Osteoporosis

Osteoporosis is determined using the World Health Organization diagnostic thresholds for osteoporosis based on bone mineral density measurement (BMD) compared with a calculated T-score.

Risk factors for fracture include low bone mass, low bone strength, a personal history of fracture as an adult, or a history of fracture in a first-degree relative. Osteoporosis, defined as low bone mass leading to an increased risk of fragility fractures, is an extremely common disease in the elderly population due to age-related bone loss in both sexes and menopause-related bone loss in women. The World Health Organization has diagnostic thresholds for osteoporosis based on BMD measurements compared with a T-score, which is the standard deviation difference between an individual’s BMD and that of a young adult reference population. Conditions that can cause or contribute to osteoporosis include lifestyle factors such as low intake of calcium, high intake of alcohol or cigarette smoking, and thinness. Other risk factors for osteoporosis include certain endocrine, hematologic, gastrointestinal tract and genetic disorders, hypogonadal states, and medications.

BMD can be measured either centrally (ie, hip or spine) or peripherally (ie, wrist, finger, heel) sites. While BMD measurements are predictive of fragility fractures at all sites, central measurements of the hip and spine are the most predictive. Fractures of the hip and spine (ie, vertebral fractures) are also considered to be the most clinically relevant. BMD is typically expressed as a T-score.

The utility of screening BMD measurements can be established by demonstrating that screening identifies a population at increased risk of fracture and that, by treating those at-risk individuals, the rate of fractures is reduced thereby lowering fracture-related morbidity and mortality. These potential benefits of screening should outweigh the risks of screening (radiation exposure) or false-positives (initiation of unnecessary treatment).

Bone Mineral Density

The decision to perform a bone density assessment should be based on an individual’s fracture risk profile and skeletal health assessment. In addition to age, sex, and BMD, risk factors included in the World Health Organization Fracture Risk Assessment Tool^1, are:

• Low body mass index;
• Parental history of hip fracture;
• Previous fragility fracture in adult life (ie, occurring spontaneously or a fracture arising from trauma, which, in a healthy individual, would not have resulted in a fracture);
• Current smoking or 3 or more units of alcohol daily, where a unit is equivalent to a standard glass of beer (285 mL), a single measure of spirits (30 mL), a medium-sized glass of wine (120 mL), or 1 measure of an aperitif (60 mL);
• A disorder strongly associated with osteoporosis, which includes rheumatoid arthritis, type I (insulin-dependent) diabetes, osteogenesis imperfecta in adults, untreated long-standing hyperthyroidism, hypogonadism or premature menopause (<45 years), chronic malnutrition or malabsorption, and chronic liver disease;
• Current exposure to oral glucocorticoids or exposure to oral glucocorticoids for more than 3 months at a dose of prednisolone 5 mg daily or more (or equivalent doses of other glucocorticoids).

A T-score is the standard deviation difference between an individual’s BMD and that of a young adult reference population.

Table 1. WHO Classification of Bone Mineral Density T-Scores

Assessment	BMD Definition
Normal	Bone density is within 1 SD (+1 or −1) of the young adult mean.
Osteopenia (low bone mass)	Bone density is between 1 and 2.5 SD below the young adult mean (−1 to −2.5 SD).
Osteoporosis	Bone density is 2.5 SD or more below the young adult mean (−2.5 SD or lower).
Severe (established) osteoporosis	Bone density is more than 2.5 SD below the young adult mean, and there have been one or more osteoporotic fractures.

BMD: bone mineral density; SD: standard deviation; WHO: World Health Organization.

Other Measurement Tools

Available diagnostic tools use either X-rays or ultrasound. X-ray based methods measure BMD. However, studies suggest that in addition to measuring structural aspects of the bone by assessing BMD, other mechanical features and elastic properties of the bone are also important to predict the risk of fractures. X-ray based methods cannot assess these properties and therefore use of alternative methodologies such as ultrasound densitometry and quantitative computed tomography (CT) have been explored.

Quantitative Computed Tomography

Quantitative CT depends on the differential absorption of ionizing radiation by calcified tissue and is used for central measurements only. Compared with DXA, quantitative CT is less readily available and associated with relatively high radiation exposure and relatively high cost. Analysis of previously obtained clinical CT scans of the pelvis might provide an alternative method of assessing biomechanical bone strength.

Ultrasound Densitometry

Ultrasound densitometry is a technique for measuring BMD at peripheral sites, typically the heel but also the tibia and phalanges. Compared with osteoporotic bone, normal bone demonstrates higher attenuation of the ultrasound wave and is associated with a greater velocity of the wave passing through bone. Ultrasound densitometry has no radiation exposure, and machines may be purchased for use in an office setting.

Single- and dual-photon absorptiometry and radiographic absorptiometry are now rarely used and may be considered obsolete.

Osteoporosis Treatment

Treatment of osteoporosis includes both lifestyle measures (eg, increased intake of calcium and vitamin D, exercise, smoking cessation) and pharmacologic measures. Current pharmacologic options include bisphosphonates such as alendronate (ie, Fosamax), selective estrogen receptor modulators such as raloxifene (ie, Evista), the recombinant human parathyroid hormone teriparatide (ie, Forteo), and calcitonin. An updated 2014 systematic review funded by the Agency for Healthcare Research and Quality found good-quality evidence that bisphosphonates, denosumab, teriparatide, and raloxifene reduce fracture risk in postmenopausal women with BMD in the osteoporotic range and/or preexisting hip or vertebral fracture.^2,

Regulatory Status

Devices that measure bone density have been cleared for marketing by theFDA through the 510(k) process. Some examples are described in Table 1:

Table 2. FDA Cleared Devices to Measure Bone Density

Device Name	Company	510(k) number
Aria	GE Medical Systems	K180782
Ge Lunar Dxa Bone Densitometers With Enc	GE Medical Systems	K161682
Tbs Insight	Medimaps Group Sa	K152299
Single Energy (Se) Femur Exams	Hologic, Inc.	K130277
Tbs Insight	Medimaps Group Sa	K121716
Virtuost	O.N. Diagnostics	K113725
Accudxa2	Lone Oak Medical Technologies, Llc	K113616
Ultrascan 650	Cyberlogic, Inc.	K161919
Bindex Bi-2	Bone Index Finland, Ltd.	K161971
Bindex Bi-100	Bone Index Finland, Ltd.	K152020
Achilles	GE Medical Systems	K123238
Beammed Sunlight Miniomni Bone Sonometer	Beam-Med Ltd	K110646
Achilles	GE Medical Systems	K103633

FDA product codes: KGI, MUA.

In addition, some ultrasound bone sonometers have been approved by the FDA through the premarket approval process. One example is the Sahara® Clinical Bone Sonometer (Hologic), which received approval in March 1998. Its intended use is for quantitative ultrasound measurement of the calcaneus (heel bone), the results of which can be used in conjunction with other clinical risk factors as an aid in the diagnosis of osteoporosis and medical conditions leading to reduced bone density, and ultimately in the determination of fracture risk.

Vertebral Fracture Assessment With Densitometry Description

Vertebral fracture assessment (VFA) with densitometry is a technique to assess vertebral fractures at the same time as bone mineral density, using additional software with dual-energy x-ray absorptiometry. The addition of VFA to bone mineral density may augment diagnostic information on fracture risk.

Populations	Interventions	Comparators	Outcomes
Individuals: · Who are at risk of having vertebral fractures but are not known to have them	Interventions of interest are: · Vertebral fracture assessment with densitometry by dual-energy x-ray absorptiometry	Comparators of interest are: · Bone mineral density assessment by dual-energy x-ray absorptiometry alone · Radiography	Relevant outcomes include: · Test accuracy · Test validity · Morbid events

Background

Vertebral Fractures
Vertebral fractures are highly prevalent in the elderly population, and epidemiologic studies have found that these fractures are associated with an increased risk of future spine or hip fractures independent of bone mineral density.

Diagnosis
Only 20% to 30% of vertebral fractures are recognized clinically; the rest are discovered incidentally on lateral spine radiographs. Lateral spine radiographs have not been recommended as a component of risk assessment for osteoporosis because of the cost, radiation exposure, and the fact that the radiograph would require a separate procedure in addition to the bone mineral density study using dual-energy x-ray absorptiometry. However, several densitometers with specialized software can perform vertebral fracture assessment (VFA) in conjunction with dual-energy x-ray absorptiometry. The lateral spine scan is performed by using a rotating arm; depending on the densitometer used, the patient can either stay in the supine position after the bone density study or is required to move to the left decubitus position.

VFA differs from radiologic detection of fractures because VFA uses a lower radiation exposure and can detect only fractures, while traditional radiograph images can detect other bone and soft tissue abnormalities in addition to spinal fractures. Manufacturers have also referred to this procedure as instant vertebral assessment, radiographic vertebral assessment, dual-energy vertebral assessment, or lateral vertebral assessment.

