Depressive symptoms and cognitive decline in nondemented elderly women: a prospective study.

BACKGROUND: The association between depressive disorders and subsequent cognitive decline is controversial. We tested the hypothesis that elderly women (aged 65 years and older) without dementia but with depressive symptoms have worse cognitive function and greater cognitive decline than women with few or no symptoms. METHODS: As part of an ongoing prospective study, we evaluated 5781 elderly, mostly white, community-dwelling women. Women completed the Geriatric Depression Scale short form. Three cognitive tests--Trails B, Digit Symbol, and a modified Mini-Mental State Examination--were administered at baseline and approximately 4 years later. Baseline, follow-up, and change scores for the cognitive tests were analyzed by analysis of covariance and Kruskal-Wallis analysis; the odds of cognitive deterioration (> or =3-point decline on the modified Mini-Mental State Examination) were determined by logistic regression. RESULTS: At baseline, 211 (3.6%) of the women had 6 or more depressive symptoms. Only 16 (7.6%) of these women were receiving antidepressant medication. Increasing symptoms of depression were associated with worse performance at baseline and follow-up on all 3 tests of cognitive function (P<.001 for all comparisons). For example, the baseline Digit Symbol score (mean +/- SD) was 45.5 +/- 10.7 among women with 0 to 2 symptoms of depression, 40.3 +/- 10.7 for women with 3 to 5 symptoms, and 39.0 +/- 11.3 for women with 6 or more symptoms. After adjusting for the baseline score, cognitive change scores were also inversely associated with the number of depressive symptoms (P<.001 for all comparisons). Odds ratios for cognitive deterioration using 0 to 2 symptoms as the reference were 1.6 (95% confidence interval, 1.3-2.1) for 3 to 5 symptoms and 2.3 (95% confidence interval, 1.6-3.3) for 6 or more symptoms. Results were similar after being adjusted for education, age, health status, exercise, alcohol use, functional status, and clinic site. CONCLUSIONS: Depressive symptoms in older women are associated with both poor cognitive function and subsequent cognitive decline. Mechanisms underlying the association between these 2 common conditions need further exploration.

Association between depressive symptoms and mortality in older women. Study of Osteoporotic Fractures Research Group.

BACKGROUND: Major depression is associated with increased mortality, but it is not known whether patients who report depressive symptoms have greater mortality. SUBJECTS AND METHODS: We performed a prospective cohort study of 7518 white women 67 years of age or older who were recruited from population-based listings in Baltimore, Md, Minneapolis, Minn, Portland, Ore, and the Monongahela Valley, Pa. Participants completed the Geriatric Depression Scale (short form) and were considered depressed if they reported 6 or more of 15 possible symptoms of depression. Women were followed up for an average of 6 years. If a participant died, we obtained a copy of the official death certificate and hospital records, if available, and used International Classification of Diseases, Ninth Revision, codes to classify death attributable to cardiovascular, cancer, or noncancer, noncardiovascular cause. RESULTS: Mortality during 7-year follow-up varied from 7% in women with no depressive symptoms to 17% in those with 3 to 5 symptoms to 24% in those with 6 or more symptoms of depression (P<.001). Of 473 women (6.3%) with 6 or more depressive symptoms at baseline, 24% died (111 deaths in 2610 woman-years of follow-up) compared with 11% of women who reported 5 or fewer symptoms of depression (760 deaths in 41 460 woman-years of follow-up) (P<.001). Women with 6 or more depressive symptoms had a 2-fold increased risk of death (age-adjusted hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.75-2.61; P<.001) compared with those who had 5 or fewer depressive symptoms. This association remained strong after adjusting for potential confounding variables, including history of myocardial infarction, stroke, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, smoking, perceived health, and cognitive function (HR, 1.47; 95% CI, 1.14-1.88; P=.003). Depressive symptoms were associated with an increased adjusted risk of death from cardiovascular diseases (HR, 1.8; 95% CI, 1.2-2.5; P= .003), and non-cancer, noncardiovascular diseases (HR, 1.8; 95% CI, 1.2-2.7; P = .01), but were not associated with deaths from cancer (HR, 1.0; 95% CI, 0.6-1.7; P=.93). CONCLUSIONS: Depressive symptoms are a significant risk factor for cardiovascular and noncancer, noncardiovascular mortality but not cancer mortality in older women. Whether depressive symptoms are a marker for, or a cause of, life-threatening conditions remains to be determined.

