.", Results: Of 2451 women with an evaluable radiograph both centrally and locally, 789 (32%) had at least one vertebral fracture. Adjudicated discrepancies (n = 350 patients) between local and central readings because of undetected vertebral fracture (68%) or equivocal terminology in the local radiology report (32%) yielded a false-negative rate of 34%., Conclusions: Underdiagnosis of vertebral fractures was observed in all geographic regions (false-negative rates: North America, 45.2%; Latin America, 46.5%; Europe/South Africa/Australia, 29.5%). The false-positive rate was 5% globally. Underdiagnosis of vertebral fracture is a worldwide problem attributable in part to a lack of radiographic detection, use of ambiguous terminology in the radiology report, or both. Efforts to improve accuracy and reduce variability in terminology and interpretation may increase the effectiveness of spinal radiography for detecting vertebral fractures in patients with osteoporosis.

Unlabelled: This study investigates the effects of kyphoplasty on pain and mobility in patients with osteoporosis and painful vertebral fractures compared with conventional medical management., Introduction: Pharmacological treatment of patients with primary osteoporosis does not prevent pain and impaired activity of patients with painful vertebral fractures. Therefore, we evaluated the clinical outcome after kyphoplasty in patients with vertebral fractures and associated chronic pain for >12 months., Materials and Methods: Sixty patients with primary osteoporosis and painful vertebral fractures presenting for >12 months were included in this prospective, nonrandomized controlled study. Twenty-four hours before performing kyphoplasty, the patients self-determined their inclusion into the kyphoplasty or control group so that 40 patients were treated with kyphoplasty, whereas 20 served as controls. This study assessed changes in radiomorphology, pain visual analog scale (VAS) score, daily activities (European Vertebral Osteoporosis Study [EVOS] score), number of new vertebral fractures, and health care use. Outcomes were assessed before treatment and at 3 and 6 months of follow-up. All patients received standard medical treatment (1g calcium, 1000 IE vitamin D(3), standard dose of oral aminobisphosphonate, pain medication, physical therapy)., Results: Kyphoplasty increased midline vertebral height of the treated vertebral bodies by 12.1%, whereas in the control group, vertebral height decreased by 8.2% (p = 0.001). Augmentation and internal stabilization by kyphoplasty resulted in a reduction of back pain. VAS pain scores improved in the kyphoplasty group from 26.2 +/- 2 to 44.2 +/- 3.3 (SD; p = 0.007) and in the control group from 33.6 +/- 4.1 to 35.6 +/- 4.1 (not significant), whereas the EVOS score increased in the kyphoplasty group from 43.8 +/- 2.4 to 54.5 +/- 2.7 (p = 0.031) and in the control group from 39.8 +/- 4.5 to 43.8 +/- 4.6 (not significant). The number of back pain-related doctor visits within the 6-month follow-up period decreased significantly after kyphoplasty compared with controls: mean of 3.3 visits/patient in the kyphoplasty group and a mean of 8.6 visits/patient in the control group (p = 0.0147)., Conclusions: The results of this study show significantly increased vertebral height, reduced pain, and improved mobility in patients after kyphoplasty. Kyphoplasty performed in appropriately selected osteoporotic patients with painful vertebral fractures is a promising addition to current medical treatment.