For both lateral spine radiographs and images with densitometry, vertebral fractures are assessed visually. While a number of grading systems have been proposed, the Genant semiquantitative method is commonly used. This system grades deformities from I to III, with grade I (mild) representing a 20% to 24% reduction in vertebral height, grade II (moderate) representing a 25% to 39% reduction in height, and grade III (severe) representing a 40% or greater reduction in height. The location of the deformity within the vertebrae may also be noted. For example, if only the mid height of the vertebrae is affected, the deformity is defined as an endplate deformity; if both the anterior and mid heights are deformed, it is a wedge deformity; and if the entire vertebrae is deformed, it is classed as a crush deformity. A vertebral deformity of at least 20% loss in height is typically considered a fracture. Accurate interpretation of both lateral spine radiographs and VFA imaging is dependent on radiologic training. Thus, device location and availability of appropriately trained personnel may influence diagnostic accuracy.

Regulatory Status
Additional software is needed to perform VFA with a densitometer, and it must be cleared for marketing by the U.S. Food and Drug Administration through the 510(k) process. Products cleared for marketing include Lunar Dual Energy Vertebral Assessment (DVA™; General Electric Medical Systems) and Instant Vertebral Assessment™ (IVA™; Hologic) software. Food and Drug Administration product code KGI.

Related Policies

• Whole Body Dual X-Ray Absorptiometry (DEXA) to Determine Body Composition (Policy #034 in the Radiology Section)

2. An initial measurement of central (hip/spine) BMD using dual x-ray absorptiometry (DXA) is considered medically necessary to assess future fracture risk and the need for pharmacologic therapy in both women and men who are considered at risk for osteoporosis. BMD testing is indicated under the following conditions:

• Women age 65 and older, independent of other risk factors;
• Men age 70 and older, independent of other risk factors;
• Younger postmenopausal women with an elevated risk factor assessment (See Policy Guidelines section);
• Men age 50 to 70 with an elevated risk factor assessment (See Policy Guidelines section);
• Adults with a pathologic condition associated with low bone mass or increased bone loss;
• Adults taking a medication associated with increased bone loss.

4. Repeat measurement of central (hip/spine) BMD using dual x-ray absorptiometry is considered medically necessary at an interval of not more frequent than every 1-2 years in individuals:

• With a baseline evaluation of osteopenia (BMD T-score -1.0 to -2.5);
• Adults with a pathologic condition associated with low bone mass or increased bone loss;
• Adults taking a medication associated with an increased bone loss.

FIDE SNP: For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

Dual x-ray absorptiometry (DXA) of axial central sites (ie, hip and spine) is the most commonly used technique. Central DXA (hip/spine) is required for both the initial diagnosis and repeat bone mineral density (BMD) assessments.

Peripheral (lower arm, wrist, finger or heel) measurement can identify patients with low bone mass but does not predict response to pharmacologic therapy and is not a substitute for central DXA measurements. Peripheralf BMD may be appropriate:

• If the hip/spine or hip/hip cannot be done or the patient is over the table limit for weight;
• Hyperparathyroidism, where the forearm is essential for diagnosis.

When indicated; repeat dual x-ray absorptiometry (DXA) of axial central sites should ideally be conducted in the same facility with the same machine. Differences between BMD results may simply reflect the inherent variability of the test measurement; thus, testing facilities must calculate the least significant change (LSC) for relevant measurement sites to determine the magnitude of difference that represents a real change. This is determined using a facility’s regular technologist(s), patients, and device.

Ultrasound densitometry is an office-based technology. Compared with osteoporotic bone, normal bone demonstrates higher attenuation of the ultrasound wave and is associated with a greater velocity of the wave passing through bone. Ultrasound densitometry has no radiation exposure, and machines may be purchased for use in an office setting. It is unknown whether this technology can be used to predict response to pharmacologic therapy (i.e., reduce fractures).

Quantitative computed tomography depends on the differential absorption of ionizing radiation by calcified tissue and is used for central measurements only. Compared with DXA, quantitative computed tomography is less readily available and associated with relatively high radiation exposure and relatively high cost. Analysis of previously obtained clinical computed tomography scans of the pelvis might provide an alternative method of assessing biomechanical bone strength.

Single- and dual-photon absorptiometry and radiographic absorptiometry are now rarely used and may be considered obsolete.

The decision to perform a bone density assessment should be based on an individual’s fracture risk profile and skeletal health assessment. In addition to age, sex, and BMD, risk factors included in the World Health Organization Fracture Risk Assessment Tool are:

• Low body mass index;
• Parental history of hip fracture;
• Previous fragility fracture in adult life (i.e., occurring spontaneously or a fracture arising from trauma, which, in a healthy individual, would not have resulted in a fracture);
• Current smoking or 3 or more units of alcohol daily, where a unit is equivalent to a standard glass of beer (285 mL), a single measure of spirits (30 mL), a medium-sized glass of wine (120 mL), or 1 measure of an aperitif (60 mL);
• A disorder strongly associated with osteoporosis, which includes rheumatoid arthritis, type I (insulin-dependent) diabetes, osteogenesis imperfecta in adults, untreated long-standing hyperthyroidism, hypogonadism or premature menopause (<45 years), chronic malnutrition or malabsorption, and chronic liver disease;
• Current exposure to oral glucocorticoids or exposure to oral glucocorticoids for more than three months at a dose of prednisolone 5 mg daily or more (or equivalent doses of other glucocorticoids).

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The RCT is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Initial Measurement of Bone Mineral Density

Clinical Context and Therapy Purpose

The purpose of BMD measurement in patients who have risk factors for osteoporosis is to assess bone health and guide treatment.

The question addressed in this policy is: Does BMD testing with dual x-ray absorptiometry (DXA) improve the net health outcome in individuals with risk factors for osteoporosis?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with risk factors for osteoporosis.

In addition to age-related bone loss, conditions that can cause or contribute to osteoporosis include lifestyle factors such as low dietary intake of calcium, high intake of alcohol or cigarette smoking, and thinness. Other risk factors for osteoporosis include certain endocrine, hematologic, gastrointestinal tract and genetic disorders, hypogonadal states, and use of certain classes of pharmacologic agents such as corticosteroids.

Interventions

The test being considered is BMD testing with central DXA performed in the outpatient primary care setting.

The decision to perform a bone density assessment should be based on an individual’s fracture risk profile assessment

Comparators

The following practices are currently being used to make treatment decisions: clinical risk factor assessment.

Outcomes

The general outcomes of interest are the occurrence of fractures and effects on QOL.

BMD measurements, using DXA, of central sites (hip or spine), are most predictive of fragility fractures at hip and spine. Fractures of the hip and spine (ie, vertebral fractures) are considered the most clinically relevant.

Study Selection Criteria

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs and systematic reviews of these studies.

In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

To assess longer-term outcomes and adverse effects, single-arm studies that captured longer periods of follow-up and/or larger populations.

To supplement the review of evidence for indications where evidence was extremely limited, clinical practice guidelines were included. Primary guidelines were selected based on the following criteria:

• Established, recognized professional organization
• Published guideline process that included conflict of interest, agreed-upon process including grading of recommendations and disclosure of when consensus or expert opinion was used
• Existence of an associated evidence appraisal (systematic review, comprehensive references, etc)
• Guideline is accessible (PubMed indexed or freely available through the organizational website)

Review of Evidence

A 2018 systematic review for the U.S. Preventive Services Task Force (USPSTF) evaluated the evidence on screening for osteoporosis.^6, The review considered centrally measured DXA to be the reference standard against which other screening measures were evaluated. RCTs included in the systematic review have shown that osteoporosis medications are effective at reducing fracture risk in postmenopausal women with BMD in the osteoporotic range identified by central DXA. A noted limitation of the review was that treatment studies relied on DXA BMD scores to enroll participants into trials and that risk factors beyond bone density, such as bone quality, contribute to osteoporotic fractures. Therefore, “approaches that rely on BMD measurement wholly or in part may not be the most accurate approaches for identifying patients at highest risk for osteoporotic fractures.”

Clinical Practice Guidelines

The 2018 systematic review formed the basis for the USPSTF recommendations for screening for osteoporosis in women aged 65 years or older and in postmenopausal women younger than 65 years at increased risk of osteoporosis.^6,The supporting document refers to multiple instruments to predict risk for low BMD, including the Fracture Risk Assessment Tool.^1, The USPSTF recommendations stated that the scientific evidence is “insufficient” to assess the balance of benefits and harms of screening for osteoporosis in men.

