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.

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

• 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)

• 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

• No control group
• Another screening strategy (active comparator)

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

• 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)

• Active drug comparators
• Nonpharmacologic interventions (e.g., exercise)

• 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

• 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

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.

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.

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

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