- [Show abstract] [Hide abstract] ABSTRACT: The association between sex hormones and sex hormone binding globin (SHBG) with vertebral fractures in men is not well studied. In these analyses, we determined whether sex hormones and SHBG were associated with greater likelihood of vertebral fractures in a prospective cohort study of community dwelling older men. We included data from participants in MrOS who had been randomly selected for hormone measurement (N = 1463 including 1054 with follow-up data 4.6 years later.). Major outcomes included prevalent vertebral fracture (semi-quantitative grade ≥ 2, N = 140, 9.6%); and new or worsening vertebral fracture (change in SQ grade ≥ 1, N = 55, 5.2%). Odds ratios per SD decrease in sex hormones and per SD increase in SHBG were estimated with logistic regression adjusted for potentially confounding factors including age, bone mineral density, and other sex hormones. Higher SHBG was associated with a greater likelihood of prevalent vertebral fractures (OR: 1.38 per SD increase, 95% CI: 1.11, 1.72). Total estradiol analyzed as a continuous variable was not associated with prevalent vertebral fractures (OR per SD decrease: 0.86, 95% CI: 0.68 to 1.10). Men with total estradiol values ≤ 17 pg/ml had a borderline higher likelihood of prevalent fracture than men with higher values (OR: 1.46, 95% CI: 0.99, 2.16). There was no association between total testosterone and prevalent fracture. In longitudinal analyses, SHBG (OR: 1.42 per SD increase, 95% CI: 1.03, 1.95) was associated with new or worsening vertebral fracture, but there was no association with total estradiol or total testosterone. In conclusion, higher SHBG (but not testosterone or estradiol) is an independent risk factor for vertebral fractures in older men.
- [Show abstract] [Hide abstract] ABSTRACT: Data concerning the link between severity of abdominal aortic calcification (AAC) and fracture risk in postmenopausal women are discordant. This association may vary by skeletal site and duration of follow-up. Our aim was to assess the association between the AAC severity and fracture risk in older women over the short- and long-term. This is a case-cohort study nested in a large multicenter prospective cohort study. The association between AAC and fracture was assessed using Odds Ratios (OR) and 95% confidence intervals (95%CI) for vertebral fractures and using Hazard Risks (HR) and 95%CI for non-vertebral and hip fractures. AAC severity was evaluated from lateral spine radiographs using Kauppila's semiquantitative score. Severe AAC (AAC score 5+) was associated with higher risk of vertebral fracture during 4 years of follow-up, after adjustment for confounders (age, BMI, walking, smoking, hip bone mineral density, prevalent vertebral fracture, systolic blood pressure, hormone replacement therapy) (OR=2.31, 95%CI: 1.24-4.30, p<0.01). In a similar model, severe AAC was associated with an increased in the hip fracture risk (HR=2.88, 95%CI: 1.00-8.36, p=0.05). AAC was not associated with the risk of any non-vertebral fracture. AAC was not associated with the fracture risk after 15-years of follow-up. In elderly women, severe AAC is associated with higher short-term risk of vertebral and hip fractures, but not with the long-term risk of these fractures. There is no association between AAC and risk of non-vertebral-non-hip fracture in older women. Our findings lend further support to the hypothesis that AAC and skeletal fragility are related. Copyright © 2015. Published by Elsevier Inc.
