in progress

Draft Research Plan

Osteoporosis to Prevent Fractures: Screening

August 12, 2021

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

This figure is an analytic framework depicting the key questions (KQs) within the context of the populations, interventions, comparisons, outcomes, time frames, and settings (PICOTS) relative to the effectiveness and harms of screening and treatment for osteoporosis. The figure illustrates the relationship between osteoporosis for adults in primary care settings without known osteoporosis or history of fragility fractures. KQ1 concerns the direct pathway of the relationship between screening and risk assessment and reduced fracture-related morbidity and mortality. On the indirect pathway, the population is shown as being at an increased risk or not at an increased risk based on screening with DXA at a central site or standardized clinical risk assessment tools, or a two-step process using both methods (KQ2). The harms of screening are assessed for the whole population undergoing screening (KQ3). If the population is not at increased risk, the pathway stops. For those at an increased risk, the benefits (KQ 4) and harms (KQ 5) of treatment are assessed relative to fracture-related morbidity and mortality outcomes.

Abbreviation: DXA=dual energy X-ray absorptiometry.

1.  Does screening for fracture risk or osteoporosis reduce fractures and fracture-related morbidity and mortality in adults?
2a. What is the predictive accuracy of risk assessment tools for identifying adults who are at increased risk for hip fractures and major osteoporotic fractures?
2b. What is the predictive accuracy of bone mineral density testing with dual X-ray absorptiometry at central skeletal sites for identifying adults who are at increased risk for hip or major osteoporotic fractures?
2c.  What is the diagnostic accuracy of risk assessment tools for identifying adults with osteoporosis?
2d.  What is the evidence to determine screening intervals, and how do these vary by baseline fracture risk?
3.  What are the harms of screening for fracture risk or osteoporosis?
4.  What is the effectiveness of pharmacotherapy with selected Food and Drug Administration (FDA)–approved medications on fracture incidence and fracture-related morbidity and mortality?
5.  What are the harms associated with selected FDA-approved medications?

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

  1. What is the evidence from modeling studies about the effectiveness of risk-screening strategies that use different ages at which to start and stop screening and different screening intervals?
  2. How do various fracture risk assessment tools use race and ethnicity in fracture risk calculations?
  3. What is the incidence of fragility fractures among persons of different races and ethnicities in the United States in the last 10 to 15 years, and what factors might explain differences in incidence among different races and ethnicities?
  4. What are the differences in rates of screening or treatment initiation among persons of different races and ethnicities, and what might explain these differences?
  5. What are the implications of using fixed fracture-risk thresholds for decisions regarding stepwise screening or treatment?
  Included Excluded
Population KQs 1–3 (Screening benefits, accuracy, harms): Adults age 40 years or older without known osteoporosis or history of fragility fractures

KQs 4, 5 (Treatment benefits and harms): Adults age 40 years or older with osteoporosis, osteopenia, or increased fracture risk (as defined by study authors)

Studies where less than 50% of the enrolled population includes persons with conditions or medications listed as exclusion criteria will be included, and results will be stratified if possible.

All KQs: Studies that exclusively enroll adults younger than age 40 years

KQs 1–3: Studies that exclusively enroll

  • Adults with known osteoporosis or prior history of fragility fracture
  • Adults with cancer, metabolic bone diseases, or medical conditions associated with bone loss, including hyperparathyroidism, premature ovarian failure, hypogonadism, untreated hyperthyroidism, acromegaly, adrenal insufficiency, Cushing’s syndrome, celiac disease, inflammatory bowel disease, history of gastric bypass surgery, anorexia, chronic liver disease, multiple myeloma, chronic kidney disease, rheumatoid arthritis, and lupus
  • Adults taking chronic medications associated with bone loss, including glucocorticosteroids, select antiepileptic medications, hypogonadism-inducing agents (e.g., aromatase inhibitors, medroxyprogesterone acetate, gonadotropin-releasing hormone agonists), thiazolidinediones, calcineurin inhibitors, and antiretroviral therapy
KQs 4, 5: Majority of the population with secondary osteoporosis because of underlying medical condition or chronic use of a medication associated with bone loss or with prior fragility fracture
Screening Interventions KQs 1–3 (Screening benefits, accuracy, and harms):
  • FRA that has been evaluated in at least two independent cohorts external to the development cohort (unless males are included, then only one independent cohort external to the development cohort is required)
  • DXA measurement of BMD at the femoral neck (T-scores based on NHANES III reference range) or lumbar spine (local reference range)
  • A combination of FRA and DXA together or in sequence (e.g., two-step approach)


