Osteoporosis to Prevent Fractures: Screening

The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious related signs or symptoms to improve the health of people nationwide. 

It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment. 

 The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms. 

The USPSTF is committed to mitigating the health inequities that prevent many people from fully benefiting from preventive services. Systemic or structural racism results in policies and practices, including healthcare delivery, that can lead to inequities in health. The USPSTF recognizes that race, ethnicity, and gender are all social rather than biological constructs. However, they are also often important predictors of health risk. The USPSTF is committed to helping reverse the negative impacts of systemic and structural racism, gender-based discrimination, bias, and other sources of health inequities, and their effects on health, throughout its work.

Osteoporosis is a skeletal disorder characterized by decreased bone mass leading to increased bone fragility and fracture risk. Osteoporotic fractures are associated with psychological distress, subsequent fractures, loss of independence, reduced ability to perform activities of daily living, and death. Morbidity from fragility fractures at central skeletal sites, particularly the hip, is much greater than morbidity from fragility fractures at other sites.¹ Evidence shows that only 40% to 60% of persons experiencing a hip fracture recover their prefracture level of mobility and ability to perform activities of daily living.²

The age-adjusted prevalence of osteoporosis is 12.6% among community-dwelling Americans age 50 years or older. Prevalence of osteoporosis is higher among persons age 65 years or older (27.1% in women and 5.7% in men), in women compared with men,³ and among White, Asian, and Hispanic persons.⁴

The U.S. Preventive Services Task Force (USPSTF) concludes with moderate certainty that screening for osteoporosis to prevent osteoporotic fractures in women age 65 years or older has moderate net benefit.

The USPSTF concludes with moderate certainty that screening for osteoporosis to prevent osteoporotic fractures in postmenopausal women younger than age 65 years at increased risk has moderate net benefit.

The USPSTF concludes that the evidence is insufficient and the balance of benefits and harms for screening for osteoporosis to prevent osteoporotic fractures in men cannot be determined.

See Table 1 for more information on the USPSTF recommendation rationale and assessment. For more details on the methods the USPSTF uses to determine the net benefit, see the USPSTF Procedure Manual.⁵

Patient Population Under Consideration

This recommendation applies to adults age 40 years or older without known osteoporosis or history of fragility fractures. It does not apply to persons with secondary osteoporosis due to an underlying medical condition (e.g., cancer, metabolic bone diseases, or hyperthyroidism) or chronic use of a medication (e.g., glucocorticoids) associated with bone loss.

In this recommendation statement, the recommendations are stratified by “men” and “women,” although the net benefit estimates are driven by sex as assigned at birth (i.e., male/female) rather than gender identity. In describing the evidence, sex terms are reported as used by study authors, which is typically “men” and “women.” Transgender men and transgender women who have not undergone any hormonal treatment associated with transitioning likely have the same risks as persons assigned female and male sex at birth; however, they should consult with their clinician to determine which recommendation best applies to them.

Definitions

In 1994, the World Health Organization defined osteoporosis in postmenopausal White women as bone density at the hip or lumbar spine that is 2.5 standard deviations or lower (T-score ≤-2.5) than the mean bone mineral density (BMD) measured at that site for a reference population of young healthy White women.⁶ This ultimately became the reference standard for persons of all racial and ethnic groups, and for males and females.⁷

Fragility fractures (also known as “low-energy” or “low-trauma” fractures) are fractures sustained from a fall from standing height or lower that would not cause a fracture in most healthy persons.⁸

Major osteoporotic fracture (MOF) is defined as a fracture of the hip, spine, wrist, or shoulder. 

Assessment of Risk

Although bone density is an important risk factor for fragility fractures, advancing age is a stronger determinant.⁹ Older adults have much higher fracture rates than younger adults with the same BMD because of concurrent increasing risk from declining bone quality and an increasing risk of falling.¹⁰ When deciding which postmenopausal women younger than age 65 years to screen, the USPSTF recommends first determining the presence of risk factors for osteoporosis and fracture. These include menopausal status, low body weight, parental history of hip fracture, cigarette smoking, and excess alcohol consumption.^11,12 For postmenopausal women younger than age 65 years with one or more risk factors (in addition to postmenopausal status), the USPSTF recommends using a clinical risk assessment tool to estimate risk and help decide whether screening is warranted. More details about risk assessment tools and increased risk are provided in the “Screening Tests and Screening Strategies” section. Other medical conditions and medications (e.g., corticosteroids or diabetes treated with insulin) may also increase risk of osteoporosis and, subsequently, fragility fractures. The prevalence of osteoporosis and incidence of osteoporotic fractures differs among racial and ethnic groups. Studies show lower fracture incidence in Asian, Hispanic, and Black populations compared with White populations among both men and women.^13,14 Differences in BMD alone are not sufficient to explain racial and ethnic differences in fracture incidence. For example, Asian women have been found to have lower BMD than White women but lower fracture risk.^15-17 Although the underlying causes for the differences in fracture incidence among racial and ethnic groups are uncertain, they are likely due in part to social and environmental factors or differences in clinical risks.¹

Screening Tests and Screening Strategies

The most used bone measurement test to screen for osteoporosis is dual-energy X-ray absorptiometry (DXA) at a central site (e.g., total hip, femoral neck, or lumbar spine). Centrally measured DXA correlates with bone strength and clinical fracture outcomes and uses low doses of radiation.¹⁸ Fracture risk at a specific site is best predicted if bone density is measured at that site.¹⁹

Some evidence suggests that BMD alone may not be the most useful predictor of fracture risk, especially in younger populations.²⁰ Several risk assessment tools that incorporate age and sex, with or without other risk factors, have been developed to either identify probability of osteoporosis or predict fracture risk. It is important to note that some of the risk assessment tools were developed on small cohorts of homogeneous populations or have limited published evidence.

