Steve Cummings

The Association of Radiographically Detected Vertebral Fractures with Back Pain and Function: A Prospective Study

Radiographically detected vertebral fractures (hereafter referred to as vertebral fractures) are a hallmark of postmenopausal osteoporosis and an important end point in clinical trials of osteoporosis treatment. Women with vertebral fractures have low bone mass compared with women without these fractures and, independently of bone mass, have an increased risk for additional vertebral and other fractures [1-4]. Vertebral fractures are common: Five percent of 50-year-old white women and 25% of 80-year-old women have had at least one vertebral fracture [5]. Surprisingly, however, the manner in which vertebral fractures affect health remains uncertain. Cross-sectional studies in community-derived samples of older women have demonstrated only a modest association [6-8] or no association [9-11] between prevalent vertebral fractures and back pain or disability. Cross-sectional studies do not distinguish more recent fractures from older vertebral fractures and may fail to capture transient increases in pain or disability [12], a limitation that may underestimate the clinical effect of these fractures [13]. Back pain is common among elderly women [14], and frequent causes of back pain, such as degenerative disc disease, facet joint osteoarthritis, spinal stenosis, and scoliosis, may obscure the impact of vertebral fracture. Only about one third of new vertebral fractures come to medical attention [15, 16], suggesting that most vertebral fractures are asymptomatic. However, attitudes toward back pain in older women and access to health care may also play a role in determining whether vertebral fractures come to medical attention. We examined the effect of incident vertebral fractures on back pain and back-related functional limitations in a large community-based sample of elderly women who underwent serial spinal radiography and annual assessments of back pain and disability over the same period. Methods Participants Study patients were participants in the Study of Osteoporotic Fractures, a cohort recruited from population-based listings in four U.S. metropolitan areas. Details of the design of this study are published elsewhere [17]. Lateral spine radiographs were obtained for 9677 white women between the ages of 65 and 99 years (median age, 70 years) who underwent baseline examination between 1986 and 1988. Repeated spinal radiographs suitable for morphometry were obtained for 7223 women (75% of the original cohort) at a follow-up clinic visit held an average of 3.7 years (range, 1.3 to 5.1 years) later. All participants gave informed consent. Vertebral Morphometry Lateral radiographs of the thoracic and lumbar spine were obtained in accordance with current guidelines [18]. Quantitative vertebral morphometry was performed using six-point digitization as described elsewhere [3, 19] to calculate the anterior (Ha), mid- (Hm), and posterior (Hp) height for each vertebral body from T4 to L4. A system of triage of radiographs, described elsewhere [3, 20], was used to reduce the number of radiographs requiring morphometric measurements. Briefly, trained technicians separated sets of radiographs into normal, uncertain, or probably fractured groups on the basis of a limited semiquantitative grading scheme that categorized women by the most abnormal vertebral level [20]. Uncertain grades were further categorized by the study radiologist as normal or probably fractured. Morphometry was done on the radiograph pairs that were categorized as probably fractured (42%). In a random sample of 503 women whose radiographs were triaged and then digitized, triage missed no incident fractures according to the study definition. Definition of Vertebral Fracture A vertebra was classified as having a prevalent fracture on the baseline radiograph if any of the following ratios were more than 3 SDs (>4 SDs for severe fractures) below the normal mean for that vertebral level: (Ha/Hp), (Hm/Hp), or a combination of (H/H [] 1) and (Hai/Hai 1) [3, 21]. A new (incident) fracture was identified if any of the three vertebral heights (Ha, Hm, or Hp) on follow-up radiographs decreased by 20% or more and by at least 4 mm compared with the baseline height. Incident fractures identified by morphometry were reviewed by a radiologist to exclude imaging artifacts or such conditions as osteophytosis and Scheuermann disease; 7% of vertebrae meeting the morphometric criteria for incident fracture were reclassified as not fractured. Incident Clinical Fractures We used previously described methods [22] to assess the occurrence of clinical fractures of any bone during follow-up. Women were considered to have a clinical vertebral fracture if they reported a new diagnosis of spinal fracture and a clinical radiology report confirmed that a vertebral fracture was present. Measurements of Pain, Disability, and Limited Activity We evaluated outcome measures by using a previously described questionnaire [7, 