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Nelson HD, Haney EM, Chou R, et al. Screening for Osteoporosis: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Jul. (Evidence Syntheses, No. 77.)

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Screening for Osteoporosis: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation [Internet].

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2Methods

Key Questions and Analytic Framework

Based on evidence gaps identified from the previous review and using the methods of the USPSTF,33–35 the USPSTF and Agency for Healthcare Research and Quality (AHRQ) developed Key Questions for this review. Investigators created an analytic framework incorporating the Key Questions and outlining the patient populations, interventions, outcomes, and harms of the screening process (Figure 1). The target populations include postmenopausal women and men age >50 years without known previous osteoporosis-related fragility fractures or secondary causes of osteoporosis.

Figure 1. Analytic Framework and Key Questions.

Figure 1

Analytic Framework and Key Questions. KEY QUESTIONS Does screening for osteoporosis and low bone density reduce osteoporosis-related fractures and/or fracture-related morbidity and mortality in: Women Postmenopausal women younger than age 60 years. (more...)

Key Questions include:

  1. Does screening for osteoporosis and low bone density reduce osteoporosis-related fractures and/or fracture-related morbidity and mortality in the target populations? These include postmenopausal women (age <60 years, 60–64 years at increased risk for osteoporotic fractures, 60–64 years not at increased risk for osteoporotic fractures, and ≥65 years) and men >50 years.
  2. What valid and reliable risk-assessment instruments stratify women and men into risk categories for osteoporosis or fractures?
    1. How well does DXA predict fractures in men?
    2. How well do peripheral bone measurement tests predict fractures?
    3. What is the evidence to determine screening intervals for osteoporosis and low bone density?
  3. What are the harms associated with osteoporosis screening?
  4. Do medications for osteoporosis and low bone density reduce osteoporosis-related fracture rates and/or fracture-related morbidity and mortality in the target populations?
  5. What are the harms associated with medications for osteoporosis and low bone density?

Harms of screening include consequences of false-positive and false-negative tests, patient anxiety and other psychosocial responses, unnecessary treatment, as well as adverse outcomes from medications.

Two additional Contextual Questions are also included. Contextual Questions are addressed as a narrative, not systematic, review of relevant studies. Their purpose is to provide background information for determining recommendations:

  1. What is the validity and reliability of T-score test results as they relate to ethnic minorities? (No studies addressed this question.)
  2. What are emerging therapies for treatment of osteoporosis and low bone density that reduce fracture risk? (This information is included in the Introduction.)

Search Strategies

We searched the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the 4th Quarter 2009), and MEDLINE (January 2001 to December 2009) for relevant studies and systematic reviews. Search strategies and additional details are described in Appendix B1. We also conducted secondary referencing by manually reviewing reference lists of key papers and searching citations using Web of Science.36

Study Selection

We selected studies on the basis of inclusion and exclusion criteria developed for each key question (Appendix B2). Appendix B3 shows the results of our literature search and selection process. Studies excluded after review of the full-text articles, and reasons for their exclusion, are listed in Appendix B4.

We included randomized controlled trials (RCTs) with fracture or fracture-related morbidity and mortality outcomes to determine the effectiveness of osteoporosis screening and studies of any design to determine harms from screening.

To determine the accuracy and clinical applicability of risk-assessment instruments, we included studies of externally validated instruments that reported performance characteristics. Instruments were included if they were derived from an initial population and then tested in a separate population; derived from computer modeling, consensus, or another study, and then tested in a novel population; or derived from any source and tested against T-scores or actual fracture rates in a population. We did not include internally validated measures (imputation methods or cross-validation) in the final tables. To determine the performance of bone measurement tests in predicting fractures, we limited studies to existing systematic reviews and technology assessments of procedures currently used in U.S. practice and large population-based studies relevant to primary care settings. We included any studies providing data about screening intervals.

To evaluate the efficacy and harms of medications to reduce fractures in a screening-detected population, we included RCTs and meta-analyses of RCTs that reported fracture and fracture-related outcomes and adverse effects for medications used in the United States. Outcomes included specific types of fractures; fracture-related morbidity, including loss of function, pain, quality of life, and other reported health outcomes; and fracture-related mortality. We excluded non-drug therapies because they are addressed in other reviews for the USPSTF (calcium, vitamin D, exercise, fall prevention) and combination therapies. We focused on trials that enrolled patients without known prior osteoporosis-related fragility fractures, such as vertebral compression or hip fractures, and without known secondary causes for osteoporosis, because this population is most relevant to screening. We defined primary prevention trials as studies that met one of the following criteria:

  1. Trial excluded individuals with previous vertebral or other presumably osteoporotic fractures.
  2. Trial permitted individuals with previous osteoporotic fractures, but the overall proportion of participants with fractures was <20 percent, or the trial reported results separately for participants with and without previous fractures. We considered trials meeting this criterion to be applicable to primary prevention based on epidemiologic data.37
  3. Trial did not report the proportion of participants with previous osteoporotic fractures, but inclusion criteria did not select individuals on the basis of presence of a previous fracture, and mean BMD T-scores were ≥−3.0. This threshold was selected because placebo-controlled trials that enrolled >20 percent of women with previous fractures reported mean baseline BMD T-scores <−3.0.38–41

We determined harms from good- and fair-quality systematic reviews that pooled primary and secondary prevention trials after verifying data abstraction and statistical analyses, and large controlled observational studies. For osteonecrosis of the jaw, we included systematic reviews summarizing evidence from case reports and series.

Data Abstraction and Quality Rating

We abstracted details about the patient population, study design, analysis, follow-up, and results. By using predefined criteria developed by the USPSTF,33 two investigators rated the quality of studies (good, fair, poor) and resolved discrepancies by consensus. We assessed the overall strength of the body of evidence for each key question (good, fair, poor) by using methods developed by the USPSTF on the basis of the number, quality, and size of studies; consistency of results between studies; and directness of evidence (described in Appendices B5, B6, and B7).33

Data Synthesis and Analysis

We pooled results of primary prevention trials of bisphosphonates for various fracture outcomes (vertebral, nonvertebral, hip, wrist, and ankle) using the random effects Mantel-Haenszel method in Review Manager (RevMan) Version 5.0 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). We chose the random-effects model because of differences in study participant characteristics such as baseline BMD, proportion of participants with previous fractures, and risk factors for osteoporosis. We also stratified results by type of bisphosphonate if sufficient data for pooling were available. For trials that evaluated several doses, we focused on outcomes for doses similar to those currently recommended in the package inserts approved by the FDA.

Sensitivity Analysis

Several trials included in the meta-analyses reported few, rare, or zero fracture events. The primary analyses excluded trials with zero events in both groups, resulting in loss of data, and applied a constant continuity correction of 0.5 for trials with zero events in one group, potentially biasing inferences.42, 43 In addition, the random-effects Mantel-Haenszel method we used may be unsuitable when events are rare.42 We therefore conducted sensitivity analyses to determine the effects of alternate pooling methods on estimates using the Peto odds ratio (OR), fixed-effects Mantel-Haenszel method with an alternative continuity correction (inverse of the sample size of the opposite treatment group), and the pooled arcsine difference with and without zero event trials.43, 44

We assessed statistical heterogeneity with the I2 statistic, and when present, we assessed effects of dose and duration of trials on results. We also assessed the effects of methodologic quality on the basis of our ratings using predefined criteria as described above.

To determine if baseline BMD affected results, we conducted an analysis that stratified trials according to the mean baseline BMD (T-score <−2.0 versus >−2.0). For trials that did not report mean baseline T-scores, we calculated them from mean baseline BMD at the femoral neck by using the FRAX Patch program (FRAX Patch version 1.4, Oregon Osteoporosis Center, Portland, Oregon). We verified that in trials that reported mean baseline T-scores and BMD, reported T-scores were similar to results by using FRAX Patch. If femoral neck BMD was not reported, we used baseline total hip BMD. The FRAX Patch program includes adjustments according to densitometer manufacturer. If the manufacturer was not reported, we calculated T-scores for all three manufacturers included in the FRAX Patch and averaged the scores.

To determine if our criteria for selecting primary prevention trials affected results, we conducted sensitivity analyses on fracture estimates that included trials that enrolled up to 40 percent of participants with previous vertebral fractures, or did not report baseline vertebral fracture rates and reported a baseline BMD T-score <−3.0.38, 40, 45–48

Outcomes Table and Screening Strategies

To estimate the effect of screening 10,000 postmenopausal women with DXA for primary fracture prevention, we created an outcomes table on the basis on assumptions from the reviewed studies. Although these calculations have important limitations and underestimate the uncertainty in the evidence, they provide an illustration of the clinical application of the evidence and may be useful to clinicians and the USPSTF. Data include age-specific prevalence rates expressed in 5-year intervals,49 and treatment effects based on results of the Fracture Intervention Trial (FIT) for women without previous vertebral fractures with T-scores ≤−2.5.50

To determine the influence of risk factors in selecting women for densitometry screening, we estimated10-year risks for major osteoporotic and hip fractures for U.S. white women by using the online FRAX calculator (http://www.shef.ac.uk/FRAX/).51 By using risk estimates for 65-year-old women aged ≥65 years with no additional risk factors as the reference case, we identified age- and risk factor-specific categories of women with similar or higher risk estimates.

Review of Draft

The draft report was reviewed by content experts listed in Appendix B8, USPSTF members, AHRQ Project Officers, and collaborative partners.

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