Screening for Osteoporosis in Men: A Systematic Review for an American College of Physicians Guideline

Osteoporosis in men is substantially underdiagnosed and undertreated in the United States and worldwide (1). Looker and colleagues (2), evaluating the Third National Health and Nutrition Examination Survey database in 1997, estimated that between 300000 and 2 million Americans older than age 50 years have osteoporosis and up to 13 million may have low bone mass. A 60-year-old white man has a 25% lifetime risk for an osteoporotic fracture (3), and the consequences of the fracture can be severe. The 1-year mortality rate in men after hip fracture is twice that in women (1). Diagnostic evaluation and treatment of men at high risk for fracture remains low, despite the prevalence of this condition in men (1, 4). Dual-energy x-ray absorptiometry (DXA) is the current gold standard test for diagnosing osteoporosis in people without a known osteoporotic fracture. It is, however, an imperfect test, identifying less than one half of the people who progress to have an osteoporotic fracture. For example, in the Rotterdam Study (5), the sensitivity of DXA-determined osteoporosis was only 44% and 21% in identifying elderly women and men, respectively, who subsequently had a nonvertebral fracture. Clearly, factors other than low bone mass are important in identifying patients at elevated risk for osteoporotic fracture. An increased risk for falling may explain why some factors are identified as risk factors for osteoporotic fractures independent of bone mineral density (BMD) (for example, tricyclic antidepressants) (6). Although imperfect, a strong and graded relationship exists between DXA-determined BMD and future osteoporotic fracture in women and men (7, 8). The Rotterdam Study (7) reported that the incidence of vertebral and hip fracture approximately doubled for every SD decrease in BMD at the lumbar spine and femoral neck, respectively. Furthermore, pharmacologic treatment of men with low DXA-determined BMD has been shown to decrease the risk for subsequent fractures (9). Some organizations have called for universal screening of older men with DXA testing (5, 10). Although these universal DXA screening strategies would probably increase the diagnosis rate of undetected male osteoporosis, such strategies may not be cost-effective in all men. Schousboe and colleagues (11) recently reported that universal screening would probably be cost-effective only in men age 80 years or older, although this result was sensitive to the cost of treatment. In addition, DXA is not portable, requires a special technician, and is not readily available in many locales (5, 1013), and efforts to find a non-DXA test that is suitable for widespread use have not succeeded to date. We conducted a systematic review of the published literature to identify evidence relevant to screening men for osteoporosis. We focused solely on studies concerning the identification of men with risk factors for fracture that may be mediated through low BMD. Recent reviews have summarized the evidence on non-BMD risk factors, including determining who is at increased risk for falls (14) and treatment of persons at elevated risk (15). Our aims were to determine the risk factors for low BMDmediated osteoporotic fracture in men that could be used to help select patients for BMD testing and whether non-DXA screening tests could be reliably used to diagnose DXA-defined osteoporosis. Methods Search Strategy and Study Selection We searched MEDLINE from 1990 through July 2007 to find articles relevant to risk factors for low BMD and osteoporotic fracture and screening tests for male osteoporosis (Table 1). In addition to our MEDLINE search, we performed reference mining of retrieved articles and previous reviews and solicited articles from experts. Table 1. Search Strategy To be included in our review, a study had to measure risk factors for low BMD or osteoporotic fracture in men or compare a non-DXA index screening test with a gold standard reference test in men (DXA or, for calcaneal ultrasonography, fracture occurrence). Eligible risk factors were judged to be mediated through low BMD on the basis of published literature or expert opinion. Eligible study designs included controlled clinical trials, cohort studies and case series, casecontrol studies, and systematic reviews or meta-analyses. We excluded case reports, nonsystematic reviews, letters to the editor, and other similar publications. Four trained researchers (working in pairs) reviewed the list of titles and selected articles for further review. They reviewed each retrieved article with a brief screening form that collected data on demographic characteristics, study design, and clinical outcomes. Data Abstraction Two physicians independently abstracted data and resolved differences by repeated review. For studies evaluating the performance of osteoporosis screening tests, a statistician extracted sensitivity, specificity, and their SEs at the relevant