Risk assessment tools designed to estimate future fracture risk that can be used with or without BMD as a risk factor input include FRAX,⁸ the Fracture Risk Calculator (FRC),²¹ and the Garvan Fracture Risk Calculator.^22,23 Of note, the predictive accuracy of these tools often improves when BMD is included in the risk assessment calculation.¹ Risk assessment tools designed to identify osteoporosis (e.g., the Osteoporosis Risk Assessment Instrument [ORAI] and the Osteoporosis Self-Assessment Tool [OST]) generally require fewer risk inputs than tools designed to predict fracture risk.¹

FRAX is the most studied fracture risk assessment tool. Country-specific versions of FRAX are available that have been calibrated using country-specific fracture incidence and mortality data, which is part of the FRAX risk calculation.²⁴ As of 2016, FRAX was incorporated into 120 guidelines worldwide and added into DXA software following regulatory approval by the U.S. Food and Drug Administration, and has been incorporated into clinical decision support tools within electronic health record systems.²⁵ FRAX predicts the 10-year probability of hip fracture or MOF for persons ages 40 to 90 years by using demographic and clinical factors alone or in combination with BMD measured at the femoral neck.²⁶ Risks predicted by FRAX alone and by BMD alone are similar, but both are less accurate than risks predicted by FRAX plus BMD.²⁷ In the United States, four different versions of FRAX calibrated using racial- and ethnic-specific fracture incidence data are available, including unique versions for non-Hispanic Caucasian, non-Hispanic Black, Hispanic, and non-Hispanic Asian persons.²⁵ Concerns exist regarding the validity of race-specific FRAX calculators. Because hip fracture incidence in the United States is lower in most non-White racial and ethnic groups, predicted fracture risk estimates for Black, Hispanic, and Asian persons will always be lower than for White persons of the same age, sex, weight, BMD, and clinical risk factors in the FRAX model.^28,29 Additionally, it is unclear what version of FRAX to use for persons who are mixed race, of other races, or immigrants from other countries who are now living in the United States.³⁰ Other limitations of the FRAX instrument include use of binary exposure to glucocorticoids and alcohol use (yes/no vs. quantified dose exposure), lack of use of lumbar spine BMD or trabecular bone score, no information collected about history of falls or frailty, use of cohort studies that are 30 to 40 years old to estimate race-specific fracture incidence, use of mortality estimates that have not been updated since 2004, and lack of inclusion of medical conditions such as diabetes that may portend an increased risk.^25,31,32

Screening strategies vary. Because most fragility fractures occur in persons without osteoporosis (i.e., with DXA T-scores >-2.5), some screening strategies focus on identifying those at risk for fracture and not just those with osteoporosis.²⁵ Results from randomized, controlled trials (RCTs) are now available that evaluated screening strategies using some combination of the FRAX risk calculation and BMD; no published studies have been designed to evaluate a treatment strategy based on fracture risk (i.e., FRAX) alone. Centrally measured DXA was the test used to determine eligibility for participants enrolled in nearly all trials of bone-conserving pharmacotherapies.¹ Therefore, screening can entail DXA with or without fracture risk assessment.

Similarly, approaches to determining whom to screen among postmenopausal women younger than age 65 years could reasonably focus on fracture risk or risk of osteoporosis, using one of several risk assessment tools. Table 2 includes examples of risk assessment tools that have been reported to have reasonable accuracy for identifying osteoporosis (OST or ORAI) or predicting hip fracture (FRAX) in women younger than age 65 years.¹ The risk assessment tools for identifying osteoporosis (OST or ORAI)^33,34 have commonly used thresholds for defining increased risk at which further screening with DXA is suggested (Table 2). For FRAX, there is no such threshold defined with respect to its use in screening. However, to help provide context, a 65-year-old White female with a body mass index (BMI) of 25 mg/kg² and no risk factors has a 10-year risk of hip fracture of 1.3% and a 10-year risk of MOF of 9.3% based on FRAX without BMD input. The USPSTF does not intend that these 10-year risk levels (in the example given) be used as mechanistic thresholds for determining who should receive further screening with DXA. Rather, it is suggested that the results of risk assessment be used to help inform decisions about further screening with DXA.

