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Osteoporosis to Prevent Fractures, Screening, 2018

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Recommendations: Screening for Osteoporosis to Prevent Fractures

Discussion:

Burden of Disease

Osteoporosis is a skeletal disorder characterized by loss of bone mass, microarchitectural deterioration of bone tissue, and decline in bone quality leading to increased bone fragility and risk of fractures.912 The World Health Organization defines osteoporosis as bone density at the hip or spine that is at least 2.5 SDs (ie, T score ≤−2.5) below the mean bone density of a reference population of young healthy women, presumably at peak bone mass.29

In the United States, the estimated prevalence of osteoporosis among the community-dwelling population 50 years and older in 2010 was 10.3% (10.2 million adults), based on National Health and Nutrition Examination Survey data.1 After age 50 years, the prevalence of osteoporosis is greater in women than in men (15.4% vs 4.3%, respectively).1 The prevalence of osteoporosis varies by race/ethnicity and is highest in Mexican American (13.4%) and non-Hispanic white adults (10.2%) and lowest in non-Hispanic black adults (4.9%).1 The prevalence of osteoporosis increases dramatically with age, from 5.1% in adults aged 50 to 59 years to 26.2% in those 80 years and older.1As the US population ages, it is projected that the number of persons living with osteoporosis will also increase. The number of adults 50 years and older with osteoporosis will increase from 10.2 million in 2010 to an estimated 12.3 million in 2020 and 13.6 million in 2030.1Based on Healthcare Effectiveness Data and Information Set data, the rate of women aged 65 to 85 years enrolled in Medicare who reported ever having a bone density test increased from 64.4% to 71.3% in 2006 and from 73.8% to 79.3% in 2016.30

In 2005, approximately 2 million osteoporotic fractures occurred in the United States.3 Nearly 40% of persons who experience a fracture are unable to walk independently at 1 year, and 60% require assistance with at least 1 essential activity of daily living.31 Hip fractures account for a large portion of the morbidity and mortality associated with osteoporotic fractures, with 21% to 30% of patients dying within 1 year of a hip fracture.2

Osteoporosis is usually asymptomatic until a fracture occurs; preventing osteoporotic fractures is the main goal of an osteoporosis screening strategy.

Scope of Review

The USPSTF commissioned a systematic evidence review46 to search for updated evidence since the previous review in 2011 and examine newer evidence on screening for and treatment of osteoporotic fractures in men and women. The review also sought evidence on risk assessment tools, screening intervals, and efficacy of screening and treatment in subgroups. The USPSTF defined the screening population as postmenopausal women and older men with no known previous osteoporotic fractures and no known comorbid conditions or medication use associated with secondary osteoporosis. The review excluded adults younger than 40 years as well as adults with no known conditions that may increase their risk of falls.

Accuracy of Screening Tests and Clinical Risk Assessment Tools

DXA

Bone measurement testing with central DXA is the most commonly used and studied method for the diagnosis of osteoporosis. Central DXA uses radiation to measure BMD at central bone sites (hip and lumbar spine), which is the established standard for diagnosis of osteoporosis and for guiding decisions about treatment. DXA can also be used at peripheral bone sites (such as the lower forearm and heel) to identify persons with low bone mass; however, most treatment guidelines recommend follow-up with central DXA before initiating treatment for osteoporosis. Screening with peripheral DXA and other imaging techniques may help increase access to screening in geographic locations (eg, rural areas) where machines that perform central DXA may not be available. The USPSTF identified 2 studies (n = 712) that reported on the accuracy of peripheral DXA at the calcaneus to identify osteoporosis; compared with central DXA, the area under the curve (AUC) ranged from 0.67 to 0.80 in women with a mean age of 61 years.43233

QUS

Quantitative ultrasound is another imaging technique used at peripheral bone sites (most commonly the calcaneus), and it does not require radiation exposure. Compared with central DXA, the AUC for QUS measured at the calcaneus in women ranged from 0.69 to 0.90, with a pooled estimate of 0.77 (95% CI, 0.72-0.81; 7 studies; n = 1969).4 In men, the AUC ranged from 0.70 to 0.93, with a pooled estimate of 0.80 (95% CI, 0.67-0.94; 3 studies; n = 5142).4 However, QUS does not measure BMD, that is the current diagnostic criteria for osteoporosis. In addition, drug therapy trials for osteoporosis treatment generally use central DXA measurement of BMD as criteria for inclusion of study populations.412 Thus, before QUS results could be routinely used to initiate treatment without any further DXA measurement, a method for converting or adapting QUS results to the DXA scale needs to be developed.

