Effect of Vitamin D on falls: a meta-analysis

Context  Falls among elderly individuals occur frequently, increase with age, and lead to substantial morbidity and mortality. The role of vitamin D in preventing falls among elderly people has not been well established. Objective  To assess the effectiveness of vitamin D in preventing an older person from falling. Data Sources  MEDLINE and the Cochrane Controlled Trials Register from January 1960 to February 2004, EMBASE from January 1991 to February 2004, clinical experts, bibliographies, and abstracts. Search terms included trial terms: randomized-controlled trial or controlled-clinical trial or random-allocation or double-blind method, or single-blind method or uncontrolled-trials with vitamin D terms: cholecalciferol or hydroxycholecalciferols or calcifediol or dihydroxycholecalciferols or calcitriol or vitamin D/aa[analogs & derivates] or ergocalciferol or vitamin D/bl[blood]; and with accidental falls or falls, and humans. Study Selection  We included only double-blind randomized, controlled trials (RCTs) of vitamin D in elderly populations (mean age, 60 years) that examined falls resulting from low trauma for which the method of fall ascertainment and definition of falls were defined explicitly. Studies including patients in unstable health states were excluded. Five of 38 identified studies were included in the primary analysis and 5 other studies were included in a sensitivity analysis. Data Extraction  Independent extraction by 3 authors using predefined data fields including study quality indicators. Data Synthesis  Based on 5 RCTs involving 1237 participants, vitamin D reduced the corrected odds ratio (OR) of falling by 22% (corrected OR, 0.78; 95% confidence interval [CI], 0.64-0.92) compared with patients receiving calcium or placebo. From the pooled risk difference, the number needed to treat (NNT) was 15 (95% CI, 8-53), or equivalently 15 patients would need to be treated with vitamin D to prevent 1 person from falling. The inclusion of 5 additional studies, involving 10 001 participants, in a sensitivity analysis resulted in a smaller but still significant effect size (corrected RR, 0.87; 95% CI, 0.80-0.96). Subgroup analyses suggested that the effect size was independent of calcium supplementation, type of vitamin D, duration of therapy, and sex, but reduced sample sizes made the results statistically nonsignificant for calcium supplementation, cholecalciferol, and among men. Conclusions  Vitamin D supplementation appears to reduce the risk of falls among ambulatory or institutionalized older individuals with stable health by more than 20%. Further studies examining the effect of alternative types of vitamin D and their doses, the role of calcium supplementation, and effects in men should be considered.      

Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial

Context  Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons, who self-select for high intakes of vitamin E through diet or supplements, have decreased risks of cardiovascular disease and cancer. Randomized trials do not generally support benefits of vitamin E, but there are few trials of long duration among initially healthy persons. Objective  To test whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women. Design, Setting, and Participants  In the Women’s Health Study conducted between 1992 and 2004, 39 876 apparently healthy US women aged at least 45 years were randomly assigned to receive vitamin E or placebo and aspirin or placebo, using a 2 x 2 factorial design, and were followed up for an average of 10.1 years. Intervention  Administration of 600 IU of natural-source vitamin E on alternate days. Main Outcome Measures  Primary outcomes were a composite end point of first major cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and total invasive cancer. Results  During follow-up, there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group, a nonsignificant 7% risk reduction (relative risk [RR], 0.93; 95% confidence interval [CI], 0.82-1.05; P = .26). There were no significant effects on the incidences of myocardial infarction (RR,  1.01; 95% CI, 0.82-1.23; P = .96) or stroke (RR, 0.98; 95% CI, 0.82-1.17; P = .82), as well as ischemic or hemorrhagic stroke. For cardiovascular death, there was a significant 24% reduction (RR, 0.76; 95% CI, 0.59-0.98; P = .03). There was no significant effect on the incidences of total cancer (1437 cases in the vitamin E group and 1428 in the placebo group; RR, 1.01; 95% CI, 0.94-1.08; P = .87) or breast (RR, 1.00; 95% CI, 0.90-1.12; P = .95), lung (RR, 1.09; 95% CI, 0.83-1.44; P = .52), or colon cancers (RR, 1.00; 95% CI, 0.77-1.31; P = .99). Cancer deaths also did not differ significantly between groups. There was no significant effect of vitamin E on total mortality (636 in the vitamin E group and 615 in the placebo group; RR, 1.04; 95% CI, 0.93-1.16; P = .53). Conclusions  The data from this large trial indicated that 600 IU of natural-source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, and decreased cardiovascular mortality in healthy women. These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women.      

