Karen F. Mauck

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.

Effects of Teriparatide in Postmenopausal Women with Osteoporosis on Prior Alendronate or Raloxifene: Differences between Stopping and Continuing the Antiresorptive Agent

OBJECTIVE The aim of the study was to assess adding vs. switching to teriparatide 20 microg/d in patients on alendronate or raloxifene. DESIGN We conducted a randomized, open-label trial. PATIENTS AND INTERVENTIONS Postmenopausal women with osteoporosis on alendronate or raloxifene for at least 18 months added teriparatide (Add groups) or switched to teriparatide (Switch groups) for 18 months. MAIN OUTCOME MEASURES We measured bone turnover markers (BTM) and bone mineral density (BMD). RESULTS In the alendronate stratum, increases in BTM were smaller in the Add vs. Switch group [6-month PINP (64 vs. 401%); bone ALP (15 vs. 71%); betaCTX (27 vs. 250%); all P < 0.001]. However, at 6 months, total hip BMD increased more in the Add vs. Switch group (1.4 vs. -0.8%; P = 0.002). In the Add vs. Switch group, 18-month BMD increments were higher in lumbar spine (8.4 vs. 4.8%; P = 0.003) and total hip (3.2 vs. 0.9%; P = 0.02), but not in femoral neck (2.7 vs. 2.3%; P = 0.75). In the raloxifene stratum, increases in BTM were also smaller in the Add vs. Switch group [6-month PINP (131 vs. 259%; P < 0.001), bone ALP (31 vs. 44%; P = 0.035), and betaCTX (67 vs. 144%; P = 0.001)]. At 6 months, total hip BMD increase was greater in the Add vs. Switch group (1.8 vs. 0.5%; P = 0.028). At 18 months, increases in lumbar spine (9.2 vs. 8.1%), total hip (2.8 vs. 1.8%), and femoral neck (3.8 vs. 2.2%) were not significantly different between groups. CONCLUSIONS In women with osteoporosis treated with antiresorptives, greater bone turnover increases were achieved by switching to teriparatide, whereas greater BMD increases were achieved by adding teriparatide.

Diagnosis, Screening, Prevention, and Treatment of Osteoporosis

Osteoporosis is the most common bone disease in humans and affects both men and women. The clinical and public health implications of the disease are substantial because of the mortality, morbidity, and cost of medical care associated with osteoporotic fractures. Osteoporosis is diagnosed on the basis of a low-impact or fragility fracture or low bone mineral density, which was best assessed by central dual-energy x-ray absorptiometry. Both nonpharmacological therapy (calcium and vitamin D supplementation, weight-bearing exercise, and fall prevention) and pharmacological treatments (antiresorptive and anabolic agents) may be helpful in the prevention and treatment of osteoporosis. Therefore, clinicians need to be vigilant in instituting primary prevention measures for those at high risk for osteoporosis and in instituting treatment for patients diagnosed as having the disease either by screening or a history of fracture. This article provides an overview of the diagnosis, screening, prevention, and treatment of osteoporosis.

Drugs Commonly Associated With Weight Change: A Systematic Review and Meta-analysis

CONTEXT Various drugs affect body weight as a side effect. OBJECTIVE We conducted this systematic review and meta-analysis to summarize the evidence about commonly prescribed drugs and their association with weight change. DATA SOURCES MEDLINE, DARE, and the Cochrane Database of Systematic Reviews were searched to identify published systematic reviews as a source for trials. STUDY SELECTION We included randomized trials that compared an a priori selected list of drugs to placebo and measured weight change. DATA EXTRACTION We extracted data in duplicate and assessed the methodological quality using the Cochrane risk of bias tool. RESULTS We included 257 randomized trials (54 different drugs; 84 696 patients enrolled). Weight gain was associated with the use of amitriptyline (1.8 kg), mirtazapine (1.5 kg), olanzapine (2.4 kg), quetiapine (1.1 kg), risperidone (0.8 kg), gabapentin (2.2 kg), tolbutamide (2.8 kg), pioglitazone (2.6 kg), glimepiride (2.1 kg), gliclazide (1.8 kg), glyburide (2.6 kg), glipizide (2.2 kg), sitagliptin (0.55 kg), and nateglinide (0.3 kg). Weight loss was associated with the use of metformin (1.1 kg), acarbose (0.4 kg), miglitol (0.7 kg), pramlintide (2.3 kg), liraglutide (1.7 kg), exenatide (1.2 kg), zonisamide (7.7 kg), topiramate (3.8 kg), bupropion (1.3 kg), and fluoxetine (1.3 kg). For many other remaining drugs (including antihypertensives and antihistamines), the weight change was either statistically nonsignificant or supported by very low-quality evidence. CONCLUSIONS Several drugs are associated with weight change of varying magnitude. Data are provided to guide the choice of drug when several options exist and institute preemptive weight loss strategies when obesogenic drugs are prescribed.