Unlabelled: Low BMD and prevalent vertebral fractures are known risk factors for incident vertebral fractures. In 3001 men and women from the Rotterdam Study, prevalent nonvertebral fractures, early menopause, current smoking, and walking aid use were also strong risk factors for incident vertebral fractures., Introduction: Thus far, age, low BMD, and prevalent vertebral fractures are the only well-known risk factors for incident vertebral fractures. Therefore, our aim was to investigate other potential risk factors for incident vertebral fractures in the elderly., Materials and Methods: This study was based on the Rotterdam Study, a large prospective population-based cohort study among men and women > or =55 years of age. For 3001 subjects, spinal radiographs were obtained at baseline and again approximately 6.3 years later. These follow-up radiographs were scored for vertebral fractures using the McCloskey-Kanis method. Whenever a vertebral fracture was detected, the radiograph was compared with the baseline radiograph. If this fracture was not already present at baseline, it was considered incident. At baseline, information on potential risk factors was obtained., Results: Low BMD and prevalent vertebral fractures were strong risk factors for incident vertebral fractures in both men and women (RR 2.3 [1.6-3.3] and 2.2 [0.9-5.0] for men and RR 2.1 [1.6-2.6] and 4.1 [2.5-6.7] for women, respectively). For women, age, early menopause (< or =45 years of age; RR 1.0 [1.1-3.5]), current smoking (2.1 [1.2-3.5]), and walking aid use (2.5 [1.1-5.5]) were additional independent risk factors. For men, only a history of nonvertebral fractures was a significant independent risk factor (OR 2.4 [1.2-4.8])., Conclusion: Apart from low BMD and prevalent vertebral fractures, prevalent nonvertebral fractures are associated with an increased incident vertebral fracture risk in men. In women, early menopause, current smoking, and walking aid use are additional independent risk factors for incident vertebral fractures.

Unlabelled: Different risk factors may influence the effectiveness of osteoporosis therapies. The interaction of 30 baseline risk factors and the effectiveness of raloxifene in the MORE study were assessed. The efficacy of raloxifene in reducing vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fractures., Introduction: The aim of this analysis was to determine the effect of different risk factors on the effectiveness of raloxifene to reduce vertebral fractures in the Multiple Outcomes of Raloxifene Evaluation (MORE) study using logistic regression models., Materials and Methods: The association was assessed using univariate analyses and a multivariate model between 30 potential risk factors at baseline and the risk of vertebral fractures after 3 years in the placebo group, as well as the interaction of risk factors with raloxifene therapy (at a dose of 60 or 120 mg/day)., Results and Conclusions: In the univariate analysis of the placebo group, after adjusting for baseline lumbar spine BMD (LS BMD), short stature (odds ratio [OR] = 1.18), age (OR = 1.38), years since menopause (OR = 1.38), impaired cognitive function, visuospatial capabilities (OR = 1.19), impaired musculoskeletal strength (OR = 1.23), low femoral neck BMD (OR = 1.21), and prior vertebral fracture (OR = 4.95) were significantly associated with the incidence of new vertebral fractures. In the univariate analysis, significant interactions were observed between raloxifene treatment and age (p = 0.04), serum triglycerides (p = 0.03), LS BMD (p = 0.08), and diabetes mellitus (p = 0.04). In the multivariate analysis, the effectiveness of raloxifene was independent of almost all risk factors, with the exception of baseline serum triglyceride level and LS BMD, suggesting an increased efficacy of raloxifene in patients with increased triglyceride levels (p = 0.006) and lower LS BMD values (p = 0.008) at baseline. These data suggest that the efficacy of raloxifene in reducing vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fractures.

Unlabelled: The efficacy of oral clodronate 800 mg daily to reduce vertebral fractures was studied in 593 women with postmenopausal or secondary osteoporosis. The incidence of vertebral fractures was significantly reduced by 46%. The effect was not modified by the underlying cause of osteoporosis or other baseline factors including bone mineral density, QUS, weight, and smoking., Introduction: This study aimed to determine if the bisphosphonate, clodronate (Bonefos), reduced the incidence of vertebral fractures in osteoporotic women., Materials and Methods: Women fulfilling the WHO criteria for osteoporosis at the lumbar spine (T-score