Clinical Risk Assessment Tools

The USPSTF evaluated the accuracy of clinical risk assessment tools to identify risk of osteoporosis. Many of these tools can also be used to calculate risk of future fractures; however, the USPSTF focused on their accuracy to identify osteoporosis because all the treatment studies evaluated by the USPSTF enrolled patients based on bone measurement testing, specifically central DXA measurement of BMD. The most frequently studied tools in women were the ORAI (10 studies; n = 16,780), OSIRIS (5 studies; n = 5649), OST (13 studies; n = 44,323), and SCORE (8 studies; n = 15,362). The pooled AUCs for these tools were all similar and ranged from 0.65 to 0.70. The FRAX tool (without BMD), which has been studied extensively as a clinical risk assessment tool to predict fracture risk, performs similarly in its ability to identify osteoporosis (AUC range, 0.58-0.82; 4 studies; n = 22,141).4 These clinical risk assessment tools could be applied to postmenopausal women younger than 65 years who are at increased risk of osteoporosis to help clinicians determine who should be screened with bone measurement testing. Fewer studies are available that evaluate the performance of these tools specifically in younger women, and 1 study has suggested that FRAX is inferior to OST and SCORE in discriminating women with osteoporosis.34 However, in the studies reviewed by the USPSTF, the range of AUCs of these tools (ORAI, OSIRIS, OST, SCORE, and FRAX) to identify osteoporosis in women younger than 65 years were similar to the pooled AUCs for women of all ages; the AUC from individual studies of clinical risk assessment tools in women younger than 65 years ranged from 0.58 to 0.85.4 Table 2 provides more information on these clinical risk assessment tools and commonly used thresholds to determine risk of osteoporosis.

Effectiveness of Early Detection and Treatment

A single fair-quality controlled study (n = 12,483) evaluated the effect of screening for osteoporosis on fracture rates in postmenopausal women aged 70 to 85 years.4-6 This study reported no significant difference in the primary outcome of any osteoporotic fracture in women screened with FRAX vs women receiving usual care (12.9% vs 13.5%; hazard ratio [HR], 0.94 [95% CI, 0.85-1.03]). There was also no significant difference for incidence of all clinical fractures (15.3% vs 16.0%; HR, 0.94 [95% CI, 0.86-1.03]) or mortality (8.8% vs 8.4%; HR, 1.05 [95% CI, 0.93-1.19]). However, the study reported a statistically significant reduction in hip fracture incidence (2.6% vs 3.5%; HR, 0.72 [95% CI, 0.59-0.89]).4-6

The USPSTF reviewed the evidence on drug therapies for the primary prevention of osteoporotic fractures. The vast majority of studies were conducted in postmenopausal women exclusively; only 2 studies were conducted in men.4 Overall, the USPSTF found that drug therapies are effective in treating osteoporosis and reducing fractures in postmenopausal women.

Bisphosphonates

Bisphosphonates were studied most frequently; the USPSTF identified 7 studies on alendronate, 2 trials on zoledronic acid, 4 trials on risedronate, and 2 trials on etidronate.4 All but 1 study were conducted in postmenopausal women. For women, bisphosphonates were found to significantly reduce vertebral fractures (relative risk [RR], 0.57 [95% CI, 0.41-0.78]; 5 studies; n = 5433) and nonvertebral fractures (RR, 0.84 [95% CI, 0.76-0.92]; 8 studies; n = 16,438) but not hip fractures (RR, 0.70 [95% CI, 0.44-1.11]; 3 studies; n = 8988).4 However, most studies reporting on hip fractures may have been underpowered to detect a difference in this outcome. In the single study of men (n = 1199), zoledronic acid was found to reduce morphometric vertebral fractures (RR, 0.33 [95% CI, 0.16-0.70]) but not clinical nonvertebral fractures (RR, 0.65 [95% CI, 0.21-1.97]).415