  • FRAs that are not publicly available
  • Studies of FRAs using split sample validation
  • Fall risk assessments
  • FRA using risk factors not readily available or feasible within primary care settings
  • Quantitative ultrasound
  • Quantitative CT
  • Magnetic resonance imaging
  • Trabecular bone score
  • Vertebral fracture assessment
  • DXA measured at peripheral skeletal sites (e.g., wrist, heel)
  • DXA measured at central skeletal sites but hip T-scores based on local reference ranges
  • Bone turnover biomarkers
  • Finite element analysis
  • Hip structural analysis
  • Opportunistic screening for osteoporosis on images taken for other indications (e.g., dental X-rays, abdominal CT)
Screening Comparators KQs 1, 3 (Screening benefits and harms):
  • No screening
  • FRA or BMD or both screening but no results shared with patient or their primary care provider

KQ 2 (Accuracy):

  • For predictive accuracy: Observed 10-year fracture incidence from nationally representative and verified sources
  • For diagnostic accuracy: DXA-measured BMD at the femoral neck (T-scores based on NHANES III reference range) or lumbar spine


KQs 1, 3:
  • No control group
  • Another screening strategy (active comparator)
KQ 2: Any comparator not specifically identified as included
Treatment Interventions KQs 4, 5 (Treatment benefits and harms): Bisphosphonates with FDA-approved indications for the prevention or treatment of osteoporosis (i.e., alendronate, ibandronate, risedronate, zoledronic acid), denosumab

Males only: teriparatide, abaloparatide, and romosozumab are also eligible

KQs 4, 5:
  • Bisphosphonates that do not have FDA-approved indications for the prevention or treatment of osteoporosis (e.g., etidronate)
  • Estrogen (with or without progesterone), raloxifene, or bazedoxifene
  • Females only: teriparatide, abaloparatide, or romosozumab
  • Medications that are sometimes used off-label to treat osteoporosis (e.g., testosterone, tamoxifen)
  • Treatments that are no longer used in practice or that have been recalled, specifically calcitonin and parathyroid hormone 1-84
  • Vitamin D or calcium supplements alone; these are considered adjuncts to treatment
  • Dietary supplements
  • Nonpharmacologic treatments (e.g., exercise, fall risk prevention interventions)
Treatment Comparators KQs 4, 5 (Treatment benefits and harms): Placebo, vitamin D or calcium or both, no treatment
  • Active drug comparators
  • Nonpharmacologic interventions (e.g., exercise)
Outcomes KQs 1, 4 (Screening and treatment benefits):
  • All-cause mortality
  • Fracture-related mortality
  • Fractures (all-cause, hip, major osteoporotic fractures*, clinical vertebral fractures, any clinical fragility fractures)
  • Fracture-related morbidity (e.g., disability)

KQ 2 (Accuracy):

  • Predictive accuracy: calibration outcomes (observed vs. expected ratio, calibration slope, calibration plot, Hosmer-Lemeshow goodness-of-fit, gradient of risk [risk ratio per standard deviation change in risk score]), overall prediction model performance (e.g., Brier score, explained variation [R2])
  • Discrimination outcomes (c-statistic, discrimination slope, sensitivity, specificity, area under the curve)