Are we inhibited? Renal insufficiency should not preclude the use of ACE inhibitors for patients with myocardial infarction and depressed left ventricular function.

CONTEXT: Angiotensin-converting enzyme (ACE) inhibitors have been shown to decrease mortality in patients with myocardial infarction and depressed left ventricular function, but physicians may be reluctant to prescribe ACE inhibitors to patients with concomitant renal insufficiency. OBJECTIVE: To evaluate whether patients with depressed left ventricular ejection fraction following acute myocardial infarction have a similar reduction in mortality from ACE inhibitors regardless of their renal function. DESIGN: Retrospective cohort study using medical record data. SETTING: All nonfederal acute care hospitals. PATIENTS: A cohort of 20,902 Medicare beneficiaries aged 65 years and older directly admitted to the hospital from February 1, 1994, through July 30, 1995, and with a documented left ventricular ejection fraction of less than 40% measured by echocardiography, radionuclide scintigraphy, or angiography following a confirmed acute myocardial infarction. MAIN OUTCOME MEASURES: One-year survival for patients who received or who did not receive an ACE inhibitor at hospital discharge, stratified by the patient's level of renal function. RESULTS: For the entire cohort, the receipt of an ACE inhibitor on hospital discharge was associated with greater 1-year survival (hazards ratio, 0.84; 95% confidence interval, 0.77-0.91) after adjusting for patient demographic characteristics, comorbidity, severity of illness (including left ventricular ejection fraction), and the receipt of other therapies. In stratified models, the receipt of an ACE inhibitor was associated with a 37% (16%-52%) lower mortality for patients who had poor renal function (serum creatinine level,<265 micromol/L [<3 mg/dL]) and a 16% (8%-23%) lower mortality for patients who had better renal function. Use of aspirin therapy attenuated the benefit of ACE inhibitors in patients with poor renal function. CONCLUSIONS: Moderate renal insufficiency should not be considered a contraindication to the use of ACE inhibitors in patients with depressed left ventricular ejection fraction following myocardial infarction. Use of aspirin therapy may attenuate the benefit of ACE inhibitors in patients with high serum creatinine levels; therefore, further studies are needed to determine whether treatment with aspirin, alternative antiplatelet agents, or anticoagulation is indicated for these patients.

Smoking cessation after surgery. A randomized trial.

BACKGROUND: Cigarette smoking is the greatest cause of preventable mortality in the United States. Because most smokers would like to quit and most hospitals are smoke free, surgical admissions represent a window of opportunity for tobacco cessation interventions. METHODS: A total of 324 patients (98% men), aged 25 to 82 years, who were current smokers and who underwent noncardiac surgery were enrolled in a randomized controlled trial at the Veterans Affairs Medical Center, San Francisco, Calif. One hundred sixty-eight participants (52%) received a multicomponent intervention designed to increase self-efficacy and coping skills that included face-to-face in-hospital counseling, viewing a smoking cessation videotape, self-help literature, nicotine replacement therapy, and 3 months of telephone follow-up. One hundred fifty-six participants (48%) received self-help literature and brief counseling lasting 10 minutes. Serum or saliva cotinine levels were measured to confirm self-reported smoking cessation. RESULTS: At 12 months of follow-up, the self-reported quit rate was 27% among the intervention group and 13% among the comparison group (relative risk, 2.1; 95% confidence interval, 1.2-3.5; P < .01). Based on biochemical confirmation, 15% of the intervention group, compared with 8% of the comparison group, quit smoking at 12 months (relative risk, 2.0; 95% confidence interval, 1.0-3.9; P = .04). CONCLUSIONS: A smoking cessation intervention targeted at smokers hospitalized for noncardiac surgery can increase long-term quit rates. Surgical hospitalizations provide an opportunity to reach smokers who want to quit smoking.

Smoking and mortality among older women: the study of osteoporotic fractures.

