Decision aids for patients considering total joint replacement: a cost-effectiveness analysis alongside a randomised controlled trial.

BACKGROUND: Shared decision-making (SDM) is a key priority to improve patient-centred care, and can play an important role in helping patients decide whether to undergo total joint arthroplasty (TJA). Patient decision aids can support SDM; however, they may incur an upfront cost. We aimed to estimate the health and economic effects of patient decision aids for TJA. METHODS: A cost-effectiveness analysis of a randomised controlled trial (RCT) with 2-year follow-up. 343 patients were recruited from two orthopedic screening clinics in Ottawa, Canada. Patients were randomized to either a patient decision aid plus surgeon preference report (decision aid) or usual care. Primary outcomes were costs (in 2014 CAD$), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER). Costs were calculated by multiplying self-reported resource use by unit costs. QALYs were calculated by mapping the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) to EuroQol 5-Dimension (EQ-5D) health utilities. Costs and QALYs were discounted at 5%. Multiple imputation was used to handle missing data, and bootstrapping was used to estimate uncertainty. RESULTS: The sample comprised 167 intervention and 167 control group patients. The decision aid arm had fewer surgeries over the 2-year period thereby incurring a negative incremental cost of -$560 (95% CI: -$1358 to $426) per patient while providing 0.05 (95% CI: -0.04 to 0.13) additional QALYs per patient. Consequently, the decision aid arm was dominant. CONCLUSION: The use of a patient decision aid was associated with fewer health care costs, while producing similar health outcomes. CLINICAL TRIAL REGISTRATION NUMBER: CT00911638 (clinicaltrials.gov).

Clinicians' perspective on key domains in ANCA-associated vasculitis: a Delphi exercise.

OBJECTIVES: The existing set of outcomes for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) needs to incorporate views of outcome measure stakeholders to meet the current standards of outcome measurement proposed by the Outcome Measures in Rheumatology (OMERACT) initiative. This study identifies domains that clinical experts (one group of stakeholders) consider to be important to determining the impact of AAV using the International Classification of Functioning, Disability and Health (ICF), a framework that describes health along four components: body functions, body structures, activities and participation, and contextual factors. METHOD: An international group of clinicians with expertise in the clinical care of patients with vasculitis were identified through consultation with three major vasculitis societies. The relevant domains were determined using a three-round e-mail-based Delphi questionnaire. RESULTS: Eighty-two clinicians were invited to participate in this study and 41 responded. Nineteen domains were identified as important by > 80% of participants: six body functions (energy, seeing, hearing, pain, respiratory, and renal function), seven body structures (peripheral nerves, eye, ear, nose, sinuses, lungs (and airways), and kidneys), three activities and participation (carrying out daily routine, remunerative employment, and recreation and leisure), and three environmental factors (medications, support and relationships, and health services, systems, and policies). CONCLUSIONS: Clinical experts focus on the physiological effects of AAV with less importance given to the effect of AAV on patients' activities and participation in life situations and the role of contextual factors. This study represents a step towards incorporating views of a range of stakeholders into disease assessment in AAV.

Impact of patient decision aids on appropriate and timely access to hip or knee arthroplasty for osteoarthritis: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of patient decision aids (PtDA) compared to usual education on appropriate and timely access to total joint arthroplasty in patients with osteoarthritis. METHOD: A randomized controlled trial (RCT) with patients undergoing orthopedic screening. Control and intervention arms received usual education; intervention arm also received a PtDA and a surgeon preference report. Wait times (primary outcome) were described using stratified Kaplan-Meier survival curves with patients censored at the time of death or loss to follow-up, and multivariable Cox proportional hazards regression. Secondary outcomes were compared using stratified Cochran-Mantel-Haenszel chi-squared tests. RESULTS: 343 patients were randomized to intervention (n = 174) or control (n = 169). The typical patient was 66 years old, retired, living with someone, and 51% had high school education or less. The intervention was associated with a trend towards reduction in wait time (hazard ratio (HR) 1.25, 95% confidence interval (CI) 0.99-1.60, P = 0.0653). Median wait times were 3 weeks shorter in intervention than in control at the community site with no difference at the academic site. Good decision quality was reached by 56.1% intervention and 44.5% control (Relative risk (RR) 1.25; 95% CI 1.00-1.56, P = 0.050). Surgery rates were 73.2% intervention and 80.5% controls (RR 0.91: 95% CI 0.81-1.03) with 12 intervention (7.3%) and eight control participants (4.9%) returning to have surgery within 2 years (P = 0.791). CONCLUSION: Compared to controls, decision aid recipients had shorter wait times at one site, fewer surgeries, and were more likely to reach good decision quality, but overall effect was not statistically significant. TRIALS REGISTRATION: The full trial protocol is available at ClinicalTrials.Gov (NCT00911638).