Unlabelled: We compared the performance of five QUS devices with DXA in a population-based sample of 2837 women. All QUS approaches discriminated women with and without osteoporotic vertebral fractures. QUS of the calcaneus performed as well as central DXA., Introduction: Quantitative ultrasound (QUS) methods have found widespread use for the assessment of bone status in osteoporosis, but their optimal use remains to be established. To determine QUS performance for current devices in direct comparison with central DXA, we initiated a large population-based investigation, the Osteoporosis and Ultrasound Study (OPUS)., Materials and Methods: A total of 463 women 20-39 years of age and 2374 women 55-79 years of age were measured on five different QUS devices along with DXA of the spine and the proximal femur. Their vertebral fracture status was evaluated radiographically. The association of QUS and DXA with vertebral fracture status was evaluated using logistic regression., Results: All QUS approaches tested discriminated women with and without osteoporotic vertebral fractures (20% height reduction), with age-adjusted standardized odds ratios ranging 1.2-1.3 for amplitude-dependent speed of sound (AD-SOS) at the finger phalanges, 1.2-1.4 for broadband ultrasound attenuation (BUA) at the calcaneus, and 1.4-1.5 for speed of sound (SOS) at the calcaneus, 1.4-1.6 for DXA of the total femur, and 1.5-1.6 for DXA at the spine. For more severe fractures (40% height reduction), age-adjusted standardized odds ratios increased to up to 1.9 for DXA of the spine and 2.3 for SOS of the calcaneus., Conclusions: In conclusion, all five QUS devices tested showed significant age-adjusted differences between subjects with and without vertebral fracture. When selecting the strongest variable, QUS of the calcaneus worked as well as central DXA for identification of women at high risk for prevalent osteoporotic vertebral fractures. QUS-based case-finding strategies would allow halving the number of radiographs in high-risk populations, and this strategy works increasingly well for women with more severe vertebral fractures. It is likely that the good performance of QUS was in part achieved by rigorous quality assurance measures that should also be used in clinical practice.

Unlabelled: Iliac cancellous osteocyte density declines with age, but its relationship to vertebral fracture pathogenesis is unknown. We performed iliac bone biopsy in 44 women with clinical vertebral fracture and 56 healthy women. The fracture patients had 34% fewer osteocytes but no reduction in percent occupied lacunae. Some patients destined to sustain vertebral fracture make cancellous bone with fewer osteocytes., Introduction: Patient's with vertebral fracture have less bone than appropriate healthy controls, but other factors may contribute to bone fragility. Iliac cancellous osteocyte density declines with age in healthy women; we asked whether this variable differed between fracture patients and healthy controls., Methods: Two groups of women were assembled. Forty-four (mean age, 66.2 years) had unequivocal evidence of bone fragility manifested as painful nontraumatic vertebral fracture, and 56 (mean age, 62.2 years) were skeletally healthy. All subjects underwent iliac bone biopsy. From archival embedded biopsy cores, new sections were stained with Goldner's trichrome, in which we enumerated osteocyte-occupied lacunae (stained), empty lacunae (unstained), and total lacunae per bone area., Results: Cancellous osteocyte density was 34% lower in the fracture group than in the controls (p < 0.001); this difference was not a consequence of higher turnover, having less bone, or the small difference in age. The area under the receiver operating characteristic (ROC) curve for discrimination between the groups was >90% for osteocyte density and <75% for bone volume/tissue volume (BV/TV). The disease-related osteocyte deficit was accompanied by a proportionate reduction in empty lacunae and no change in percent occupied lacunae; therefore, it was not the result of premature death. Both superficial bone (<25 microm from the surface) and deep bone (>45 microm from the surface) were affected. In contrast, the age-related deficit is accompanied by an increase in empty lacunae and fall in percent osteocyte-occupied lacunae and occurs only in deep bone, but not in superficial bone., Conclusions: In some patients destined to sustain spontaneous vertebral compression fracture, iliac cancellous bone is made with fewer osteocytes than normal; the mechanism of osteocyte incorporation into bone needs more detailed study. Osteocyte deficiency could contribute to bone fragility, either by impairing the detection of fatigue microdamage or by reducing canalicular fluid flow. Current practices of defining vertebral fracture based on morphometry alone regardless of symptoms, and diagnosing osteoporosis based on bone densitometry alone regardless of fracture history, should be reexamined.

