Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration, leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts - bone cells that break down bone tissue. This is an update of a Cochrane review first published in 2008. For clinical relevance, we investigated etidronate's effects on postmenopausal women stratified by fracture risk (low versus high). OBJECTIVES: To assess the benefits and harms of intermittent/cyclic etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture, respectively. SEARCH METHODS: We searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE, Embase, two clinical trial registers, the websites of drug approval agencies, and the bibliographies of relevant systematic reviews. We identified eligible trials published between 1966 and February 2023. SELECTION CRITERIA: We included randomized controlled trials that assessed the benefits and harms of etidronate in the prevention of fractures for postmenopausal women. Women in the experimental arms must have received at least one year of etidronate, with or without other anti-osteoporotic drugs and concurrent calcium/vitamin D. Eligible comparators were placebo (i.e. no treatment; or calcium, vitamin D, or both) or another anti-osteoporotic drug. Major outcomes were clinical vertebral, non-vertebral, hip, and wrist fractures, withdrawals due to adverse events, and serious adverse events. We classified a study as secondary prevention if its population fulfilled one or more of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, a low bone mineral density T-score (≤ -2.5), or aged 75 years or older. If none of these criteria were met, we considered the study to be primary prevention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The review has three main comparisons: (1) etidronate 400 mg/day versus placebo; (2) etidronate 200 mg/day versus placebo; (3) etidronate at any dosage versus another anti-osteoporotic agent. We stratified the analyses for each comparison into primary and secondary prevention studies. For major outcomes in the placebo-controlled studies of etidronate 400 mg/day, we followed our original review by defining a greater than 15% relative change as clinically important. For all outcomes of interest, we extracted outcome measurements at the longest time point in the study. MAIN RESULTS: Thirty studies met the review's eligibility criteria. Of these, 26 studies, with a total of 2770 women, reported data that we could extract and quantitatively synthesize. There were nine primary and 17 secondary prevention studies. We had concerns about at least one risk of bias domain in each study. None of the studies described appropriate methods for allocation concealment, although 27% described adequate methods of random sequence generation. We judged that only 8% of the studies avoided performance bias, and provided adequate descriptions of appropriate blinding methods. One-quarter of studies that reported efficacy outcomes were at high risk of attrition bias, whilst 23% of studies reporting safety outcomes were at high risk in this domain. The 30 included studies compared (1) etidronate 400 mg/day to placebo (13 studies: nine primary and four secondary prevention); (2) etidronate 200 mg/day to placebo (three studies, all secondary prevention); or (3) etidronate (both dosing regimens) to another anti-osteoporotic agent (14 studies: one primary and 13 secondary prevention). We discuss only the etidronate 400 mg/day versus placebo comparison here. For primary prevention, we collected moderate- to very low-certainty evidence from nine studies (one to four years in length) including 740 postmenopausal women at lower risk of fractures. Compared to placebo, etidronate 400 mg/day probably results in little to no difference in non-vertebral fractures (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.20 to 1.61); absolute risk reduction (ARR) 4.8% fewer, 95% CI 8.9% fewer to 6.1% more) and serious adverse events (RR 0.90, 95% CI 0.52 to 1.54; ARR 1.1% fewer, 95% CI 4.9% fewer to 5.3% more), based on moderate-certainty evidence. Etidronate 400 mg/day may result in little to no difference in clinical vertebral fractures (RR 3.03, 95% CI 0.32 to 28.44; ARR 0.02% more, 95% CI 0% fewer to 0% more) and withdrawals due to adverse events (RR 1.41, 95% CI 0.81 to 2.47; ARR 2.3% more, 95% CI 1.1% fewer to 8.4% more), based on low-certainty evidence. We do not know the effect of etidronate on hip fractures because the evidence is very uncertain (RR not estimable based on very low-certainty evidence). Wrist fractures were not reported in the included studies. For secondary prevention, four studies (two to four years in length) including 667 postmenopausal women at higher risk of fractures provided the evidence. Compared to placebo, etidronate 400 mg/day may make little or no difference to non-vertebral fractures (RR 1.07, 95% CI 0.72 to 1.58; ARR 0.9% more, 95% CI 3.8% fewer to 8.1% more), based on low-certainty evidence. The evidence is very uncertain about etidronate's effects on hip fractures (RR 0.93, 95% CI 0.17 to 5.19; ARR 0.0% fewer, 95% CI 1.2% fewer to 6.3% more), wrist fractures (RR 0.90, 95% CI 0.13 to 6.04; ARR 0.0% fewer, 95% CI 2.5% fewer to 15.9% more), withdrawals due to adverse events (RR 1.09, 95% CI 0.54 to 2.18; ARR 0.4% more, 95% CI 1.9% fewer to 4.9% more), and serious adverse events (RR not estimable), compared to placebo. Clinical vertebral fractures were not reported in the included studies. AUTHORS' CONCLUSIONS: This update echoes the key findings of our previous review that etidronate probably makes or may make little to no difference to vertebral and non-vertebral fractures for both primary and secondary prevention.

Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Risedronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts. This is an update of a Cochrane Review that was originally published in 2003. OBJECTIVES: We assessed the benefits and harms of risedronate in the primary and secondary prevention of osteoporotic fractures for postmenopausal women at lower and higher risk for fractures, respectively. SEARCH METHODS: With broader and updated strategies, we searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE and Embase. A grey literature search, including the online databases ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), and drug approval agencies, as well as bibliography checks of relevant systematic reviews was also performed. Eligible trials published between 1966 to 24 March 2021 were identified. SELECTION CRITERIA: We included randomised controlled trials that assessed the benefits and harms of risedronate in the prevention of fractures for postmenopausal women. Participants must have received at least one year of risedronate, placebo or other anti-osteoporotic drugs, with or without concurrent calcium/vitamin D. Major outcomes were clinical vertebral, non-vertebral, hip and wrist fractures, withdrawals due to adverse events, and serious adverse events. In the interest of clinical relevance and applicability, we classified a study as secondary prevention if its population fulfilled more than one of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, low bone mineral density (BMD)T score ≤ -2.5, and age ≥ 75 years old. If none of these criteria was met, the study was considered to be primary prevention. DATA COLLECTION AND ANALYSIS: We used standard methodology expected by Cochrane. We pooled the relative risk (RR) of fractures using a fixed-effect model based on the expectation that the clinical and methodological characteristics of the respective primary and secondary prevention studies would be homogeneous, and the experience from the previous review suggesting that there would be a small number of studies. The base case included the data available for the longest treatment period in each placebo-controlled trial and a >15% relative change was considered clinically important. The main findings of the review were presented in summary of findings tables, using the GRADE approach. In addition, we looked at benefit and harm comparisons between different dosage regimens for risedronate and between risedronate and other anti-osteoporotic drugs. MAIN RESULTS: Forty-three trials fulfilled the eligibility criteria, among which 33 studies (27,348 participants) reported data that could be extracted and quantitatively synthesized. We had concerns about particular domains of risk of bias in each trial. Selection bias was the most frequent concern, with only 24% of the studies describing appropriate methods for both sequence generation and allocation concealment. Fifty per cent and 39% of the studies reporting benefit and harm outcomes, respectively, were subject to high risk. None of the studies included in the quantitative syntheses were judged to be at low risk of bias in all seven domains. The results described below pertain to the comparisons for daily risedronate 5 mg versus placebo which reported major outcomes. Other comparisons are described in the full text. For primary prevention, low- to very low-certainty evidence was collected from four studies (one to two years in length) including 989 postmenopausal women at lower risk of fractures. Risedronate 5 mg/day may make little or no difference to wrist fractures [RR 0.48 ( 95% CI 0.03 to 7.50; two studies, 243 participants); absolute risk reduction (ARR) 0.6% fewer (95% CI 1% fewer to 7% more)] and withdrawals due to adverse events [RR 0.67 (95% CI 0.38 to 1.18; three studies, 748 participants); ARR 2% fewer (95% CI 5% fewer to 1% more)], based on low-certainty evidence. However, its preventive effects on non-vertebral fractures and serious adverse events are not known due to the very low-certainty evidence. There were zero clinical vertebral and hip fractures reported therefore the effects of risedronate for these outcomes are not estimable.  For secondary prevention, nine studies (one to three years in length) including 14,354 postmenopausal women at higher risk of fractures provided evidence. Risedronate 5 mg/day probably prevents non-vertebral fractures [RR 0.80 (95% CI 0.72 to 0.90; six studies, 12,173 participants); RRR 20% (95% CI 10% to 28%) and ARR 2% fewer (95% CI 1% fewer to 3% fewer), moderate certainty], and may reduce hip fractures [RR 0.73 (95% CI 0.56 to 0.94); RRR 27% (95% CI 6% to 44%) and ARR 1% fewer (95% CI 0.2% fewer to 1% fewer), low certainty]. Both of these effects are probably clinically important. However, risedronate's effects are not known for wrist fractures [RR 0.64 (95% CI 0.33 to 1.24); three studies,1746 participants); ARR 1% fewer (95% CI 2% fewer to 1% more), very-low certainty] and not estimable for clinical vertebral fractures due to zero events reported (low certainty). Risedronate results in little to no difference in withdrawals due to adverse events [RR 0.98 (95% CI 0.90 to 1.07; eight studies, 9529 participants); ARR 0.3% fewer (95% CI 2% fewer to 1% more); 16.9% in risedronate versus 17.2% in control, high certainty] and probably results in little to no difference in serious adverse events [RR 1.00 (95% CI 0.94 to 1.07; six studies, 9435 participants); ARR 0% fewer (95% CI 2% fewer to 2% more; 29.2% in both groups, moderate certainty). AUTHORS' CONCLUSIONS: This update recaps the key findings from our previous review that, for secondary prevention, risedronate 5 mg/day probably prevents non-vertebral fracture, and may reduce the risk of hip fractures. We are uncertain on whether risedronate 5mg/day reduces clinical vertebral and wrist fractures.  Compared to placebo, risedronate probably does not increase the risk of serious adverse events.  For primary prevention, the benefit and harms of risedronate were supported by limited evidence with high uncertainty.