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

Sex and Gender Appraisal Tool-Systematic Reviews-2 and Participation-To-Prevalence Ratio assessed to whom the evidence applies in sepsis reviews.

OBJECTIVES: To revise a sex and gender appraisal tool for systematic reviews (SGAT-SR) and apply it to Cochrane sepsis reviews. STUDY DESIGN AND SETTING: The revision process was informed by existing literature on sex, gender, intersectionality, and feedback from an expert advisory board. We revised the items to consider additional factors associated with health inequities and appraised sex and gender considerations using the SGAT-SR-2 and female Participation-to-Prevalence Ratio (PPR) in Cochrane sepsis reviews. RESULTS: SGAT-SR-2 consists of 19 questions appraising the review's sections and use of the terms sex and gender. amongst 71 SRs assessed, 50.7% included at least one tool item, the most frequent being the number of participants by sex or gender at included study-level (24/71 reviews). Only four reviews provided disaggregated data for the full set of included trials, while two considered other equity-related factors. Reviews rarely appraised possible similarities and differences across sex and gender. In half of a subset of reviews, female participants were under-represented relative to their share of the sepsis population (PPR<0.8). CONCLUSION: The SGAT-SR-2 tool and the PPR can support the design and appraisal of systematic reviews to assess sex and gender considerations, address to whom evidence applies, and determine future research needs.

OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009.

OBJECTIVE: To update evidence for available therapies in the treatment of hip and knee osteoarthritis (OA) and to examine whether research evidence has changed from 31 January 2006 to 31 January 2009. METHODS: A systematic literature search was undertaken using MEDLINE, EMBASE, CINAHL, AMED, Science Citation Index and the Cochrane Library. The quality of studies was assessed. Effect sizes (ESs) and numbers needed to treat were calculated for efficacy. Relative risks, hazard ratios (HRs) or odds ratios were estimated for side effects. Publication bias and heterogeneity were examined. Sensitivity analysis was undertaken to compare the evidence pooled in different years and different qualities. Cumulative meta-analysis was used to examine the stability of evidence. RESULTS: Sixty-four systematic reviews, 266 randomised controlled trials (RCTs) and 21 new economic evaluations (EEs) were published between 2006 and 2009. Of 51 treatment modalities, new data on efficacy have been published for more than half (26/39, 67%) of those for which research evidence was available in 2006. Among non-pharmacological therapies, ES for pain relief was unchanged for self-management, education, exercise and acupuncture. However, with new evidence the ES for pain relief for weight reduction reached statistical significance, increasing from 0.13 [95% confidence interval (CI) -0.12, 0.36] in 2006 to 0.20 (95% CI 0.00, 0.39) in 2009. By contrast, the ES for electromagnetic therapy which was large in 2006 (ES=0.77, 95% CI 0.36, 1.17) was no longer significant (ES=0.16, 95% CI -0.08, 0.39). Among pharmacological therapies, the cumulative evidence for the benefits and harms of oral and topical non-steroidal anti-inflammatory drugs, diacerhein and intra-articular (IA) corticosteroid was not greatly changed. The ES for pain relief with acetaminophen diminished numerically, but not significantly, from 0.21 (0.02, 0.41) to 0.14 (0.05, 0.22) and was no longer significant when analysis was restricted to high quality trials (ES=0.10, 95% CI -0.0, 0.23). New evidence for increased risks of hospitalisation due to perforation, peptic ulceration and bleeding with acetaminophen >3g/day have been published (HR=1.20, 95% CI 1.03, 1.40). ES for pain relief from IA hyaluronic acid, glucosamine sulphate, chondroitin sulphate and avocado soybean unsponifiables also diminished and there was greater heterogeneity of outcomes and more evidence of publication bias. Among surgical treatments further negative RCTs of lavage/debridement were published and the pooled results demonstrated that benefits from this modality of therapy were no greater than those obtained from placebo. CONCLUSION: Publication of a large amount of new research evidence has resulted in changes in the calculated risk-benefit ratio for some treatments for OA. Regular updating of research evidence can help to guide best clinical practice.

