Martha Timmer

Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis

Context Sorting through the proven benefits and harms of the agents available for treating osteoporosis is difficult. Contribution This systematic review of 76 randomized trials and 24 meta-analyses found good evidence that multiple agents, including alendronate, zoledronic acid, and estrogen, prevented vertebral and hip fractures more than placebo. Harms included increased risk for thromboembolic events with raloxifene, estrogen, and estrogenprogestin and increased gastrointestinal symptoms with bisphosphonates. No large trials directly compared 2 or more agents and established superiority of any agent. Implication Available data insufficiently characterize the benefits and harms of various therapies for osteoporosis relative to one another. The Editors Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture (1). Approximately 44 million people in the United States are affected by osteoporosis and low bone mass (2). The clinical complications include fractures, disability, and chronic pain. About 54% of women age 50 years or older will have an osteoporotic fracture during their lifetime (3). Furthermore, approximately 4% of patients older than 50 years of age who have a hip fracture die while in the hospital and 24% die within 1 year after the hip fracture (4). The economic burden of osteoporosis is large and growing. Most estimates are based on the cost of fracture alone: A 1995 estimate of costs incurred by osteoporotic fractures in the United States was

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13.8 billion (5). A 2003 review estimated the total costs in the United States at

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17 billion (6). Although the bulk of these costs were incurred by retired individuals older than age 65 years, direct costs and work loss are significant among employed postmenopausal women (7). The increasing prevalence and cost of osteoporosis have heightened interest in the efficacy and safety of the many agents available to treat the loss of bone mineral associated with osteoporosis. This systematic review, developed under the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care Program, describes the benefits in fracture reduction and the harms from adverse events among and within the various classes of pharmacotherapies for osteoporosis. The agents evaluated were bisphosphonates (alendronate, etidronate, ibandronate, pamidronate, risedronate, and zoledronic acid), calcitonin, estrogen, teriparatide, selective estrogen receptor modulators (raloxifene and tamoxifen), testosterone, and vitamins (vitamin D) and minerals (calcium). Methods We followed a standardized protocol for the review. The full technical report (8) provides detailed methods, evidence tables, and risk estimates for individual studies. The full report also enumerates studies included in the meta-analyses described in this review. Data Sources and Study Selection We searched MEDLINE (1966 to December 2006), the ACP Journal Club database, the Cochrane Central Register of Controlled Trials (no date limits), the Cochrane Database of Systematic Reviews (no date limits), and the Web sites of the National Institute for Health and Clinical Excellence (no date limits) and Health Technology Assessment Programme (January 1998 to December 2006) for materials pertaining to the specified agents, limiting our searches to English-language publications and human studies. We first identified systematic reviews and meta-analyses of trials that reported pooled estimates of the effect of the agents on fracture risk. When such reviews were identified for specific agents, we truncated our searches for randomized trials to include only those published after the last search date used in the review or meta-analysis. We manually searched reference lists of all review articles obtained for any reports of original research not already identified, and we reviewed U.S. Food and Drug Administration (FDA) medical and statistical reviews, scientific information packets from pharmaceutical companies, and additional studies recommended by our technical expert panel and by stakeholders during a public review period. To supplement the information in systematic reviews on estrogen, we reviewed the Womens Health Initiative and Heart and Estrogen/progestin Replacement Study trials, as suggested by our technical expert panel. Finally, we conducted an additional search for large observational studies that reported any of the following adverse events: 1) cardiovascular events (myocardial infarction and stroke); 2) thromboembolic events (pulmonary embolism and venous thromboembolic events); 3) malignant conditions (breast cancer, colon cancer, lung cancer, and osteosarcoma); 4) upper gastrointestinal events (perforations, ulcers, bleeding, and esophageal ulcerations); and 5) osteonecrosis. The search was updated for this paper, but not for the full report, by searching MEDLINE (1 January 2007 to 10 November 2007) for large clinical trials that reported fracture outcomes for the specified agents. For information on efficacy, we selected meta-analyses that reported pooled risk estimates for fracture and randomized trials that compared any of the agents with placebo or with each other and reported fracture outcomes. For information on harms, we selected systematic reviews, randomized trials, and large casecontrol or cohort studies with more than 1000 participants. We also reviewed cases of osteonecrosis at AHRQs request. Data Extraction and Study Quality Two physicians independently abstracted data about study populations, interventions, follow-up, and outcome ascertainment by using a structured form. For each group in a randomized trial, a statistician extracted the sample size and number of persons who reported fractures. Two reviewers, under the supervision of the statistician, independently abstracted information about adverse events. Disagreements were resolved by the statistician or the principal investigator. Adverse events were recorded onto a spreadsheet that identified numbers of participants in each trial group and the description of the adverse event as listed in the original article. Each event was counted as if it represented a unique individual. Because an individual may have experienced more than 1 event within a category of adverse events (for example, both stroke and myocardial infarction), this assumption may have overestimated the number of people who had an adverse event in that category. If a trial report mentioned a particular type of adverse event but did not report data on it, we did not include the trial in that particular events analysis. In other words, we did not assume an occurrence of zero events unless it was specifically reported as such. By taking this approach, we may have overestimated the number of patients for whom a particular adverse event was observed. We used predefined criteria to assess the quality of systematic reviews and randomized trials, based on internal and external validity assessment detailed in the QUOROM (Quality of Reporting of Meta-Analyses) statement (9), and items related to randomization, blinding, and accounting for withdrawals and dropouts (10, 11). Each element is detailed in appendices to the full report (8). For this review, we characterized the overall strength of evidence for estimating fracture risk as good, fair, or weak on the basis of the characteristics previously described, as well as the number of studies, total number of participants across studies, whether fractures were a primary outcome, reproducibility of results across studies, and precision of the CIs surrounding the point estimates. Evidence was classified as good if the total sample size was greater than 1000, the results across all studies were consistent, and the studies were of high methodological quality. Evidence was classified as fair if results were inconsistent across the studies. The evidence was classified as weak if no studies assessed fracture as a primary outcome, the total sample size across studies was less than 500, and the CIs around the point estimates were wide and crossed null. Data Synthesis and Statistical Analysis Comparisons of interest were single agent versus placebo and single agent versus another agent for agents within the same class and across classes. We also compared estrogenprogestin versus placebo or single drugs. Studies that included either calcium or vitamin D in all study groups were classified as comparisons between the other agents in each group; for example, alendronate plus calcium versus risedronate plus calcium would be classified as alendronate versus risedronate. In this review, we summarize data on vertebral, nonvertebral, and hip fractures; data on total, wrist, and humerus fractures are included in the full report (8). The number of people with at least 1 fracture was our primary outcome of interest. Because fractures rarely occurred and zero events were often observed in at least 1 treatment group, we calculated odds ratios (ORs) by using the Peto method (12). Trials with zero events in both groups have an undefined OR. Because fractures are rare events, the OR approximates the relative risk (RR) for fracture. We combined data from multiple study groups in an individual study to calculate a single OR for comparisons of interest. In these instances, the same outcome had been reported for each group, and the individuals in each group were unique. For example, to develop an OR for the risk for vertebral fractures regardless of dose, we combined the participants in the various dose groups and compared them with those in the placebo group. We conducted the meta-analysis by using StatXact PROCs (Cytel, Cambridge, Massachusetts) for SAS software (SAS Institute, Cary, North Carolina). Recognizing that characteristics of the study population may affect risk for fracture, we defined risk groups to categorize the