Unlabelled: More severe vertebral fractures have more personal impact. In the European Prospective Osteoporosis Study, more severe vertebral collapse was predictable from prior fracture characteristics. Subjects with bi-concave or crush fractures at baseline had a 2-fold increase in incident fracture size and thus increased risk of a disabling future fracture., Introduction: According to Euler's buckling theory, loss of horizontal trabeculae in vertebrae increases the risk of fracture and suggests that the extent of vertebral collapse will be increased in proportion. We tested the hypothesis that the characteristics of a baseline deformity would influence the size of a subsequent deformity., Methods: In 207 subjects participating in the European Prospective Osteoporosis Study who suffered an incident spine fracture in a previously normal vertebra, we estimated loss of volume (fracture size) from plane film images of all vertebral bodies that were classified as having a new fracture. The sum of the three vertebral heights (anterior, mid-body, and posterior) obtained at follow-up was subtracted from the sum of the same measures at baseline. Each of the summed height loss for vertebrae with a McCloskey-Kanis deformity on the second film was expressed as a percentage., Results and Conclusions: In univariate models, the numbers of baseline deformities and the clinical category of the most severe baseline deformity were each significantly associated with the size of the most severe incident fracture and with the cumulated sum of all vertebral height losses. In multivariate modeling, age and the clinical category of the baseline deformity (crush > bi-concave > uni-concave > wedge) were the strongest determinants of both more severe and cumulative height loss. Baseline biconcave and crush fractures were associated at follow-up with new fractures that were approximately twice as large as those seen with other types of deformity or who previously had undeformed spines. In conclusion, the characteristics of a baseline vertebral deformity determines statistically the magnitude of vertebral body volume lost when a subsequent fracture occurs. Because severity of fracture and number of fractures are determinants of impact, the results should improve prediction of the future personal impact of osteoporosis once a baseline prevalent deformity has been identified.

Visual identification of vertebral fractures from spinal radiographs (visual XR) makes use of the reader's expertise in ruling out non-fracture deformities or normal variants. Scan images of the spine acquired by DXA may be analyzed quantitatively (morphometric X-ray absorptiometry [quantitative MXA]) or visually (visual MXA). The aims of this study were to compare visual and quantitative MXA with visual XR for the identification of vertebral fractures. Spinal radiographs and MXA scans were acquired at baseline and 1 year in 70 women referred with osteoporosis. These were assessed visually by two expert readers (observer A, a radiologist; observer B, a physician with expertise in osteoporosis) for evidence of prevalent and incident vertebral fractures. Observer C (a radiographer with expertise in vertebral morphometry) performed visual and quantitative assessments of the MXA scans. Visual assessment of spinal radiographs by observer A was used as the gold standard for comparison of methods. Sensitivity for the identification of prevalent fractures by MXA was best for visual MXA by observer A (92%), whereas quantitative MXA had the lowest sensitivity (82%). Specificity was >90% for both visual and quantitative MXA. Kappa scores for agreement for identification of prevalent fractures between visual XR (observer A) and visual MXA (all three observers), and between visual XR and visual MXA performed by reader B were similar (kappa = 0.85-0.87). Agreement with visual XR performed by observer A was slightly lower for quantitative MXA (kappa = 0.77). Interobserver agreement between the two expert readers (observers A and B) was the same for both visual XR and visual MXA (kappa = 0.86). Seven incident vertebral fractures were identified in four patients at follow-up. All four patients were identified by visual MXA, and three patients were identified by quantitative MXA. Observers A and B identified all seven incident fractures by visual MXA, and observer C missed one fracture that was also missed by quantitative MXA. An incident fracture of vertebra T6 was excluded from analysis by quantitative MXA because of poor image quality. We conclude that visual identification of vertebral fractures from MXA scans is superior to quantitative assessment. Used as a screening tool for conventional radiography, this approach could help reduce the radiation dose to the patient in the diagnosis and monitoring of osteoporosis.