Article: Response to BONE-D-14-00884
- [Show abstract] [Hide abstract] ABSTRACT: We describe the methods and reliability of radiographic vertebral fracture assessment in MrOS, a cohort of community dwelling men aged ≥ 65 yrs. Lateral spine radiographs were obtained at Visit 1 (2000-2) and 4.6 years later (Visit 2). Using a workflow tool (SpineAnalyzerTM, Optasia Medical), a physician reader completed semi-quantitative (SQ) scoring. Prior to SQ scoring, technicians performed “triage” to reduce physician reader workload, whereby clearly normal spine images were eliminated from SQ scoring with all levels assumed to be SQ = 0 (no fracture, “triage negative”); spine images with any possible fracture or abnormality were passed to the physician reader as “triage positive” images. Using a quality assurance sample of images (n = 20 participants; 8 with baseline only and 12 with baseline and follow-up images) read multiple times, we calculated intra-reader kappa statistics and percent agreement for SQ scores. A subset of 494 participants’ images were read regardless of triage classification to calculate the specificity and sensitivity of triage. Technically adequate images were available for 5958 of 5994 participants at Visit 1, and 4399 of 4423 participants at Visit 2. Triage identified 3215 (53.9%) participants with radiographs that required further evaluation by the physician reader. For prevalent fractures at Visit 1 (SQ ≥ 1), intra-reader kappa statistics ranged from 0.79-0.92; percent agreement ranged from 96.9%-98.9%; sensitivity of the triage was 96.8% and specificity of triage was 46.3%. In conclusion, SQ scoring had excellent intra-rater reliability in our study. The triage process reduces expert reader workload without hindering the ability to identify vertebral fractures.
- [Show abstract] [Hide abstract] ABSTRACT: In men, the association between poor physical performance and likelihood of incident vertebral fractures is unknown.Using data from the MrOS study (N=5958), we describe the association between baseline physical performance [walking speed, grip strength, leg power, repeat chair stands, narrow walk (dynamic balance)] and incidence of radiographic and clinical vertebral fractures. At baseline and follow-up an average of 4.6 years later, radiographic vertebral fractures were assessed using semi-quantitative (SQ) scoring on lateral thoracic and lumbar radiographs. Logistic regression modeled the association between physical performance and incident radiographic vertebral fractures (change in SQ grade≥ from baseline to follow-up). Every four months after baseline, participants self-reported fractures; clinical vertebral fractures were confirmed by centralized radiologist review of the baseline study radiograph and community acquired spine images. Proportional hazards regression modeled the association between physical performance with incident clinical vertebral fractures. Multivariate models were adjusted for age, BMD (by DXA), clinical center, race, smoking, height, weight, history of falls, activity level and co-morbid medical conditions; physical performance was analyzed as quartiles.Of 4332 men with baseline and repeat radiographs, 192 (4.4%) had an incident radiographic vertebral fracture. With the exception of walking speed, poorer performance on repeat chair stands, leg power, narrow walk and grip strength were each associated in a graded manner with an increased risk of incident radiographic vertebral fracture (p for trend across quartiles <0.001). In addition, men with performance in the worst quartile on three or more exams had an increased risk of radiographic fracture (OR: 1.81, 9% CI: 1.33, 2.45) compared to men with better performance on all exams. Clinical vertebral fracture (N=149 of 5,813, 2.6%) was not consistently associated with physical performance.We conclude that poorer physical performance is associated with an increased risk of incident radiographic (but not clinical) vertebral fracture in older men. © 2014 American Society for Bone and Mineral Research
Conference Paper: Post-Alendronate DXA Monitoring Strategy Based on 5-year Changes in BMD
- [Show abstract] [Hide abstract] ABSTRACT: The case definition, community incidence, and characteristics of atypical femoral shaft fractures (FSFs) are poorly understood. This retrospective study utilized electronic medical records and radiograph review among women ≥50 years of age and men ≥65 years of age from January 1996 to June 2009 at Kaiser Permanente Northwest to describe the incidence rates and characteristics of subgroups of femur fractures. Fractures were categorized based on the American Society for Bone and Mineral Research (ASBMR) as atypical fracture major features (AFMs) (low force, shaft location, transverse or short oblique, noncomminuted) and AFMs with additional minor radiograph features (AFMms) (beaking, cortical thickening, or stress fracture). There were 5034 fractures in the study. The incidence rates of FSFs (without atypical features) and AFMs appeared flat (cumulative incidence: 18.2 per 100,000 person-years, 95% CI = 16.0-20.7; 5.9 per 100,000 person-years, 95% CI = 4.6-7.4; respectively) with 1,271,575 person-years observed. The proportion of AFMs that were AFMms increased over time. Thirty percent of AFMs had any dispensing of a bisphosphonate prior to the fracture, compared to 15.8% of the non-atypical FSFs. Years of oral glucocorticosteroid dispensing appeared highest in AFM and AFMm fractures. Those with AFMs only were older and had a lower frequency of bisphosphonate dispensing compared to those with AFMms. We conclude that rates of FSFs, with and without atypia, were low and stable over 13.5 years. Patients with only AFMs appear to be different from those with AFMms; it may be that only the latter group is atypical. There appear to be multiple associated risk factors for AFMm fractures.