Vitamin A Intake and Hip Fractures Among Postmenopausal Women

Context  Ingestion of toxic amounts of vitamin A affects bone remodeling and can have adverse skeletal effects in animals. The possibility has been raised that long-term high vitamin A intake could contribute to fracture risk in humans. Objective  To assess the relationship between high vitamin A intake from foods and supplements and risk of hip fracture among postmenopausal women. Design  Prospective analysis begun in 1980 with 18 years of follow-up within the Nurses' Health Study. Setting  General community of registered nurses within 11 US states. Participants  A total of 72 337 postmenopausal women aged 34 to 77 years. Main Outcome Measures  Incident hip fractures resulting from low or moderate trauma, analyzed by quintiles of vitamin A intake and by use of multivitamins and vitamin A supplements, assessed at baseline and updated during follow-up. Results  From 1980 to 1998, 603 incident hip fractures resulting from low or moderate trauma were identified. After controlling for confounding factors, women in the highest quintile of total vitamin A intake (3000 µg/d of retinol equivalents [RE]) had a significantly elevated relative risk (RR) of hip fracture (RR, 1.48; 95% confidence interval [CI], 1.05-2.07; P for trend = .003) compared with women in the lowest quintile of intake (<1250 µg/d of RE). This increased risk was attributable primarily to retinol (RR, 1.89; 95% CI, 1.33-2.68; P for trend <.001 comparing 2000 µg/d vs <500 µg/d). The association of high retinol intake with hip fracture was attenuated among women using postmenopausal estrogens. Beta carotene did not contribute significantly to fracture risk (RR, 1.22; 95% CI, 0.90-1.66; P for trend = .10 comparing 6300 µg/d vs <2550 µg/d). Women currently taking a specific vitamin A supplement had a nonsignificant 40% increased risk of hip fracture (RR, 1.40; 95% CI, 0.99-1.99) compared with those not taking that supplement, and, among women not taking supplemental vitamin A, retinol from food was significantly associated with fracture risk (RR, 1.69; 95% CI, 1.05-2.74; P for trend = .05 comparing 1000 µg/d vs <400 µg/d). Conclusions  Long-term intake of a diet high in retinol may promote the development of osteoporotic hip fractures in women. The amounts of retinol in fortified foods and vitamin supplements may need to be reassessed.      

Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial

Context  Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration. Objective  To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events. Design, Setting, and Patients  A randomized, double-blind, placebo-controlled international trial (the initial Heart Outcomes Prevention Evaluation [HOPE] trial conducted between December 21, 1993, and April 15, 1999) of patients at least 55 years old with vascular disease or diabetes mellitus was extended (HOPE–The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9541 patients, 174 centers participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centers, 916 were deceased at the beginning of the extension, 1382 refused participation, 3994 continued to take the study intervention, and 738 agreed to passive follow-up. Median duration of follow-up was 7.0 years. Intervention  Daily dose of natural source vitamin E (400 IU) or matching placebo. Main Outcome Measures  Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations. Results  Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24); and for major cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P = .34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = .03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P = .045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure. Conclusion  In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.      

Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials

Context  Epidemiologic studies have suggested that folate intake decreases risk of cardiovascular diseases. However, the results of randomized controlled trials on dietary supplementation with folic acid to date have been inconsistent. Objective  To evaluate the effects of folic acid supplementation on risk of cardiovascular diseases and all-cause mortality in randomized controlled trials among persons with preexisting cardiovascular or renal disease. Data Sources  Studies were retrieved by searching MEDLINE (January 1966-July 2006) using the Medical Subject Headings cardiovascular disease, coronary disease, coronary thrombosis, myocardial ischemia, coronary stenosis, coronary restenosis, cerebrovascular accident, randomized controlled trial, clinical trials, homofolic acid, and folic acid, and the text words folic acid and folate. Bibliographies of all retrieved articles were also searched, and experts in the field were contacted. Study Selection  From 165 relevant retrieved reports, 12 randomized controlled trials compared folic acid supplementation with either placebo or usual care for a minimum duration of 6 months and with clinical cardiovascular disease events reported as an end point. Data Extraction  Data on study design, characteristics of participants, changes in homocysteine levels, and cardiovascular disease outcomes were independently abstracted by 2 investigators using a standardized protocol. Data Synthesis  Studies including data from 16 958 participants with preexisting vascular disease were analyzed using a random-effects model. The overall relative risks (95% confidence intervals) of outcomes for patients treated with folic acid supplementation compared with controls were 0.95 (0.88-1.03) for cardiovascular diseases, 1.04 (0.92-1.17) for coronary heart disease, 0.86 (0.71-1.04) for stroke, and 0.96 (0.88-1.04) for all-cause mortality. The relative risk was consistent among participants with preexisting cardiovascular or renal disease. Conclusions  Folic acid supplementation has not been shown to reduce risk of cardiovascular diseases or all-cause mortality among participants with prior history of vascular disease. Several ongoing trials with large sample sizes might provide a definitive answer to this important clinical and public health question.      