23] that asked about back pain and back-related disability in the past 12 months and the number of days of limited activity due to back pain. The questionnaire was administered at baseline and at three annual follow-up contacts held before assessment of vertebral fractures. The third follow-up contact coincided with follow-up radiography. Back pain was assessed on scales of frequency (0, never or rarely; 1, some of the time; 2, most of the time; or 3, all of the time) and severity (0, no pain; 1, mild pain; 2, moderate pain; or 3, severe pain). The two pain questions had high internal consistency (Cronbach = 0.81) and were summed for a total score that could range from 0 to 6. We defined clinically significant back pain as pain that was experienced most or all of the time or pain that was moderate or severe. Women without significant back pain at baseline were considered to have increased back pain if clinically significant pain had developed between any follow-up contacts. For women with clinically significant back pain at baseline, increased back pain was defined as an increase in total pain score of at least two points. Both types of increase had a similar association with incident fractures and thus were combined for a single outcome. Back-related disability was assessed with questions about the degree of difficulty (0, no difficulty; 1, some difficulty; 2, much difficulty; or 3, unable to perform activity) in six activities of daily living that involved the back (bending down to pick up light-weight objects, lifting a 10-pound object from the floor, reaching for objects just above the head, putting on socks or stockings, getting in and out of an automobile, and standing for 2 hours). These measures were combined in a back-related disability score ranging from 0 to 18. As reported elsewhere [7], this scale has high internal consistency (Cronbach = 0.82) and is highly correlated (Spearman r = 0.73) with a more extensive instrument used to assess disability caused by low back pain [24]. We defined clinically significant disability as much difficulty or unable in one or more of the six activities. Women without significant disability at baseline were considered to have increased disability if clinically significant disability had developed between any follow-up contacts. For women with clinically significant disability at baseline, increased disability was defined as an increase in disability score of at least three points. Both types of increase had a similar association with incident fractures and thus were combined for a single outcome. We also asked participants if they had limited their activities because of back pain since the last contact; if the answer was yes, we asked for the number of days they had stayed in bed and the number of days on which activity was limited (not including days in bed) because of back pain. Questions were adapted from previous surveys [25, 26]. For all follow-up contacts, we summed the number of days of bed rest and, in a separate measure, the number of days of limited activity; we then divided these numbers by the total years of follow-up to estimate the average number of affected days per year. Other Measurements The baseline questionnaire assessed potential confounding factors that may be associated with the risk for incident vertebral fracture and with back pain or disability, including smoking (current or past smoker); inactivity, defined as walking less than one block daily (yes or no); a previous physician diagnosis of osteoporosis or spinal fracture (yes or no); current use of estrogen (yes or no); hip pain in the past 12 months (yes or no); and height at 25 years of age. At the baseline examination, we assessed height and weight and calculated body mass index (kg/m2). We assessed grip strength by using an isometric dynamometer (Jamar Hydraulic Hand Dynamometer, JA Preston, Jackson, Mississippi) at baseline and at the follow-up examination and calculated change in grip strength between the two measurements. A random sample of 16% of baseline spine radiographs was assessed for spinal disc degeneration by using previously published methods [27]. Statistical Analysis Unless otherwise indicated, analyses were done separately in groups stratified by the presence of one or more baseline prevalent vertebral fractures. Descriptive and bivariate associations were assessed by using the t-test for continuous variables and the chi-square test for dichotomous variables. The association between incident vertebral fractures and dichotomous outcomes (increased back pain and increased back disability) was analyzed with logistic regression techniques. We analyzed the association of incident vertebral fracture with days of bed rest and days of limited activity per year by using Poisson regression. The distribution of days of bed rest (mean SD, 0.44 5.15) and limited-activity days (16.3 53.7) indicate that considerable overdispersion is present. Poisson regression allowing for this overdispersion provides a good estimation and inferential scheme [2

Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data

Summary Background Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence. Methods We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat. Results We analysed data for 83 399 women with 306 617 women-years of follow-up. Median follow-up was 65 months (IQR 54–93). Overall, we noted a 38% reduction (hazard ratio [HR] 0·62, 95% CI 0·56–0·69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5–10 (42%, HR 0·58, 0·51–0·66; p<0·0001 vs 25%, 0·75, 0·61–0·93; p=0·007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1·73, 95% CI 1·47–2·05; p<0·0001). We recorded a significant reduction of 34% in vertebral fractures (0·66, 0·59–0·73), but only a small effect for non-vertebral fractures (0·93, 0·87–0·99). Interpretation For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs. Funding Cancer Research UK.

A meta-analysis of the association of fracture risk and body mass index in women.

Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20–105) years and follow up of 2.2 million person‐years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m2) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non‐obese women. Compared to a BMI of 25 kg/m2, the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m2 was 0.87 (95% confidence interval [CI], 0.85–0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09–1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored.

Association Between Telomere Length, Specific Causes of Death, and Years of Healthy Life in Health, Aging, and Body Composition, a Population-Based Cohort Study

Although telomere length (TL) is known to play a critical role in cellular senescence, the relationship of TL to aging and longevity in humans is not well understood. In a large biracial population-based cohort, we tested the hypotheses that elderly persons with shorter TL in peripheral white blood cells have poorer survival, shorter life span, and fewer years of healthy life (YHL). Associations were evaluated using Cox proportional hazard models and linear regression analyses where appropriate. TL (in kilo base pairs) was not associated with overall survival (hazard ratio 1.0; 95% confidence interval 0.9-1.1) or death from any specific underlying cause including infectious diseases, cancer, or cardiac and cerebrovascular diseases. TL, however, was positively associated with more YHL (beta = 0.08 +/- 0.04, p = .03). Findings suggest that TL may not be a strong biomarker of survival in older individuals, but it may be an informative biomarker of healthy aging.

Serum estrogen levels, cognitive performance, and risk of cognitive decline in older community women

OBJECTIVE: To determine the association between serum estrogen levels, cognitive performance, and risk of cognitive decline in older women.

Breast Cancer Risk by Breast Density, Menopause, and Postmenopausal Hormone Therapy Use

PURPOSE We determined whether the association between breast density and breast cancer risk and cancer severity differs according to menopausal status and postmenopausal hormone therapy (HT) use. METHODS We collected data on 587,369 women who underwent 1,349,027 screening mammography examinations; 14,090 women were diagnosed with breast cancer. We calculated 5-year breast cancer risk from a survival model for subgroups of women classified by their Breast Imaging Reporting and Data System (BIRADS) breast density, age, menopausal status, and current HT use, assuming a body mass index of 25 kg/m(2). Odds of advanced (ie, IIb, III, IV) versus early (ie, I, IIa) stage invasive cancer was calculated according to BIRADS density. RESULTS Breast cancer risk was low among women with low density (BIRADS-1): women age 55 to 59 years, 5-year risk was 0.8% (95% CI, 0.6 to 0.9%) for non-HT users and 0.9% (95% CI, 0.7% to 1.1%) for estrogen and estrogen plus progestin users. Breast cancer risk was high among women with very high density (BIRADS-4), particularly estrogen plus progestin users: women age 55 to 59 years, 5-year risk was 2.4% (95% CI, 2.0% to 2.8%) for non-HT users, 3.0% (95% CI, 2.6% to 3.5%) for estrogen users, and 4.2% (95% CI, 3.7% to 4.6%) for estrogen plus progestin users. Advanced-stage breast cancer risk was increased 1.7-fold for postmenopausal HT users who had very high density (BIRADS-4) compared to those with average density (BIRADS-2). CONCLUSION Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT, especially estrogen plus progestin.

Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels.

Circulating levels of inflammatory markers can predict cardiovascular disease risk. To identify genes influencing the levels of these markers, we genotyped 1,343 single-nucleotide polymorphisms (SNPs) in 1,184 African Americans from the Health, Aging and Body Composition (Health ABC) Study. Using admixture mapping, we found a significant association of interleukin 6 soluble receptor (IL-6 SR) with European ancestry on chromosome 1 (LOD 4.59), in a region that includes the gene for this receptor (IL-6R). Genotyping 19 SNPs showed that the effect is largely explained by an allele at 4% frequency in West Africans and at 35% frequency in European Americans, first described as associated with IL-6 SR in a Japanese cohort. We replicate this association (P<<1.0x10-12) and also demonstrate a new association with circulating levels of a different molecule, IL-6 (P<3.4x10-5). After replication in 1,674 European Americans from Health ABC, the combined result is even more significant: P<<1.0x10-12 for IL-6 SR, and P<2.0x10-9 for IL-6. These results also serve as an important proof of principle, showing that admixture mapping can not only coarsely localize but can also fine map a phenotypically important variant.

Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene

Objective: Osteoporosis is a significant health problem in postmenopausal women. Consequently, new and effective therapies are being sought to preserve bone mass and prevent osteoporosis in this population of women. The objective of this study was to compare the effects of lasofoxifene with raloxifene and placebo on indices of bone health in postmenopausal women. Design: A randomized, double-blind, placebo- and active treatment-controlled study of 2 years duration was conducted. Women included 410 postmenopausal women aged 47 to 74 years. The four treatment groups were: lasofoxifene 0.25 mg/day, or 1.0 mg/day, raloxifene 60 mg/day, or placebo daily. All women received daily calcium and vitamin D supplements. The primary endpoint was percent change from baseline to 2 years in lumbar spine bone mineral density (BMD) in all women having baseline and at least one follow-up bone density measurement. Total hip BMD, biochemical markers of bone turnover, low-density lipoprotein cholesterol, and safety were also evaluated in all women. Results: Both doses of lasofoxifene significantly increased lumbar spine BMD compared with raloxifene (P ≤ 0.05) and with placebo treatment (P ≤ 0.05). Least squares mean increases (95% CI) from baseline in lumbar spine BMD, compared with placebo, were 3.6% (1.9, 5.2) for lasofoxifene 0.25 mg/day, 3.9% (2.4, 5.5) for lasofoxifene 1.0 mg/day, and 1.7% (0.3, 3.0) for raloxifene. The two doses of lasofoxifene and raloxifene were equally effective at increasing total hip BMD. Lasofoxifene and raloxifene significantly reduced the levels of biochemical markers of bone turnover compared with placebo. In general, the effects of lasofoxifene were greater than the responses to raloxifene. At 2 years, lasofoxifene significantly (P ≤ 0.05) reduced low-density lipoprotein cholesterol levels by 20.6% and 19.7% with 0.25 mg/day and 1 mg/day, respectively, compared with raloxifene (12.1%) and placebo (3.2%). Lasofoxifene and raloxifene had a similar adverse event profile with low rate of discontinuations due to adverse events. Conclusions: Lasofoxifene may be an effective and well-tolerated treatment option for the prevention of bone loss in postmenopausal women.

Association between oxidized LDL, obesity and type 2 diabetes in a population-based cohort, the Health Aging and Body Composition study

Accumulating evidence suggests a cross‐sectional association between oxidative stress and type 2 diabetes (T2D). Systemic oxidative stress, as measured by oxidized LDL (oxLDL), has been correlated with visceral fat. We examined the relationship between oxLDL, and T2D‐ and obesity‐related traits in a bi‐racial sample of 2985 subjects at baseline and after 7 years of follow‐up.

Do we need to adjudicate major clinical events

Purpose The use of centralized systems to adjudicate clinical events is common in large clinical trials, in spite of relatively little published literature concerning the rationale and justification. The purpose of this manuscript is to review the reasons for central adjudication and to discuss whether trials could be simplified by limiting or streamlining the adjudication process. Methods We reviewed the literature concerning central adjudication and documented the experience of adjudication in several clinical trials. Since definitions for nonfatal events are generally heterogeneous and subjective, one reason for a central process of adjudication is to assist in assuring systematic application of the definition used in the trial. In open-label trials, assuring that the adjudication is done blinded to treatment assignment may provide protection against differential misclassification. Regulatory authorities, including the FDA, derive confidence in the validity of results when central adjudication is performed. The clinical community has become accustomed to a certain amount of adjudication and may criticize trials that lack adjudication. Limitations It is difficult to document the value of adjudication in trials that have reported adjudicated and nonadjudicated event rates and related treatment effects. Making rationale decisions about when and how to adjudicate is hampered by the lack of published study of when and how central adjudication is helpful to improve the quality and validity of trials and at what cost. Conclusions Adjudication has not been shown to improve the ability to determine treatment effects. Thus, adjudication may be overly complex and overused in many large simple trials. The appropriate role of central adjudication — which trials, which outcomes, what methods — deserves scrutiny and further study. Clinical Trials 2008; 5: 56—60. http://ctj.sagepub.com