Raloxifene

Only 1 study (n = 7705) on raloxifene met inclusion criteria for the review. The study evaluated treatment with raloxifene in postmenopausal women and found a reduction in vertebral fractures (RR, 0.64 [95% CI, 0.53-0.76]) but not nonvertebral fractures (RR, 0.93 [95% CI, 0.81-1.06]).4

Denosumab

The USPSTF identified 4 studies that evaluated denosumab; however, only 1 study was adequately powered to detect a difference in fractures. This study (n = 7868) evaluated treatment with denosumab in women and found a significant reduction in vertebral fractures (RR, 0.32 [95% CI, 0.26-0.41]), nonvertebral fractures (RR, 0.80 [95% CI, 0.67-0.95]), and hip fractures (RR, 0.60 [95% CI, 0.37-0.97]).435

Parathyroid Hormone

The USPSTF reviewed evidence from 2 trials on parathyroid hormone. One trial (n = 2532) conducted in women found a significant reduction in vertebral fractures (RR, 0.32 [95% CI, 0.14-0.75]) but not nonvertebral fractures (RR, 0.97 [95% CI, 0.71-1.33]).436 The other trial, conducted in men, found a nonsignificant reduction in nonvertebral fractures (RR, 0.65 [95% CI, 0.11-3.83]) when comparing the FDA-approved dose of 20 μg/d vs placebo (n = 298).416 However, the number of fractures in the study was small and the study was stopped early due to concerns about osteosarcoma found in animal studies.

Estrogen

Although the USPSTF did not identify any studies on estrogen for the primary prevention of fractures that met inclusion criteria, the previous review found that estrogen reduces vertebral fractures based on data from the Women’s Health Initiative trial.12

Potential Harms of Screening and Treatment

One trial evaluated the effect of screening on anxiety and quality of life and found no difference between screened and unscreened intervention groups.4-6 Additional potential harms of screening for osteoporosis include false-positive test results, which can lead to unnecessary treatment, and false-negative test results. The USPSTF did review several studies that reported on harms of various osteoporosis medications.46 Overall, the USPSTF determined that the potential harms of osteoporosis drug therapies are small.

Bisphosphonates

Similar to the evidence on the benefits of drug therapy for the primary prevention of fractures, the most available evidence on the harms is for bisphosphonates. The USPSTF identified 16 studies on alendronate, 4 studies on zoledronic acid, 6 studies on risedronate, 2 studies on etidronate, and 7 studies on ibandronate that reported on harms. Overall, based on pooled analyses, studies on bisphosphonates showed no increased risk of discontinuation (RR, 0.99 [95% CI, 0.91-1.07]; 20 studies; n = 17,369), serious adverse events (RR, 0.98 [95% CI, 0.92-1.04]; 17 studies; n = 11,745), or upper gastrointestinal events (RR, 1.01 [95% CI, 0.98-1.05]; 13 studies; n = 20,485).4 Evidence on bisphosphonates and cardiovascular events is more limited and generally shows no significant difference or nonsignificant increases in atrial fibrillation with bisphosphonate therapy. Concerns have been raised about osteonecrosis of the jaw and atypical fractures of the femur with bisphosphonate therapy. The USPSTF found only 3 studies that reported on osteonecrosis of the jaw, and none of these studies found any cases.4 The previous review12 noted an FDA case series that reported on osteonecrosis of the jaw with bisphosphonate use in patients with cancer. A more recent systematic review that did not meet inclusion criteria (because it included populations with a previous fracture) found higher incidence of osteonecrosis of the jaw with intravenous bisphosphonate use and with longer use. No studies that met inclusion criteria for the current review reported on atypical fractures of the femur, although some studies and systematic reviews that did not meet inclusion criteria (because of wrong study population, study design, or intervention comparator) reported an increase in atypical femur fractures with bisphosphonate use. No studies reported any cases of kidney failure, although the FDA has added a warning label noting that zoledronic acid is contraindicated in certain patients. Three trials that reported on harms of bisphosphonates included men (either combining results for men and women or including men only); results were consistent with those of women for risk of discontinuation, serious adverse events, and upper gastrointestinal events.