BACKGROUND: Relatively few studies have been focused on the effect of smoking among older individuals. The goal of this study is to investigate the relationship between smoking status and cause-and age-specific mortality among elderly women. METHODS: Women aged 65 years and older and living in four geographical areas (Baltimore, Md, Minneapolis, Minn, Pittsburgh, Pa, and Portland, Ore) were recruited from various population-based listings for participation in the multicenter Study of Osteoporotic Fractures between September 1986 and October 1988 (N=9704). During a mean follow-up of 4.9 years (<99% complete), 751 deaths occurred. The date and cause of death were ascertained, and the relationship between mortality and current and past smoking status was analyzed using Cox proportional hazards modeling techniques. RESULTS: Compared with nonsmokers, women smokers aged 65 to 74 years have a more than twofold increase in mortality attributable to increases in both cardiovascular and cancer mortality; death from smoking-related cancers increased eight- to 10-fold. Women 75 years and older who smoke have a small overall increased relative risk (RR) of mortality (RR=1.4; 95% confidence interval [CI], 0.9 to 2.3), but more than five-fold increased risk of dying from a smoking-related cancer (RR=5.2; 95% CI, 1.6 to 16.8). All-cause and cardiovascular death rates approach those of nonsmokers within 10 years after a woman quits smoking; morality from smoking-related cancers remains elevated for at least 23 years. CONCLUSIONS: The harmful effects of continuing to smoke are apparent even among women aged 75 years and older.

Mortality following fractures in older women. The study of osteoporotic fractures.

BACKGROUND: Most investigators have hypothesized that the increase in mortality following osteoporotic fractures reflects poor underlying health status in addition to the acute effects of the fracture. METHODS: We observed 9704 ambulatory women aged 65 years or older enrolled in the Study of Osteoporotic Fractures. We obtained reports of fractures and deaths every 4 months and reviewed death certificates and hospital discharge summaries. Multivariable proportional hazards models were used to determine the association between fractures and age-adjusted mortality. RESULTS: During a mean follow-up of 5.9 years, 1737 women had nonspine fractures, with a postfracture mortality rate of 3 per 100 woman-years, compared with 1.8 per 100 woman-years in those who did not have fractures (P < .001). After adjusting for other factors associated with mortality, women (n = 361) with fractures of the hip or pelvis had a 2.4-fold (95% confidence interval, 1.7-3.3) increase in mortality. However, only 9 (14%) of the 64 deaths that occurred after hip or pelvic fractures were caused or hastened by the fracture. By contrast, 11 (17%) of these deaths seemed to have been a result of chronic conditions that has contributed to the hip or pelvic fracture, and 44 (69%) of the deaths were not clearly related to the fracture. CONCLUSIONS: Mortality is increased following several types of fractures in older women. Most of the increase following hip and pelvic fractures is due to underlying conditions and probably would not be affected by reductions in the incidence of these fractures.

Is postmenopausal estrogen therapy associated with neuromuscular function or falling in elderly women? Study of Osteoporotic Fractures Research Group.

BACKGROUND: Muscle strength declines with advancing age; the causes of this are uncertain. In women, strength begins to decline around the time of menopause, suggesting that hormonal changes might influence strength. To determine the effect of postmenopausal estrogen use on muscle strength, neuromuscular function, and the risk of falling, we examined 9704 participants aged 65 years or more enrolled in the Study of Osteoporotic Fractures. METHODS: We measured hip abductor, triceps extensor, and hand-grip muscle strength, balance, gait speed, and self-reported functional disability. Falls during the first year of follow-up were determined from postcards that participants mailed every 4 months indicating whether they had fallen in the previous 4 months (> 99% complete follow-up). RESULTS: After adjusting for age, medications, medical history, and personal habits, current estrogen users did not differ in a clinically meaningful way from those who had never used estrogen on tests of hip abductor strength (mean difference, 0.15 kg; 95% confidence interval, -0.05 to 0.34 kg), triceps extensor strength (0.005 kg; -0.17 to 0.18 kg), or grip strength (0.30 kg; 0.00 to 0.59 kg). Gait speed, time to stand five times from a chair, balance, self-reported disability, and incidence of falls (odds ratio, 1.12; 95% confidence interval, 0.87 to 1.44) also did not differ between current users and never users. In addition, current users were similar to past users on all measures. CONCLUSION: We found no evidence that postmenopausal estrogen use has beneficial effects on muscle strength or neuromuscular function or that it reduces the risk of falling.