Screening Intervals

Cohort studies evaluating screening intervals suggest there is no additional accuracy for predicting fractures from repeating BMD testing at an interval of 4 to 8 years.¹ Other studies attempted to identify appropriate screening intervals based on the time in which it takes individuals to transition to osteoporosis or a certain fracture risk threshold. The screening intervals varied across studies, but generally, transition to osteoporosis occurred over shorter intervals for individuals with lower baseline T-scores and older age (e.g., almost 17 years for 10% of women with normal BMD at baseline to develop osteoporosis vs. about 5 years for women with a baseline T-score in the -1.50 to -1.99 range).³⁵

Treatment

The U.S. Food and Drug Administration has approved several drug therapies for the treatment or prevention of osteoporosis, including bisphosphonates, denosumab, romosozumab, parathyroid hormone, raloxifene, calcitonin, and estrogen (with or without progesterone).

Clinicians should be aware that treatment recommendations based on risk assessment tools with race-specific calculators (e.g., FRAX) but that use fixed fracture risk treatment thresholds not specific to race and ethnicity may be less likely to identify Black, Hispanic, and Asian persons as high risk and, subsequently, may be less likely to offer treatment compared with White persons of the same age, BMD, and clinical risk profile. Similarly, prediction models that do not include conditions that increase fracture risk and that disproportionately affect certain racial and ethnic groups (e.g., diabetes) may result in biased underestimates of risk. For these reasons, it may be reasonable to avoid strict application of risk assessment tool treatment thresholds at the individual level to account for additional risks (e.g., fall risk) that are not considered in risk assessment tools like FRAX.^36,37

Suggestions for Practice Regarding the I Statement

When deciding whether to screen for osteoporosis to prevent osteoporotic fractures in men, clinicians should consider the following factors. 

Potential Preventable Burden

Based on National Health and Nutrition Examination Survey data from 2017 to 2018, age-adjusted prevalence of osteoporosis is 12.6% among Americans age 50 years or older. Prevalence is higher in women (19.6%) compared with men (4.4%) and among persons age 65 years or older (27.1% in women and 5.7% in men) compared with persons ages 50 to 64 years (13.1% in women and 3.3% in men).³

Morbidity and mortality resulting from a fragility fracture is the primary concern from having osteoporosis. Based on Medicare data, approximately 1.8 million beneficiaries experienced a new osteoporotic fracture in 2016.³⁸ Although osteoporosis and fragility fractures are more common in women than men, excess mortality related to osteoporosis and fragility fractures is higher in men.^39,40

Men have similar risk factors associated with fragility fractures as women, including increasing age, low BMI, excessive alcohol intake, current smoking, chronic corticosteroid use, history of prior fractures, history of falls within the past year, hypogonadism, history of cerebrovascular accident, and history of diabetes.⁴¹

Potential Harms

Potential harms of screening in men may be similar to those in women. Evidence on harms of drug therapies in men is limited.¹

Current Practice

Data on how frequently men are screened for osteoporosis are limited. Guidelines developed by various organizations and specialty societies vary. Some organizations recommend screening for osteoporosis in men older than age 70 years. Other organizations do not specify for or against screening in men or recommend against it.¹

Additional Tools and Resources

The National Institutes of Health has information on osteoporosis (https://www.niams.nih.gov/health-topics/osteoporosis, https://www.niams.nih.gov/health-topics/osteoporosis/diagnosis-treatment-and-steps-to-take, and https://www.nia.nih.gov/health/osteoporosis/osteoporosis).

Other Related USPSTF Recommendations

The USPSTF recommends exercise interventions to prevent falls in community-dwelling adults age 65 years or older at increased risk of falls and selectively offering multifactorial interventions based on circumstances of prior falls, presence of comorbid medical conditions, and the patient’s values and preferences.⁴² The USPSTF also recommends against supplementation with 400 IU or less of vitamin D and 1,000 mg or less of calcium in postmenopausal women to prevent fractures. The USPSTF found insufficient evidence on supplementation with higher doses of vitamin D and calcium, alone or combined, to prevent fractures in postmenopausal women, or at any dose in men and premenopausal women.⁴³

When final, this draft recommendation will update the 2018 recommendation on screening for osteoporosis. In 2018, the USPSTF recommended screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women age 65 years or older, and in postmenopausal women younger than age 65 years who are at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool.⁴⁴ The current draft recommendation is generally consistent with the 2018 recommendation.

Scope of Review

The USPSTF commissioned a systematic review to evaluate the benefits and harms of screening for osteoporosis to prevent fractures in adults age 40 years or older with no known diagnosis of osteoporosis or history of fragility fracture.¹ This review presents data to update the USPSTF’s 2018 recommendation. The previous recommendation evaluated multiple imaging modalities (e.g., peripheral DXA and quantitative ultrasound); however, this review only reports evidence for central DXA—the most used bone measurement test to screen for osteoporosis.