Effect of daily vitamin E and multivitamin-mineral supplementation on acute respiratory tract infections in elderly persons: a randomized controlled trial

Context  Immune response in elderly individuals has been reported to improve after micronutrient supplementation. However, efficacy trials evaluating infectious diseases as outcomes are scarce and inconclusive. Objective  To investigate the effect of daily multivitamin-mineral and vitamin E supplementation on incidence and severity of acute respiratory tract infections in elderly individuals. Design  A randomized, double blind, placebo-controlled, 2 x 2 factorial trial. Setting and Participants  A total of 652 noninstitutionalized individuals aged 60 years or older enrolled from 2 community-based sampling strategies in the Wageningen area of the Netherlands, conducted from 1998 to 2000. At baseline, 6% of participants had suboptimal ascorbic acid and 1.3% had suboptimal -tocopherol plasma concentration. Intervention  Physiological doses of multivitamin-minerals, 200 mg of vitamin E, both, or placebo. Main Outcome Measures  Incidence and severity of self-reported acute respiratory tract infections at 15 months, as assessed by a nurse (telephone contact), home visits, and microbiological and serological testing in subsets of patients. Results  During a median observation period of 441 days, 443 (68%) of 652 participants recorded 1024 respiratory tract infection episodes. The incidence rate ratio of acute respiratory tract infection for multivitamin-mineral supplementation was 0.95 (95% confidence interval, 0.75-1.15; P = .58) and for vitamin E supplementation, 1.12 (95% confidence interval, 0.88-1.25; P = .21). Severity of infections was not influenced by multivitamin-mineral supplementation. For vitamin E vs no vitamin E, severity was worse: median (interquartile range) for illness-duration was 19 (9-37) vs 14 (6-29) days, P = .02; number of symptoms, 6 (3-8) vs 4 (3-8), P = .03; presence of fever, 36.7% vs 25.2%, P = .009; and restriction of activity, 52.3% vs 41.1%, P = .02. Conclusions  Neither daily multivitamin-mineral supplementation at physiological dose nor 200 mg of vitamin E showed a favorable effect on incidence and severity of acute respiratory tract infections in well-nourished noninstitutionalized elderly individuals. Instead we observed adverse effects of vitamin E on illness severity.      

Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial

Context  The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. Objective  To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years. Design and Setting  Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT). Participants  One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment. Intervention  Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003). Main Outcome Measures  The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. Results  Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (–2.4%; 95% confidence interval [CI], –2.9% to –1.8%; P<.001) and spine (–3.7%; 95% CI, –4.5% to –3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum N = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens. Conclusions  Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years. Trial Registration  clinicaltrials.gov Identifier: NCT 00398931      

Risk of hip fracture among dialysis and renal transplant recipients

Context  Renal failure places people at particularly high risk of hip fracture. However, the possible differential impact of dialysis and renal transplantation on this risk is not well understood. Objective  To determine if patients who receive kidney transplants are at greater risk of hip fracture compared with those who continue to undergo dialysis. Design, Setting, and Participants  Cohort study of 101 039 patients with end-stage renal disease placed on the renal transplant waiting list in the United States between January 1, 1990, and December 31, 1999. Main Outcome Measures  Hip fractures, identified from Medicare claims data. Results  Among the patients included in this analysis, 971 hip fractures were observed during the follow-up period of 314 767 person-years. The incidence rate of hip fracture in patients receiving dialysis was 2.9 per 1000 patients per year compared with 3.3 hip fractures per 1000 patients per year in those who had previously received a renal transplant. Initially, the relative risk (RR) of hip fracture associated with transplantation was 1.34-fold greater when compared with dialysis (adjusted RR, 1.34; 95% confidence interval [CI], 1.12-1.61) but then decreased by 1% per month (adjusted RR, 0.99; 95% CI, 0.98-0.99) until the estimated risk became equal for dialysis and transplant recipients approximately 630 days after transplantation (adjusted RR, 1.00; 95% CI, 0.87-1.15). Among transplant recipients, risk of fracture was relatively higher in persons with a prolonged period of dialysis before transplantation. Conclusion  The high risk of hip fracture among dialysis patients is exceeded by that among renal transplant patients during the first 1 to 3 years after transplantation.      

Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake

Context  Adequate vitamin D status for optimum bone health has received increased recognition in recent years; however, the ideal intake is not known. Serum 25-hydroxyvitamin D is the generally accepted indicator of vitamin D status, but no universal reference level has been reached. Objective  To investigate the relative importance of high calcium intake and serum 25-hydroxyvitamin D for calcium homeostasis, as determined by serum intact parathyroid hormone (PTH). Design, Setting, and Participants  Cross-sectional study of 2310 healthy Icelandic adults who were divided equally into 3 age groups (30-45 years, 50-65 years, or 70-85 years) and recruited from February 2001 to January 2003. They were administered a semi-quantitative food frequency questionnaire, which assessed vitamin D and calcium intake. Participants were further divided into groups according to calcium intake (<800 mg/d, 800-1200 mg/d, and >1200 mg/d) and serum 25-hydroxyvitamin D level (<10 ng/mL, 10-18 ng/mL, and >18 ng/mL). Main Outcome Measure  Serum intact PTH as determined by calcium intake and vitamin D. Results  A total of 944 healthy participants completed all parts of the study. After adjusting for relevant factors, serum PTH was lowest in the group with a serum 25-hydroxyvitamin D level of more than 18 ng/mL but highest in the group with a serum 25-hydroxyvitamin D level of less than 10 ng/mL. At the low serum 25-hydroxyvitamin D level (<10 ng/mL), calcium intake of less than 800 mg/d vs more than 1200 mg/d was significantly associated with higher serum PTH (P = .04); and at a calcium intake of more than 1200 mg/d, there was a significant difference between the lowest and highest vitamin D groups (P = .04). Conclusions  As long as vitamin D status is ensured, calcium intake levels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism. Vitamin D supplements are necessary for adequate vitamin D status in northern climates.      

Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial

Christine M. Albert, MD, MPH; Nancy R. Cook, ScD; J. Michael Gaziano, MD, MPH; Elaine Zaharris, BA; Jean MacFadyen, BA; Eleanor Danielson, MIA; Julie E. Buring, ScD; JoAnn E. Manson, MD, DrPH

JAMA. 2008;299(17):2027-2036.

Context  Recent randomized trials among patients with preexisting cardiovascular disease (CVD) have failed to support benefits of B-vitamin supplementation on cardiovascular risk. Observational data suggest benefits may be greater among women, yet women have been underrepresented in published randomized trials.

Objective  To test whether a combination of folic acid, vitamin B₆, and vitamin B₁₂ lowers risk of CVD among high-risk women with and without CVD.

Design, Setting, and Participants  Within an ongoing randomized trial of antioxidant vitamins, 5442 women who were US health professionals aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, were enrolled in a randomized, double-blind, placebo-controlled trial to receive a combination pill containing folic acid, vitamin B₆, and vitamin B₁₂ or a matching placebo, and were treated for 7.3 years from April 1998 through July 2005.

Intervention  Daily intake of a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B₆, and 1 mg of vitamin B₁₂.

Main Outcome Measures  A composite outcome of myocardial infarction, stroke, coronary revascularization, or CVD mortality.

Results  Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10 000 person-years vs 219.2/10 000 person-years for the active vs placebo group; relative risk [RR], 1.03; 95% confidence interval [CI], 0.90-1.19; P = .65), as well as for the secondary outcomes including myocardial infarction (34.5/10 000 person-years vs 39.5/10 000 person-years; RR, 0.87; 95% CI, 0.63-1.22; P = .42), stroke (41.9/10 000 person-years vs 36.8/10 000 person-years; RR, 1.14; 95% CI, 0.82-1.57; P = .44), and CVD mortality (50.3/10 000 person-years vs 49.6/10 000 person-years; RR, 1.01; 95% CI, 0.76-1.35; P = .93). In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5% (95% CI, 12.5%-24.1%; P < .001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 µmol/L (95% CI, 1.54-2.96 µmol/L).

Conclusion  After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B₆, and vitamin B₁₂ did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering.