- [Show abstract] [Hide abstract] ABSTRACT: The objective of this study was to determine the effect of once-yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double-blind, placebo-controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15-minute intravenous infusion of zoledronic acid (5 mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were self-reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3-year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p = .0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p = .0017). In Cox proportional-hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR) = 0.94, 95% confidence interval (CI) 0.90-0.99] or limited activity owing to back pain (RR = 0.94, 95% CI 0.87-1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed-rest days owing to a fracture (RR = 0.58, 95% CI 0.47-0.72) and 7 or more limited-activity days owing to a fracture (RR = 0.67, 95% CI 0.58-0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once-yearly infusion with zoledronic acid over a 3-year period significantly reduced the number of days that patients reported back pain, limited activity owing to back pain, and limited activity and bed rest owing to a fracture.
- [Show abstract] [Hide abstract] ABSTRACT: Medication compliance may be a surrogate for factors that improve health outcomes such as fractures. Little is known about the size of this potential "healthy adherer" effect. We evaluated the hypothesis that compliance with placebo is associated inversely with bone loss and fractures among women participating in the Fracture Intervention Trial (FIT). Compliance with placebo and alendronate was evaluated using daily medication diaries. Women were defined as having high compliance if they took 80% or more of dispensed study medication. Change in bone mineral density (BMD) was assessed using mixed models comparing women with high versus lower compliance with placebo. Cox proportional-hazards models analyzed the association between placebo compliance and various types of fractures. Among 3169 women randomized to placebo, 82% had high compliance. Compared with women with lower placebo compliance, bone loss at the total hip was lower in compliant placebo-treated women (-0.43%/year versus -0.58%/year, p = .04). Among placebo-treated women, there were 46 hip, 110 wrist, 77 clinical vertebral, and 492 total clinical fractures. Compared with women with lower placebo compliance, women with high placebo compliance had a nonsignificant reduced risk for hip fracture [adjusted hazard ratio (HR) = 0.67, 95% confidence interval (CI) 0.30-1.45]. This trend was not observed for other fractures. Medication compliance may be a proxy for factors that confers benefit on reducing hip fracture (but not other types of fractures) independent of the effect of the medication itself. Nonrandomized studies of interventions designed to maintain or improve bone density and/or hip fracture may need to consider medication compliance as a confounder to better estimate true intervention effects.
- [Show abstract] [Hide abstract] ABSTRACT: To determine the reproducibility of proton MR spectroscopy ((1) H-MRS) for assessing vertebral bone marrow adiposity at 3 Tesla (T); to evaluate variation of marrow adiposity at different vertebral levels; and to demonstrate the feasibility of using (1) H-MRS at 3T for evaluating marrow adiposity in subjects with low bone density. Single voxel MRS was acquired at vertebral body L1 to L4 at 3T in 51 postmenopausal females including healthy controls (n = 13) and patients with osteoporosis/osteopenia (n = 38). Marrow fat contents were compared between vertebral levels and between groups using analysis of variance (ANOVA). Six subjects were scanned twice to evaluate technique reproducibility. The average coefficient of variation of vertebral marrow fat content quantification was 1.7%. Marrow fat content significantly increased from L1 to L4. The average fat content was significantly elevated in patients with osteoporosis/osteopenia compared with controls, adjusted for age and body mass index (P < 0.05). In vivo MRS at high field strength provides reliable measurement of marrow adiposity with excellent reproducibility and can be a valuable tool for providing complementary information on bone quality and potentially also fracture risk.