In 2016, the American Association of Clinical Endocrinologists and the American College of Endocrinology issued updated joint guidelines on the diagnosis and treatment of postmenopausal osteoporosis.^7,The guidelines listed the potential uses for BMD measurements in postmenopausal women as:

• "Screening for osteoporosis
• Establishing the severity of osteoporosis or bone loss
• Determining fracture risk
• Identifying candidates for pharmacologic intervention
• Assessing changes in bone density over time
• Enhancing acceptance of, and perhaps adherence with, treatment
• Assessing skeletal consequences of diseases, conditions, or medications known to cause bone loss"

Section Summary: Initial Measurement of BMD

Central DXA is the most widely accepted method for measuring BMD. BMD measurements with central DXA identify individuals at increased risk of fracture, and osteoporosis medications reduce fracture risk in the population identified as osteoporotic by central DXA. Therefore, test results with initial central DXA have been successfully used to make decisions about initiation of fracture intervention pharmacologic therapy.

Repeat Measurement of BMD for Individuals Without Osteoporosis on Initial Screen

Clinical Context and Therapy Purpose

The purpose of BMD measurement in patients without osteoporosis on the initial screen is to assess changes in bone health and guide treatment.

The question addressed in this policy is: Does repeat BMD testing with central DXA improve the net health outcome in individuals with risk factors for osteoporosis?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals without osteoporosis as defined by the initial BMD measurement screen.

Interventions

The test being considered is repeat BMD testing with central DXA performed in the outpatient primary care setting.

Comparators

The following practices are currently being used to make treatment decisions: clinical risk factor assessment without BMD testing.

Outcomes

The general outcomes of interest are the occurrence of fractures and effects of fractures on QOL.

Monitoring of fractures may occur until the end of life; these are typically measured within 10 years after screening.

Study Selection Criteria

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs and systematic reviews of these studies.

In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

To assess longer-term outcomes and adverse effects, single-arm studies that captured longer periods of follow-up and/or larger populations.

To supplement the review of evidence for indications where evidence was extremely limited, clinical practice guidelines were included. Primary guidelines were selected based on the following criteria:

• Established, recognized professional organization
• Published guideline process that included conflict of interest, agreed-upon process including grading of recommendations and disclosure of when consensus or expert opinion was used
• Existence of an associated evidence appraisal (systematic review, comprehensive references, etc)
• Guideline is accessible (PubMed indexed or freely available through the organizational website)

Review of Evidence

The USPSTF concluded the evidence base is sparse on screening intervals in asymptomatic women. While 2 studies showed no advantage to repeated testing, other evidence suggested that the optimal screening interval may vary by baseline BMD, age, and use of hormone replacement therapy.^6, The 2018 USPSTF systematic review of the evidence on screening interval identified 2 studies with variable BMD that suggested no advantage to repeated bone measurement testing.^9,10, However, prognostic modeling from other studies suggested that the optimal screening interval varies by baseline BMD, and that age and use of hormone replacement therapy might also influence optimal screening intervals.^11,12,13,

A review of evidence by the Agency for Healthcare Research and Quality Southern California Evidence-Based Practice Center for the American College of Physicians identified moderate-quality evidence that women do not require frequent monitoring, with 10% of women with normal or mildly osteopenic DXA scores progressing to osteopenia within 15 years.^14,15,

Clinical Practice Guidelines

The USPSTF did not make a specific recommendation on repeat screening in asymptomatic individuals.

In 2016, the American Association of Clinical Endocrinologists and the American College of Endocrinology joint guidelines on the diagnosis and treatment of postmenopausal osteoporosis state that repeat BMD testing may be done to determine if or when to initiate treatment.^7,The frequency of testing should be individualized based on results of initial testing and on risk assessment. BMD testing every 1 to 2 years may be appropriate for those close to an intervention threshold on the initial test or with a high likelihood of future fracture based on risk factors.

The guidelines also note: "Differences between BMD results may simply reflect the inherent variability of the test measurement; thus, test­ing facilities must calculate the least significant change for relevant measurement sites to determine the magnitude of difference that represents a real change. This is determined using a facility’s regular technologist(s), patients, and device"

The Endocrine Society Guidelines for Osteoporosis in Men did not make a specific recommendation on repeat BMD testing in asymptomatic men.^8, However, the supporting document notes that the least significant change approach can be used to identify significant bone loss in men who are untreated. Because the expected rate of bone loss is slower in untreated men than the expected gains during treatment, less frequent measurements (e.g., 2-3 years) in untreated men may be a more appropriate screening interval.

Section Summary: Repeat Measurement of BMD for Individuals Without Osteoporosis on Initial Screen

Little research has been done on the frequency of BMD monitoring for osteoporosis. The available research has evaluated repeat measurement with central DXA. Evidence on whether repeat measurements add to risk prediction compared with a single measurement is mixed. Current evidence does not support frequent monitoring, but the optimal interval may differ depending on risk factors. lthough the optimal interval may differ depending on risk factors, current evidence does not support frequent monitoring. Although the evidence is limited, clinical practice guidelines from the American Association of Clinical Endocrinologists, the American College of Endocrinology, and the Endocrine Society recommend repeat DXA in 3-5 years in patients at low-risk. BMD testing every 1 to 2 years is often appropriate, depending on patient risk factors including age, baseline BMD T-score, and use of medications that adversely affect bone.

Repeat Measurement of Central BMD to Monitor Response to Pharmacologic Treatment

Clinical Context and Therapy Purpose

The purpose of BMD measurement in patients who are being evaluated for osteoporosis is to guide treatment.

The question addressed in this policy is: Does repeat BMD testing with central DXA improve the net health outcome in individuals who are being treated for osteoporosis?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals who are being treated for osteoporosis. Multiple classes of pharmacologic agents are available to treat patient with osteoporosis.

Interventions

The test being considered is repeat BMD testing with central DXA performed in the outpatient primary care setting.

Comparators

The following practices are currently being used to make treatment decisions: clinical risk assessment without BMD testing.

Outcomes

The general outcomes of interest are the occurrence of fractures and effects on QOL.

Monitoring of fractures may occur until the end of life; these are typically measured within 10 years after screening.

Study Selection Criteria

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs and systematic reviews of these studies.

In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

To assess longer-term outcomes and adverse effects, single-arm studies that captured longer periods of follow-up and/or larger populations.

To supplement the review of evidence for indications where evidence was extremely limited, clinical practice guidelines were included. Primary guidelines were selected based on the following criteria:

• Established, recognized professional organization
• Published guideline process that included conflict of interest, agreed-upon process including grading of recommendations and disclosure of when consensus or expert opinion was used
• Existence of an associated evidence appraisal (systematic review, comprehensive references, etc)
• Guideline is accessible (PubMed indexed or freely available through the organizational website)

Review of Evidence

Several moderate quality studies included in the Agency for Healthcare Research and Quality report showed that fracture risk may be reduced with pharmacologic treatment even when BMD does not increase.^14,15, In the Fracture Intervention Trial, 6459 women randomized to bisphosphonates or to placebo underwent annual bone density scans. A secondary analysis found an average within-person variation in BMD measurement of 0.013 g/cm², which was substantially higher than the average annual increase in BMD (0.0085 g/cm²) in the alendronate group.^16,

Clinical Practice Guidelines

In 2019, the Endocrine Society published clinical practice guidelines on the pharmacological management of osteoporosis in postmenopausal women.^17, Recommendations on these guidelines were based on systematic reviews and meta-analyses, and application of the GRADE methodological framework, including quality of evidence assessments and strength of recommendation designations. When evidence was extremely limited, recommendations were based on expert review.

For women who are being treated for osteoporosis, the guidelines recommended BMD testing with central DXA every 1 to 3 years to assess response to treatment. In women who are taking bisphosphonates, the guideline authors recommended reassessment of fracture risk after 3 to 5 years (5 years for oral, 3 for IV) with clinical risk assessment and BMD testing. Women who remain at high-risk of fractures should continue therapy, whereas those who are at low- tomoderate-risk of fractures should be considered for a “bisphosphonate holiday." Once a bisphosphonate holiday is initiated, fracture risk should be reassessed every 2 to 4 years. Clinicians should consider reinitiating osteoporosis therapy earlier than the 5-year suggested maximum if there is a significant decline in BMD, a fracture, or other factors that alter the clinical risk status. For women taking denosumab, the guideline authors recommended reassessment of fracture risk with BMD and clinical risk assessment after 5 to 10 years. Women who remain at high-risk of fractures should either continue denosumab or be treated with other osteoporosis therapies.