Trial Registration  clinicaltrials.gov Identifier: NCT00000541

     

Walking and leisure-time activity and risk of hip fracture in postmenopausal women

Context  Physical activity can reduce the risk of hip fractures in older women, although the required type and duration of activity have not been determined. Walking is the most common activity among older adults, and evidence suggests that it can increase femoral bone density and reduce fracture risk. Objective  To assess the relationship of walking, leisure-time activity, and risk of hip fracture among postmenopausal women. Design, Setting, and Participants  Prospective analysis begun in 1986 with 12 years of follow-up in the Nurses' Health Study cohort of registered nurses within 11 US states. A total of 61 200 postmenopausal women (aged 40-77 years and 98% white) without diagnosis of cancer, heart disease, stroke, or osteoporosis at baseline. Main Outcome Measures  Incident hip fracture resulting from low or moderate trauma, analyzed by intensity and duration of leisure-time activity and by time spent walking, sitting, and standing, measured at baseline and updated throughout follow-up. Results  From 1986 to 1998, 415 incident hip fracture cases were identified. After controlling for age, body mass index, use of postmenopausal hormones, smoking, and dietary intakes in proportional hazards models, risk of hip fracture was lowered by 6% (95% confidence interval [CI], 4%-9%; P<.001) for each increase of 3 metabolic equivalent (MET)–hours per week of activity (equivalent to 1 h/wk of walking at an average pace). Active women with at least 24 MET-h/wk had a 55% lower risk of hip fracture (relative risk [RR], 0.45; 95% CI, 0.32-0.63) compared with sedentary women with less than 3 MET-h/wk. Even women with a lower risk of hip fracture due to higher body weight experienced a further reduction in risk with higher levels of activity. Risk of hip fracture decreased linearly with increasing level of activity among women not taking postmenopausal hormones (P<.001), but not among women taking hormones (P = .24). Among women who did no other exercise, walking for at least 4 h/wk was associated with a 41% lower risk of hip fracture (RR, 0.59; 95% CI, 0.37-0.94) compared with less than 1 h/wk. More time spent standing was also independently associated with lower risks. Conclusion  Moderate levels of activity, including walking, are associated with substantially lower risk of hip fracture in postmenopausal women.      

Effect of homocysteine-lowering therapy with folic acid,vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial

Context  Plasma homocysteine level has been recognized as an important cardiovascular risk factor that predicts adverse cardiac events in patients with established coronary atherosclerosis and influences restenosis rate after percutaneous coronary intervention. Objective  To evaluate the effect of homocysteine-lowering therapy on clinical outcome after percutaneous coronary intervention. Design, Setting, and Participants  Randomized, double-blind placebo-controlled trial involving 553 patients referred to the University Hospital in Bern, Switzerland, from May 1998 to April 1999 and enrolled after successful angioplasty of at least 1 significant coronary stenosis (50%). Intervention  Participants were randomly assigned to receive a combination of folic acid (1 mg/d), vitamin B₁₂ (cyanocobalamin, 400 µg/d), and vitamin B₆ (pyridoxine hydrochloride, 10 mg/d) (n = 272) or placebo (n = 281) for 6 months. Main Outcome Measure  Composite end point of major adverse events defined as death, nonfatal myocardial infarction, and need for repeat revascularization, evaluated at 6 months and 1 year. Results  After a mean (SD) follow-up of 11 (3) months, the composite end point was significantly lower at 1 year in patients treated with homocysteine-lowering therapy (15.4% vs 22.8%; relative risk [RR], 0.68; 95% confidence interval [CI], 0.48-0.96; P = .03), primarily due to a reduced rate of target lesion revascularization (9.9% vs 16.0%; RR, 0.62; 95% CI, 0.40-0.97; P = .03). A nonsignificant trend was seen toward fewer deaths (1.5% vs 2.8%; RR, 0.54; 95% CI, 0.16-1.70; P = .27) and nonfatal myocardial infarctions (2.6% vs 4.3%; RR, 0.60; 95% CI, 0.24-1.51; P = .27) with homocysteine-lowering therapy. These findings remained unchanged after adjustment for potential confounders. Conclusion  Homocysteine-lowering therapy with folic acid, vitamin B₁₂, and vitamin B₆ significantly decreases the incidence of major adverse events after percutaneous coronary intervention.      

Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial

Context  Basic research and observational evidence as well as results from trials of colon polyp recurrence suggest a role for aspirin in the chemoprevention of cancer. Objective  To examine the effect of aspirin on the risk of cancer among healthy women. Design, Setting, and Participants  In the Women’s Health Study, a randomized 2 x 2 factorial trial of aspirin and vitamin E conducted between September 1992 and March 2004, 39 876 US women aged at least 45 years and initially without previous history of cancer, cardiovascular disease, or other major chronic illness were randomly assigned to receive either aspirin or aspirin placebo and followed up for an average of 10.1 years. Intervention  A dose of 100 mg of aspirin (n=19 934) or aspirin placebo (n=19 942) administered every other day. Main Outcome Measures  Confirmed newly diagnosed invasive cancer at any site, except for nonmelanoma skin cancer. Incidence of breast, colorectal, and lung cancer were secondary end points. Results  No effect of aspirin was observed on total cancer (n = 2865; relative risk [RR], 1.01; 95% confidence interval [CI], 0.94-1.08; P = .87), breast cancer (n = 1230; RR, 0.98; 95% CI, 0.87-1.09; P = .68), colorectal cancer (n = 269; RR, 0.97; 95% CI, 0.77-1.24; P = .83), or cancer of any other site, with the exception of lung cancer for which there was a trend toward reduction in risk (n = 205; RR, 0.78; 95% CI, 0.59-1.03; P = .08). There was also no reduction in cancer mortality either overall (n = 583; RR, 0.95; 95% CI, 0.81-1.11; P = .51) or by site, except for lung cancer mortality (n = 140; RR, 0.70; 95% CI, 0.50-0.99; P = .04). No evidence of differential effects of aspirin by follow-up time or interaction with vitamin E was found. Conclusions  Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out.      

Long-term proton pump inhibitor therapy and risk of hip fracture

Context  Proton pump inhibitors (PPIs) may interfere with calcium absorption through induction of hypochlorhydria but they also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps. Objective  To determine the association between PPI therapy and risk of hip fracture. Design, Setting, and Patients  A nested case-control study was conducted using the General Practice Research Database (1987-2003), which contains information on patients in the United Kingdom. The study cohort consisted of users of PPI therapy and nonusers of acid suppression drugs who were older than 50 years. Cases included all patients with an incident hip fracture. Controls were selected using incidence density sampling, matched for sex, index date, year of birth, and both calendar period and duration of up-to-standard follow-up before the index date. For comparison purposes, a similar nested case-control analysis for histamine 2 receptor antagonists was performed. Main Outcome Measure  The risk of hip fractures associated with PPI use. Results  There were 13 556 hip fracture cases and 135 386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59). The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80-3.90; P<.001). The strength of the association increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15-1.30]; 2 years, 1.41 [95% CI, 1.28-1.56]; 3 years, 1.54 [95% CI, 1.37-1.73]; and 4 years, 1.59 [95% CI, 1.39-1.80]; P<.001 for all comparisons). Conclusion  Long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.      

Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial

Context  Stroke increases the risk of subsequent hip fracture by 2 to 4 times. Hyperhomocysteinemia is a risk factor for both ischemic stroke and osteoporotic fractures in elderly men and women. Treatment with folate and mecobalamin (vitamin B₁₂) may improve hyperhomocysteinemia. Objective  To investigate whether treatment with folate and vitamin B₁₂ reduces the incidence of hip fractures in patients with hemiplegia following stroke. Design, Setting, and Patients  A double-blind, randomized controlled study of 628 consecutive patients aged 65 years or older with residual hemiplegia at least 1 year following first ischemic stroke, who were recruited from a single Japanese hospital from April 1, 2000, to May 31, 2001. Patients were assigned to daily oral treatment with 5 mg of folate and 1500 µg of mecobalamin, or double placebo; 559 completed the 2-year follow-up. Main Outcome Measure  Incidence of hip fractures in the 2 patient groups during the 2-year follow-up. Results  At baseline, patients in both groups had high levels of plasma homocysteine and low levels of serum cobalamin and serum folate. After 2 years, plasma homocysteine levels decreased by 38% in the treatment group and increased by 31% in the placebo group (P<.001). The number of hip fractures per 1000 patient-years was 10 and 43 for the treatment and placebo groups, respectively (P<.001). The adjusted relative risk, absolute risk reduction, and the number needed to treat for hip fractures in the treatment vs placebo groups were 0.20 (95% confidence interval [CI], 0.08-0.50), 7.1% (95% CI, 3.6%-10.8%), and 14 (95% CI, 9-28), respectively. No significant adverse effects were reported. Conclusion  In this Japanese population with a high baseline fracture risk, combined treatment with folate and vitamin B₁₂ is safe and effective in reducing the risk of a hip fracture in elderly patients following stroke.      

Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis

Context  Antioxidant supplements are used for prevention of several diseases. Objective  To assess the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials. Data Sources and Trial Selection  We searched electronic databases and bibliographies published by October 2005. All randomized trials involving adults comparing beta carotene, vitamin A, vitamin C (ascorbic acid), vitamin E, and selenium either singly or combined vs placebo or vs no intervention were included in our analysis. Randomization, blinding, and follow-up were considered markers of bias in the included trials. The effect of antioxidant supplements on all-cause mortality was analyzed with random-effects meta-analyses and reported as relative risk (RR) with 95% confidence intervals (CIs). Meta-regression was used to assess the effect of covariates across the trials. Data Extraction  We included 68 randomized trials with 232 606 participants (385 publications). Data Synthesis  When all low- and high-bias risk trials of antioxidant supplements were pooled together there was no significant effect on mortality (RR, 1.02; 95% CI, 0.98-1.06). Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.05-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality. Conclusions  Treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The potential roles of vitamin C and selenium on mortality need further study.      

Impact of the pulmonary artery catheter in critically ill patients: meta-analysis of randomized clinical trials

Context  Randomized clinical trials (RCTs) evaluating the pulmonary artery catheter (PAC) have been limited by small sample size. Some nonrandomized studies suggest that PAC use is associated with increased morbidity and mortality. Objective  To estimate the impact of the PAC device in critically ill patients. Data Sources  MEDLINE (1985-2005), the Cochrane Controlled Trials Registry (1988-2005), the National Institutes of Health ClinicalTrials.gov database, and the US Food and Drug Administration Web site for RCTs in which patients were randomly assigned to PAC or no PAC were searched. Results from the ESCAPE trial of patients with severe heart failure were also included. Search terms included pulmonary artery catheter, right heart catheter, catheter, and Swan-Ganz. Study Selection  Eligible studies included patients who were undergoing surgery, in the intensive care unit (ICU), admitted with advanced heart failure, or diagnosed with acute respiratory distress syndrome and/or sepsis; and studies that reported death and the number of days hospitalized or the number of days in the ICU as outcome measures. Data Extraction  Information on eligibility criteria, baseline characteristics, interventions, outcomes, and methodological quality was extracted by 2 reviewers. Disagreements were resolved by consensus. Data Synthesis  In 13 RCTs, 5051 patients were randomized. Hemodynamic goals and treatment strategies varied among trials. A random-effects model was used to estimate the odds ratios (ORs) for death, number of days hospitalized, and use of inotropes and intravenous vasodilators. The combined OR for mortality was 1.04 (95% confidence interval [CI], 0.90-1.20; P = .59). The difference in the mean number of days hospitalized for PAC minus the mean for no PAC was 0.11 (95% CI, –0.51 to 0.74; P = .73). Use of the PAC was associated with a higher use of inotropes (OR, 1.58; 95% CI, 1.19-2.12; P = .002) and intravenous vasodilators (OR, 2.35; 95% CI, 1.75-3.15; P<.001). Conclusions  In critically ill patients, use of the PAC neither increased overall mortality or days in hospital nor conferred benefit. Despite almost 20 years of RCTs, a clear strategy leading to improved survival with the PAC has not been devised. The neutrality of the PAC for clinical outcomes may result from the absence of effective evidence-based treatments to use in combination with PAC information across the spectrum of critically ill patients.      

Preventing pressure ulcers: a systematic review

Context  Pressure ulcers are common in a variety of patient settings and are associated with adverse health outcomes and high treatment costs. Objective  To systematically review the evidence examining interventions to prevent pressure ulcers. Data Sources and Study Selection  MEDLINE, EMBASE, and CINAHL (from inception through June 2006) and Cochrane databases (through issue 1, 2006) were searched to identify relevant randomized controlled trials (RCTs). UMI Proquest Digital Dissertations, ISI Web of Science, and Cambridge Scientific Abstracts were also searched. All searches used the terms pressure ulcer, pressure sore, decubitus, bedsore, prevention, prophylactic, reduction, randomized, and clinical trials. Bibliographies of identified articles were further reviewed. Data Synthesis  Fifty-nine RCTs were selected. Interventions assessed in these studies were grouped into 3 categories, ie, those addressing impairments in mobility, nutrition, or skin health. Methodological quality for the RCTs was variable and generally suboptimal. Effective strategies that addressed impaired mobility included the use of support surfaces, mattress overlays on operating tables, and specialized foam and specialized sheepskin overlays. While repositioning is a mainstay in most pressure ulcer prevention protocols, there is insufficient evidence to recommend specific turning regimens for patients with impaired mobility. In patients with nutritional impairments, dietary supplements may be beneficial. The incremental benefit of specific topical agents over simple moisturizers for patients with impaired skin health is unclear. Conclusions  Given current evidence, using support surfaces, repositioning the patient, optimizing nutritional status, and moisturizing sacral skin are appropriate strategies to prevent pressure ulcers. Although a number of RCTs have evaluated preventive strategies for pressure ulcers, many of them had important methodological limitations. There is a need for well-designed RCTs that follow standard criteria for reporting nonpharmacological interventions and that provide data on cost-effectiveness for these interventions.      

