Yee-Wei Lim

Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures: An Updated Systematic Review

Osteoporosis is a skeletal disorder characterized by compromised bone strength, increasing the risk for fracture (1). Risk factors include, but are not limited to, increasing age, female sex, postmenopause for women, low body weight, parental history of a hip fracture, cigarette smoking, race, hypogonadism, certain medical conditions (particularly rheumatoid arthritis), and certain medications for chronic diseases (such as glucocorticoids). During ones expected remaining life, 1 in 2 postmenopausal women and 1 in 5 older men are at risk for an osteoporosis-related fracture (2). The increasing prevalence and cost of osteoporosis have heightened interest in the effectiveness and safety of the many interventions currently available to prevent osteoporotic fracture. In 2007, we conducted a systematic review of the comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis (3, 4). Since that time, new drugs have been approved for treatment, and new studies have been published about existing drugs. Additional issues about pharmacologic treatments for osteoporosis that have become particularly salient include the optimal duration of therapy; the safety of long-term therapy; and the role of bone mineral density (BMD) measurement, both for screening and for monitoring treatment. Therefore, we updated our original systematic review. Methods This article is a condensed and further updated version of an evidence review conducted for the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Centers program (5). This article focuses on the comparative benefits and risks of short- and long-term pharmacologic treatments for low bone density. In addition, we address issues regarding monitoring and duration of therapy. For this updated review, we followed the same methods as our 2007 review, with a few exceptions. A protocol for this review was developed and posted on the Effective Health Care Program Web site (6). Data Sources and Searches We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the ACP Journal Club database, the National Institute for Clinical Excellence, the Food and Drug Administrations (FDA) MedWatch database, and relevant pharmacologic databases from 2 January 2005 to 3 June 2011. The search strategy followed that of the original report, with the addition of terms for new FDA-approved drugs (such as denosumab) and newly reported adverse events. The full search strategies are in our evidence report (5). We later updated this search to 21 January 2013 and used a machine learning method that a previous study showed had high sensitivity for detecting relevant evidence for updating a search of the literature on osteoporosis treatments (7) and then updated the searches to 4 March 2014 using the full search strategy. Study Selection Eligible studies were systematic reviews and randomized, controlled trials (RCTs) that studied FDA-approved pharmacotherapy (excluding calcitonin and etidronate) for women or men with osteoporosis that was not due to a secondary cause (such as glucocorticoid therapy and androgen-deprivation therapy) and also measured fractures as an outcome at a minimum follow-up of 6 months. In addition, we included observational studies with more than 1000 participants for adverse events and case reports for rare events. As in our original review, only English-language studies were included. Data Extraction and Quality Assessment Reviews were done in duplicate by pairs of reviewers. Study characteristics were extracted in duplicate, and outcomes data (both benefits and harms) were extracted by the study statistician. Study quality was assessed as it was in the 2007 report using the Jadad scale for clinical trials (with several questions added to assess allocation concealment and other factors) and the NewcastleOttawa Scale for observational studies (8, 9). Systematic reviews were assessed using a modified version of the 11 AMSTAR (A Measurement Tool to Assess Systematic Reviews) criteria (the modifications included eliminating the requirements to list all of the excluded studies and assess the conflicts of interest for all of the included studies) (10). The assessments of efficacy and effectiveness used reduction in fracture (all, vertebral, nonvertebral, spine, hip, wrist, or other) as the outcome (studies reporting changes in BMD but not fracture were excluded). Data Synthesis and Analysis Evidence on efficacy and effectiveness was synthesized narratively. For adverse events, we pooled data as in the 2007 report: We compared agent versus placebo and agent versus agent for agents within the same class and across classes. For groups of events that occurred in 3 or more trials, we estimated the pooled odds ratio (OR) and its associated 95% CI. Because many events were rare, we used exact conditional inference to perform the pooling rather than applying the usual asymptotic methods that assume normality. StatXact PROCs software was used for the analysis (11, 12). Large cohort and casecontrol studies were included to assess adverse events. Strength of evidence was assessed