Estrogen replacement therapy and mortality among older women. The study of osteoporotic fractures.

BACKGROUND: Most previous studies of estrogen replacement therapy (ERT) and mortality have focused on younger women. Recently, it has been suggested that the effect of ERT on mortality may represent a "healthy-user" effect, ie, those with healthier lifestyles having a greater likelihood of receiving ERT. METHODS: Nine thousand seven hundred four women, 65 years or older, participated; 1258 (14.1%) reported current use of ERT for at least 1 year at entry. During an average follow-up of 6.0 years, 1054 women (11.8%) died. RESULTS: After adjusting for multiple variables, mortality rate was lower among current (relative risk [RR], 0.69; 95% confidence interval [CI], 0.54-0.87) and past users (RR, 0.79; 95% CI, 0.66-0.95), mainly due to reductions in deaths due to cardiovascular disease. The protective effect of ERT was greatest among women younger than 75 years (RR, 0.55; 95% CI, 0.40-0.76) compared with women from 75 to 84 years of age (RR, 0.93; 95% CI, 0.62-1.41) and 85 years or older (RR, 1.33; 95% CI, 0.43-4.12). The RR for overall mortality was 0.95 (95% CI, 0.68-1.32) among short-term users (1-9 years) compared with 0.55 (95% CI, 0.40-0.75) among long-term users (> or = 10 years). Deaths considered unrelated to ERT tended also to be reduced in current users younger than 75 years (RR, 0.72; 95% CI, 0.49-1.06) and current long-term users (RR, 0.75; 95% CI, 0.51-1.10). CONCLUSIONS: Estrogen replacement therapy is associated with lower overall mortality rates and reduced deaths due to cardiovascular disease. Women using ERT had healthier lifestyles, and the risk for death thought to be unrelated to ERT also tended to be lower in ERT users, suggesting in part a healthy-user effect.

Depression, falls, and risk of fracture in older women. Study of Osteoporotic Fractures Research Group.

BACKGROUND: Previous studies have suggested that depression is associated with falls and with low bone density, but it is not known whether depression leads to an increased risk of fracture. SUBJECTS AND METHODS: We conducted a prospective cohort study in elderly white women who were recruited from population-based listings in the United States. At a second visit (1988-1990), 7414 participants completed the 15-item Geriatric Depression Scale and were considered depressed if they reported 6 or more symptoms of depression. We measured bone mineral density (BMD) in the spine and hip using dual energy x-ray absorptiometry at the second visit, and asked participants about incident falls (yes/no) at 4 follow-up visits. Nonvertebral fractures were ascertained for an average of 6 years following the depression measure, and verified radiologically. We determined incident vertebral fractures by comparing lateral spine films obtained at the first visit (1986-1988) with repeat films obtained an average of 3.7 years later (1991-1992). RESULTS: The prevalence of depression (Geriatric Depression Scale score > or = 6) was 6.3% (467/7414). We found no difference in mean BMD of the hip and lumbar spine in women with depression compared with those without depression. Women with depression were more likely to experience subsequent falls than women without depression (70% vs 59%; age-adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-1.9; P<.001), an association that persisted after adjusting for potential confounding variables (OR, 1.4; 95% CI, 1.1-1.8; P=.004). Women with depression had a 40% (age-adjusted hazard ratio [HR], 1.4; 95% CI, 1.2-1.7; P<.001) increased rate of nonvertebral fracture (124 fractures in 3805 woman-years of follow-up) compared with women without depression (1367 fractures in 59 503 woman-years of follow-up). This association remained strong after adjusting for potential confounding variables, including medication use and neuromuscular function (HR, 1.3; 95% CI, 1.1-1.6; P=.008). Further adjustment for subsequent falls appeared to explain part of this association (HR, 1.2; 95% CI, 1.0-1.5; P = .06). Women with depression were also more likely to suffer vertebral fractures than women without depression, adjusting for history of vertebral fracture, history of falling, arthritis, diabetes, steroid use, estrogen use, supplemental calcium use, cognitive function, and hip BMD (OR, 2.1; 95% CI, 1.4-3.2; P<.001). CONCLUSIONS: Depression is a significant risk factor for fracture in older women. The greater frequency of falls among individuals with depression partially explains this finding. Other mechanisms responsible for the association between depression and fracture remain to be determined.