Accuracy of Screening Tests and Risk Assessment 

BMD

Central DXA measures BMD at central bone sites (hip and lumbar spine) and is the established standard for the diagnosis of osteoporosis. Additionally, centrally measured DXA was the test used for determining T-scores and determining eligibility among participants enrolled in nearly all trials of bone-conserving pharmacotherapies. Still, given that screening trials enrolled participants based on fracture risk, and that the goal of treating osteoporosis is to prevent fracture, the USPSTF reviewed studies that reported on the accuracy of centrally measured BMD for predicting fracture. The USPSTF found 14 studies that reported on the discrimination of BMD alone (as a continuous variable) for predicting MOF. These studies reported areas under the receiver operating curve (AUCs) ranging from 0.60 to 0.80.  Fourteen studies also reported AUCs for predicting hip fracture, which were somewhat more accurate than MOF outcomes, with AUCs ranging from 0.64 to 0.86.¹

Fewer studies reported on the predictive accuracy of BMD in younger women, or men. One study of women ages 45 to 54 years in the United Kingdom reported an AUC for predictive accuracy of continuous BMD at the femoral neck of 0.66 (95% CI, 0.64 to 0.68) over a followup of 3 to 12 years.⁴⁵ One retrospective study exclusively in men age 65 years or older reported an AUC for continuous BMD over a followup of 15.8 years of 0.76 (95% CI, 0.71 to 0.80) for the prediction of MOF and 0.76 (95% CI, 0.721 to 0.81) for the prediction of hip fracture.⁴⁶  

Diagnostic Accuracy of Risk Assessment Instruments

Forty-three unique cohort studies reported on diagnostic accuracy of 15 risk assessment instruments for identifying osteoporosis. More than half of the studies enrolled populations with a mean age between 60 and 69 years, and studies included women, men, or both. In women, AUCs ranged from 0.32 to 0.87 across 35 studies evaluating 11 instruments. In men, AUCs ranged from 0.62 to 0.94 across 18 studies evaluating 12 instruments.¹

The most studied instruments were OST, ORAI, Simple Calculated Osteoporosis Risk Estimation (SCORE), and FRAX. For studies reporting AUCs based on FRAX MOF risk, the AUCs ranged from 0.55 to 0.79; for studies based on FRAX hip fracture risk, AUCs ranged from 0.70 to 0.86. For OST, the reported AUCs for women across 14 studies ranged from 0.64 to 0.81. Six studies reported an AUC for OST of 0.63 to 0.83 in women younger than age 65 years. For ORAI, the reported AUCs for women across 19 studies (excluding one outlier) ranged from 0.32 to 0.84. Five studies reported results in women younger than age 65 years, and the AUCs ranged from 0.60 to 0.82. For SCORE, AUCs across 16 studies ranged from 0.58 to 0.87 (excluding one outlier). For all instruments evaluated, variation in AUC was partly attributable to different risk or score thresholds used to evaluate accuracy across studies.¹

Predictive Accuracy of Risk Assessment Instruments

The USPSTF found four systematic reviews and 14 cohort studies that reported on the accuracy of nine risk assessment models (EPIC, FRAX, FRC, FREM, Garvan, OST, QFracture, SCORE, and the Women’s Health Initiative Prediction Model) to predict MOF, hip fracture, or both using primarily AUC. Findings were heterogeneous, spanning a range of AUCs from 0.54 to 0.89; however, most were between 0.60 and 0.80.  For risk assessment instruments with the option to include BMD as an input (FRAX, FRC, and Garvan), the predictive accuracy often improved when BMD was included compared with when it was not included. Further, some instruments (FRAX, FRC, and QFracture) had higher accuracy for predicting hip fracture than for predicting MOF.¹ For example, in two systematic reviews reviewed by the USPSTF, the AUCs for 10-year risk of MOF for FRAX in women ranged from 0.58 to 0.75 without BMD and from 0.61 to 0.78 when BMD was included, and the AUCs for 10-year risk of hip fracture for FRAX in women ranged from 0.64 to 0.90 without BMD and were similar (0.64 to 0.88) when BMD was included.^47,48

For studies reporting outcomes specifically for women younger than age 65 years, reported AUCs ranged from 0.54 to 0.71 across instruments. For example, for FRAX without BMD, the AUCs for 10-year risk of MOF ranged from 0.56 to 0.59 across three studies,^49-51 and the AUCs for 10-year risk of hip fracture were 0.65 and 0.68 in two analyses reported in one study.⁵⁰ For studies reporting outcomes for men, the AUCs ranged from 0.63 to 0.87.¹

Effectiveness of Early Detection and Treatment

The USPSTF found three RCTs that reported on the effects of screening on clinical fracture outcomes: the Screening in the Community to Reduce Fractures in Older Women (SCOOP) study (N=12,483 randomized),⁵² the Risk-stratified Osteoporosis Strategy Evaluation (ROSE) study (N=34,229 randomized population; N=18,605 per protocol 1 analysis population),⁵³ and the Stichting Artsen Laboratorium en Trombosedienst Osteoporosis Study (SOS) (N=11,032 randomized).⁵⁴ All three RCTs included older European women (median age, 71 to 76 years); racial or ethnicity characteristics were not reported in two of the three trials. The USPSTF found no studies that included men. Two RCTs (SCOOP and ROSE) used a two-step screening intervention consisting of a FRAX risk assessment (without BMD input) on participants assigned to screening and then invited those with a high fracture risk score (≥15% risk for MOF in ROSE; at or above the age-based hip risk threshold in SCOOP) for DXA. The mean or median 10-year FRAX-estimated risk of MOF was 19% in SCOOP, 20% in ROSE, and 24.6% in SOS; the respective 10-year estimated hip fracture risks were 8.5%, 6.7%, and 11.6%, respectively.^52-54 Test results and treatment recommendations were shared with participants’ primary care physicians, who made final decisions about treatment; the comparison group in all three studies was routine care. A pooled analysis of these studies found a statistically significant reduction in hip fractures and MOFs. The pooled relative risk (RR) for the effect of screening on hip fractures was 0.83 (95% CI, 0.73 to 0.93; 3 RCTs; 42,009 participants), and the pooled RR for MOF was 0.94 (95% CI, 0.88 to 0.99; 3 RCTs; 42,009 participants). This corresponded to an absolute risk difference (ARD) of five fewer hip fractures (95% CI, 7 to 2 fewer) and six fewer MOFs (95% CI, 12 to 1 fewer) per 1,000 participants over 3.7 to 5 years.¹