quantitative ultrasonography or questionnaire threshold. We calculated the SEs of sensitivity and specificity for studies that did not report them (16). If the sensitivity or specificity was not reported in a study and if they could not be calculated from the given data, we excluded the study from quantitative analysis. We contacted the original authors of some studies to obtain the sample sizes per group needed to perform this calculation. Quality Assessment To evaluate the quality of the included diagnostic studies, we evaluated for potential sources of bias. Our quality appraisal included components from the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) evaluation tool (17) and additional quality variables noted as important in other published studies (11). The QUADAS tool is a 14-item questionnaire that evaluates the bias, data variability, and quality of reporting in diagnostic accuracy studies (18). Data Synthesis For studies of risk factors for low BMDmediated osteoporotic fracture, we identified a meta-analysis and summarized the results. We assessed the study by using the Overview Quality Assessment Questionnaire (19) and judged it to be of sufficiently high quality and acceptable to use the results. We summarized studies published after this meta-analysis and presented them narratively. For studies of non-DXA screening tests that met inclusion criteria and were clinically appropriate, we reviewed test thresholds for determining osteoporosis across studies to see whether they were comparable and evaluate whether statistical pooling was appropriate. This analysis revealed these studies to be too heterogeneous for statistical pooling. Therefore, where data were available, we abstracted information on the sensitivity and specificity of the screening tests and graphed the data points of studies evaluating the same screening method on receiver-operating characteristic (ROC) curves (20). Rating the Body of Evidence We assessed the overall quality of evidence for outcomes by using a method developed by the Grading of Recommendations, Assessment, Development, and Evaluation group (GRADE) (21), which classifies the grade of evidence across outcomes (Table 2). Table 2. GRADE Categories of Quality of Evidence Role of the Funding Source The U.S. Department of Veterans Affairs Health Services Research and Development Evidence Synthesis Activity Pilot Program provided funding. The funding source was involved in development of the key questions and provided review on a draft version of the evidence report, but it had no role in the decision to submit the manuscript for publication. Results Literature Flow Our initial literature search identified 614 titles (Figure 1): 540 from the electronic search, 69 from reference mining, and 5 from content experts. Of these, 177 assessed risk factors for low BMDmediated osteoporotic fracture and 20 evaluated screening tools for osteoporosis. The studies that addressed screening tools for osteoporosis enrolled a total of 28359 participants (2248). Table 3 shows details of these screening studies. Figure 1. Study flow diagram. Some articles assessed multiple risk factors. A total of 614 titles were identified for review; 20 articles evaluated male osteoporosis screening tools and were included in the analysis. BMD = bone mineral density; PSA = prostate-specific antigen. Table 3. Characteristics of NonDual-Energy X-Ray Absorptiometry Osteoporosis Screening Tests Risk Factors for Low BMDMediated Fracture We identified a systematic review and meta-analysis by Espallargues and colleagues (49) of risk factors for low BMDmediated osteoporotic fracture to guide bone densitometry assessments. Espallargues and colleagues searched several databases up to 1997 and identified 94 cohort studies, 72 casecontrol studies, and 1 randomized clinical trial. Most studies were performed in participants older than age 50 years and used American or European study populations. Where feasible, the authors used fixed-effects methods to provide meta-analytic pooled estimates of risk. They classified risk factors into the following groups: high risk, an associated relative risk or odds ratio of 2 or greater; moderate risk, risk values of between 1.0 and 2.0; no risk, risk values close or equal to the null value, or even a protective effect; and unclassifiable, data were insufficient to reach a conclusion or contradictory. Strengths of this review include the search strategy and identification of a very large number of articles, categorization of risk factors, and use of meta-analytic techniques to provide summary results. The main limitation is that data specific for men are not presented. The authors performed separate analyses for men and women, found no important differences, and presented results for both sexes combined. The most important high-risk factors relevant to men are age older than 70 years and low body weight (body mass index <20 to 25 m/kg2). Additional important high-risk factors are physical inactivity, corticosteroid use, and prev