- [Show abstract] [Hide abstract] ABSTRACT: Osteoporosis-related fractures are associated with reductions in health-related quality of life (HRQL). We examined the benefits of zoledronic acid (ZOL) on HRQL in patients sustaining vertebral and clinical fractures from HORIZON-Pivotal Fracture Trial using mini-Osteoporosis quality of life Questionnaire (OQLQ). In this multicenter, double-blind, placebo-controlled trial, 1434 patients from a cohort of postmenopausal women with osteoporosis (mean age 73years) were randomized to receive annual infusions of ZOL 5mg or placebo for 3years. Baseline HRQL scores were comparable between ZOL and placebo groups based on the presence or absence of fractures, with exception of prevalent vertebral fractures where patients (irrespective of the treatment group) had lower baseline HRQL scores than those without prevalent vertebral fractures. Greater number of prevalent vertebral fractures was associated with lower baseline HRQL (p<0.001). No significant difference between ZOL and placebo in the overall summary score was observed but a significant benefit was noted in certain domains with ZOL, especially in patients sustaining incident clinical fractures. Improvements in HRQL were marked at first assessment after a morphometric vertebral fracture with significant differences favouring ZOL in pain (p=0.0115), standing pain (p=0.0125)), physical (lifting, p=0.0333) and emotional function (fear of fractures, p=0.0243; fear of falls, p=0.0075) but not for activities of daily living or leisure domains. HRQL is reduced in patients with vertebral fractures. Treatment with ZOL over 3years was associated with improvements in specific domains of quality of life vs. placebo, particularly in patients sustaining incident fractures.
- [Show abstract] [Hide abstract] ABSTRACT: Zoledronic acid (ZOL), a third-generation aminobisphosphonate, showed pronounced antifracture efficacy in a phase III clinical trial [Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT)] when administered yearly (5-mg infusions of ZOL), producing significant reductions in morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively, over a 3-year period. The purpose of this study was to analyze the biopsies obtained during the HORIZON clinical trial (152 patients, 82 ZOL and 70 placebo) by means of Raman microspectroscopy (a vibrational spectroscopic technique capable of analyzing undecalcified bone tissue with a spatial resolution of approximately 0.6 µm) to determine the effect of ZOL therapy on bone material properties (in particular mineral/matrix ratio, lamellar organization, carbonate and proteoglycan (based on spectral identification of glycosaminoglycan) content, and mineral maturity/crystallinity) at similar tissue age (based on the presence of tetracycline double labels). The results indicated that while ZOL administration increased the mineral/matrix ratio compared with placebo, it also resulted in mineral crystallites with a quality profile (based on carbonate content and maturity/crystallinity characteristics) of younger (with respect to tissue age) bone. Since the comparisons between ZOL- and placebo-treated patients were performed at similar tissue age at actively forming bone surfaces, these results suggest that ZOL may be exerting an effect on bone matrix formation in addition to its well-established antiresorptive effect, thereby contributing to its antifracture efficacy.
- [Show abstract] [Hide abstract] ABSTRACT: To determine the prevalence in the neonatal literature of statistical approaches accounting for the unique clustering patterns of multiple births and to explore the sensitivity of an actual trial to several analytic approaches to multiples. A systematic review of recent perinatal trials assessed the prevalence of studies accounting for clustering of multiples. The Nitric Oxide to Prevent Chronic Lung Disease (NO CLD) trial served as a case study of the sensitivity of the outcome to several statistical strategies. We calculated odds ratios using nonclustered (logistic regression) and clustered (generalized estimating equations, multiple outputation) analyses. In the systematic review, most studies did not describe the random assignment of twins and did not account for clustering. Of those studies that did, exclusion of multiples and generalized estimating equations were the most common strategies. The NO CLD study included 84 infants with a sibling enrolled in the study. Multiples were more likely than singletons to be white and were born to older mothers (P < .01). Analyses that accounted for clustering were statistically significant; analyses assuming independence were not. The statistical approach to multiples can influence the odds ratio and width of confidence intervals, thereby affecting the interpretation of a study outcome. A minority of perinatal studies address this issue.