We have observed that some osteoporotic vertebral compression fractures (VCFs) are mobile. The purpose of this report was to document the existence of dynamic fracture mobility, estimate the frequency of dynamic mobility in patients referred for vertebroplasty, define the magnitude and nature of dynamic mobility, and consider the implications of the dynamic mobility of osteoporotic VCFs. This was a prospective radiographic analysis of 41 consecutive patients with 65 VCFs who underwent vertebroplasty. Preoperative standing lateral radiographs of the fractured vertebrae were compared with supine cross-table lateral radiographs to determine the presence or absence of dynamic mobility. Postoperative standing lateral radiographs were evaluated to document fracture mobility and assess final vertebral height restoration. Radiographs were manually digitized to calculate vertebral body morphometrics. Dynamic fracture mobility was demonstrated in 44% of patients (35% of treated vertebrae) who underwent vertebroplasty. Postoperatively, in mobile fractures, average anterior vertebral height increased 106% compared with initial fracture height (absolute increase, 8.41 +/- 0.4 mm). Mean lateral vertebral area increased from 48% to 80% of normal, and kyphotic angle decreased 40%. Mobile fractures dominated at the thoracolumbar junction. Intravertebral clefts were defined and identified in every mobile fracture and were absent from every nonmobile (fixed) fracture. This radiographic series documents the previously unrecognized occurrence of dynamic fracture mobility in many osteoporotic VCFs. Fracture mobility can be substantial and clinically significant. Any intervention that claims vertebral height restoration must control for the occurrence of dynamic fracture mobility.

Raloxifene is a selective estrogen receptor modulator that has been shown to increase bone density. The purpose of this study was to examine the effects of raloxifene on bone tissue by studying bone biopsy specimens before and after 2 years of raloxifene or placebo therapy. The women in this study were participants of the double-blind, placebo-controlled, multicenter study, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Subjects from two U.S. sites and two European sites were included if they consented to a bone biopsy. Iliac crest bone biopsies were performed at baseline and after 2 years. Tetracycline labeling preceded each biopsy. A total of 65 paired biopsy specimens were evaluated with 25, 22, and 18 patients in the placebo, raloxifene HCl (60 mg) and raloxifene HCl (120 mg) treatment groups, respectively. They were analyzed using standard histomorphometry. None of the biopsy specimens showed evidence of toxic effects on bone or bone cells or met criteria for osteomalacia. Biopsy specimens in the placebo and raloxifene groups had the appearance of normal bone, with no evidence of marrow fibrosis or increases in the amount of woven bone or numbers of empty osteocyte lacunae. Compared with the baseline, the bone formation rate (BFR) decreased significantly in both raloxifene groups. The change in BFR in the group treated with 120 mg of raloxifene was -62.3%, which was significantly lower than the change in the placebo group of -21.0% (p = 0.03). No change in resorption parameters could be measured by histomorphometry, but there was a decrease in urinary type I collagen excretion. The results from this study suggest that raloxifene has actions on bone tissue that are similar to those observed with estrogen. The depressive effects on bone remodeling are less marked than the effects seen with alendronate.

Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.

Cancellous bone morphometry was investigated in the sagittal plane of lumbar vertebrae using histoquantitation. The aim of this study was to identify variations in cancellous bone architecture at increasing states of intervertebral disc (IVD) disorganization after age adjustment and to investigate regional variations within the whole vertebral body. Measurements were taken of the ratio of bone volume (BV) to total volume (TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), and trabecular number (Tb.N). Lumbar spines (T12-L5) of 19 men and 8 women were removed at autopsy from an adult sample with no clinical history of bone-related disease or histologically identifiable bone disease. It was found that degeneration of the IVD becomes more common with increasing age. After age-adjustment, significant increases in the proportion of BV/TV were observed in the presence of advancing IVD disorganization. Significant architectural changes were observed in the anterior regions of the vertebral body with increases in Tb.Th and Tb.N and decreases in Tb.Sp. Minimal alterations were found at posterior regions. Bone loss was observed in central regions (most distant from the cortex) as IVD disorganization increased through reduction in both Tb.N and Tb.Th. The BV/TV increase in anterior areas of the centrum may be a response to a redistribution of load to the vertebral body periphery as a result of IVD disorganization. It appears that trabecular morphology is related to the condition of the associated IVD, rather than being the sole consequence of a loss of BV/TV with age. This relationship could influence the occurrence of vertebral body crush fracture.