The USPSTF also reviewed evidence on the benefits of treating low bone density. Nineteen RCTs compared bisphosphonates with placebo. Most used T-score thresholds as a criterion to enroll participants, and six of the 19 trials required T-scores in the osteoporotic range. Most trials were conducted among postmenopausal women, one trial was conducted in men, and three trials included a very small proportion of men. The mean age across trials ranged from 53 to 72 years.

The effect of bisphosphonates on vertebral fracture outcomes was reported in nine trials. Studies reported clinical fractures (e.g., hip, wrist, vertebral, and other sites), radiographic vertebral fractures, or both. Four trials compared alendronate with placebo, two compared risedronate with placebo, and three compared zoledronic acid with placebo. The pooled RR was 0.50 (95% CI, 0.39 to 0.66; 9 RCTs; 8,831 participants), corresponding to an ARD of 19 fewer vertebral fractures per 1,000 participants treated (95% CI, 23 to 13 fewer).¹ The effect of bisphosphonates on hip fracture was reported in six trials. Three studies compared alendronate with placebo, two compared risedronate with placebo, and one compared zoledronic acid with placebo. The pooled RR was 0.67 (95% CI, 0.45 to 1.00; 6 trials; 12,055 participants), corresponding to an ARD of three fewer hip fractures per 1,000 participants (95% CI, 5 to 0 fewer).¹

One trial reported on the effectiveness of zoledronic acid in 1,199 men with mean femoral neck T-scores of -2.2. It found a reduced risk of morphometric vertebral fractures in the treatment arm (1.5% vs. 4.6%; RR, 0.33 [95% CI, 0.16 to 0.70]) but no significant difference in nonvertebral fractures (0.9% vs. 1.3%; RR 0.65 [95% CI, 0.21 to 1.97]).⁵⁵

Only one trial (the FREEDOM trial; N=7,808) was powered to look at the effect of denosumab on fracture outcomes. It reported a statistically significant decrease in incident radiographic vertebral fractures (2.3% vs. 7.2%; RR, 0.32 [95% CI, 0.26 to 0.41]), incident clinical vertebral fractures (0.8% vs. 2.5%; RR, 0.31 [95% CI, 0.20 to 0.47]), nonvertebral fractures (6.1% vs. 7.5%; RR, 0.80 [95% CI, 0.67 to 0.95]), and hip fractures (0.7% vs. 1.1%; RR, 0.60 [95% CI, 0.37 to 0.97]) in women randomized to denosumab.⁵⁶ One small study (n=242) investigated the effects of denosumab on BMD in men but was not powered to look at fracture outcomes.⁵⁷ 

Harms of Screening and Treatment

Evidence on the harms of screening for osteoporosis is limited.¹ The SCOOP trial reported no difference in anxiety between screening participants and the control group.⁵²

Several trials reported on the harms of treatment of bisphosphonates. A pooled analysis of 20 RCTs found no significant difference in serious adverse events. One trial reported a statistically significant increase in gastrointestinal adverse events in the treatment arm compared with placebo;⁵⁸ however, a pooled analysis of 26 RCTs found no significantly increased risk of gastrointestinal adverse events in those taking bisphosphonates compared with those taking placebo. Six RCTs that reported on the incidence of atrial fibrillation found no statistically significant increased risk. Three RCTs reporting on incidence of myocardial infarction had very imprecise RR estimates with wide confidence intervals because of small sample sizes and rare events.¹

Although one study of zoledronic acid in men reported a statistically significant increase in incident myocardial infarction (RR, 4.68 [95% CI, 1.02 to 21.5]), this outcome was not statistically significant in two other RCTs. Relative risk estimates were imprecise and confidence intervals were wide in all these studies.¹ One cohort study of zoledronic acid users found no statistically significant differences in atrial fibrillation (adjusted hazard ratio [aHR], 1.18 [95% CI, 0.99 to 1.40]), myocardial infarction (aHR, 0.92 [95% CI, 0.64 to 1.31]), or cardiovascular mortality (aHR, 0.97 [95% CI, 0.81 to 1.15]) but did find a statistically significant increased risk for heart failure (aHR, 1.32 [95% CI, 1.08 to 1.61]), although it did not control for known confounders of heart failure such as BMI, smoking and alcohol exposure, or hypertension.⁵⁹