KQ 3 (Screening harms):

  • Overdiagnosis
  • Unnecessary treatment from inaccurate risk prediction
  • Radiation exposure
  • Anxiety from labeling

KQ 5 (Treatment harms):

  • Total adverse events
  • Total serious adverse events
  • Specific serious adverse events (osteonecrosis of the jaw, atypical femur fractures, incident gastrointestinal cancer, serious gastrointestinal events, rebound fractures after discontinuing treatment)
  • Discontinuations because of adverse events
KQs 1, 4:
  • Radiographic (i.e., morphometric) vertebral fractures
  • Fractures based on patient self-report without verification/confirmation
  • BMD
  • Other outcomes not specifically identified as included

KQs 2, 3, 5: Outcomes not specifically identified as included

Timing KQs 1, 4 (Screening and treatment benefits): Followup for at least 1 year

KQ 2 (Accuracy): For predictive accuracy, observed fracture incidence in calibration population over at least 10 years. For diagnostic accuracy, no longer than 8 weeks between FRA and BMD measurement.

KQs 3, 5 (Screening and treatment harms): Any length of followup
KQs 1, 4: Followup less than 1 year

KQ 2: For predictive accuracy, observed fracture incidence less than 10 years. For diagnostic accuracy, more than 8 weeks between risk assessment and BMD measurement.

Study Design KQs 1, 3 (Screening benefits and harms): RCTs, clinical controlled trials, or systematic reviews of RCTs or controlled trials. Cohort studies and systematic reviews of cohort studies are also eligible for KQ 3 only.

KQ 2 (Accuracy): Recent (published in the last 5 years) systematic reviews of cohort or test accuracy studies, cohort studies designed for evaluating predictive accuracy (i.e., prognosis for fracture risk) or diagnostic accuracy (for identification of osteoporosis), comparative studies where a single group is treated as a cohort for purposes of evaluating predictive or diagnostic accuracy are also eligible

KQs 4, 5 (Treatment benefits and harms): RCTs and controlled trials; large, controlled cohort studies are also eligible for KQ 5 only
Case series; case reports; case-control studies; conference abstracts, posters, or proceedings without data or information available to assess risk of bias; unpublished data; editorials; commentaries; narrative reviews
Settings KQs 1, 3, 4, 5 (Screening and treatment benefits and harms): Primary care settings in countries designated as “very high” on the 2020 Human Development Index (as defined by the United Nations Development Programme)

KQ 2 (Accuracy): Predictive accuracy: United States or countries with similar hip fracture incidence as the United States for synthesis of any primary research studies

KQs 1, 3, 4, 5: Long-term care settings such as nursing homes, inpatient settings

KQs 1, 3: Specialty medical settings (e.g., endocrinology, rheumatology)

KQ 2: Predictive accuracy: studies in single countries with high or low fracture incidence
Study Quality Good or fair quality as determined by standard risk of bias instruments and existing USPSTF criteria tailored to study design Poor quality

* Major osteoporotic fracture is typically defined as fractures of the hip, wrist, and humerus and clinical vertebral fractures.
† Countries with “moderate” hip fracture incidence in addition to the United States include Finland, France, Canada, New Zealand, Lithuania, Malaysia, South Korea, Portugal, Japan, Israel, Australia, Russia, The Netherlands, Kuwait, Spain, Mexico, Estonia, Poland, Chile, and Thailand.1

Abbreviations: BMD=bone mineral density; CT=computerized tomography; DXA=dual-energy X-ray absorptiometry; FDA=Food and Drug Administration; FRA=fracture risk assessment; KQ=key question; NHANES=National Health and Nutrition Examination Survey; RCT=randomized, controlled trial; USPSTF=U.S. Preventive Services Task Force.

1. Kanis JA, Oden A, McCloskey EV, et al. A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporos Int. 2012;23(9):2239-56. doi: 10.1007/s00198-012-1964-3. PMID: 22419370.