Trabecular bone microarchitecture and bone mineral density (BMD) are two main factors related to osteoporotic fractures. Currently, however, microarchitecture is not evaluated. We have developed and validated a trabecular bone texture analysis from radiographic images. The objective was to determine if the fractal analysis of texture was able to distinguish osteoporotic fracture groups from control groups, either in vertebrae, hip, or wrist fractures, and to determine if this indicator and BMD were independent and complementary. In this cross-sectional unicenter case-control population study in postmenopausal women, 107 fracture cases were enrolled and age-matched with 197 control cases. This population comprised 40 vertebral fractures (with 70 controls), 30 hip fractures (55 controls), and 37 wrist fractures (62 controls). Hip and lumbar spine BMD were measured by double-energy X-ray absorptiometry. Fractal analysis of texture was performed on calcaneus radiographs and the result was expressed as the H parameter (H = 2-fractal dimension). The H parameter showed a lower value (0.679 +/- 0.053 SD) in fracture cases versus control cases (0.696 +/- 0.030; p = 0.007), the statistical significance persisting after adjustment for age and for lumbar spine (LS) or hip BMD. This result was confirmed in vertebral fractures (p = 0.0001) and hip fractures (p = 0.003) but not wrist fractures (p = 0.07). We determined the threshold between high and low H values and then the odds ratios (OR) of fracture for low H for BMD < or = -2.5 SD in T score and for the combinations of both parameters. The OR of fracture for low H was 1.6 (95% CI, 1.1-2.6). For LS BMD < or = -2.5 SD the OR of 6.1 (3.4-10.8) shifted to 9.0 (4.0-20.4) when we added low H and for hip BMD it shifted from 5.6 (3.3-9.4) to 8.1 (4.0-16.8). In vertebral, hip, and wrist fracture cases the results were also significant. These data have shown that the fractal analysis of texture on calcaneus radiographs can distinguish osteoporotic fracture groups from control groups. This analysis and BMD provide independent and complementary information. These data suggest that we can improve the fracture risk evaluation by adding information related to microarchitecture, derived from analysis of conventional radiographic images.

Fractures and subsequent morbidity determine the impact of established postmenopausal osteoporosis. Health-related quality of life (HRQOL) has become an important outcome criterion in the assessment and follow-up of osteoporotic patients. As part of the baseline measurements of the Multiple Outcomes of Raloxifene Evaluation (MORE) study, HRQOL was assessed in 751 osteoporotic (bone mineral density [BMD] T score > or = -2.5) women from Europe with or without vertebral fractures (VFX). This was done using the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO), Nottingham Health Profile (NHP) and the EQ-5D (former EuroQol). QUALEFFO contains questions in five domains: pain, physical function, social function, general health perception, and mental function. Each domain score and QUALEFFO total scores are expressed on a 100-point scale, with 0 corresponding to the best HRQOL. In comparison with patients without VFX, those with VFX were older (66.2 +/- 5.9 years vs. 68.8 +/- 6.3 years; p < 0.001), had higher prevalence of nonvertebral fractures (25% vs. 36%; p = 0.002), and higher QUALEFFO scores (worse HRQOL; total score, 26 +/- 14 vs. 36 +/- 17; p < 0.001). QUALEFFO scores increased progressively with increasing number of VFX, especially lumbar fractures (p < 0.001). Patients with a single VFX already had a significant increase in QUALEFFO scores (p < 0.05). Similar, though weaker, associations were seen for NHP and EQ-5D scores. This study confirms decreased HRQOL for patients with prevalent VFX. In osteoporotic patients, QUALEFFO scores change in relation to the number of VFX. QUALEFFO is suitable for clinical studies in patients with postmenopausal osteoporosis.