The American Association of Clinical Endocrinologists and the American College of Endocrinology published joint guidelines on the diagnosis and treatment of postmenopausal osteoporosis.^7, For patients on osteoporosis pharmacotherapy, the guidelines recommended obtaining a baseline DXA and repeating DXA every 1 to 2 years until findings are stable. Successful treatment of osteoporosis was defined as stable or increasing BMD with no evidence of new frac­tures or fracture progression. The guidelines recommended continued follow-up every 1-2 years or at a less-frequent interval, depending on clinical circum­stances. They also noted that follow-up of patients should ideally be conducted in the same facility with the same machine

Recommendations on length of treatment were as follows:

• "Treatment with teriparatide should be limited to 2 years
• For oral bisphosphonates, consider a “bisphos­phonate holiday” after 5 years of stability in moderate-risk patients
• For oral bisphosphonates, consider a “bisphos­phonate holiday” after 6 to 10 years of stability in higher-risk patients
• For intravenous (IV) zoledronic acid, consider a drug holiday after 3 annual doses in moderate-risk patients and after 6 annual doses in higher-risk patients.
• Teriparatide or raloxifene may be used during the 'bisphosphonate holiday' period for higher-risk patients
• A drug 'holiday' is not recommended with deno­sumab
• The ending of the 'holiday' for bisphospho­nate treatment should be based on individual patient circumstances (fracture risk or change in BMD or BTMs) "

Section Summary:Repeat Measurement of Central BMD to Monitor Response to Pharmacologic Treatment

There is no high-quality evidence to guide how often to monitor BMD during osteoporosis treatment. Within-person variation in measurement may exceed treatment effects, and fracture risk may be reduced in the absence of changes in BMD.Although the evidence is limited, multiple professional organizations have published guidelines recommending repeat DXA to monitor treatment response in patients who are receiving pharmacological treatment for osteoporosis. Guidelines from the American Association of Clinical Endocrinologists, the American College of Endocrinology, and the Endocrine Society recommend repeating DXA every 1-3 years after initiation or change in treatment, with longer intervals once therapeutic effect is established.

Ultrasound Densitometry, Quantitative Computed Tomography, or DXA Analysis of Peripheral Sites

Clinical Context and Therapy Purpose

The purpose of bone density measurement with methods other than central DXA in patients who have risk factors for osteoporosis is guide treatment.

The question addressed in this policy is: Does BMD testing with tests other than central DXA improve the net health outcome in individuals with risk factors for osteoporosis?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with risk factors for osteoporosis.

Interventions

The test being considered are bone tests other than central DXA performed in the outpatient primary care setting.

Comparators

The following practices are currently being used to make treatment decisions: clinical risk factor assessment following DXA analysis of central sites.

Outcomes

The general outcomes of interest are the occurrence of fractures and effects on QOL.

Monitoring of fractures may occur until the end of life; these are typically measured within 10 years after screening.

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs and systematic reviews of these studies.

In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

To assess longer-term outcomes and adverse effects, single-arm studies that captured longer periods of follow-up and/or larger populations.

Review of Evidence

In the review of evidence for the USPSTF, 10 studies were identified that compared calcaneal quantitative ultrasound to central DXA.^6, Pooled estimates of area under the curves were 0.77 (95% confidence interval, 0.72-0.81; 1969 participants) in women and 0.80 (95% confidence interval, 0.67-0.94; 5142 participants) in men. Similar findings were observed for digital x-ray radiogrammetry, peripheral DXA, and radiographic absorptiometry. For predicting osteoporotic fractures, no meaningful differences in accuracy by type of bone test were observed. A study by Adams et al (2018) is consistent with the results of the USPSTF systematic review, showing the prediction of fracture with a “biomechanical” computed tomography (CT) analyzed on previously taken clinical CT scans that were at least as good as DXA.^18, No studies were identified that guided treatment based on CT scan results.

Clinical Practice Guidelines

The USPSTF did not recommend specific screening tests but said the most commonly used test is central DXA.

Section Summary: Ultrasound Densitometry, or Quantitative CT, or DXA Analysis of Peripheral Sites

In comparison with central DXA, other measures of bone health showed area under the curves around 0.80 for the identification of osteoporosis. No studies have shown that they can select patients who benefit from treatment for osteoporosis. There is little to no evidence on the usefulness of repeat measurement of BMD using these techniques.

Summary of Evidence

BMD studies can be used to identify individuals with osteoporosis and monitor response to osteoporosis treatment, with the goal of reducing the risk of fracture. Bone density is most commonly evaluated withDXA; other technologies are available.

For individuals who are eligible for screening of BMD based on risk factor assessment who receive DXA analysis of central sites (hip or spine), the evidence includes systematic reviews of RCTs and cohort studies. Relevant outcomes are morbid events, functional outcomes, QOL, hospitalizations, and medication use. Central DXA is the most widely accepted method for measuring BMD and is the reference standard against which other screening tests are evaluated. BMD measurements with central DXA identify individuals at increased risk of fracture, and osteoporosis medications reduce fracture risk in the population identified as osteoporotic by central DXA. Therefore, test results with initial central DXA can be used to guide therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals without osteoporosis on initial screen who receive repeat DXA analysis of central sites (hip or spine), the evidence includes systematic reviews of large cohort and observational studies. Relevant outcomes are morbid events, functional outcomes, QOL, hospitalizations, and medication use. Little research has been done on the frequency of BMD monitoring for osteoporosis. The available research has evaluated repeat measurement with central DXA. Evidence on whether repeat measurements add to risk prediction compared with a single measurement is mixed. Although the optimal interval may differ depending on risk factors, current evidence does not support repeat monitoring in patients with BMD on DXA in the normal range. The evidence is insufficient to determine the effects of the technology on health outcomes. Although the evidence is limited, multiple clinical practice guidelines recommend repeat DXA in 3-5 years in patients at low-risk using risk factor assessment. Similarly, multiple guidelines recommend a repeat screening interval of 1-2 years for high-risk individuals and in individuals with a baseline evaluation near a fracture intervention threshold (osteopenia).

For individuals who are receiving pharmacologic treatment for osteoporosis who receive repeat DXA analysis of central sites (hip or spine), the evidence includes systematic reviews of RCTs and observational studies. Relevant outcomes are morbid events, functional outcomes, QOL, hospitalizations, and medication use. There is no high-quality evidence to guide how often to monitor BMD during osteoporosis treatment. Within-person variation in measurement may exceed treatment effects, and fracture risk has been shown to be reduced in some treatment studies in the absence of changes in BMD. Together, these results suggest that frequent (ie, every 2 years) repeat monitoring has low value. It is unclear whether DXA at the end of the initial 5 years of therapy is sufficiently accurate to guide subsequent therapy. The evidence is insufficient to determine the effects of the technology on health outcomes. Although the evidence is limited, multiple clinical practice guidelines recommend repeat DXA at intervals of 1-3 years to monitor treatment response in patients who are receiving pharmacological treatment for osteoporosis or after a change in or cessation of treatment.

For individuals who are eligible for screening of BMD based on risk factor assessment who receive ultrasound densitometry, or quantitative CT, or DXA analysis of peripheral sites, the evidence includes observational studies and systematic reviews. Relevant outcomes are morbid events, functional outcomes, QOL, hospitalizations, and medication use. In comparison with central DXA, other measures of bone health showed area under the curves around 0.80 for the identification of osteoporosis. These technologies are not commonly used for BMD measurements in practice, and no studies have shown that they can select patients who benefit from treatment for osteoporosis. There is little to no evidence on the usefulness of repeat measurement of BMD using these techniques. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

American College of Obstetricians and Gynecologists

In 2012 (reaffirmed 2016), the ACOG updated its guidelines on managing osteoporosis in women.^19, The guidelines recommended that bone mineral density (BMD) screening should begin for all women at age 65 years. In addition, the ACOG recommended screening for women younger than 65 years in whom the Fracture Risk Assessment Tool indicates a 10-year risk of osteoporotic fracture of at least 9.3%. Alternatively, ACOG recommended BMD screening women younger than 65 or with any of the following risk factors (they are similar, but not identical to risk factors in the Fracture Risk Assessment Tool):

· Personal medical history of a fragility fracture

· Parental medical history of hip fracture

· Weight less than 127 lb

· Medical causes of bone loss (i.e., medications or disease)

· Current smoker

· Alcoholism

· Rheumatoid arthritis

· For women who begin medication treatment for osteoporosis, a repeat BMD is recommended 1 to 2 years later to assess effectiveness. If BMD is improved or stable, additional BMD testing (in the absence of new risk factors) is not recommended. The guideline notes that it generally takes 18 to 24 months to document a clinically meaningful change in BMD and thus a 2-year interval after treatment initiation is preferred to 1 year.

· The guidelines do not specifically discuss repeat BMD screening for women who have a normal finding on the initial test.

· Routine BMD screening is not recommended for newly menopausal women as a “baseline” screen.