Comparative systematic review and meta-analysis of compression modalities for the promotion of venous ulcer healing and reducing ulcer recurrence

OBJECTIVE This was a systematic review of the literature to determine which compression method is superior in promoting ulcer healing and reducing recurrence in patients with lower extremity venous ulcer disease. METHODS We conducted a comprehensive search of multiple databases for randomized and nonrandomized comparative studies from 1990 to December 2013. RESULTS We identified 36 studies and two Cochrane systematic reviews. Many studies had moderate risk of bias. We found no overall difference between compression stockings vs compression bandages with respect to ulcer healing, time to ulcer healing, or ulcer recurrence outcomes. When we compared stockings vs short stretch bandages, stockings were superior with respect to ulcer healing. However, stockings compared with four-layer systems showed no difference in ulcer healing outcomes. When four-layer systems were compared with compression with less than four layers, there was also no significant difference in ulcer healing outcomes. Similarly, short stretch bandages were not superior to long stretch bandages with respect to ulcer healing, time to ulcer healing, or ulcer recurrence. One Cochrane review presented many additional comparisons and reported increased wound healing with compression compared with no compression, with multicomponent systems over single component systems, and compression systems with an elastic component over no elastic component. Another Cochrane review demonstrated a reduction in recurrence with compression in patients with healed ulcers. CONCLUSIONS At least moderate-quality evidence supports compression over no compression, multicomponent systems over single component systems, and systems with an elastic component over those without. We did not find significant differences with respect to ulcer healing outcomes for other comparisons. Low-quality evidence supports the effect of compression on ulcer recurrence.

Systematic review and meta-analysis of surgical interventions versus conservative therapy for venous ulcers

OBJECTIVE This goal of this study was to systematically review the literature to determine if surgical intervention (open or endovascular) is superior to compression alone with respect to ulcer healing, ulcer recurrence, and time to ulcer healing in patients with lower extremity venous ulcer disease. METHODS We conducted a comprehensive search of multiple databases for randomized controlled trials (RCTs) and comparative observational studies from 1990 to December 2013. The interventions of interest were any open or endovascular surgical interventions on the venous system in the lower extremity compared with compression alone. RESULTS We included 11 studies (seven RCTs and four observational studies) with moderate to increased risk of bias. The meta-analysis of all studies demonstrated increased healing rate (pooled risk ratio [RR], 1.06; 95% confidence interval [CI], 1.00-1.13; I(2) = 10%) and lower risk of recurrence (RR, 0.54; 95% CI, 0.34-0.85; I(2) = 27%) with open surgical procedures compared with compression. However, the meta-analysis of only RCTs showed no difference, possibly due to imprecision. The meta-analysis of three RCTs showed no difference in time to ulcer healing, -0.41 (95% CI, -0.89 to 0.07). Two studies of endovascular surgical procedures compared with compression showed no significant difference in ulcer healing (RR, 1.65; 95% CI, 0.43-6.32). One study of open surgical venous ligation and stripping compared with endovenous laser also showed no significant difference in ulcer recurrence (RR, 0.83; 95% CI, 0.21-3.27). CONCLUSIONS Open surgical interventions may improve lower extremity venous ulcer healing. The quality of this evidence is low because the analysis was dominated by the results of observational studies. The current evidence does not definitively support the superiority of endovascular surgical interventions compared with compression alone.

Incidence of venous thromboembolism after elective knee arthroscopic surgery: a historical cohort study

The incidence of symptomatic venous thromboembolism (VTE) after knee arthroscopy is uncertain.

Fibrin D-Dimer Concentration, Deep Vein Thrombosis Symptom Duration, and Venous Thrombus Volume

Introduction: To determine the relationship between fibrin D-dimer levels, symptom duration, and thrombus volume, consecutive patients with incident deep venous thrombosis (DVT) were evaluated. Methods: In a cross-sectional study design, patient symptom onset was determined by careful patient questioning. Venous thrombosis was confirmed by compression duplex ultrasonography. Thrombus volume was estimated based on patient’s femur length using a forensic anthropology method. Fibrin D-dimer was measured by latex immunoassay. Results: 72 consecutive patients with confirmed leg DVT agreed to participate. The median symptom duration at the time of diagnosis was 10 days. The median D-dimer concentration was 1050 ng/dL. The median thrombus volume was 12.92 cm3. D-Dimer levels correlated with estimated thrombus volume (P < .0006 CI 0.12-0.41; R2 adjusted = .15) but not symptom duration, patient’s age, or gender. Conclusions: Despite varying symptom duration prior to diagnosis, fibrin D-dimer remains a sensitive measure of venous thrombosis and correlates with thrombus volume.

Safety of Clopidogrel in Hip Fracture Surgery

OBJECTIVE To compare postoperative outcomes of hip fracture surgery in patients who were and were not taking clopidogrel at the time of surgery. PATIENTS AND METHODS Using the Rochester Epidemiology Project database, we performed a population-based, retrospective cohort study comparing patients who were and were not taking clopidogrel at the time of hip fracture surgery between January 1, 1996, and June 30, 2010. Primary outcomes were perioperative bleeding and mortality. Secondary outcomes were perioperative thrombotic events. RESULTS During the study period, 40 residents of Olmsted County, Minnesota (median age, 83 years), who were taking clopidogrel underwent hip fracture repair. These 40 patients were matched 2:1 with 80 control patients (median age, 84 years). The groups were similar in age, sex, American Society of Anesthesiologists score, type of surgical procedure, and use of deep venous thrombosis prophylaxis. The mean time from admission to surgery was less than 36 hours for each cohort. Perioperative bleeding complications and mortality were not significantly different between patients who were and were not taking clopidogrel at the time of hip fracture surgery. Combined bleeding outcome criteria was met in 48% of the clopidogrel cohort and 45% of the control cohort (relative risk, 1.06; 95% CI, 0.70-1.58; P=.80). One-year mortality was 28% in the clopidogrel cohort and 29% in the control cohort (hazard ratio, 1.33; 95% CI, 0.84-2.12; P=.23). CONCLUSION Although the small sample size precludes making a definitive conclusion, we found no evidence that prompt surgical treatment of hip fracture in patients taking clopidogrel compromises perioperative outcomes.