using the criteria of the Agency for Healthcare Research and Quality Evidence-based Practice Centers program, which are similar to those proposed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group (13). Role of the Funding Source The update that included studies identified in the 3 June 2011 search was funded by AHRQ. Subsequent updating received no external funding. Although AHRQ formulated the initial study questions for the original report, it did not participate in the literature search, determination of study eligibility criteria, data analysis, or interpretation of the data. Staff from AHRQ reviewed and provided comments on the report. Results The first search yielded 26366 titles, 2440 of which were considered potentially relevant (Figure). Of these, 661 full-text articles were reviewed, resulting in 255 articles that were included in the update report. Of these, 174 articles were relevant to this article. The second update search plus hand searching initially yielded 16589 titles, and machine learning and full-text review identified 107 as relevant. The third update yielded 12131 titles. After title, abstract, and full-text screening, 34 were relevant. Thus, 55086 titles were screened and 315 articles met eligibility criteria for inclusion. Not every eligible study is cited in this article. A complete list of studies that met eligibility criteria is available at www.rand.org/health/centers/epc. Figure. Summary of evidence search and selection. FRAX = Fracture Risk Assessment Tool; HRT = hormone replacement therapy; LBD = low bone density. *Original LBD report (4). Fracture Prevention Our previous review (3) identified 76 randomized trials and 24 meta-analyses and concluded that there was good-quality evidence that alendronate, etidronate, ibandronate, risedronate, zoledronic acid, estrogen, parathyroid hormone, and raloxifene prevented osteoporotic fractures, although not all of these agents prevented hip fractures. The principal new efficacy findings since that time are additional data about zoledronic acid and data about a new agent, denosumab (Tables 1 and 2). The data for zoledronic acid came from 6 placebo-controlled studies of various doses in postmenopausal women (1419), the 2 largest of which enrolled 7230 women (15) and 2127 women (14). Both studies showed statistically significant reductions in nearly all types of fractures assessed, with relative risk reductions ranging from 0.23 to 0.73 at time points from 24 to 36 months after initiation of treatment. The data for denosumab came from 2 placebo-controlled trials in postmenopausal women, one small (332 enrolled women) (20) and one much larger that followed 7521 women for 36 months (21). This latter study found statistically significant reductions in each anatomical fracture type measured (hip, nonvertebral, vertebral, and new clinical vertebral), with hazard ratios of 0.31 to 0.80. Many secondary analyses and open-label extension results of this trial report the effectiveness of denosumab in various subpopulations and other circumstances (2228). Table 1. Principal Conclusions About Drug Efficacy/Effectiveness and Adverse Events Table 2. Principal Conclusions About Monitoring and Treatment Duration Despite some difficulties in comparing results across trials because of differences in the outcomes reported, high-strength evidence shows that bisphosphonates (alendronate, ibandronate, risedronate, and zoledronic acid), denosumab, and teriparatide (the 1,34 amino acid fragment of the parathyroid hormone) reduce fractures compared with placebo in postmenopausal women with osteoporosis, with relative risks for fractures generally in the range of 0.40 to 0.60 for vertebral fractures and 0.60 to 0.80 for nonvertebral fractures. This range translates into a number needed to treat of 60 to 89 to prevent 1 vertebral fracture and 50 to 67 to prevent 1 hip fracture over 1 to 3 years of treatment, using a pooled average of the incidence of these fractures in the placebo groups from included studies. The effect of ibandronate on hip fracture risk reduction is unclear because hip fracture was not a separately reported outcome in placebo-controlled trials of this agent. The selective estrogen receptor modulator raloxifene has been shown in placebo-controlled trials to reduce only vertebral fractures; reduction in the risk for hip or nonvertebral fractures was not statistically significant. There is only one randomized, controlled trial of men with osteoporosis that was designed with a primary fracture reduction outcome. Nearly 1200 men with osteoporosis were randomly assigned to placebo or zoledronic acid intravenously once per year for 2 years. At follow-up, 1.6% of treated men had new radio

Reducing the burden of childhood malaria in Africa: the role of improved

Malaria kills > 1 million children aged < 5 years in sub-Saharan Africa annually. Current control efforts are hampered by increasing drug resistance, unreliable diagnostics, widespread overtreatment and rising drug costs. In this environment, new and widely available malaria diagnostics have the potential to save lives and drastically reduce overtreatment.