Systematic review and meta-analysis of cohort studies of long term outdoor nitrogen dioxide exposure and mortality.

OBJECTIVE: To determine whether long term exposure to outdoor nitrogen dioxide (NO2) is associated with all-cause or cause-specific mortality. METHODS: MEDLINE, Embase, CENTRAL, Global Health and Toxline databases were searched using terms developed by a librarian. Screening, data extraction and risk of bias assessment were completed independently by two reviewers. Conflicts were resolved through consensus and/or involvement of a third reviewer. Pooling of results across studies was conducted using random effects models, heterogeneity among included studies was assessed using Cochran's Q and I2 measures, and sources of heterogeneity were evaluated using meta-regression. Sensitivity of pooled estimates to individual studies was examined and publication bias was evaluated using Funnel plots, Begg's and Egger's tests, and trim and fill. RESULTS: Seventy-nine studies based on 47 cohorts, plus one set of pooled analyses of multiple European cohorts, met inclusion criteria. There was a consistently high degree of heterogeneity. After excluding studies with probably high or high risk of bias in the confounding domain (n = 12), pooled hazard ratios (HR) indicated that long term exposure to NO2 was significantly associated with mortality from all/ natural causes (pooled HR 1.047, 95% confidence interval (CI), 1.023-1.072 per 10 ppb), cardiovascular disease (pooled HR 1.058, 95%CI 1.026-1.091), lung cancer (pooled HR 1.083, 95%CI 1.041-1.126), respiratory disease (pooled HR 1.062, 95%CI1.035-1.089), and ischemic heart disease (pooled HR 1.111, 95%CI 1.079-1.144). Pooled estimates based on multi-pollutant models were consistently smaller than those from single pollutant models and mostly non-significant. CONCLUSIONS: For all causes of death other than cerebrovascular disease, the overall quality of the evidence is moderate, and the strength of evidence is limited, while for cerebrovascular disease, overall quality is low and strength of evidence is inadequate. Important uncertainties remain, including potential confounding by co-pollutants or other concomitant exposures, and limited supporting mechanistic evidence. (PROSPERO registration number CRD42018084497).