Osteonecrosis of the jaw and atypical fractures of the femur are potential rare harms of bisphosphonates. Five trials of bisphosphonates reported no cases of osteonecrosis of the jaw, and no trials reported on atypical femur fractures.¹ A cohort study of new users of zoledronic acid reported an increased risk of atypical femur fractures (aHR, 2.46 [95% CI, 1.17 to 5.15]),⁵⁹ and a cohort study of new bisphosphonate users reported an increased risk of atypical femur fractures with bisphosphonate use (aHR, 1.53 [95% CI, 1.36 to 1.73]) over a mean followup of 1 year,⁶⁰ although both studies may have been subject to residual confounding. One systematic review that did not meet inclusion criteria for the current review because no comparator group of non-users was included reported incidence estimates for osteonecrosis of the jaw in individuals using bisphophonates ranging from 0.01% to 0.06%.⁶¹

For denosumab, pooled analyses found no significant increase in serious adverse events (6 RCTs) or upper gastrointestinal adverse events (4 trials), although the confidence intervals were wide for this outcome. Two trials reported no significant increase in cardiovascular events, although the estimate was imprecise in one of these trials. Three trials reported no cases of osteonecrosis of the jaw, and two trials reported no cases of atypical femur fracture.¹

See Table 3 for research needs and gaps related to screening for osteoporosis to prevent fractures.

Several organizations have osteoporosis and fracture risk screening guidelines that vary based on age, gender, menopausal status, and other characteristics. Some organizations recommend a combination of fracture risk assessment and DXA screening. In 2023, the Canadian Task Force on Preventive Health Care recommended screening women age 65 years or older for fracture risk with the Canadian FRAX tool to facilitate shared decision making about pharmacotherapy. If pharmacotherapy is considered, it then recommended ordering DXA testing to re-estimate fracture risk with BMD input into the FRAX. It recommended against screening men age 40 years or older and women younger than age 65 years.⁶² The 2020 American Association of Clinical Endocrinologists guideline recommends evaluating all women age 50 years or older for fracture risk and considering BMD measurement based on clinical fracture risk profile.⁶³

Other guidelines focus on osteoporosis screening via DXA measurement of BMD in older adults. The 2021 American College of Obstetricians and Gynecologists guidelines recommend BMD screening with DXA beginning at age 65 years in all women and selective screening with BMD in women younger than age 65 years who have an elevated risk of osteoporosis based on a formal clinical risk assessment tool.⁶⁴ The American Academy of Family Physicians follows the USPSTF’s 2018 recommendation; however, it specifically recommends against DXA screening in women younger than age 65 years and men younger than age 70 years with no risk factors.^65,66