American Society for Bone and Mineral Research

The 2016 guidelines from an American Society for Bone and Mineral Research task force included the following statement on managing osteoporosis in patients on long-term bisphosphonate treatment:^20,

"Reassessment includes clinical evaluation, risk assessment including risk factors, and may include bone density measurement by DXA. The monitoring interval with DXA should be based upon changes that are detectable and clinically significant. Reassessment may be necessary at less than 2 years in patients with a new fracture, or in light of anticipated accelerated bone loss (e.g. institution of aromatase inhibitor or glucocorticoid therapy)."

National Osteoporosis Foundation

In 2014, the NOF updated its practice guidelines.^21, The NOF guidelines recommended that all postmenopausal women and men ages 50 and older be evaluated clinically for osteoporosis risk to determine the need for BMD testing.

Indications for BMD testing included:

· “[W]omen age 65 and older and men age 70 and older” regardless of clinical risk factors

· “[P]ostmenopausal women and men above age 50-69, based on risk factors profile”

· “[P]ostmenopausal women and men age 50 and older who have had an adult age fracture…”

· “Adults with a condition … or taking a medication … associated with low bone mass or bone loss”

The NOF stated that measurements for monitoring patients should be performed in accordance with medical necessity, expected response, and in consideration of local regulatory requirements. The NOF recommended that repeat BMD assessments generally agree with Medicare guidelines of every 2 years, but recognized that testing more frequently may be warranted in certain clinical situations.

The NOF also indicated that:

“Central DXA [dual x-ray absorptiometry] assessment of the hip or lumbar spine is the ‘gold standard’ for serial assessment of BMD. Biological changes in bone density are small compared to the inherent error in the test itself, and interpretation of serial bone density studies depends on appreciation of the smallest change in BMD that is beyond the range of error of the test. This least significant change (LSC) varies with the specific instrument used, patient population being assessed, measurement site, technologist’s skill with patient positioning and test analysis, and the confidence intervals used. Changes in the BMD of less than 3-6 % at the hip and 2-4 % at the spine from test to test may be due to the precision error of the testing itself.”

American College of Physicians

The 2017 guidelines from the American College of Physicians on the treatment of osteoporosis recommended against bone density monitoring during the 5-year pharmacologic treatment period of osteoporosis in women (weak recommendation, low-quality evidence).^14, The American College of Physicians noted that data from several studies showed a reduction in fractures with pharmacologic treatment, even when BMD did not increase. In addition, current evidence “does not support frequent monitoring of women with normal bone density for osteoporosis, because data showed that most women with normal CSA scores did not progress to osteoporosis within 5 years.”

American College of Radiology

The 2017 update of appropriateness criteria from the American College of Radiology,^22,, state that BMD measurement is indicated whenever a clinical decision is likely to be directly influenced by the result of the test. Indications for DXA of the lumbar spine and hip included but were not limited to the following patient populations:

1. All women age 65 years and older and men age 70 years and older (asymptomatic screening)

2. Women younger than age 65 years who have additional risk for osteoporosis, based on medical history and other findings. Additional risk factors for osteoporosis include:

a. Estrogen deficiency

b. A history of maternal hip fracture that occurred after the age of 50 years

c. Low body mass (less than 127 lb or 57.6 kg)

d. History of amenorrhea (more than 1 year before age 42 years)

a. Current use of cigarettes

b. Loss of height, thoracic kyphosis

5. Individuals age 50 years and older who develop a wrist, hip, spine, or proximal humerus fracture with minimal or no trauma, excluding pathologic fractures

6. Individuals of any age who develop one or more insufficiency fractures

7. Individuals being considered for pharmacologic therapy for osteoporosis.

8. Individuals being monitored to:

a. Assess the effectiveness of osteoporosis drug therapy.

b. Follow-up medical conditions associated with abnormal BMD.

The 2019 update of the International Society for Clinical Densitometry guidelines recommended bone density testing in the following patients^23,:

· Women age 65 and older

· For post-menopausal women younger than age 65 a bone density test is indicated if they have a risk factor for low bone mass fracture such as;

o Low body weight

o Prior fracture

o High-risk medication use

o Disease or condition associated with bone loss.

· Men aged 70 and older.

· Men under < 70 years … if they have risk factors for low bone mass such as;

o Low body weight

o Prior fracture

o High-risk medication use

o Disease or condition associated with bone loss.

· Adults with a disease or condition associated with low bone mass or bone loss….

· Anyone being considered for pharmacologic therapy.

· Anyone being treated, to monitor treatment effect.

· Anyone not receiving therapy in whom evidence of bone loss would lead to treatment.”

The 2019 position statement makes the following recommendations on serial BMD measurements:

• Serial BMD testing in combination with clinical assessment of fracture risk, bone turnover markers, and other factors including height loss and trabecular bone score, can be used to determine whether treatment should be initiated in untreated patients, according to locally applicable guidelines.
• Serial BMD testing can monitor response to therapy by finding an increase or stability of bone density.
• Serial BMD testing should be used to monitor individuals following cessation of osteoporosis pharmacologic therapy.
• Serial BMD testing can detect loss of bone density, indicating the need for assessment of treatment adherence, evaluation of secondary causes of osteoporosis, and re-evaluation of treatment options.
• Follow-up BMD testing should be done when the results are likely to influence patient management.
• Intervals between BMD testing should be determined according to each patient’s clinical status: typically one year after initiation or change of therapy is appropriate, with longer intervals once therapeutic effect is established.
• In conditions associated with rapid bone loss, such as glucocorticoid therapy, testing more frequently is appropriate.

A search of ClinicalTrials.gov in November 2019 did not identify any ongoing or unpublished trials that would likely influence this review.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Vertebral Fracture Assessment

Clinical Context and Test Purpose
The purpose of performing vertebral fracture assessment (VFA) using densitometry by dual-energy x-ray absorptiometry (DXA) is to diagnose whether the patient has a vertebral fracture.

The question addressed in this policy is whether there is sufficient evidence that screening for VFA using DXA improves the net health outcome in patients at risk of having vertebral fractures compared with alternative approaches.

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals at risk of vertebral fractures who do not manifest physical symptoms.

Interventions
The relevant intervention of interest is VFA with densitometry using DXA.

Comparators
The following tools and tests are currently being used to make decisions about managing patients at risk for vertebral fracture: DXA alone for the assessment of bone mineral density (BMD) as well as spine radiography. Radiography is used to confirm the occurrence of vertebral fractures but is not recommended as a routine component of osteoporosis assessment because of radiation exposure and inconvenience (ie, the need for an additional procedure).

Outcomes
Outcomes of interest for diagnostic accuracy include test accuracy and test validity (eg, sensitivity, specificity). The primary outcome of interest for clinical utility is morbid events, specifically the incidence of future clinical fractures.

Timing
VFA with densitometry by DXA would occur at the time of osteoporosis screening. The recommended age at which to start screening with DXA and the frequency of screening is addressed in national guidelines.

Setting
The imaging tests are performed in an outpatient setting.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Systematic Reviews
Several recent studies have compared the diagnostic accuracy of VFA with standard radiography. A systematic review of studies was published by Lee et al (2016).¹ They included studies with postmenopausal women and/or men 50 years and older that compared the diagnostic accuracy of VFA with DXA with spinal radiography. Seventeen studies met selection criteria; 5 were excluded because of inadequate description of methods or results. Of the remaining 12 studies, 4 examined postmenopausal women, 5 included osteoporotic patients (men and women), and 2 included both populations. Studies were heterogeneous, and thus reviewers did not pool study findings. Among the 8 studies that reported findings on a per-vertebral level, the sensitivity of VFA with DXA ranged from 70% to 93% and the specificity ranged from 95% to 100%. Nine studies reported findings on a per-patient level. Sensitivity ranged from 65% to 100% and specificity from 74% to 100%. Reviewers did not report separate analyses for the diagnostic accuracy of VFA with DXA in osteoporotic vs nonosteoporotic patients.

Nonrandomized Trials
One study included in the systematic review and judged to have a low risk of bias was published by Domiciano et al (2013).² The authors reported on 429 adults at least 65 years old who had VFA with densitometry and spine radiography on the same day. On VFA, vertebral fractures were identified in 77 (29.7%) of 259 women and in 48 (28.2%) of 170 men. Comparable numbers on spine radiographs were 74 (28.6%) of 259 women and 52 (30.6%) of 170 men. Compared with spine radiography, the sensitivity of VFA was 81.7% (95% confidence interval [CI], 73.9% to 88.1%) and the specificity was 92.7% (95% CI, 9.2% to 95.4%).