Correction to: Systematic review and meta-analysis of case-crossover and time-series studies of short term outdoor nitrogen dioxide exposure and ischemic heart disease morbidity.

An amendment to this paper has been published and can be accessed via the original article.

Systematic review and meta-analysis of case-crossover and time-series studies of short term outdoor nitrogen dioxide exposure and ischemic heart disease morbidity.

BACKGROUND: Nitrogen dioxide (NO2) is a pervasive urban pollutant originating primarily from vehicle emissions. Ischemic heart disease (IHD) is associated with a considerable public health burden worldwide, but whether NO2 exposure is causally related to IHD morbidity remains in question. Our objective was to determine whether short term exposure to outdoor NO2 is causally associated with IHD-related morbidity based on a synthesis of findings from case-crossover and time-series studies. METHODS: MEDLINE, Embase, CENTRAL, Global Health and Toxline databases were searched using terms developed by a librarian. Screening, data extraction and risk of bias assessment were completed independently by two reviewers. Conflicts between reviewers were resolved through consensus and/or involvement of a third reviewer. Pooling of results across studies was conducted using random effects models, heterogeneity among included studies was assessed using Cochran's Q and I2 measures, and sources of heterogeneity were evaluated using meta-regression. Sensitivity of pooled estimates to individual studies was examined using Leave One Out analysis and publication bias was evaluated using Funnel plots, Begg's and Egger's tests, and trim and fill. RESULTS: Thirty-eight case-crossover studies and 48 time-series studies were included in our analysis. NO2 was significantly associated with IHD morbidity (pooled odds ratio from case-crossover studies: 1.074 95% CI 1.052-1.097; pooled relative risk from time-series studies: 1.022 95% CI 1.016-1.029 per 10 ppb). Pooled estimates for case-crossover studies from Europe and North America were significantly lower than for studies conducted elsewhere. The high degree of heterogeneity among studies was only partially accounted for in meta-regression. There was evidence of publication bias, particularly for case-crossover studies. For both case-crossover and time-series studies, pooled estimates based on multi-pollutant models were smaller than those from single pollutant models, and those based on older populations were larger than those based on younger populations, but these differences were not statistically significant. CONCLUSIONS: We concluded that there is a likely causal relationship between short term NO2 exposure and IHD-related morbidity, but important uncertainties remain, particularly related to the contribution of co-pollutants or other concomitant exposures, and the lack of supporting evidence from toxicological and controlled human studies.

ALK inhibitors for non-small cell lung cancer: A systematic review and network meta-analysis.

