Melanie A. Lane

Adverse Effects of Testosterone Therapy in Adult Men: A Systematic Review and Meta-Analysis

CONTEXT The risks of testosterone therapy in men remain poorly understood. OBJECTIVE The aim of this study was to conduct a systematic review and meta-analyses of testosterone trials to evaluate the adverse effects of testosterone treatment in men. DATA SOURCES We searched MEDLINE, EMBASE, and Cochrane CENTRAL from 2003 through August 2008. Review of reference lists and contact with experts further identified candidate studies. STUDY SELECTION Eligible studies were comparative, randomized, and nonrandomized and reported the effects of testosterone on outcomes of interest (death, cardiovascular events and risk factors, prostate outcomes, and erythrocytosis). Reviewers, working independently and in duplicate, determined study eligibility. DATA EXTRACTION Reviewers working independently and in duplicate determined the methodological quality of studies and collected descriptive, quality, and outcome data. DATA SYNTHESIS The methodological quality of the 51 included studies varied from low to medium, and follow-up duration ranged from 3 months to 3 yr. Testosterone treatment was associated with a significant increase in hemoglobin [weighted mean difference (WMD), 0.80 g/dl; 95% confidence interval (CI), 0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01), and a decrease in high-density lipoprotein cholesterol (WMD, -0.49 mg/dl; 95% CI, -0.85 to -0.13). There was no significant effect on mortality, prostate, or cardiovascular outcomes. CONCLUSIONS The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein cholesterol. These findings are of unknown clinical significance. Current evidence about the safety of testosterone treatment in men in terms of patient-important outcomes is of low quality and is hampered by the brief study follow-up.

Stopping randomized trials early for benefit and estimation of treatment effects : systematic review and meta-regression analysis

CONTEXT Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping. OBJECTIVE To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect. DATA SOURCES Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008. STUDY SELECTION Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs. DATA EXTRACTION Reviewers with methodological expertise conducted data extraction independently. RESULTS The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks <0.75) occurred with truncated RCTs having fewer than 500 events. In 39 of the 63 questions (62%), the pooled effects of the nontruncated RCTs failed to demonstrate significant benefit. CONCLUSIONS Truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies.

Vitamin D and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

CONTEXT Several studies found association between vitamin D levels and hypertension, coronary artery calcification, and heart disease. OBJECTIVE The aim of this study was to summarize the evidence on the effect of vitamin D on cardiovascular outcomes. DESIGN AND METHODS We searched electronic databases from inception through August 2010 for randomized trials. Reviewers working in duplicate and independently extracted study characteristics, quality, and the outcomes of interest. Random-effects meta-analysis was used to pool the relative risks (RR) and the weighted mean differences across trials. RESULTS We found 51 eligible trials with moderate quality. Vitamin D was associated with nonsignificant effects on the patient-important outcomes of death [RR, 0.96; 95% confidence interval (CI), 0.93, 1.00; P = 0.08], myocardial infarction (RR, 1.02; 95% CI, 0.93, 1.13; P = 0.64), and stroke (RR, 1.05; 95% CI, 0.88, 1.25; P = 0.59). These analyses were associated with minimal heterogeneity. There were no significant changes in the surrogate outcomes of lipid fractions, glucose, or diastolic or systolic blood pressure. The latter analyses were associated with significant heterogeneity, and the pooled estimates were trivial in absolute terms. CONCLUSIONS Trial data available to date are unable to demonstrate a statistically significant reduction in mortality and cardiovascular risk associated with vitamin D. The quality of the available evidence is low to moderate at best.

The Effect of Vitamin D on Falls: A Systematic Review and Meta-Analysis

CONTEXT Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly. OBJECTIVE The aim of this systematic review is to summarize the existing evidence on vitamin D use and the risk of falls. DATA SOURCES We searched electronic databases from inception through August 2010. STUDY SELECTION Eligible studies were randomized controlled trials in which the intervention was vitamin D and the incidence of falls was reported. DATA EXTRACTION Reviewers working in duplicate and independently extracted study characteristics, quality, and outcomes data. DATA SYNTHESIS Odds ratio and associated 95% confidence interval were estimated from each study and pooled using the random effects model. RESULTS We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96). This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. The quality of evidence was low to moderate because of heterogeneity and publication bias. CONCLUSIONS Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women.

The effect of vitamin D on falls

CONTEXT Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly. OBJECTIVE The aim of this systematic review is to summarize the existing evidence on vitamin D use and the risk of falls. DATA SOURCES We searched electronic databases from inception through August 2010. STUDY SELECTION Eligible studies were randomized controlled trials in which the intervention was vitamin D and the incidence of falls was reported. DATA EXTRACTION Reviewers working in duplicate and independently extracted study characteristics, quality, and outcomes data. DATA SYNTHESIS Odds ratio and associated 95% confidence interval were estimated from each study and pooled using the random effects model. RESULTS We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96). This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. The quality of evidence was low to moderate because of heterogeneity and publication bias. CONCLUSIONS Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women.

Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A Systematic Review and Network Meta-Analysis

CONTEXT Osteoporosis and osteopenia are associated with increased fracture incidence. OBJECTIVE The aim of this study was to determine the comparative effectiveness of different pharmacological agents in reducing the risk of fragility fractures. DATA SOURCES We searched multiple databases through 12/9/2011. STUDY SELECTION Eligible studies were randomized controlled trials enrolling individuals at risk of developing fragility fractures and evaluating the efficacy of bisphosphonates, teriparatide, selective estrogen receptor modulators, denosumab, or calcium and vitamin D. DATA EXTRACTION Reviewers working independently and in duplicate determined study eligibility and collected descriptive, methodological quality, and outcome data. DATA SYNTHESIS This network meta-analysis included 116 trials (139,647 patients; median age, 64 yr; 86% females and 88% Caucasians; median follow-up, 24 months). Trials were at low to moderate risk of bias. Teriparatide had the highest risk reduction of fractures (odds ratios, 0.42, 0.30, and 0.50 for hip, vertebral, and nonvertebral fractures, respectively) and the highest probability of being ranked first for efficacy (probabilities of 42, 49, and 79% for hip, vertebral, and nonvertebral fractures, respectively). However, differences to denosumab, zoledronate, risedronate, ibandronate, and alendronate were not statistically significant. Raloxifene and bazedoxifene were likely less effective, although these data were limited. Calcium and vitamin D were ineffective given separately but reduced the risk of hip fractures if given in combination (odds ratio, 0.81; 95% confidence interval, 0.68–0.96). CONCLUSIONS Teriparatide, bisphosphonates, and denosumab are most effective in reducing the risk of fragility fractures. Differences in efficacy across drugs are small; therefore, patients and clinicians need to consider their associated harms and costs.

Risk Factors for Low Bone Mass-Related Fractures in Men: A Systematic Review and Meta-Analysis

CONTEXT Testing men at increased risk for osteoporotic fractures has been recommended. OBJECTIVE The aim of this study was to estimate the magnitude of association and quality of supporting evidence linking multiple risk factors with low bone mass-related fractures in men. DATA SOURCES We searched MEDLINE, EMBASE, Web of Science, SCOPUS and Cochrane CENTRAL through February 2010. We identified further studies by reviewing reference lists from selected studies and reviews. STUDY SELECTION Eligible studies had to enroll men and quantitatively evaluate the association of risk factors with low bone density-related fractures. DATA EXTRACTION Reviewers working independently and in duplicate determined study eligibility and extracted study description, quality, and outcome data. DATA SYNTHESIS Fifty-five studies provided data sufficient for meta-analysis. The quality of these observational studies was moderate with fair levels of multivariable adjustment and adequate exposure and outcome ascertainment. Statistically significant associations were established for age, low body mass index, current smoking, excessive alcohol use, chronic corticosteroid use, history of prior fractures, history of falls, history of hypogonadism, history of stroke, and history of diabetes. Statistical heterogeneity of the meta-analytic estimates of all associations was significant except for chronic corticosteroid use. None of these associations were of large magnitude (i.e. adjusted odds ratios were generally <2). No evidence supporting a particular effective testing or screening strategy was identified. CONCLUSIONS Multiple risk factors for fractures in men were identified, but their usefulness for stratifying and selecting men for bone density testing remains uncertain.

Glycemic Control in Non-Critically Ill Hospitalized Patients: A Systematic Review and Meta-Analysis

BACKGROUND The effect of intensive therapy to achieve tight glycemic control in patients hospitalized in non-critical care settings is unclear. METHODS We conducted a systematic review and meta-analysis to determine the effect of intensive glycemic control strategies on the outcomes of death, stroke, myocardial infarction, incidence of infection, and hypoglycemia. We included randomized and observational studies. Bibliographic databases were searched through February 2010. Random effects model was used to pool results across studies. RESULTS Nineteen studies (nine randomized and 10 observational studies) were included. The risk of bias across studies was moderate. Meta-analysis demonstrates that intensive glycemic control was not associated with significant effect on the risk of death, myocardial infarction, or stroke. There was a trend for increased risk of hypoglycemia (relative risk, 1.58; 95% confidence interval, 0.97-2.57), particularly in surgical studies and when the planned glycemic target was achieved. Intensive glycemic control was associated with decreased risk of infection (relative risk, 0.41; 95% confidence interval, 0.21-0.77) that was mainly derived from studies in surgical settings. CONCLUSION Intensive control of hyperglycemia in patients hospitalized in non-critical care settings may reduce the risk of infection. The quality of evidence is low and mainly driven by studies in surgical settings.

Adult Height in Patients with Congenital Adrenal Hyperplasia: A Systematic Review and Metaanalysis

CONTEXT Treatment for patients with congenital adrenal hyperplasia (CAH) may affect the final height of these patients. OBJECTIVE Our objective was to determine the distribution of achieved height in patients with classic CAH diagnosed at infancy or early childhood and treated with glucocorticoids. DATA SOURCES We searched MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, and Scopus through September 2008; the reference sections of included studies; and expert files. STUDY SELECTION Eligible studies included patients diagnosed with CAH before age 5 and followed to final height. DATA EXTRACTION Reviewers working in duplicate independently extracted data on study characteristics and outcomes and determined each studys risk of bias. DATA SYNTHESIS The sd score (SDS) for final height and corrected height (defined as final height SDS - midparental height SDS) were estimated from each study and pooled using random-effects metaanalysis. The I(2) statistic was used to assess inconsistency in results across studies. RESULTS We found 35 eligible studies, most of which were retrospective single-cohort studies. The final height SDS achieved by CAH patients was -1.38 (-1.56 to -1.20; I(2) = 90.2%), and the corrected height SDS was -1.03 (-1.20 to -0.86; I(2) = 63.1%). This was not significantly associated with age at diagnosis, gender, type and dose of steroid, and age of onset of puberty. Mineralocorticoid users had a better height outcome in comparison with the nonusers (P = 0.02). CONCLUSION Evidence derived from observational studies suggests that the final height of CAH patients treated with glucocorticoids is lower than the population norm and is lower than expected given parental height.

Outcomes of surgical treatment for nonfunctioning pituitary adenomas: a systematic review and meta-analysis

Background  Surgery is commonly used in the management of pituitary nonfunctioning adenomas (NFPA). The goal of this systematic review and meta‐analysis is to evaluate the effect of surgery on mortality, surgical complications, pituitary function and vision.