- [Show abstract] [Hide abstract] ABSTRACT: Body composition appears to be an important determinant of bone mineral density (BMD). BMD at the femoral neck, lumbar spine, and whole-body and the whole-body soft-tissue composition were measured cross-sectionally in 334 healthy premenopausal and early perimenopausal women, aged 44-50 years, using a Hologic QDR densitometer. Correlations between lean mass and BMD at the hip, spine, and whole-body were greater (r = 0.40, r = 0.44, and r = 0.45, respectively, p < 0.0001) than those for fat mass (r = 0.19, r = 0.16, and r = 0.16, respectively, p < 0.01). There was a significant linear trend in femoral BMD from the lowest to highest category of lean mass (0.75 +/- 0.10 g/cm2, 0.80 +/- 0.10 g/cm2, and 0.86 +/- 0.09 g/cm2, p < 0.0001). Similar trends were demonstrated for spinal and whole-body density. For categories of fat mass, there was a significant linear trend at the hip (0.78 +/- 0.10 g/cm2, 0.79 +/- 0.10 g/cm2, and 0.83 +/- 0.10 g/cm2, p = 0.0106), but not at the spine or whole body. There was a 5.00% (3.62, 6.38; 95% confidence limits) difference in hip BMD per unit (standard deviation) of lean mass, while only a 0.73% (-0.66, 2.11) difference in hiP BMD per unit (SD) of fat mass. Differences in BMD were examined by categories of lean and fat mass (low, medium, high) for a total of nine possible combinations of lean and fat measures. BMD at the hip, spine, and whole-body were significantly higher in those with high lean mass than in those with low lean mass, irrespective of fat mass. Women with high lean/low fat had similar hip, spinal, and whole-body BMD as those with high lean/high fat, despite their significantly lower body weight (62.5 +/- 3.3 kg vs 85.7 +/- 5.4 kg, respectively, p < 0.0001). In premenopausal and early perimenopausal women, body weight alone may not be associated with increased bone mass unless a significant proportion of that weight is comprised of lean mass. The stronger association between lean mass and BMD than that for fat mass may be attributed to differences in determinants of lean mass, such as exercise, lifestyle factors, estrogen levels, or a combination of these factors.
- [Show abstract] [Hide abstract] ABSTRACT: Based on engineering principles, geometric measurements of femoral size should be related to femoral strength and the risk for hip fracture. To evaluate whether a simple measurement of femoral geometry is associated with hip fracture risk, we obtained dual x-ray absorptiometry scans of the proximal femur on 8074 white women age 67 or older. During an average of 1.6 years of follow-up, 64 participants suffered hip fractures. In all fracture cases and in a random sample of 134 women who did not subsequently suffer a hip fracture, we measured hip axis length (the distance from greater trochanter to inner pelvic brim), neck width, and the neck/shaft angle on the scan printout, with the observer blinded to subsequent fracture status of the participant. Results were analyzed using multiple logistic models, and odds ratios were determined. After adjustment for age, each standard deviation decrease in femoral neck bone mineral density increased hip fracture risk 2.7-fold (95% confidence interval 1.7, 4.3), and each standard deviation increase in hip axis length nearly doubled the risk of hip fracture (odds ratio = 1.8; 95% CI 1.3, 2.5). The relationship between hip axis length and fracture risk persisted even after adjustment for age, femoral neck density, height, and weight. A longer hip axis length was associated with an increased risk of both femoral neck (OR = 1.9; 95% CI 1.3, 3.0) and trochanteric fractures (1.6; 1.0, 2.4). We found no significant association between the neck width (1.1; 0.8, 1.5) or the neck/shaft angle (1.4; 0.9, 2.2) and risk of hip fracture.(ABSTRACT TRUNCATED AT 250 WORDS)