Outcome following acute myocardial infarction: are differences among physician specialties the result of quality of care or case mix?

BACKGROUND: Studies to determine whether care by cardiologists improves the survival of patients with acute myocardial infarction (MI) have produced conflicting results, and it is not known what accounts for differences in patient outcome by physician specialty. OBJECTIVES: To evaluate whether cardiologists provide more recommended therapies to elderly patients with acute MI and, if so, to determine whether variations in processes of care account for differences in patient outcome. DESIGN: Retrospective cohort study using medical chart data and administrative data files. SETTING: All nonfederal acute care hospitals in California. PATIENTS: A cohort of 7663 Medicare beneficiaries 65 years and older directly admitted to the hospital with a confirmed acute MI from April 1994 to July 1995 with complete data regarding potential contraindications to recommended therapies. MAIN OUTCOME MEASURES: Percentage of "good" and "ideal" candidates for a given acute MI therapy who actually received that therapy, percentage who received exercise stress testing or coronary angiography, percentage who underwent revascularization, and 1-year mortality, stratified by specialty of the attending physician. RESULTS: During hospitalization, good candidates for aspirin were more likely to receive aspirin if they were treated by cardiologists (87%) than by medical subspecialists (73%; P<.001), general internists (84%; P = .003), or family practitioners (81%; P<.001). Cardiologists were also more likely to treat good candidates with thrombolytic therapy (51%) than were medical subspecialists (29%; P<.001), general internists (40%; P<.001), or family practitioners (27%; P<.001). Patients of cardiologists were 2- to 4-fold more likely to undergo a revascularization procedure. Despite these differences in utilization, we found similar 30-day mortality rates across physician specialties. However, 1-year mortality rates were greater for patients treated by medical subspecialists (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6-2.3), general internists (OR, 1.4; 95% CI, 1.3-1.6), and family practitioners (OR, 1.7; 95% CI, 1.4-1.9) than for those treated by cardiologists. Adjusting for differences in patient and hospital characteristics markedly reduced the ORs for those treated by medical subspecialists (OR, 1.2; 95% CI, 0.9-1.4), general internists (OR, 1.1; 95% CI, 1.0-1.3), and family practitioners (OR, 1.3; 95% CI, 1.1-1.6), whereas further adjustment for medication use and revascularization procedures had little effect. CONCLUSIONS: Differences in the use of recommended therapies by physician specialty are generally small and do not explain differences in patient outcome. In comparison, differences among patients treated by physicians of various specialties (case mix) have a large impact on patient outcome and may account for the residual survival advantage of patients treated by cardiologists. With the exception of the in-hospital use of aspirin, recommended MI therapies are markedly underused, regardless of the specialty of the physician.

Vertebral fractures and mortality in older women: a prospective study. Study of Osteoporotic Fractures Research Group.

BACKGROUND: Osteoporotic fractures, including clinically detected vertebral fractures, are associated with increased mortality. However, only one third of vertebral fractures are diagnosed. It is unknown whether vertebral fractures, whether clinically apparent or not, are associated with greater mortality. OBJECTIVES: To test the hypothesis that women with prevalent vertebral fractures have greater mortality than those without fractures and to describe causes of death associated with vertebral fractures. DESIGN: Prospective cohort study with mean follow-up of 8.3 years. SETTING: Four clinical centers in the United States. PARTICIPANTS: A total of 9575 women aged 65 years or older and enrolled in the Study of Osteoporotic Fractures. MEASUREMENTS: Vertebral fractures by radiographic morphometry; calcaneal bone mineral density; demographic, medical history, and lifestyle variables; blood pressure; and anthropometric measures. In a subset of 606 participants, thoracic curvature was measured during a second clinic visit. MAIN OUTCOME MEASURES: Hazard ratios for mortality and cause-specific mortality. RESULTS: At baseline, 1915 women (20.0%) were diagnosed as having vertebral fractures. Compared with women who did not have a vertebral fracture, women with 1 or more fractures had a 1.23-fold greater age-adjusted mortality rate (95% confidence interval, 1.10-1.37). Mortality rose with greater numbers of vertebral fractures, from 19 per 1000 woman-years in women with no fractures to 44 per 1000 woman-years in those with 5 or more fractures (P for trend, <.001). In particular, vertebral fractures were related to the risk of subsequent cancer (hazard ratio, 1.4;95% confidence interval, 1.1-1.7) and pulmonary death (hazard ratio, 2.1;95% confidence interval, 1.4-3.0). In the subset of women who underwent thoracic curvature measurements, severe kyphosis was also related to pulmonary deaths (hazard ratio, 2.6;95% confidence interval, 1.3-5.1). CONCLUSION: Women with radiographic evidence of vertebral fractures have an increased mortality rate, particularly from pulmonary disease and cancer.