Moving Towards Common Data Elements and Core Outcome Measures in Frailty Research.

With aging populations around the world, frailty is becoming more prevalent increasing the need for health systems and social systems to deliver optimal evidence based care. However, in spite of the growing number of frailty publications, high-quality evidence for decision making is often lacking. Inadequate descriptions of the populations enrolled including frailty severity and frailty conceptualization, lack of use of validated frailty assessment tools, utilization of different frailty instruments between studies, and variation in reported outcomes impairs the ability to interpret, generalize and implement the research findings. The utilization of common data elements (CDEs) and core outcome measures (COMs) in clinical trials is increasingly being adopted to address such concerns. To catalyze the development and use of CDEs and COMs for future frailty studies, the Canadian Frailty Network (www.cfn-nce.ca; CFN), a not-for-profit pan-Canadian nationally-funded research network, convened an international group of experts to examine the issue and plan the path forward. The meeting was structured to allow for an examination of current frailty evidence, ability to learn from other COMs and CDEs initiatives, discussions about specific considerations for frailty COMs and CDEs and finally the identification of the necessary steps for a COMs and CDEs consensus initiative going forward. It was agreed at the onset of the meeting that a statement based on the meeting would be published and herein we report the statement.

Validation of a simple activity participation measure for rheumatoid arthritis clinical trials.

OBJECTIVE: To examine the validity, reliability and sensitivity to change of the Activity Participation Questionnaire (APaQ), a simple measure of activity participation for patients with RA. METHODS: The questionnaire contained two items: (i) number of days in the past month of being unable to perform one's usual activities because of RA; and (ii) a score measuring how often one's usual activities could be completed. The APaQ was administered to 1043 RA patients in two clinical trials of abatacept. Construct validity was evaluated by examining changes from baseline in activity scores by clinical response measured by the European League Against Rheumatism (EULAR) and ACR criteria and minimal disease activity (MDA) state and by correlations with patient-reported outcome measures of physical function, disease activity, pain and fatigue at study end-point. Internal consistency, test-retest reliability and sensitivity to change were assessed. RESULTS: Both activity participation items were significantly associated with levels of EULAR and ACR response and the achievement of MDA state (P < 0.0005 for all comparisons). Moderate correlations with patient-reported outcomes were consistently found (correlations 0.5-0.6). Cronbach's alpha was 0.7 indicating good internal consistency, the intraclass correlation coefficient of 0.6 suggesting acceptable test-retest reliability. Sensitivity to change was demonstrated by the treatment differences and the standardized response mean (0.39 and 0.30) for the two activity items. CONCLUSION: The APaQ is a simple, reliable and valid measure of patient activity, which is sensitive to change, suggesting its suitability for use in clinical trials.

Responsiveness of patient reported outcomes including fatigue, sleep quality, activity limitation, and quality of life following treatment with abatacept for rheumatoid arthritis.

OBJECTIVE: To evaluate the responsiveness of patient reported outcomes (PROs), including fatigue, sleep, activity limitation, and quality of life, in patients with rheumatoid arthritis (RA). METHODS: Data were considered from a randomised controlled trial comparing abatacept (n = 258) with placebo (n = 133) on a background of DMARD treatment in RA patients who were inadequate responders to anti-TNF therapy (ATTAIN study). PROs assessed included SF-36, activity limitation, fatigue, and sleep. For each outcome the treatment difference, relative per cent improvement, standardised response mean (SRM), and relative efficiency for assessing an outcome's ability to detect a treatment effect relative to tender joint count (TJC) were calculated. A relative efficiency >1 suggests a measure that is more efficient than TJC in detecting treatment effect. RESULTS: Moderate to large SRMs (>or=0.6) were observed for the PRO measures. In particular, SRMs (95% confidence interval) were: physician global, 0.72 (0.51 to 0.94); HAQ, 0.63 (0.42 to 0.85); SF-36 physical component score, 0.62 (0.40 to 0.83); SF-36 bodily pain, 0.68 (0.46 to 0.90); and fatigue, 0.59 (0.38 to 0.81). Relative efficiencies for physician global (1.6), SF-36 bodily pain domain (1.4), pain intensity (1.4), HAQ (1.2), SF-36 physical component score (1.2), fatigue (1.1), and patient global assessment (1.04) were all more responsive than TJC. The SF-36 mental component score (0.3), swollen joint count (0.6), activity limitation (0.8), sleep (0.7), and C reactive protein (0.9) were less responsive. CONCLUSIONS: Using PROs for evaluating treatments for RA can detect improvements and will identify changes that are important to patients. In general, physical assessments are more responsive to an effective treatment than mental assessments.

Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardised operating procedures, which use a three-step approach: (1) expert-based definition of relevant research questions (November 2006); (2) systematic literature search (November 2006 to May 2007); and (3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature the expert panel recommended that each trial should report the following items: (1) disease activity response and disease activity states; (2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; (3) baseline disease activity levels (in general); (4) the percentage of patients achieving a low disease activity state and remission; (5) time to onset of the primary outcome; (6) sustainability of the primary outcome; (7) fatigue. CONCLUSIONS: These recommendations endorsed by EULAR and ACR will help harmonise the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Alendronate 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. Alendronate belongs to the bisphosphonate class of drugs, which act to inhibit bone resorption by interfering with the activity of osteoclasts. OBJECTIVES: To assess the efficacy of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007. SELECTION CRITERIA: Women receiving at least one year of alendronate, for postmenopausal osteoporosis, were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence. DATA COLLECTION AND ANALYSIS: We undertook study selection and data abstraction in duplicate. We performed meta-analysis of fracture outcomes using relative risks and a > 15% relative change was considered clinically important. We assessed study quality through reporting of allocation concealment, blinding and withdrawals. MAIN RESULTS: Eleven trials representing 12,068 women were included in the review. Relative (RRR) and absolute (ARR) risk reductions for the 10 mg dose were as follows. For vertebral fractures, a significant 45% RRR was found (RR 0.55, 95% CI 0.45 to 0.67). This was significant for both primary prevention, with 45% RRR (RR 0.55, 95% CI 0.38 to 0.80) and 2% ARR, and secondary prevention with 45% RRR (RR 0.55, 95% CI 0.43 to 0.69) and 6% ARR. For non-vertebral fractures, a significant 16% RRR was found (RR 0.84, 95% CI 0.74 to 0.94). This was significant for secondary prevention, with 23% RRR (RR 0.77, 95% CI 0.64 to 0.92) and 2% ARR, but not for primary prevention (RR 0.89, 95% CI 0.76 to 1.04). There was a significant 40% RRR in hip fractures (RR 0.60, 95% CI 0.40 to 0.92), but only secondary prevention was significant with 53% RRR (RR 0.47, 95% CI 0.26 to 0.85) and 1% ARR. The only significance found for wrist was in secondary prevention, with a 50% RRR (RR 0.50 95% CI 0.34 to 0.73) and 2% ARR. For adverse events, we found no statistically significant differences in any included study. However, observational data raise concerns regarding potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw. AUTHORS' CONCLUSIONS: At 10 mg per day, both clinically important and statistically significant reductions in vertebral, non-vertebral, hip and wrist fractures were observed for secondary prevention ('gold' level evidence, www.cochranemsk.org). We found no statistically significant results for primary prevention, with the exception of vertebral fractures, for which the reduction was clinically important ('gold' level evidence).

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. OBJECTIVES: To assess the efficacy of etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007. SELECTION CRITERIA: Women receiving at least one year of etidronate for postmenopausal osteoporosis were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence. DATA COLLECTION AND ANALYSIS: Study selection and data abstraction was done in duplicate. Meta-analysis of fracture outcomes was performed with data presented as relative risks and a relative change greater than 15% was considered clinically important. Study quality was assessed through the reporting of allocation concealment, blinding and withdrawals. MAIN RESULTS: Eleven studies representing a total of 1248 patients were included in the review.A significant 41% relative risk reduction (RRR) in vertebral fractures across eight studies (RR 0.59, 95% CI 0.36 to 0.96) was found. The six secondary prevention trials demonstrated a significant RRR of 47% in vertebral fractures (RR 0.53, 95% CI 0.32 to 0.87) and a 5% absolute risk reduction (ARR); compared with the pooled result for the two primary prevention trials (RR 3.03, 95% CI 0.32 to 28.44), which was not significant. There were no statistically significant risk reductions for non-vertebral (RR 0.98, 95% CI 0.68 to 1.42), hip (RR 1.20, 95% CI 0.37 to 3.88) or wrist fractures (RR 0.87, 95% CI: 0.32 to 2.36). For adverse events, no statistically significant differences were found in the included studies. However, observational data has led to concerns regarding potential risk for upper gastrointestinal injury. AUTHORS' CONCLUSIONS: Etidronate, at 400 mg per day, demonstrated a statistically significant and clinically important benefit in the secondary prevention of vertebral fractures. No statistically significant reductions in vertebral fractures were observed when it was used for primary prevention. In addition, no statistically significant reductions in non-vertebral, hip, or wrist fractures were found, regardless of whether etidronate was used for primary or secondary prevention. The level of evidence for all outcomes is Silver (www.cochranemsk.org.).