How accessible is medical care for homeless women

Background. Women have become a major segment of the homeless population, yet little is known about their access to health care or the relationship between access to care and vulnerability of homelessness. Objective. To examine homeless women’s access to health care using the Expanded Behavioral Model for Vulnerable Populations. Research Design. Population-based cross-sectional study using a probability sample of homeless women. Setting. Seventy-eight homeless shelters and soup lines in Los Angeles County. Subjects. Nine hundred seventy-four homeless women interviewed between January and October of 1997. Outcome Measures. Hospitalization, not for delivery, in the past 12 months; number of outpatient visits in the past 12 months; and number of preventive health screens in the past 12 months. Results. Among homeless women, those living on the streets were least likely to be hospitalized and had the fewest ambulatory visits and health screens. Multivariate analyses showed that key enabling factors associated with improved access were having: (1) health insurance, which increased the odds of being hospitalized by almost 3 times, and the number of ambulatory visits received; and (2) a regular source of care which increased the number of outpatient visits and health screens (all at P <0.01). Conclusions. The findings from the analysis of this large representative sample of homeless women indicate that women living on the streets have especially limited access to all types of medical care. The provision of health insurance and a regular source of care may substantially improve access for this vulnerable population.

Developing and Interpreting Models to Improve Diagnostics in Developing Countries

Developing a strategy for investment in diagnostic technologies requires an understanding of the need for, and the health impact of, potential new tools, as well as the necessary performance characteristics and user requirements. In this paper, we outline an approach for modelling the health benefits of new diagnostic tools.

Reducing stunting among children: the potential contribution of diagnostics

Stunting affects ~ 147 million children in developing countries. Studies have pointed to a relationship between stunting and different pathogens that are associated with diarrhoeal illness. New easy-to-use tools for diagnosing these pathogens could help to identify children at risk for growth shortfall, and reduce the prevalence of stunting and the large burden of disease associated with it.PREFACE The numbers of acquired immunodeficiency syndrome (AIDS)-related deaths among infants in developing countries are exceptionally high, largely because human immunodeficiency virus (HIV) infection remains undiagnosed in many cases. Current HIV testing methods are either impractical for developingcountry settings or inaccurate for use in infants. There is an urgent need to develop and deploy a new, easy-to-use HIV test, which could transform the management of paediatric HIV/AIDS in developing countries and avert millions of infant deaths.

The Challenge of Measuring Quality of Care From the Electronic Health Record

The electronic health record (EHR) is seen by many as an ideal vehicle for measuring quality of health care and monitoring ongoing provider performance. It is anticipated that the availability of EHR-extracted data will allow quality assessment without the expensive and time-consuming process of medical record abstraction. A review of the data requirements for the indicators in the Quality Assessment Tools system suggests that only about a third of the indicators would be readily accessible from EHR data. Other factors involving complexity of required data elements, provider documentation habits, and EHR variability make the task of quality measurement more difficult than may be appreciated. Accurately identifying eligible cases for quality assessment and validly scoring those cases with EHR-extracted data will pose significant challenges but could potentially plummet the cost and therefore expand the use of quality assessment.