Lower-extremity amputation in people with diabetes. Epidemiology and prevention.

The age-adjusted rate of lower-extremity amputation (LEA) in the diabetic population is approximately 15 times that of the nondiabetic population. Over 50,000 LEAs were performed on individuals with diabetes in the United States in 1985. Among individuals with diabetes, peripheral neuropathy and peripheral vascular disease (PVD) are major predisposing factors for LEA. Lack of adequate foot care and infection are additional risk factors. Several large clinical centers have experienced a 44-85% reduction in the rate of amputations among individuals with diabetes after the implementation of improved foot-care programs. Programs to reduce amputations among people with diabetes in primary-care settings should identify those at high risk; clinically evaluate individuals to determine specific risk status; ensure appropriate preventive therapy, treatment for foot problems, and follow-up; provide patient education; and, when necessary, refer patients to specialists, including health-care professionals for diagnostic and therapeutic interventions and shoe fitters for proper footwear. Programs should monitor and evaluate their activities and outcomes. Many issues related to the etiology and prevention of LEAs require further research.

Evaluating outcomes of pregnancy in diabetic women. Epidemiologic considerations and recommended indicators.

Many programs have been applied in various settings to reduce adverse outcomes of pregnancy in women with diabetes. Efforts to standardize criteria and methods for evaluating these programs are relatively recent. Without such standardization, evaluation of the impact of many programs and comparisons among programs have not been possible. We review the suitability of available data sources for monitoring adverse outcomes of pregnancy in women with diabetes in light of epidemiological considerations relevant to selection of indicators of program impact. This article is intended to be a resource to help evaluate in a standardized fashion the impact of programs at a regional, state, or local level. We conclude that primary data (information collected by programs themselves) collected in a standardized manner are necessary for evaluation of programs for diabetes in pregnancy. Secondary data sources alone are of limited value for monitoring outcomes because of underreporting of maternal diabetes, especially in the absence of identified complications. Ultimately, the ability to rigorously assess the impact of efforts to improve outcomes of diabetes in pregnancy may depend on the creation of comprehensive statewide systems to identify women of childbearing age who have diabetes.

Axial and appendicular bone density predict fractures in older women.

To determine whether measurement of hip and spine bone mass by dual-energy x-ray absorptiometry (DEXA) predicts fractures in women and to compare the predictive value of DEXA with that of single-photon absorptiometry (SPA) of appendicular sites, we prospectively studied 8134 nonblack women age 65 years and older who had both DEXA and SPA measurements of bone mass. A total of 208 nonspine fractures, including 37 wrist fractures, occurred during the follow-up period, which averaged 0.7 years. The risk of fracture was inversely related to bone density at all measurement sites. After adjusting for age, the relative risks per decrease of 1 standard deviation in bone density for the occurrence of any fracture was 1.40 for measurement at the proximal femur (95% confidence interval 1.20-1.63) and 1.35 (1.15-1.58) for measurement at the spine. Results were similar for all regions of the proximal femur as well as SPA measurements at the calcaneus, distal radius, and proximal radius. None of these measurements was a significantly better predictor of fractures than the others. Furthermore, measurement of the distal radius was not a better predictor of wrist fracture (relative risk 1.64: 95% CI 1.13-2.37) than other sites, such as the lumbar spine (RR 1.56; CI 1.07-2.26), the femoral neck (RR 1.65; CI 1.12-2.41), or the calcaneus (RR 1.83; CI 1.26-2.64). We conclude that the inverse relationship between bone mass and risk of fracture in older women is similar for absorptiometric measurements made at the hip, spine, and appendicular sites.