1. Kahwati LC, Kistler CE, Booth G, et al. Screening for Osteoporosis to Prevent Fractures: An Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 238. AHRQ Publication No. 23-05312-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2024.
2. Dyer SM, Crotty M, Fairhall N, et al; Fragility Fracture Network (FFN) Rehabilitation Research Special Interest Group. A critical review of the long-term disability outcomes following hip fracture. BMC Geriatr. 2016;16(1):58.
3. Sarafrazi N, Wambogo EA, Shepherd JA. Osteoporosis or Low Bone Mass in Older Adults: United States, 2017–2018. NCHS Data Brief No. 45.Hyattsville, MD: National Center for Health Statistics; 2021.
4. QuickStats: percentage* of adults aged ≥50 years with osteoporosis,† by race and Hispanic origin§ – United States, 2017–2018. MMWR Morbid Mortal Wkly Rep. 2021;70(19):731.
5. U.S. Preventive Services Task Force. Procedure Manual. Accessed May 15, 2024. https://www.uspreventiveservicestaskforce.org/uspstf/about-uspstf/methods-and-processes/procedure-manual
6. Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994;843:1-129.
7. International Society for Clinical Densitometry. Indications for Bone Mineral Density (BMD) Testing. Accessed May 15, 2024. https://iscd.org/learn/official-positions/adult-positions
8. Kanis JA; World Health Organization Scientific Group. Assessment of Osteoporosis at the Primary Health Care Level: Technical Report.  Sheffield, United Kingdom: World Health Organization Collaborating Centre for Metabolic Bone Diseases; 2008.
9. Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B. Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int. 2001;12(12):989-995.
10.  Heaney RP. Bone mass, bone loss, and osteoporosis prophylaxis. Ann Intern Med. 1998;128(4):313-314.
11.  Richelson LS, Wahner HW, Melton LJ 3rd, Riggs BL. Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med. 1984;311(20):1273-1275.
12. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med. 1995;332(12):767-773.
13. Liu LH, Chandra M, Gonzalez JR, Lo JC. Racial and ethnic differences in hip fracture outcomes in men. Am J Manag Care. 2017;23(9):560-564.
14. Lo JC, Zheng P, Grimsrud CD, et al. Racial/ethnic differences in hip and diaphyseal femur fractures. Osteoporos Int. 2014;25(9):2313-2318.
15. Lo JC, Chandra M, Lee C, Darbinian JA, Ramaswamy M, Ettinger B. Bone mineral density in older U.S. Filipino, Chinese, Japanese, and White women. J Am Geriatr Soc. 2020;68(11):2656-2661.
16. Donovan Walker M, Babbar R, Opotowsky AR, et al. A referent bone mineral density database for Chinese American women. Osteoporos Int. 2006;17(6):878-887.
17. Lo JC, Kim S, Chandra M, Ettinger B. Applying ethnic-specific bone mineral density T-scores to Chinese women in the USA. Osteoporos Int. 2016;27(12):3477-3484.
18. Expert Panel on Musculoskeletal Imaging; Ward RJ, Roberts CC, Bencardino JT, et al. ACR Appropriateness Criteria® osteoporosis and bone mineral density. J Am Coll Radiol. 2017;14(5s):S189-S202.
19. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet. 2002;359(9321):1929-1936.
20. Sanders KM, Nicholson GC, Watts JJ, et al. Half the burden of fragility fractures in the community occur in women without osteoporosis. When is fracture prevention cost-effective? Bone. 2006;38(5):694-700.
21. Lo JC, Pressman AR, Chandra M, Ettinger B. Fracture risk tool validation in an integrated healthcare delivery system. Am J Manag Care. 2011;17(3):188-194.
22. Nguyen ND, Frost SA, Center JR, Eisman JA, Nguyen TV. Development of prognostic nomograms for individualizing 5-year and 10-year fracture risks. Osteoporos Int. 2008;19(10):1431-1444.
23. Nguyen ND, Frost SA, Center JR, Eisman JA, Nguyen TV. Development of a nomogram for individualizing hip fracture risk in men and women. Osteoporos Int. 2007;18(8):1109-1117.
24. FRAX® Fracture Risk Assessment Tool. Charts to download. Accessed May 15, 2024. https://www.sheffield.ac.uk/FRAX/charts.aspx
25. Fuggle NR, Curtis EM, Ward KA, Harvey NC, Dennison EM, Cooper C. Fracture prediction, imaging and screening in osteoporosis. Nat Rev Endocrinol. 2019;15(9):535-547.
26. Kanis JA, Harvey NC, Johansson H, Odén A, Leslie WD, McCloskey EV. FRAX update. J Clin Densitom. 2017;20(3):360-367.
27. Kanis JA, McCloskey E, Johansson H, Odén A, Leslie WD. FRAX® with and without bone mineral density. Calcif Tissue Int. 2012;90(1):1-13.
28. Dawson-Hughes B, Tosteson AN, Melton LJ 3rd, et al; National Osteoporosis Foundation Guide Committee. Implications of absolute fracture risk assessment for osteoporosis practice guidelines in the USA. Osteoporos Int. 2008;19(4):449-458.|
29. Vyas DA, Eisenstein LG, Jones DS. Hidden in plain sight—reconsidering the use of race correction in clinical algorithms. N Engl J Med. 2020;383(9):874-882.
30. Lewiecki EM, Erb SF. Racial disparities and inequalities in the management of patients with osteoporosis. Orthop Nurs. 2022;41(2):125-134.
31. LeBoff MS, Greenspan SL, Insogna KL, et al. The clinic’an's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2022;33(10):2049-2102.
32. Reid HW, Selvan B, Batch BC, Lee RH. The break in FRAX: equity concerns in estimating fracture risk in racial and ethnic minorities. J Am Geriatr Soc. 2021;69(9):2692-2695.
33. Koh LK, Sedrine WB, Torralba TP, et al; Osteoporosis Self-Assessment Tool for Asians (OSTA) Research Group. A simple tool to identify Asian women at increased risk of osteoporosis. Osteoporosis Int. 2001;12(8):699-705.
34. Cadarette SM, Jaglal SB, Kreiger N, McIsaac WJ, Darlington GA, Tu JV. Development and validation of the Osteoporosis Risk Assessment Instrument to facilitate selection of women for bone densitometry. CMAJ. 2000;162(9):1289-1294.
35.  Gourlay ML, Fine JP, Preisser JS, et al; Study of Osteoporotic Fractures Research Group. Bone-density testing interval and transition to osteoporosis in older women. N Engl J Med. 2012;366(3):225-233.
37. Lewiecki EM, Wright NC, Singer AJ. Racial disparities, FRAX, and the care of patients with osteoporosis. Osteoporos Int. 2020;31(11):2069-2071.