The diagnostic performance of VFA with DXA has tended to be lower in older studies. For example, Ferrar et al (2008) evaluated the performance of vertebral assessment using a visual algorithmbased approach.³ Subjects in the low-risk group were women ages 55 to 79 years who were randomly selected from their general practitioners’ offices. Most had a normal BMD or were osteopenic. Subjects in the high-risk group were recruited after a low-trauma fracture to the hip, forearm, or humerus. Most high-risk patients had osteopenia or osteoporosis. In the per-patient analysis and including all poor or unreadable images, the sensitivity of VFA was 60% in the low-risk group and 81% in the high-risk group; specificity was 97% in both groups. Also, Binkley et al (2005) compared VFA (GE Lunar densitometer) with radiography in 27 osteoporotic, 38 osteopenic, and 15 normal women.⁴ Blinded analysis correctly identified 17 of 18 radiographically evident grade 2 to 3 fractures (a false-negative rate, 6%). The study did not describe whether the grade 2 or 3 fractures were found in women with osteoporosis, osteopenia, or normal BMD. Also, only 11 (50%) of 22 grade 1 fractures were identified. Thirty vertebrae were classified as fractured when no fractures were present (38% false-positive), 29 of these were grade 1 fractures by VFA with normal radiography. Also, VFA identified 40 grade 1 fractures, but only 11 (28%) were true-positive results. Also problematic is that results were compared only in vertebrae evaluable by VFA; 1 patient could not be evaluated due to poor image quality, and 66% of T4 to T6 vertebrae in other subjects could not be adequately visualized.

Section Summary: Clinically Valid
Several studies have compared VFA with radiography, and they were evaluated in a 2016 systematic review. The sensitivity of VFA compared with standard radiography reported in these studies varied. More recent studies have also reported higher diagnostic accuracy than older studies (ie, sensitivities in the 80% to 99% range and specificities over 90%).

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

No randomized controlled trials comparing health outcomes in individuals screened with VFA plus bone densitometry using DXA with those screened with bone densitometry using DXA alone were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

A chain of evidence for the clinical utility of VFA screening is based on evidence that VFA identifies appropriate candidates for treatment who would not otherwise be identified, and there is evidence that treatment in this population is beneficial. The chain involves evaluating: (1) evidence that VFA is accurate, (2) evidence that VFA identifies appropriate candidates for treatment who would not otherwise be identified, and (3) evidence that treatment in this population is actually beneficial.

The National Osteoporosis Foundation’s (NOF) 2014 guidelines⁵ has recommended considering the U.S. Food and Drug Administration‒approved medical treatment for the following groups of patients:

· “In those with hip or vertebral (clinical or asymptomatic) fractures
· In those with T-scores ≤-2.5 at the femoral neck, total hip or lumbar spine by DXA
· In postmenopausal women and men age 50 and older with low bone mass (T-score between -1.0 and -2.5, osteopenia) at the femoral neck, total hip, or lumbar spine by DXA and a 10-year hip fracture probability ≥ 3% or a 10-year major osteoporosis-related fracture probability of ≥ 20% based on the USA-adapted WHO [World Health Organization] absolute fracture risk model (Fracture Risk Algorithm [FRAX]….)”

Because patients with osteoporosis (T score, ≤ -2.5) diagnosed by DXA and patients with low bone mass and other risk factors for fracture would be treated regardless of vertebral fractures, any incremental benefit using a VFA-inclusive strategy would accrue in the population without osteoporosis.

VFA to Identify Candidates Who Would Not Otherwise Be Identified
As stated above, the NOF (2014) guidelines have recommended treating patients with osteoporosis, osteopenia, and other risk factors as well as those with hip or vertebral fractures (clinical or asymptomatic).

VFA has been used to identify candidates for treatment when patients with vertebral fractures do not fall into one of the other established categories. No studies were identified that specifically dealt with whether VFA could identify candidates for medication treatment who would not otherwise have been identified, but several studies are somewhat informative. Representative studies with larger sample sizes are described next.

Kanterewicz et al (2014) in Spain collected data on a population-based cohort of 2968 postmenopausal women between the ages of 59 and 70 years.⁷ A total of 127 (4.3%) women had a vertebral fracture according to VFA. Among them, 48.0% had osteoporosis, and 42.5% had osteopenia. Moreover, 42.5% had previous fragility fractures, and 34.6% had a first-degree family history of fractures. Thus, VFA could identify women who would be eligible for fracture prevention therapy according to NOF guidelines (ie, women who did not have osteoporosis, osteopenia plus a 10-year fracture risk, or other risk factors). The authors did not attempt to define this subgroup of women with normal BMD and other risk factors.

Mrgan et al (2013) in Denmark published a retrospective study evaluating VFA with BMD in 3275 patients presenting for osteoporosis screening or evaluation of anti-osteoporotic medication; 85% were women.⁸ Vertebral fractures were found using VFA in 260 (7.9%) patients. Of them, 156 patients (4.8% of the total sample) had osteoporosis (ie, BMD at least -2.5) and 104 (3.2% of the total sample) did not, according to BMD. The data suggested that up to 40% (104/250) of patients with vertebral fractures identified would be eligible for treatment by NOF guidelines and might not have been identified were DXA alone used. Some patients, however, might have had osteopenia and other risk factors that would have led to their eligibility for treatment.

Jager et al (2011) reported on 2424 consecutive patients (65% female) referred for BMD for a variety of reasons at a single center in the Netherlands.⁹ Participants underwent VFA with BMD during the same session. Vertebral fractures (reduction in the height of at least 20%) were detected in 541 (22%) patients. The prevalence of vertebral fractures was 14% (97/678) in patients with normal BMD and 21% (229/1100) in patients with osteopenia. Thus, 60.5% (326/541) of the patients with vertebral fracture did not have osteoporosis and would have been eligible for treatment based on NOF guidelines if they did not fall into another eligibility category (eg, osteopenia with other risk factors). Most fractures had not been identified in the past. The vertebral fractures were previously unknown in 74% of patients with normal BMD and 71% of patients with osteopenia.

Pharmacologic Treatment for Vertebral Fracture and Low Bone Mass
Bisphosphonates decrease bone resorption and are the major class of drugs now used to treat osteoporosis.

Several subgroup analyses of large randomized controlled trials evaluating the efficacy of bisphosphonates in patients with low bone mass and/or baseline vertebral fractures have been published. The trials were not designed a priori to assess efficacy according to baseline vertebral fracture status or BMD categories. The Fracture Intervention Trial (FIT) study group was the first large multicenter study comparing the effects of treatment between osteoporotic women and women with low bone mass without existing vertebral fractures using the revised National Health and Nutrition Examination Survey cutoffs.¹⁰ This trial randomized 4432 women to alendronate or placebo and analyzed the treatment group in 3 BMD categories (<-2.5 SD, -2.0 to -2.5 SD; -1.6 to -2.0 SD below the mean). Women with a BMD less than -2.5 SD had a statistically significant reduction in clinical and vertebral fractures over 4 years. The relative risk (RR) for all clinical fractures among patients with a BMD less than -2.5 SD was 0.6 (95% CI, 0.5 to 0.8). There was no significant reduction in all clinical fractures for women with higher BMD values (RR=1.1; 95% CI, 0.9 to 1.4), suggesting no benefit among patients with low bone mass or normal BMD.

Quandt et al (2005) reanalyzed FIT study data for the outcome of clinical vertebral fractures (symptomatic and diagnosed by a physician) and radiographically detected (assessed at surveillance intervals) vertebral fractures.¹¹ A total of 3737 women at least 2 years postmenopausal with low bone mass (T score between -1.6 and -2.5) were included in the analysis. Among the women with low bone mass and existing radiographically detected vertebral fractures (n=940), the rate of subsequent clinical vertebral fractures was 6 (a rate of 43/10,000 person-years of risk) in the alendronate group and 16 (124/10,000 person-years of risk) in the placebo group. Alendronate treatment compared with placebo was accompanied by an RR of 0.3 (95% CI, 0.1 to 0.8) for clinical vertebral fractures and an RR of 0.5 (95% CI, 0.3 to 0.8) for radiographically detected fractures. Similar risk estimates were found for women having low bone mass without vertebral fractures, but absolute risks were lower (12 vs 81 fractures per 10,000 person-years for those without and with baseline fractures, respectively).

Kanis et al (2005) reanalyzed data on 1802 women at least 5 years postmenopausal from the Vertebral Efficacy with Risedronate Therapy (VERT) trials who were identified on the basis of a prior radiographically detected vertebral fracture regardless of BMD and had radiographs available at baseline and 3 years.¹² Overall, there was a significantly lower rate of a new vertebral fracture in women with prior vertebral fracture randomized to treatment with risedronate (14.5%) than to placebo (22.3%; p<0.001). In the group with a T score greater than -2.5, the rate of new femoral neck fractures was 50 (11%) of 519 in the risedronate group and 71 (15.5%) of 537 in the placebo group (p=0.049). In the osteoporotic group, for those with a T score of -2.5 or lower, the rate of new femoral neck fracture was 53 (18.7%) of 355 in the risedronate group and 92 (33.4%) of 318 in the placebo group (p<0.001). Findings were similar when the T score at the most severe skeletal site (femoral neck or lumbar spine) was used for stratification.