Rate of bone loss is associated with mortality in older women: a prospective study.

Older women with low bone density have an increased risk of fracture, cardiovascular disease, and mortality. However, it is not known whether this association is caused by ongoing bone loss or by lower bone mass earlier in life. To determine whether rate of bone loss is associated with total and cause-specific mortality, we prospectively studied 6046 women aged 65 years or older who had serial bone mineral density (BMD) measurements as a part of the Study of Osteoporotic Fractures. Rates (mean +/- SD) of loss of BMD at the heel (for a mean of 5.7 years) and hip (for a mean of 3.5 years) were estimated. Cause-specific mortality was ascertained from death certificates and hospital records. BMD loss at the heel was 5.9 +/- 6.0 mg/cm2 per year (1.5 +/- 1.5%) and BMD loss at the hip was 4.1 +/- 10.2 mg/cm2 per year (0.6 +/- 1.4%). During an average follow-up of 3.2 years after the second measurement of BMD, 371 deaths occurred. Each SD increase in BMD loss at the hip was associated with a 1.3-fold (95% CI, 1.1-1.4) increase in total mortality, adjusted for age, baseline BMD, diabetes, hypertension, incident fractures, smoking, physical activity, health status, weight loss, and calcium use. In particular, hip BMD loss was associated with increased mortality from coronary heart disease (relative hazard [RH] = 1.3 per SD; 95% CI, 1.0-1.8) and pulmonary diseases (RH = 1.6 per SD; 95% CI, 1.1-2.5). The findings were similar for bone loss at the heel, except there was no significant association with pulmonary mortality. These results raise the possibility that bone loss may share common etiologies with coronary and pulmonary diseases.

Intermittent use of nitrates increases bone mineral density: the study of osteoporotic fractures.

Nitric oxide slows bone remodeling and bone loss in animals. Because nitroglycerin and other nitrates increase nitric oxide levels, we hypothesized that nitrate use may be associated with greater bone mineral density (BMD) and decreased risk of fracture in humans. Further, intermittent nitrate use may be associated with greater benefits than daily nitrate use, which results in tachyphylaxis. We tested this hypothesis using data from the Study of Osteoporotic Fractures. We prospectively studied 6201 elderly women of whom 317 took nitrates on a daily basis and 74 used them intermittently. We measured BMD at the hip and the heel and adjusted all comparisons for multiple potential confounders. We found that women taking daily nitrates had slightly greater hip BMD (difference, 13%; 95% confidence interval [CI], 0.14-4.1%) but the same heel BMD (difference, 0%; 95% CI -2.6-2.6%) as nonusers. By contrast, women using nitrates intermittently had substantially greater hip (difference, 2.6%; 95% CI, 0.4-6.8%) and heel BMD (difference, 53%; 95% CI, 2.6-11%) than nonusers. This study suggests that the intermittent administration of nitrates may enhance BMD.

C-reactive protein levels and viable Chlamydia pneumoniae in carotid artery atherosclerosis.

BACKGROUND AND PURPOSE: An elevated serum level of C-reactive protein, an inflammatory marker, is an independent predictor of stroke and coronary artery disease. To determine whether chronic infection with Chlamydia pneumoniae, which has been identified in atherosclerotic plaques, is responsible for systemic inflammation, we studied the association between serum C-reactive protein levels and infection of carotid artery atherosclerotic plaque with viable C pneumoniae. METHODS: Serum C-reactive protein levels were obtained before endarterectomy for carotid artery stenosis. Plaques were tested for C pneumoniae mRNA, an indicator of viability, and DNA by polymerase chain reaction of DNA and cDNA, respectively. RESULTS: Forty-eight samples were studied, of which 18 (38%; 95% CI, 23 to 50) were infected with viable C pneumoniae as evidenced by isolated chlamydial mRNA. All 18 of these samples, plus 1 additional sample, were positive for chlamydial DNA. Serum C-reactive protein levels were higher in those with viable C pneumoniae compared with those without infection (median, 8 mg/L versus undetectable; P=0.045 by Wilcoxon rank-sum test). In multivariable models, the only independent predictor of the presence of viable C pneumoniae was a detectable C-reactive protein level (odds ratio, 4.2; 95% CI, 1.1 to 17; P=0.04). CONCLUSIONS: Viable C pneumoniae are present in a substantial portion of carotid artery atherosclerotic plaques and are associated with increased serum C-reactive protein levels. These findings may explain the link between elevated C-reactive protein levels and the risk of cardiovascular disease and stroke but should be reproduced in a larger cohort.