- [Show abstract] [Hide abstract] ABSTRACT: The assessment of radiographs for vertebral fractures is important in the clinical evaluation of patients with suspected osteoporosis, in the epidemiological evaluation of elderly populations, and in clinical trials of osteotrophic drugs. The purpose of this study is to compare visual semiquantitative (SQ) approaches and quantitative morphometric approaches for assessing prevalent and incident vertebral fractures in postmenopausal osteoporosis. We analyzed lateral thoracolumbar spine radiographs (baseline and approximately 3.5 year follow-up) of 503 women (age > or = 65) randomly selected from the Study of Osteoporotic Fractures (SOF) population. SQ assessment by an experienced radiologist graded vertebral fractures from 0 (normal) to 3 (severe). Incident fractures by SQ were defined as an increase of > or = 1 grade on follow-up radiographs. Trained research assistants visually triaged women as normal, uncertain, or probably fractured and visually flagged vertebrae with moderate/severe (grade > or = 2) prevalent fractures or with any (grade > or = 1 change) incident fracture. The radiographs were also digitized by research assistants, and quantitative morphometry (QM) was used to classify vertebral deformities at several cut-offs based on standard deviation (SD) reductions in height ratios from normal means, e.g., QM > or = 3 SD. Incident fractures by QM were defined as a decrease in height of more than 15% (QM15) on follow-up radiographs. Finally, a combination of these methods was used to detect moderate/severe prevalent fractures and any grade of incident fractures. In the overall analysis, the prevalence of fractures varied from 14 to 33% and the incidence from 5 to 10% by woman, depending upon the method and cut-off criteria. In the detailed analysis, considering visually triaged uncertain as abnormal, triage by research assistants detected 97.0% (163/168) of women with SQ grade > or = 1 fractures and 100% (70/70) with SQ grade > or = 2 fractures. Visual flagging by research assistants detected 88.5% (108/122) of SQ > or = 2 prevalent fractures (kappa score, kappa = 0.82) and 85.2% (52/61) of SQ incident fractures (kappa = 0.79). QM > or = 3 SD detected 37.9% (141/372) of SQ > or = 1 prevalent fractures (kappa = 0.51) and 79.5% (97/122) of SQ > or = 2 prevalent fractures (kappa = 0.68), plus 18 vertebrae without SQ fractures. QM 15 detected 59% (36/61) of SQ incident fractures (kappa = 0.70), plus five vertebrae without SQ incident fractures. The combination assessment detected 92% (112/122) of SQ > or = 2 prevalent fractures (kappa = 0.76) and 84% (51/61) of SQ incident fractures (kappa = 0.91). The precision errors of QM vertebral height measurements (baseline versus follow-up) ranged from 2.71 to 2.92%. Nevertheless, excluding the 5719 vertebrae that were clearly normal by morphometry, i.e., within 2 SD of the normal means at both baseline and follow-up, two-thirds (358/556) of the remaining vertebrae changed classification by at least 1 SD category. Visual triage and visual flagging by research assistants appear to be highly effective methods for vertebral fracture assessment in osteoporosis, potentially reducing the number of false-positive and false-negative fractures detected by QM, at least relative to SQ by the radiologists. There is higher concordance among the visual approaches studied than between the visual SQ and quantitative morphometric approaches, with QM having limited ability to detect mild fractures but good ability to detect moderate/severe fractures, as classified by SQ. Use of a combination of sensitive qualitative and quantitative criteria, with adjudication by an experienced radiologist, is feasible and draws upon the relative strengths of each of the methods. Quantitative morphometry should not be performed in isolation, particularly when applying highly sensitive morphometric criteria at low threshold levels, without visual assessment to confirm the detected prevalent or incident vertebral defor
University of California, San FranciscoSan Francisco, California, United States