Bone mineral density and the risk of incident nonspinal fractures in black and white women

Context  Black women have a lower rate of fracture than white women, but whether bone mineral density (BMD) predicts fracture risk as well in black women as it does in white women is not established. Objective  To examine the association between BMD and incident nonspinal fractures in older black and white women. Design, Setting, and Participants  Prospective cohort study of baseline data collected from 1986 through 1990 (7334 white women aged 67-99 years) and from 1996 through 1998 (636 black women aged 65-94 years) at 4 US clinical centers in the Study of Osteoporotic Fractures; mean (SD) follow-up of 6.1 (1.5) years until October 1, 2004. Main Outcome Measures  Incident nonspinal fractures were confirmed by radiograpic report. Total hip and femoral neck BMD and bone mineral content were measured by dual energy x-ray absorptiometry. Results  A total of 58 black women had a combined total of 61 fractures and 1606 white women had a combined total of 1712 fractures. In age-adjusted proportional hazard models, a 1-SD decrease in femoral neck BMD was associated with a 37% increased risk of fracture in black women (relative risk [RR], 1.37; 95% confidence interval [CI], 1.08-1.74) and a 49% increase in fracture in white women (RR, 1.49; 95% CI, 1.40-1.58). Adjustment for body weight and other risk factors for fracture weakened the association between BMD and fracture, especially among black women (multivariable adjusted RR per 1-SD decrease in femoral neck BMD for black vs white women: RR, 1.20 [95% CI, 0.93-1.55] vs RR, 1.42 [95% CI, 1.32-1.52]). The absolute incidence of fracture across the pooled BMD distribution was 30% to 40% lower among black women at every BMD tertile. The lower risk of fracture among black compared with white women was independent of BMD and other risk factors (RR, 0.48; 95% CI, 0.36-0.64). Conclusions  Decreased total hip and femoral neck BMD is associated with an increased risk of fracture in both older black and white women, but this relationship was largely explained by other risk factors in black women. Black women have a lower fracture risk than white women at every level of BMD. Race-specific normative databases may be appropriate for the densitometric definition of osteoporosis.      

Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women

Context  Evidence is limited on the effects of different patterns of use of postmenopausal hormone therapy on fracture incidence and particularly on the effects of ceasing use. Objective  To investigate the effect of different patterns of hormone therapy use on fracture incidence. Design, Setting, and Participants  Prospective study of 138 737 postmenopausal women aged 50 to 69 years recruited from the UK general population in 1996-1998 (the Million Women Study) and followed up for 1.9 to 3.9 years (average, 2.8 years) for fracture incidence. Main Outcome Measure  Adjusted relative risk (RR) for incident fracture (except fracture of the fingers, toes, and ribs) in hormone therapy users compared with never users at baseline. Results  A total of 5197 women (3.7%) reported 1 or more fractures, 79% resulting from falls. Current users of hormone therapy at baseline had a significantly reduced incidence of fracture (RR, 0.62; 95% confidence interval [CI], 0.58-0.66; P<.001). This protection was evident soon after hormone therapy began, and the RR decreased with increasing duration of use (P = .001). Among current users at baseline the RR of fracture did not vary significantly according to whether estrogen-only, estrogen-progestin, or other types of hormones were used (RR [95% CI], 0.64 [0.58-0.71], 0.58 [0.53-0.64], and 0.67 [0.56-0.80], respectively; P = .19), nor did it vary significantly according to estrogen dose or estrogen or progestin constituents. The RR associated with current use of hormone therapy did not vary significantly according to 11 personal characteristics of study participants, including their age at menopause, body mass index, and physical activity. Past users of hormone therapy at baseline experienced no significant protection against fractures (RR, 1.07; 95% CI, 0.99-1.15); incidence rates returned to those of never-users within about a year of ceasing use. Conclusions  All types of hormone therapy studied confer substantial protection against fracture while they are used. This protection appears rapidly after use commences and wears off rapidly after use ceases. The older women are, the greater is their absolute reduction in fracture incidence while using hormone therapy.