No randomized controlled trials were identified that evaluated the efficacy of bisphosphonate treatment in men with vertebral fractures and low bone density. Several trials have evaluated whether bisphosphonate treatment increases BMD in men at risk for bone loss (eg, on androgen deprivation therapy).^13,14 However, vertebral fractures were not assessed and, therefore, conclusions cannot be drawn about the potential benefit of VFA added to densitometry in at-risk men.

Section Summary: Clinically Useful
Routine use of VFA with DXA will identify substantial numbers of patients with previously unrecognized vertebral fractures. Many of these vertebral fractures are found in patients without osteoporosis. Data are not available on how many of the vertebral fractures in nonosteoporotic patients were in patients who would not otherwise be eligible for treatment (ie, those with osteopenia and other risk factors for fracture).

Evidence from the FIT and VERT studies has suggested that treatment of patients with low bone mass (but not osteoporosis) reduces further fractures. However, the FIT and VERT studies were post hoc subgroup analyses, which are considered to be exploratory. Also, vertebral fracture screening was done using radiography rather than VFA software. Advantages of the studies are that the 2 subgroup reanalyses had large sample sizes and used data from well-conducted randomized trials.

Currently, this chain of evidence is insufficient to determine whether treatment of patients with low bone density and vertebral fractures improves outcomes.

Summary of Evidence
For individuals who are at risk of having vertebral fractures but are not known to have them who receive VFA with densitometry by dual-energy x-ray absorptiometry, the evidence includes diagnostic accuracy studies and subgroup reanalyses of treatment studies. Relevant outcomes are test accuracy, test validity, and morbid events. There is a lack of direct evidence from screening trials that use densitometry with and without VFA improves health outcomes. Because direct evidence was not available, a chain of evidence was sought. Evidence was examined on the diagnostic accuracy of VFA in nonosteoporotic patients (ie, those not already eligible for treatment), the ability of VFA to identify patients for treatment who would not otherwise be identified, and the effectiveness of treatment in this population. Diagnostic accuracy studies have reported variable findings; recent studies have suggested higher diagnostic accuracy of VFA overall compared with standard radiographs than older studies. Studies have found that VFA can identify patients without osteoporosis who may be appropriate candidates for treatment according to recommendations from the National Osteoporosis Foundation. However, there is limited evidence on the effectiveness of treatment in this population. No treatment data have been published on patients whose vertebral fractures were identified using VFA software with densitometry. The evidence is insufficient to determine the effects of the technology on health outcomes.

Supplemental Information

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 5 physician specialty societies and 6 academic medical centers when this policy was under review in 2014. One of the 5 specialty societies only submitted a practice statement and did not respond to questions. Input was mixed on whether vertebral fracture assessment using dual-energy x-ray absorptiometry is considered investigational. Input was also mixed on whether the diagnostic accuracy of vertebral fracture assessment using dual-energy x-ray absorptiometry is sufficiently high to justify its use as an alternative to plain radiographs. There was near-consensus agreement with National Osteoporosis Foundation recommendations regarding imaging to evaluate for vertebral fractures. Responders did not cite published literature to support the National Osteoporosis Foundation recommendations. Also, there was near-consensus that patients with vertebral fracture alone (ie, no low bone mineral density and no other signs of osteoporosis) should be treated with medications to reduce fracture risk.

Practice Guidelines and Position Statements

National Osteoporosis Foundation
The National Osteoporosis Foundation’s (2014) guide to prevention and treatment of osteoporosis stated:

“A vertebral fracture is consistent with a diagnosis of osteoporosis, even in the absence of a bone density diagnosis, and is an indication for pharmacologic treatment with osteoporosis medication to reduce fracture risk. Most vertebral fractures are asymptomatic when they first occur and often are undiagnosed for many years. Proactive vertebral imaging is the only way to diagnose these fractures. The finding of a previously unrecognized vertebral fracture may change the diagnostic classification, alters future fracture risk and subsequent treatment decisions.”⁵

· “All women age 70 and older and all men age 80 and older….
· Women age 65 to 69 and men age 75 to 79 when BMD [bone mineral density] T-score is -1.5 or below.
· Postmenopausal women age 50 to 64 and men age 50 to 69 … with specific risk factors:
o Low-trauma fracture…
o Historical height loss of 1.5 in. or more (4 cm)
o Prospective height loss of 0.8 in. or more (2 cm)
o Recent or ongoing long-term glucocorticoid treatment.”

· “Women age ≥ 70 years or men ≥ 80 year
· Historical height loss > 4 cm (>1.5 inches)
· Self-reported but undocumented prior vertebral fracture
· Glucocorticoid therapy equivalent to ≥ 5 mg of prednisone or equivalent per day for ≥3 months.”

Endocrine Society
The Endocrine Society (2012) recommended pharmacologic therapy for men at high risk for fracture.¹⁸ Risk included but were not limited to the following criteria:

· “Men who have had a hip or vertebral fracture without major trauma.
· Men who have not experienced a spine or hip fracture but whose BMD of the spine, femoral neck, and/or total hip is 2.5 SD or more below the mean of normal young white males.
· In the United States, men who have a T-score between -1.0 and -2.5 in the spine, femoral neck, or total hip plus a 10-yr risk of experiencing any fracture ≥20% or 10-yr risk of hip fracture ≥3% using FRAX [Fracture Risk Algorithm]; further studies will be needed to determine appropriate intervention levels using other fracture risk assessment algorithms….
· Men who are receiving long-term glucocorticoid therapy in pharmacologic doses (e.g. prednisone or equivalent >7.5 mg/d), according to the 2010 guidelines of the American Society of Rheumatology.”

Table 1. Guidelines on the Treatment of Low Bone Density or Osteoporosis

Recommendation	GOE	QOE
“ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinically recognized osteoporosis.”	Weak	Low
“ACP recommends that clinicians should make the decision whether to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences, fracture risk profile, and benefits, harms, and costs of medications.”	Weak	Low

ACP: American College of Physicians; GOE: grade of evidence; QOE: quality of evidence.

North American Menopause Society
The North American Menopause Society’s (2010) position statement on management of osteoporosis did not include a recommendation for or against VFA as part of the screening process.²⁰ The statement indicated that vertebral fracture must be confirmed by lateral spine radiographs or VFA visualization of fracture at the time of BMD testing.

U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force (2018) updated its recommendations on screening for osteoporosis to prevent fractures.^21,22 The recommendations included: “Most treatment guidelines recommend using BMD, as measured by central DXA, to define osteoporosis and the treatment threshold to prevent osteoporotic fractures.” Peripheral DXA and quantitative ultrasound are also described as common bone measurement screening tests for osteoporosis. VFA was not specifically mentioned.

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in August 2018 did not identify any ongoing or unpublished trials that would likely influence this review.]

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Bone Mineral Density Studies and Vertebral Fracture Assessment With Densitometry
Bone Mineral Density Studies
Bone Density Studies
Absorptiometry, Dual-Energy Radiographic (DEXA)
Absorptiometry, Dual-Photon (DPA)
Absorptiometry, Single-Photon (SPA)
DEXA (Dual-Energy Radiographic Absorptiometry)
DPA (Dual-Photon Absorptiometry)
Dual-Energy Radiographic Absorptiometry (DEXA)
Dual-Photon Absorptiometry (DPA)
Osteoporosis, Bone Density Studies for
Photodensitometry
QCT (Quantitative Computed Tomography)
Quantitative Computed Tomography (QCT)
RA (Radiographic Absorptiometry)
Radiographic Absorptiometry (RA)
Single Photon Absorptiometry (SPA)
Sonometry, Bone Density
SPA (Single Photon Absorptiometry)
Ultrasound Bone Densitometry
Morphometric X-Ray Absorptiometry (MXA)
Instant Vertebral Assessment (IVA)
Lateral Vertebral Assessment (LVA)
Vertebral Fracture Assessment With Densitometry
Densitometry for Vertebral Fracture Assessment

References:

Bone Mineral Density Studies
1. World Health Organization (WHO). FRAX: Fracture Risk Assessment Tool. n.d.; http://www.shef.ac.uk/FRAX/tool.jsp. Accessed January 2, 2020.