Raloxifene

Six trials of raloxifene therapy in women reported on various harms. Pooled analyses showed no increased risk of discontinuation due to adverse events (RR, 1.12 [95% CI, 0.98-1.28]; 6 studies; n = 6438) or increased risk of leg cramps (RR, 1.41 [95% CI, 0.92-2.14]; 3 studies; n = 6000).4 However, analyses found a nonsignificant trend for increased risk of deep vein thrombosis (RR, 2.14 [95% CI, 0.99-4.66]; 3 studies; n = 5839), as well as an increased risk of hot flashes (RR, 1.42 [95% CI, 1.22-1.66]; 5 studies; n = 6249).4 The previous review12 found an increased risk of thromboembolic events with raloxifene (RR, 1.60 [95% CI, 1.15-2.23]).4

Denosumab

Four studies (n = 8663) reported on harms of denosumab therapy in postmenopausal women. Pooled analyses showed no significant increase in discontinuation (RR, 1.14 [95% CI, 0.85-1.52]) or serious adverse events (RR, 1.12 [95% CI, 0.88-1.44]) but found a nonsignificant increase in serious infections (RR, 1.89 [95% CI, 0.61-5.91]).4 Three studies reported higher infection rates in women taking denosumab, and further analysis found a higher rate of cellulitis and erysipelas.4 One study reported no occurrences of osteonecrosis of the jaw.4

Parathyroid Hormone

A single study of parathyroid hormone therapy in women (n = 2532) reported an increased risk of discontinuation (RR, 1.23 [95% CI, 1.08-1.40]) and other adverse events, such as nausea and headache (RR, 2.47 [95% CI, 2.02-3.03]).436 whereas a single smaller study in men found no increased risk of discontinuation (RR, 1.94 [95% CI, 0.81-4.69]) or cancer (RR, 0.97 [95% CI, 0.2-4.74])4 using the FDA-approved dose of 20 μg/d (n = 298).416

Estrogen

Similar to the evidence on the benefits of estrogen for the primary prevention of fractures, no studies met inclusion criteria for the current review. However, based on findings from the Women’s Health Initiative trial, the previous review found an increased rate of gallbladder events, stroke, and venous thromboembolism with estrogen therapy, and an increased risk of urinary incontinence during 1 year of follow-up.412 Women taking combined estrogen and progestin had an increased risk of invasive breast cancer, coronary heart disease, probable dementia, gallbladder events, stroke, and venous thromboembolism compared with women taking placebo, and an increased risk of urinary incontinence during 1 year of follow-up.412

Estimate of Magnitude of Net Benefit

The USPSTF found convincing evidence that bone measurement tests are accurate for detecting osteoporosis and predicting osteoporotic fractures in women and men. The USPSTF found adequate evidence that clinical risk assessment tools are moderately accurate in identifying risk of osteoporosis and osteoporotic fractures.

The USPSTF found convincing evidence that drug therapies reduce subsequent fracture rates in postmenopausal women. The benefit of treating screen-detected osteoporosis is at least moderate in women 65 years and older and in younger postmenopausal women who have similar fracture risk. The harms of treatment range from no greater than small for bisphosphonates and parathyroid hormone to small to moderate for raloxifene and estrogen. Therefore, the USPSTF concludes with moderate certainty that the net benefit of screening for osteoporosis in these groups of women is at least moderate. The single study that directly evaluated the effect of screening (with FRAX) on fracture outcomes was generally consistent with this conclusion.

The USPSTF found that the evidence is inadequate to assess the effectiveness of drug therapies in reducing subsequent fracture rates in men without previous fractures. Treatments that have been proven effective in women cannot necessarily be presumed to have similar effectiveness in men, and the direct evidence is too limited to draw definitive conclusions. Thus, the USPSTF concludes that the evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis in men.

How Does Evidence Fit With Biological Understanding?

Low bone density is a risk factor for fractures, especially in older adults. Screening for low BMD and subsequent treatment can result in increased BMD and decrease the risk of subsequent fractures and fracture-related morbidity and mortality. Most evidence supports screening for and treatment of osteoporosis in postmenopausal women; the evidence for primary prevention in men is lacking, and future research is needed. It cannot be assumed that the bones of men and women are biologically the same, especially because bone density is affected by differing levels and effects of testosterone and estrogen in men and women. Moreover, rapid bone loss occurs in women due to the loss of estrogen during menopause. Men tend to experience fractures at an older age than women, when risk of comorbid conditions and overall mortality are higher; thus, the net balance of benefits and harms of screening for and treatment of osteoporosis in men is unclear.