Effect of risk status on treatment criteria. Implications of hypertension trials.

When deciding whether to treat a patient with hypertension, clinicians must balance the benefit of treatment against its adverse effects. In the absence of an interaction, the multiplicative model of risk implies that the absolute benefit of treatment is related to the underlying risk of an adverse outcome. Thus, each additional risk factor multiplies the absolute benefit of treating hypertension. Analyses of data from subgroups in clinical trials of hypertension treatment suggest that this model is usually valid. In contrast, the adverse effects of treatment are usually unrelated to other risk factors. Thus, the cutoff point for treatment differs in different individuals: setting a single treatment threshold and goal for the entire population is not appropriate. Patients who are at high absolute risk because of prior coronary artery disease or other risk factors have a greater potential absolute benefit, and such patients deserve a low threshold and goal, such as a diastolic blood pressure of 90 mm Hg. Conversely, persons at low risk, such as white women without other risk factors, do not require such aggressive management.

Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women.

Osteoprotegerin (OPG) and its ligand are cytokines that regulate osteoclastogenesis and that may be involved in the regulation of vascular calcification. We examined whether serum OPG levels were associated with stroke, mortality, and cardiovascular risk factors, including diabetes, as well as with bone mineral density and fractures in a sample of 490 participants in a prospective cohort of white women, at least 65 yr of age. We found that OPG levels, assayed blinded from serum obtained at baseline, were about 30% greater in women with diabetes (mean +/- SD, 0.30 +/- 0.17 ng/mL) than in those without diabetes (0.23 +/- 0.10 ng/mL; P = 0.0001). OPG levels were associated with all-cause mortality [age-adjusted odds ratio, 1.4/SD (0.11 ng/mL) increase in serum OPG level; 95% confidence interval, 1.2--1.8] and cardiovascular mortality (odds ratio, 1.4; 95% confidence interval, 1.1--1.8); these effects were not confounded by diabetes. OPG levels were not associated with baseline bone mineral density or with subsequent strokes or fractures. The association of serum OPG levels with diabetes and with cardiovascular mortality raises the possibility that OPG may be a cause of or a marker for vascular calcification.

Prospective studies of muscle capillary basement membrane width in prediabetics.

In 1968, this laboratory reported that muscle capillary basement membrane thickening was present in approximately 50% of nondiabetic individuals who had a strong genetic predisposition for developing diabetes mellitus. In the present manuscript we report the 20-yr follow-up observations in this group of prediabetics. We were able to obtain information regarding the presence or absence of diabetes in 17 of 33 subjects (51.5%). In these 17 individuals, 8 (47%) developed diabetes over the ensuing 20+ yr of observation. Initial (1964) glucose tolerance tests in the subjects that developed diabetes were not significantly different from those that did not develop diabetes. One- and 2-h glucose values on follow-up (4-8 yr later) glucose tolerance tests were significantly higher in the group that developed diabetes. On initial biopsy, muscle capillary basement membrane width was similar in the 2 groups; in the follow-up specimens the mean muscle capillary basement membrane width tended to be greater in the group that ultimately developed diabetes, but this difference was not statistically significant. However, in the group that developed diabetes the follow-up muscle capillary basement membrane width increased significantly compared to the initial measurement, whereas in the nondiabetic group the muscle capillary basement membrane width decreased with time (diabetics, +75.50 +/- 23.66; nondiabetic, -14.44 +/- 28.71 A/yr; P less than 0.05). Seven of 8 (87%) of the individuals who developed diabetes showed progressive thickening of their muscle capillary basement membrane thickness, whereas in the nondiabetic group 5 of 8 had a decrease in width. These results suggest that an increase in muscle capillary basement membrane width over time might serve as a marker to detect individuals who are at increased risk to develop diabetes. The detection of an increased susceptibility for diabetes could potentially allow for interventions that could delay or prevent the development of diabetes.