BACKGROUND: We sought to assess the relative effects of individual anaplastic lymphoma kinase (ALK) inhibitors for the treatment of non-small cell lung cancer (NSCLC). METHODS: We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (July 23, 2019) for randomized controlled trials (RCTs) that included participants with ALK- or ROS1-positive NSCLC who received any ALK inhibitor compared with placebo, another ALK inhibitor, or the same ALK inhibitor at a different dose. The primary outcome was treatment-related death. Secondary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events. Data were pooled via meta-analysis and network meta-analysis, and risk of bias was assessed. PROSPERO: CRD42017077046. RESULTS: Thirteen RCTs reporting outcomes of interest among participants with ALK-positive NSCLC were identified. Treatment-related deaths were rare, with 10 deaths attributed to crizotinib (risk difference v. chemotherapy: 0.49, 95% credible interval [CrI] -0.16 to 1.46; odds ratio 2.58 (0.76-11.37). All ALK inhibitors improved PSF relative to chemotherapy (hazard ratio [95% CrI]: crizotinib 0.46 [0.39-0.54]; ceritinib 0.52 [0.42-0.64]; alectinib 300 BID 0.16 [0.08-0.33]; alectinib 600 BID 0.23 [0.17-0.30]; brigatinib 0.23 [0.15-0.35]), while alectinib and brigatinib improved PFS over crizotinib and ceritinib (alectinib v. crizotinib 0.34 [0.17-0.70]; alectinib v. ceritinib 0.30 [0.14-0.64]; brigatinib v. crizotinib 0.49 [0.33-0.73]; brigatinib v. ceritinib 0.43 [0.27-0.70]). OS was improved with alectinib compared with chemotherapy (HR 0.57 [95% CrI 0.39-0.83]) and crizotinib (0.68 [0.48-0.96]). Use of crizotinib (odds ratio 2.08 [95% CrI 1.56-2.79]) and alectinib (1.60 [1.00-2.58]) but not ceritinib (1.25 [0.90-1.74), increased the risk of serious adverse events compared with chemotherapy. Results were generally consistent among treatment-experienced or naïve participants. CONCLUSION(S): Treatment-related deaths were infrequent among ALK-positive NSCLC. PFS may be improved by alectinib and brigatinib relative to other ALK inhibitors; however, the assessment of OS is likely confounded by treatment crossover and should be interpreted with caution.

Influence of prolonged treatment with omalizumab on the development of solid epithelial cancer in patients with atopic asthma and chronic idiopathic urticaria: A systematic review and meta-analysis.

OBJECTIVE: We investigated whether prolonged treatment with omalizumab influences development or progression of solid epithelial cancer in patients with atopic asthma or chronic idiopathic urticaria. DESIGN: Systematic review and meta-analysis of intervention and observational studies. Randomized controlled trials were assessed for risk of bias using the Cochrane Risk of Bias tool, comparative observational studies were assessed using the Newcastle-Ottawa Scale, and non-comparative observational studies were assessed using the Joanna Briggs Institute Checklist for Prevalence Studies. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Library and grey literature for eligible studies to November 2017. All searches were updated in January 2019. ELIGIBILITY CRITERIA FOR INCLUDED STUDIES: Randomized, quasi-randomized, controlled clinical trials and observational studies were included if they involved patients ≥ 12 years with moderate-to-severe persistent asthma or chronic idiopathic urticaria treated with omalizumab for ≥ 40 weeks. Eligible comparators included standard of care, placebo, cromoglycate or no treatment. RESULTS: One hundred and sixty seven unique studies were eligible for inclusion; however, only twelve (7.2%, n = 11 758) reported any outcome of interest, none of which involved patients with urticaria. 195 cancer events were reported. We found no statistically significant increase in the odds of study-emergent solid epithelial cancer in patients randomized to long-term treatment with omalizumab compared to standard of care (Peto OR: 0.65, 95% CI: 0.11, 3.74, I2  = 41%). Less than one per cent of participants of non-comparative observational studies (n = 2350) were diagnosed with a solid epithelial tumour (meta-proportion: 0.86% [95% CI: 0.24, 1.86%, I2  = 56%]). In the only comparative observational study reporting on cancer, the proportion of study-emergent solid epithelial tumour events was nearly identical in both study groups (omalizumab: 2.3%, standard of care: 2.2%). CONCLUSIONS: There is insufficient evidence to determine whether long-term treatment with omalizumab influences development or progression of solid epithelial cancer in these patient populations. PROSPERO registration # CRD 42018082211.