2. Crandall CJ, Newberry SJ, Diamant A, et al. Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review. Ann Intern Med. Nov 18 2014;161(10):711-723. PMID 25199883

3. National Osteoporosis Foundation. Osteoporosis: review of the evidence for prevention, diagnosis and treatment and cost-effectiveness analysis. Introduction. Osteoporos Int. 1998;8 Suppl 4(suppl 4):S7-80. PMID 10197173

4. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Ultrasonography of the heel for diagnosing osteoporosis and selecting patients for pharmacologic treatment. TEC Assessments. 1999;Volume 14:Tab 19.

5. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Ultrasonography of peripheral sites for diagnosing and selecting patients for pharmacologic treatment for osteoporosis. TEC Assessments. 2002;Volume 17:Tab 5.

6. U.S. Preventive Services Task Force (USPSTF). Osteoporosis: Screening to Prevent Fractures. 2018; http://www.uspreventiveservicestaskforce.org/uspstf/uspsoste.htm. Accessed January 2, 2020.

7. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016. Endocr Pract. Sep 02 2016;22(Suppl 4):1-42. PMID 27662240

8. Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab., 2012 Jun 8;97(6). PMID 22675062

9. Hillier TA, Stone KL, Bauer DC, et al. Evaluating the value of repeat bone mineral density measurement and prediction of fractures in older women: the study of osteoporotic fractures. Arch Intern Med. Jan 22 2007;167(2):155-160. PMID 17242316

10. Berry SD, Samelson EJ, Pencina MJ, et al. Repeat bone mineral density screening and prediction of hip and major osteoporotic fracture. JAMA. Sep 25 2013;310(12):1256-1262. PMID 24065012

11. Frost SA, Nguyen ND, Center JR, et al. Timing of repeat BMD measurements: development of an absolute risk-based prognostic model. J Bone Miner Res. Nov 2009;24(11):1800-1807. PMID 19419321

12. Gourlay ML, Fine JP, Preisser JS, et al. Bone-density testing interval and transition to osteoporosis in older women. N Engl J Med. Jan 19 2012;366(3):225-233. PMID 22256806

13. Gourlay ML, Overman RA, Ensrud KE. Bone Density Screening and Re-screening in Postmenopausal Women and Older Men. Current osteoporosis reports. Dec 2015;13(6):390-398. PMID 26408154

14. Qaseem A, Snow V, Shekelle P, et al. Screening for osteoporosis in men: a clinical practice guideline from the American College of Physicians. Ann Intern Med. May 06 2008;148(9):680-684. PMID 18458281

15. Agency for Healthcare Research and Quality. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: Update of a 2007 Report. 2012; https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/osteoporosis-bone-fracture_research.pdf. Accessed January 2, 2020.

16. Bell KJ, Hayen A, Macaskill P, et al. Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data. BMJ. 2009;338:b2266. PMID 19549996

17. Eastell R, Rosen CJ, Black DM, et al. Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society* Clinical Practice Guideline.. J. Clin. Endocrinol. Metab., 2019 Mar 26;104(5). PMID 30907953

18. Adams AL, Fischer H, Kopperdahl DL, et al. Osteoporosis and Hip Fracture Risk From Routine Computed Tomography Scans: The Fracture, Osteoporosis, and CT Utilization Study (FOCUS). J Bone Miner Res. Jul 2018;33(7):1291-1301. PMID 29665068

19. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Osteoporosis (Practice Bulletin N. 129). Obstet Gynecol. Sep 2012, reaffirmed 2014;120(3):718-734. PMID 22914492

20. Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research.. J. Bone Miner. Res., 2016 Oct 21;31(10). PMID 27759931

21. National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis. 2014; https://my.nof.org/file/bonesource/Clinicians-Guide.pdf. Accessed January 2, 2020.

22. Expert Panel on Musculoskeletal I, Ward RJ, Roberts CC, et al. ACR Appropriateness Criteria((R)) Osteoporosis and Bone Mineral Density. J Am Coll Radiol. May 2017;14(5S): S189-S202. PMID 28473075

23. International Society for Clinical Densitometry. 2013 ISCD Official Positions-Adult 2013; http://www.iscd.org/official-positions/2013-iscd-official-positions-adult/. Accessed January 2, 2020.

24. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination for Bone (Mineral) Density Studies (150.3). 2007; http://www.cms.gov/Regulations-and- Guidance/Guidance/Transmittals/downloads/R70BP.pdf. Accessed January 2, 2020.

Vertebral Fracture Assessment with Densitometry
1. Lee JH, Lee YK, Oh SH, et al. A systematic review of diagnostic accuracy of vertebral fracture assessment (VFA) in postmenopausal women and elderly men. Osteoporos Int. May 2016;27(5):1691-1699. PMID 26782682

2. Domiciano DS, Figueiredo CP, Lopes JB, et al. Vertebral fracture assessment by dual X-ray absorptiometry: a valid tool to detect vertebral fractures in community-dwelling older adults in a population-based survey. Arthritis Care Res (Hoboken). May 2013;65(5):809-815. PMID 23212896

3. Ferrar L, Jiang G, Clowes JA, et al. Comparison of densitometric and radiographic vertebral fracture assessment using the algorithm-based qualitative (ABQ) method in postmenopausal women at low and high risk of fracture. J Bone Miner Res. Jan 2008;23(1):103-111. PMID 17892377

4. Binkley N, Krueger D, Gangnon R, et al. Lateral vertebral assessment: a valuable technique to detect clinically significant vertebral fractures. Osteoporos Int. Dec 2005;16(12):1513-1518. PMID 15834512

5. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. Oct 2014;25(10):2359-2381. PMID 25182228

6. Centre for Metabolic Bone Diseases, University of Sheffield U. FRAX Fracture Risk Assessment Tool: Calculation Tool. n.d.; https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9. Accessed August 31, 2017.

7. Kanterewicz E, Puigoriol E, Garcia-Barrionuevo J, et al. Prevalence of vertebral fractures and minor vertebral deformities evaluated by DXA-assisted vertebral fracture assessment (VFA) in a population-based study of postmenopausal women: the FRODOS study. Osteoporos Int. May 2014;25(5):1455-1464. PMID 24599272

8. Mrgan M, Mohammed A, Gram J. Combined vertebral assessment and bone densitometry increases the prevalence and severity of osteoporosis in patients referred to DXA scanning. J Clin Densitom. Oct-Dec 2013;16(4):549-553. PMID 23769657

9. Jager PL, Jonkman S, Koolhaas W, et al. Combined vertebral fracture assessment and bone mineral density measurement: a new standard in the diagnosis of osteoporosis in academic populations. Osteoporos Int. Apr 2011;22(4):1059-1068. PMID 20571773

10. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. Jama. Dec 23-30 1998;280(24):2077-2082. PMID 9875874

11. Quandt SA, Thompson DE, Schneider DL, et al. Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of-1.6 to -2.5 at the femoral neck: the Fracture Intervention Trial. Mayo Clin Proc. Mar 2005;80(3):343-349. PMID 15757015

12. Kanis JA, Barton IP, Johnell O. Risedronate decreases fracture risk in patients selected solely on the basis of prior vertebral fracture. Osteoporos Int. May 2005;16(5):475-482. PMID 15875093

13. Bhoopalam N, Campbell SC, Moritz T, et al. Intravenous zoledronic acid to prevent osteoporosis in a veteran population with multiple risk factors for bone loss on androgen deprivation therapy. J Urol. Nov 2009;182(5):2257-2264. PMID 19758618

14. Greenspan SL, Nelson JB, Trump DL, et al. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med. Mar 20 2007;146(6):416-424. PMID 17371886

15. Rosen HN, Vokes TJ, Malabanan AO, et al. The official positions of the International Society for Clinical Densitometry: vertebral fracture assessment. J Clin Densitom. Oct-Dec 2013;16(4):482-488. PMID 24063846

16. International Society for Clinical Densitometry. 2015 ISCD Official Positions – Adult. 2015; https://www.iscd.org/official-positions/2015-iscd-official-positions-adult/. Accessed August 17, 2018.

17. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. Endocr Pract. Sep 02 2016;22(Suppl 4):1-42. PMID 27662240

18. Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. Jun 2012;97(6):1802-1822. PMID 22675062

19. Qaseem A, Forciea MA, McLean RM, et al. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. Jun 06 2017;166(11):818-839. PMID 28492856

20. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. Jan-Feb 2010;17(1):25-54; quiz 55-56. PMID 20061894

21. U.S. Preventive Services Task Force. Osteoporosis to Prevent Fractures: Screening. 2018; https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/osteoporosis-screening1. Accessed August 17, 2018.

22. U. S. Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for osteoporosis to prevent fractures: US Preventive Services Task Force Recommendation Statement. JAMA. Jun 26 2018;319(24):2521-2531. PMID 29946735

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

76977
77078
77080
77081
77085
77086
78350
78351
0508T

G0130