Our aim was to compare normal vertebral reference values for morphometric radiography (MRX) and morphometric X-ray absorptiometry (MXA) and to compare these methods for the identification of vertebral deformities. We calculated MXA reference values (Hologic QDR 4500 A) for 327 women (ages 22-88 years) randomly selected from local General Practice lists in Sheffield, U.K. MRX reference values were calculated from spinal radiographs for 123 of these subjects (ages 56-88 years). We used these reference values to identify deformities in the MRX and MXA reference populations and in 83 women with osteoporosis (ages 49-87 years). We observed differences in mean deformity of vertebral height ratios measured by MRX and MXA, especially for the mid-to-posterior ratio. We compared agreement between quantitative methods (MRX and MXA) and qualitative radiological assessment. Severity of deformity was defined by semiquantitative (SQ) assessment. Agreement was moderate for MRX (k = 0.59; 95% CI = 0.43-0.77) and for MXA (k = 0.47; 95% CI = 0.29-0.66) in the reference population. Agreement was good for MRX (k = 0.86; 95% CI = 0.82-0.89) and MXA (k = 0.71; 95% CI = 0.66-0.75) in the osteoporotic population. MRX and MXA correctly identified a greater proportion of moderate or severe deformities compared with mild deformities. Sensitivity, specificity, predictive values, and accuracy were slightly better for MRX than for MXA. Although MXA agrees well with qualitative radiological assessment, the large proportion of vertebrae excluded from analysis because of poor image quality limits the diagnostic value of the technique. Reference intervals should be technique specific.

Some studies have indicated that the risk of fragility fractures in men increases as bone mineral levels decrease, but there is an overlap in the bone mineral density (BMD) measurements between patients with or without fractures. Furthermore, it has been suggested that the biomechanical competence of trabecular bone is dependent not only on the absolute amount of bone present but also on the trabecular microarchitecture. In the present study, 108 men (mean age 52.1 years) with lumbar osteopenia (T score < -2.5) were recruited to examine the relationships between BMD, architectural changes in trabecular bone, and the presence of vertebral fractures. Lumbar BMD was assessed from L2 to L4 in the anteroposterior view with dual-energy X-ray absorptiometry. At the upper left femur, hip BMD was measured at the transcervical site. Spinal X-ray films were analyzed independently by two trained investigators, and vertebral fracture was defined as a reduction of at least 20% in the anterior, middle, or posterior vertebral height. Transiliac bone biopsy specimens were obtained for all patients. Histomorphometric studies were performed on an image analyzer, and the following parameters were determined: trabecular bone volume (BV/TV), trabecular thickness (Tb.Th), number (Tb.N), and separation (Tb.Sp), interconnectivity index (ICI), characterization of the trabecular network (node count and strut analysis), and star volume of the marrow spaces. Spinal radiographs evidenced at least one vertebral crush fracture in 62 patients (group II) and none in 46 patients (group I). After adjusting for age, body mass index, and BMD, there were no significant differences between the two groups in BV/TV, Tb.Th, or star volume. In contrast, the mean values of ICI, free end-to-free end struts (FF/TSL), and Tb.Sp were significantly higher, whereas Tb.N and node-to-node struts (NN/TSL) were lower in patients with at least one vertebral fracture. Logistic regression analysis showed that only ICI, FF/TSL, NN/TSL, and Tb.N were significant predictors of the presence of vertebral fracture: odds ratios for an alteration of 1 SD ranged from 1.7 (1.0-3.2) for NN/TSL to 3.2 (1.1-10.1) for ICI. Patients with at least three vertebral fractures (n = 23) were categorized as "multiple fractures." The results of logistic regression showed that spine BMD, BV/TV, and all architectural parameters were significant predictors of multiple vertebral fractures: odds ratios for an alteration of 1 SD ranged from 2.2 (1.1-4.6) for star volume to 3.7 (1.4-9.7) for ICI. These results strongly suggest that bone trabecular microarchitecture is a major and independent determinant of vertebral fractures in middle-aged men with osteopenia.