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. OBJECTIVES: To assess the efficacy of residronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE. Relevant randomized controlled trials published between 1966 to 2007 were identified. SELECTION CRITERIA: Women receiving at least one year of risedronate for postmenopausal osteoporosis were compared to those receiving placebo or concurrent calcium/vitamin D or both. The outcome was fracture incidence. DATA COLLECTION AND ANALYSIS: We carried out study selection and data abstraction in duplicate. Study quality was assessed through the reporting of allocation concealment, blinding and withdrawals. Meta-analysis was preformed using relative risks and a >15% relative change was considered clinically important. MAIN RESULTS: Seven trials were included in the review representing 14,049 women. Relative (RRR) and absolute (ARR) risk reductions for the 5 mg dose were as follows. Risk estimates for primary prevention were available only for vertebral and non vertebral fractures and showed no statistically significant effect of risedronate on fractures. For secondary prevention, a significant 39% RRR in vertebral fractures (RR 0.61, 95% CI 0.50 to 0.76) with 5% ARR was found. For non-vertebral fractures, a significant 20% RRR (RR 0.80, 95% CI 0.72 to 0.90) with 2% ARR and for hip fractures there was a significant 26% RRR (RR: 0.74, 95% CI 0.59 to 0.94) with a 1% ARR. When primary and secondary prevention studies were combined, the reduction in fractures remained statistically significant for both vertebral (RR 0.63, 0.51 to 0.77) and non vertebral fractures (RR 0.80, 0.72 to 0.90)For adverse events, no statistically significant differences were found in any of the included studies. However, observational data has led to concerns regarding the potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw. AUTHORS' CONCLUSIONS: At 5 mg/day a statistically significant and clinically important benefit in the secondary prevention of vertebral, non-vertebral and hip fractures was observed, but not for wrist. The level of evidence for secondary prevention is Gold (www.cochranemsk.org) for vertebral and non-vertebral and Silver for hip and wrist. There were no statistically significant reductions in the primary prevention of vertebral and non-vertebral fractures. The level of evidence is Silver.

WITHDRAWN: Low level laser therapy (Classes III) for treating osteoarthritis.

BACKGROUND: Osteoarthritis (OA) affects a large portion of the population. Low Level Laser Therapy (LLLT) is a light source that generates extremely pure light, of a single wavelength. The effect is not thermal, but rather related to photochemical reactions in the cells. LLLT was introduced as an alternative non-invasive treatment for OA about 30 years ago, but its effectiveness has to be examined more closely, especially in the treatment of OA. OBJECTIVES: To assess the effectiveness of class III LLLT for osteoarthritis when irradiation is directed at the osteoarthritic joint capsule. SEARCH STRATEGY: Searches were conducted in the following databases: MEDLINE, EMBASE, the Cochrane Musculoskeletal registry, the Rehabilitation and Related Therapies field registry and the Cochrane Controlled Trials Register up to May, 2005. SELECTION CRITERIA: Following an a prior protocol, only controlled clinical trials of LLLT for the treatment of patients with a clinical diagnosis of OA were eligible. Abstracts lacking data were excluded unless further data could be obtained from the authors. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials and extracted data using predetermined forms. A fixed effects model was used throughout for continuous variables, except where heterogeneity existed; in which case, a random effects model was used. Results were analyzed as weighted mean differences (WMD) with 95% confidence intervals (CI), whereas the difference between the treatment and control groups was weighted by the inverse of the variance. Standardized mean differences (SMD) were calculated by dividing the difference between treatment and control by the baseline variance, and were used in the analysis of pain because different scales were used to measure it. Dichotomous outcomes were analyzed with relative risk (RR). MAIN RESULTS: Eight trials were included with 233 patients randomized to laser and 172 patients to placebo laser. Treatment duration ranged from two to six weeks. Pain was assessed in seven trials. When the results were pooled from different pain scales used in these seven trials, a statistically significant difference in favor of laser treatment was found with a SMD of -0.28 (95% CI: -0.48 to -0.09). One of these studies also measured pain during movement and found a statistically significant difference in favor of laser treatment with a WMD of -1.16 (95% CI: -2.02 to -0.30). Two studies found significant results for increased knee range of motion. Two others studies found a statistically significant difference in favor of laser treatment for patient-assessed global disease activity with laser compared to placebo (RR 1.70, 95%CI: 1.1. to 2.63). One trial evaluated the effectiveness of laser treatment in temporomandibular joint OA and found a statistically significant difference (WMD 38.69, 95% CI: 29.25 to 48.13) using the change in VAS score to measure pain. One study found a statistically significant difference in favor of laser treatment at the end of treatment and at 4 and 8 weeks post-treatment for morning stiffness. Other outcome measures of joint tenderness and strength did not yield significant differences. AUTHORS' CONCLUSIONS: Five trials included in this review showed a statistically significant difference favoring laser treatment when compared to placebo for at least one outcome measure. Three trials did not report beneficial effects. The varying results of these trials may be due to the method of laser application and/or other features of LLLT application. Clinicians and researchers should consistently report the characteristics of LLLT devices and application techniques used. New trials on LLLT should make use of standardized, validated outcomes. There is clearly a need to investigate the effects of different dosages on LLLT effectiveness for OA in future randomized, controlled clinical trials. Also, more studies should be done to investigate the anti-inflammatory action of laser as well as the appropriate parameters needed to achieve an anti-inflammatory effect.