38. Lewiecki EM, Chastek B, Sundquist K, et al. Osteoporotic fracture trends in a population of US managed care enrollees from 2007 to 2017. Osteoporos Int. 2020;31(7):1299-1304.|
39. Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA. 2009;301(5):513-521.
40. Kannegaard PN, van der Mark S, Eiken P, Abrahamsen B. Excess mortality in men compared with women following a hip fracture. National analysis of comedications, comorbidity and survival. Age Ageing. 2010;39(2):203-209.
41. Drake MT, Murad MH, Mauck KF, et al. Clinical review. Rrisk factors for low bone mass-related fractures in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(6):1861-1870.
42. US Preventive Services Task Force. Interventions to prevent falls in community-dwelling older adults: US Preventive Services Task Force recommendation statement. JAMA. Published June 4, 2024.
43. US Preventive Services Task Force. Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: US Preventive Services Task Force recommendation statement. JAMA. 2018;319(15):1592-1599.
44. US Preventive Services Task Force. Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: US Preventive Services Task Force recommendation statement. JAMA. 2018;319(15):1592-1599.
45. Stewart A, Kumar V, Reid DM. Long-term fracture prediction by DXA and QUS: a 10-year prospective study. J Bone Miner Res. 2006;21(3):413-418.
46. Gourlay ML, Ritter VS, Fine JP, et al; Osteoporotic Fractures in Men (MrOS) Study Group. Comparison of fracture risk assessment tools in older men without prior hip or spine fracture: the MrOS study. Arch Osteoporos. 2017;12(1):91.
47. Marques A, Ferreira RJ, Santos E, Loza E, Carmona L, da Silva JA. The accuracy of osteoporotic fracture risk prediction tools: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74(11):1958-1967.
48. Sun X, Chen Y, Gao Y, et al. Prediction models for osteoporotic fractures risk: a systematic review and critical appraisal. Aging Dis. 2022;13(4):1215-1238.
49. Crandall CJ, Larson JC, Watts NB, et al. Comparison of fracture risk prediction by the US Preventive Services Task Force strategy and two alternative strategies in women 50-64 years old in the Women's Health Initiative. J Clin Endocrinol Metab. 2014;99(12):4514-4522.
50. Crandall CJ, Larson J, LaCroix A, et al. Predicting fracture risk in younger postmenopausal women: comparison of the Garvan and FRAX risk calculators in the Women's Health Initiative Study. J Gen Intern Med. 2019;34(2):235-242.
51. Crandall CJ, Larson JC, Schousboe JT, et al. Race and ethnicity and fracture prediction among younger postmenopausal women in the Women’s Health Initiative Study. JAMA Intern Med. 2023;183(7):696-704.
52. Shepstone L, Lenaghan E, Cooper C, et al; SCOOP Study Team. Screening in the community to reduce fractures in older women (SCOOP): a randomised controlled trial. Lancet. 2018;391(10122):741-747.
53. Rubin KH, Rothmann MJ, Holmberg T, et al. Effectiveness of a two-step population-based osteoporosis screening program using FRAX: the randomized Risk-stratified Osteoporosis Strategy Evaluation (ROSE) study. Osteoporos Int. 2018;29(3):567-578.
54. Merlijn T, Swart KM, van Schoor NM, et al. The effect of a screening and treatment program for the prevention of fractures in older women: a randomized pragmatic trial. J Bone Miner Res. 2019;34(11):1993-2000.
55. Boonen S, Reginster JY, Kaufman JM, et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med. 2012;367(18):1714-1723.
56. Cummings SR, San Martin J, McClung MR, et al; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765.
57. Orwoll E, Teglbjærg CS, Langdahl BL, et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab. 2012;97(9):3161-3169.
58. Grey A, Bolland M, Wong S, Horne A, Gamble G, Reid IR. Low-dose zoledronate in osteopenic postmenopausal women: a randomized controlled trial. J Clin Endocrinol Metab. 2012;97(1):286-292.
59. Rubin KH, Möller S, Choudhury A, et al. Cardiovascular and skeletal safety of zoledronic acid in osteoporosis observational, matched cohort study using Danish and Swedish health registries. Bone. 2020;134:115296.
60. Lee YK, Byun DW, Jung SM, et al. Bisphosphonates use and risk of subtrochanteric and diaphyseal femur fractures in Korea: results from the National Claim Registry. Calcif Tissue Int. 2019;104(3):313-319.
61. Anastasilakis AD, Pepe J, Napoli N, et al. Osteonecrosis of the jaw and antiresorptive agents in benign and malignant diseases: a critical review organized by the ECTS. J Clin Endocrinol Metab. 2022;107(5):1441-1460.
62. Thériault G, Limburg H, Klarenbach S, et al; Canadian Task Force on Preventive Health Care. Recommendations on screening for primary prevention of fragility fractures. CMAJ. 2023;195(18):e639-e649.
63. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis—2020 update. Endocr Pract. 2020;26(Suppl 1):1-46.
64. American College of Obstetricians and Gynecologists. Osteoporosis prevention, screening, and diagnosis: ACOG Clinical Practice Guideline No. 1. Obstet Gynecol. 2021;138(3):494-506.
65. American Academy of Family Physicians. Osteoporosis Screening to Prevent Fractures. Accessed May 15, 2024. https://www.aafp.org/family-physician/patient-care/clinical-recommendations/all-clinical-recommendations/osteoporosis.html
66. American Academy of Family Physicians. Choosing Wisely: DEXA for Osteoporosis. Accessed May 15, 2024.  https://www.aafp.org/family-physician/patient-care/clinical-recommendations/all-clinical-recommendations/cw-osteoporosis.html
67. Chen SJ, Chen YJ, Cheng CH, Hwang HF, Chen CY, Lin MR. Comparisons of different screening tools for identifying fracture/osteoporosis risk among community-dwelling older people. Medicine (Baltimore). 2016;95(20):e3415.

Abbreviations: BMD=bone mineral density; DXA=dual-energy X-ray absorptiometry; USPSTF=U.S. Preventive Services Task Force.

^* Table adapted from Chen SJ, et al.[67]]
^† Refer to https://frax.shef.ac.uk/FRAX/index.aspx.

Abbreviations: BMI=body mass index; MOF=major osteoporotic fracture; OST=Osteoporosis Self-Assessment Tool; ORAI=Osteoporosis Risk Assessment Instrument.