Response to Public Comment

A draft version of this recommendation statement was posted for public comment on the USPSTF website from November 7, 2017, to December 4, 2017. In response to comments, the USPSTF added information on the accuracy of certain clinical risk assessment tools to identify osteoporosis in women younger than 65 years to the Discussion section. In addition, the USPSTF clarified that adults with certain conditions that may increase their risk of falls or those using certain medications (such as aromatase inhibitors) that may increase one’s risk of fractures are excluded from this recommendation. Some comments expressed concern that the USPSTF did not recommend screening for osteoporosis in men. Although the USPSTF agrees that prevention of osteoporotic fractures in men is an important public health issue, there is currently not enough evidence demonstrating that screening for and subsequent treatment of osteoporosis in men prevents primary fractures. Studies that have evaluated screening and treatment in men have focused on populations that are out of scope for this recommendation, such as men with a history of previous fractures or men taking certain medications that may cause secondary osteoporosis. The USPSTF is calling for more research in osteoporosis screening and treatment in men, and clarified why it found the evidence insufficient to make a recommendation for or against screening in men. Last, the USPSTF updated the recommendation to include information from a recent trial that evaluated the direct effect of screening for osteoporosis on the incidence of fractures.

Other Sections:

Other Considerations

Implementation

Tools that can help identify women younger than 65 years who are at increased risk of osteoporosis include SCORE, ORAI, OSIRIS, and OST.22-26 The most commonly used thresholds to identify increased risk of osteoporosis or osteoporotic fractures are greater than or equal to 6 for SCORE, greater than or equal to 9 for ORAI, less than 1 for OSIRIS, and less than 2 for OST (Table 2). Additionally, the FRAX tool8is a computerized algorithm that calculates the 10-year probability of hip fracture and MOF using clinical risk factors. FRAX models are country specific, as they include country epidemiology. In the United States, the risk of MOF is 8.4% in a 65-year-old white woman of mean height and weight without any other risk factors.478

Research Needs and Gaps

The majority of reviewed studies focused on women. Treatment trials that focus on or include men and report on fracture outcomes (rather than BMD) as well as harms are needed. More studies are also needed that evaluate the direct effect of screening for osteoporosis (either with BMD or clinical risk assessment tools) on fracture outcomes. Additional research is needed to determine whether clinical risk assessment tools alone (without BMD) could help identify patients at risk of fractures and help guide decisions to initiate medications to prevent fractures. The development of prognostic models incorporating age, baseline BMD, and hormone replacement therapy use2728may also help identify optimal screening intervals.

 

Update on Previous USPSTF Recommendations

This recommendation is consistent with the 2011 USPSTF recommendation on screening for osteoporosis.37 The major change in the current recommendation is that the USPSTF expanded its consideration of evidence related to fracture risk assessment, with or without BMD testing. The USPSTF found there is still insufficient evidence on screening for osteoporosis in men.

 

Recommendations of Others

In 2014, the National Osteoporosis Foundation recommended BMD testing in all women 65 years and older and all men 70 years and older.38 It also recommended BMD testing in postmenopausal women younger than 65 years and men aged 50 to 69 years based on their risk factor profile, including if they had a fracture as an adult. The International Society for Clinical Densitometry recommends BMD testing in all women 65 years and older and all men 70 years and older. It also recommends BMD testing in postmenopausal women younger than 65 years and men younger than 70 years who have risk factors for low bone mass.39 As part of Choosing Wisely, the American Academy of Family Physicians recommends against DXA screening in women younger than 65 years and men younger than 70 years with no risk factors.40 In 2012 (and reaffirmed in 2014), the American College of Obstetricians and Gynecologists recommended BMD testing with DXA beginning at age 65 years in all women and selective screening in postmenopausal women younger than 65 years who have osteoporosis risk factors or an adult fracture.9 The American Association of Clinical Endocrinologists also recommends evaluating all women 50 years and older for osteoporosis risk and considering BMD testing based on clinical fracture risk profile.10 The Endocrine Society recommends screening in men older than 70 years and adults aged 50 to 69 years with significant risk factors or fracture after age 50 years.41

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