WITHDRAWN: Risedronate for the prevention and treatment of postmenopausal osteoporosis.

BACKGROUND: Postmenopausal osteoporosis results in an increased susceptibility to low-trauma fractures due to reduced bone volume and microarchitectural deterioration. Risedronate, a third generation bisphosphonate, has been shown in multiple clinical trials to reduce fracture risk and improve bone mineral density in postmenopausal women with osteoporosis. First and second generation bisphosphonates are known to have gastrointestinal side-effects and risedronate may be better tolerated. OBJECTIVES: To systematically review the efficacy of risedronate on bone density, and fracture reduction in postmenopausal women. SEARCH STRATEGY: The Cochrane Controlled Trials Registry Medline, and Current Contents were searched from 1990 - 2001. The electronic search was supplemented by handsearching four osteoporosis journals and their conference proceedings, as well as contacting content experts and industry sources for unpublished data. SELECTION CRITERIA: We included eight trials that randomised women to risedronate or an alternative (placebo or calcium and /or vitamin D) and measured bone mineral density for at least one year. DATA COLLECTION AND ANALYSIS: For each trial three independent reviewers assessed the methodological quality and abstracted data. Data was extracted for outcomes of fracture, bone mineral density and adverse events. The more conservative random effects model was used to pool data. The quality of trials was assessed according to the Jadad five-point scale. MAIN RESULTS: Both vertebral and non-vertebral fractures were statistically and clinically reduced with risedronate. Eleven out of one hundred women who received risedronate had a vertebral fracture compared to 17 out of one hundred of those who received calcium and vitamin D (pooled relative risk for vertebral fractures of 0.64 (95% CI 0.52 - 0.77). Three percent of participants who received risedronate had a non-vertebral fracture compared to 4.6% of those who received calcium and vitamin D (pooled relative risk for nonvertebral fractures of 0.73 (95% CI 0.61 - 0.87). The weighted mean difference for the percent change from baseline for bone mineral density with 5 mg daily for lumbar spine, femoral neck and trochanter was 4.54% (95%CI 4.12 - 4.97), p<0.01; 2.75% (95% CI 2.32 - 3.17), p<0.01; and 4.38% (95% CI 3.51 - 5.25), p<0.01 respectively. AUTHORS' CONCLUSIONS: There is good evidence for the efficacy of risedronate in the reduction of both vertebral and non-vertebral fractures. In addition, there is evidence from randomized trials that risedronate is able to achieve this without increasing risk for overall withdrawals due to adverse effects.

WITHDRAWN: Calcium supplementation on bone loss in postmenopausal women.