The Singapore Mental Health Study: an overview of the methodology

The Singapore Mental Health Study (SMHS) is a population‐based, cross‐sectional, epidemiological study on the Singapore multi‐ethnic adult population. This article provides an overview of the research design and methods used which took into consideration the unique characteristics of the country and its multi‐ethnic population. A face‐to‐face household survey of Singapore residents aged 18 years and above was undertaken from 2009 to 2010. The nationally representative probability sample was derived using a disproportionate stratified sampling method. In order to increase precision for subgroup estimations the design was stratified with over‐sampling of Malays, Indians and those aged 65 years and above. Respondents were assessed using the English, Chinese (computerized) and Malay (paper and pencil based) version of the Composite International Diagnostic Interview (CIDI) 3.0 to establish lifetime and 12‐month prevalence of mental disorders, the current use of mental health services (both Western and traditional services), the treatment gaps and loss of role functioning. Copyright

Reducing the global burden of acute lower respiratory infections in children: the contribution of new diagnostics

Acute lower respiratory infections (ALRIs) are the primary killer of children in developing countries. Many children with ALRIs are not properly diagnosed, and overuse of antibiotics has led to increasing drug resistance. The introduction of simple and widely accessible diagnostic tests could significantly reduce deaths among children with ALRIs and reduce the inappropriate use of antibiotics.

Rigorous Development does not Ensure that Guidelines are Acceptable to a Panel of Knowledgeable Providers

BACKGROUNDRigorous guideline development methods are designed to produce recommendations that are relevant to common clinical situations and consistent with evidence and expert understanding, thereby promoting guidelines’ acceptability to providers. No studies have examined whether this technical quality consistently leads to acceptability.OBJECTIVETo examine the clinical acceptability of guidelines having excellent technical quality.DESIGN AND MEASUREMENTSWe selected guidelines covering several musculoskeletal disorders and meeting 5 basic technical quality criteria, then used the widely accepted AGREE Instrument to evaluate technical quality. Adapting an established modified Delphi method, we assembled a multidisciplinary panel of providers recommended by their specialty societies as leaders in the field. Panelists rated acceptability, including “perceived comprehensiveness” (perceived relevance to common clinical situations) and “perceived validity” (consistency with their understanding of existing evidence and opinions), for ten common condition/therapy pairs pertaining to Surgery, physical therapy, and chiropractic manipulation for lumbar spine, shoulder, and carpal tunnel disorders.RESULTSFive guidelines met selection criteria. Their AGREE scores were generally high indicating excellent technical quality. However, panelists found 4 guidelines to be only moderately comprehensive and valid, and a fifth guideline to be invalid overall. Of the topics covered by each guideline, panelists rated 50% to 69% as “comprehensive” and 6% to 50% as “valid”.CONCLUSIONDespite very rigorous development methods compared with guidelines assessed in prior studies, experts felt that these guidelines omitted common clinical situations and contained much content of uncertain validity. Guideline acceptability should be independently and formally evaluated before dissemination.

A Prospective Validation Study of a Rainbow Model of Integrated Care Measurement Tool in Singapore

Introduction: The conceptual ambiguity of the integrated care concept precludes a full understanding of what constitutes a well-integrated health system, posing a significant challenge in measuring the level of integrated care. Most available measures have been developed from a disease-specific perspective and only measure certain aspects of integrated care. Based on the Rainbow Model of Integrated Care, which provides a detailed description of the complex concept of integrated care, a measurement tool has been developed to assess integrated care within a care system as a whole gathered from healthcare providers’ and managerial perspectives. This paper describes the methodology of a study seeking to validate the Rainbow Model of Integrated Care measurement tool within and across the Singapore Regional Health System. The Singapore Regional Health System is a recent national strategy developed to provide a better-integrated health system to deliver seamless and person-focused care to patients through a network of providers within a specified geographical region. Methods: The validation process includes the assessment of the content of the measure and its psychometric properties. Conclusion: If the measure is deemed to be valid, the study will provide the first opportunity to measure integrated care within Singapore Regional Health System with the results allowing insights in making recommendations for improving the Regional Health System and supporting international comparison.