BACKGROUND: Although calcium is one the simplest and least expensive strategies for preventing osteoporotic fractures calcium supplementation is nevertheless not without controversy (Kanis 1989; Nordin 1990). The Food and Drug Administration in the US has permitted a bone health claim for calcium-rich foods, and the NIH in its Consensus Development Process approved a statement that high calcium intake reduces the risk of osteoporosis. OBJECTIVES: To assess the effects of calcium on bone density and fractures in postmenopausal women. SEARCH STRATEGY: We searched Cochrane Controlled Register, MEDLINE and EMBASE up to 2001, and examined citations of relevant articles and proceedings of international meetings. SELECTION CRITERIA: Trials that randomized postmenopausal women to calcium supplementation or usual calcium intake in the diet and reported bone mineral density of the total body, vertebral spine, hip, or forearm or recorded the number of fractures, and followed patients for at least one year were considered for inclusion. DATA COLLECTION AND ANALYSIS: Three independent reviewers assessed the methodologic quality and extracted data for each trial. For each bone density site (lumbar spine, total body, combined hip and combined forearm), we calculated the weighted mean difference in bone density between treatment and control groups using the percentage change from baseline. We constructed regression models in which the independent variables were year and dose, and the dependent variable was the effect size. This regression was used to determine the years across which pooling was appropriate. Heterogeneity was assessed. For each fracture analysis we calculated a risk ratio. MAIN RESULTS: Fifteen trials, representing 1806 participants, were included. Calcium was more effective than placebo in reducing rates of bone loss after two or more years of treatment. The pooled difference in percentage change from baseline was 2.05% (95% CI 0.24 to 3.86) for total body bone density, 1.66% (95% CI 0.92 to 2.39) for the lumbar spine at 2 years, 1.60% (95% CI 0.78 to 2.41) for the hip, and 1.91% (95% CI 0.33 to 3.50) for the distal radius. The relative risk of fractures of the vertebrae was 0.79 (95% CI 0.54 to 1.09); the relative risk for non-vertebral fractures was 0.86 (95% CI 0.43 to 1.72). AUTHORS' CONCLUSIONS: Calcium supplementation alone has a small positive effect on bone density. The data show a trend toward reduction in vertebral fractures, but it is unclear if calcium reduces the incidence of non vertebral fractures.

School feeding for improving the physical and psychosocial health of disadvantaged elementary school children.

BACKGROUND: Early malnutrition and/or micronutrient deficiencies can adversely affect physical, mental, and social aspects of child health. School feeding programs are designed to improve attendance, achievement, growth, and other health outcomes. OBJECTIVES: The main objective was to determine the effectiveness of school feeding programs in improving physical and psychosocial health for disadvantaged school children. SEARCH STRATEGY: We searched a number of databases including CENTRAL (2006 Issue 2), MEDLINE (1966 to May 2006), EMBASE (1980 to May 2006), PsycINFO (1980 to May 2006) and CINAHL (1982 to May 2006). Grey literature sources were also searched. Reference lists of included studies and key journals were handsearched and we also contacted selected experts in the field. SELECTION CRITERIA: Data from randomized controlled trials (RCTs), non-randomised controlled clinical trials (CCTs), controlled before and after studies (CBAs), and interrupted time series studies (ITSs) were included. Feeding had to be done in school; the majority of participants had to be socio-economically disadvantaged. DATA COLLECTION AND ANALYSIS: Two reviewers assessed all searches and retrieved studies. Data extraction was done by one of four reviewers and reviewed by a second. Two reviewers independently rated quality. If sufficient data were available, they were synthesized using random effects meta-analysis, adjusting for clustering if needed. Analyses were performed separately for RCTs and CBAs and for higher and lower income countries. MAIN RESULTS: We included 18 studies. For weight, in the RCTs and CBAs from Lower Income Countries, experimental group children gained an average of 0.39 kg (95% C.I: 0.11 to 0.67) over an average of 19 months and 0.71 kg (95% C.I.: 0.48 to 0.95) over 11.3 months respectively. Results for weight were mixed in higher income countries. For height, results were mixed; height gain was greater for younger children. Attendance in lower income countries was higher in experimental groups than in controls; our results show an average increase of 4 to 6 days a year. Math gains were consistently higher for experimental groups in lower income countries; in CBAs, the Standardized Mean Difference was 0.66 (95% C.I. = 0.13 to 1.18). In short-term studies, small improvements in some cognitive tasks were found. AUTHORS' CONCLUSIONS: School meals may have some small benefits for disadvantaged children. We recommend further well-designed studies on the effectiveness of school meals be undertaken, that results should be reported according to socio-economic status, and that researchers gather robust data on both processes and carefully chosen outcomes.

Bisphosphonate therapy for children and adolescents with secondary osteoporosis.

BACKGROUND: Children with chronic illnesses are at increased risk for reductions in bone strength and subsequent fractures (osteoporosis), either due to the impact of the underlying condition on skeletal development or due to the osteotoxic effect of medications (e.g., glucocorticoids) used to treat the chronic illness. Bisphosphonates are being administered with increasing frequency to children with secondary osteoporosis; however, the efficacy and harm of these agents remains unclear. OBJECTIVES: To examine the efficacy and harm of bisphosphonate therapy in the treatment and prevention of secondary osteoporosis in children and adolescents. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (Issue 4, 2006), MEDLINE, EMBASE, CINAHL and ISI Web of Science (inception-December 2006). Further literature was identified through expert contact, key author searches, scanning reference lists of included studies, and contacting bisphosphonate manufacturers. SELECTION CRITERIA: Randomized, quasi-randomized, controlled clinical trials, cohort, and case controls of bisphosphonate(s) in children 0-18 years of age with at least one low-trauma fracture event or reductions in bone mineral density in the context of secondary osteoporosis. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed quality. Case series were used for supplemental harms-related data. MAIN RESULTS: Six RCTs, two CCTs, and one prospective cohort (n=281 children) were included and classified into osteoporosis due to: 1) neuromuscular conditions (one RCT) and 2) chronic illness (five RCTs, two CCTs, one cohort). Bisphosphonates examined were oral alendronate, clodronate, and intravenous (IV) pamidronate. Study quality varied. Harms data from 23 case series (n=241 children) were used. Heterogeneity precluded statistically combining the results. Percent change or Z-score change in lumbar spine areal BMD from baseline were consistently reported. Two studies carried out between-group analyses; one showed no significant difference (using oral alendronate in anorexia nervosa) while the other demonstrated a treatment effect on lumbar spine with IV pamidronate in burn patients. Frequently reported harms included the acute phase reaction, followed by gastrointestinal complaints, and bone/muscle pain. AUTHORS' CONCLUSIONS: The results justify further evaluation of bisphosphonates among children with secondary osteoporosis. However, the evidence does not support bisphosphonates as standard therapy. Short-term (3 years or less) bisphosphonate use appears to be well-tolerated. An accepted criterion for osteoporosis in children, a standardized approach to BMD reporting, and examining functional bone health outcomes (e.g., fracture rates) will allow for appropriate comparisons across studies.

Health research priority setting in developing countries of the eastern Mediterranean region: partnering with the Cochrane Collaboration.

Healthcare research in the Eastern Mediterranean Region (EMR) is fragmented and often weak. A coordinated approach is required to strengthen and focus efforts. Given the low resource base, priority-setting is an essential component. Healthcare policy and programmes in the EMR should be underpinned by reliable evidence of "what works for whom and why", with special attention to the health needs of the disadvantaged. Collaboration with international health research organizations, such as The Cochrane Collaboration, is essential and would provide an opportunity to examine evidence, prioritize knowledge areas, and identify research gaps.

When is a randomised controlled trial health equity relevant? Development and validation of a conceptual framework.

BACKGROUND: Randomised controlled trials can provide evidence relevant to assessing the equity impact of an intervention, but such information is often poorly reported. We describe a conceptual framework to identify health equity-relevant randomised trials with the aim of improving the design and reporting of such trials. METHODS: An interdisciplinary and international research team engaged in an iterative consensus building process to develop and refine the conceptual framework via face-to-face meetings, teleconferences and email correspondence, including findings from a validation exercise whereby two independent reviewers used the emerging framework to classify a sample of randomised trials. RESULTS: A randomised trial can usefully be classified as 'health equity relevant' if it assesses the effects of an intervention on the health or its determinants of either individuals or a population who experience ill health due to disadvantage defined across one or more social determinants of health. Health equity-relevant randomised trials can either exclusively focus on a single population or collect data potentially useful for assessing differential effects of the intervention across multiple populations experiencing different levels or types of social disadvantage. Trials that are not classified as 'health equity relevant' may nevertheless provide information that is indirectly relevant to assessing equity impact, including information about individual level variation unrelated to social disadvantage and potentially useful in secondary modelling studies. CONCLUSION: The conceptual framework may be used to design and report randomised trials. The framework could also be used for other study designs to contribute to the evidence base for improved health equity.