The literature search of the 2018 systematic review by the US Preventive Services Task Force in the noncancer population was used as the evidentiary base upon which the Expert Panel based many of its recommendations. A total of 61 additional studies on topics and populations not covered in the US Preventive Services Task Force review were also included. Patients with cancer with metastatic disease and cancer survival outcomes related to bone-modifying agents are not included in this guideline.

RECOMMENDATIONS

Patients with nonmetastatic cancer may be at risk for osteoporotic fractures due to baseline risks or due to the added risks that are associated with their cancer therapy. Clinicians are advised to assess fracture risk using established tools. For those patients with substantial risk of osteoporotic fracture, the clinician should obtain a bone mineral density test. The bone health of all patients may benefit from optimizing nutrition, exercise, and lifestyle. When a pharmacologic agent is indicated, bisphosphonates or denosumab at osteoporosis-indicated dosages are the preferred interventions.

INTRODUCTION

Section:

In 2019, there are approximately 16 million survivors of cancer in the United States and approximately 32 million worldwide.¹ Survivors of cancer in the United States are increasingly in their sixth, seventh, and eighth decade of life. The two largest groups of survivors are women with early-stage breast cancers and men with nonmetastatic prostate cancers (NMPC), and these patients frequently have received cancer treatments that cause particularly high rates of bone loss. It is the coalescence of survivors of cancer and osteoporosis, a health problem of near-epidemic proportion that forms the underlying rationale for this evidence-based guideline.

The prevalence of osteoporosis worldwide is estimated at 200 million. At least 40% of postmenopausal women and 15% to 30% of men will experience a fragility fracture.² Osteoporosis can be thought of as an equation.³ The equation, simply stated, is the peak bone mass achieved by age 30 years minus the ongoing losses related to age and menopause. Osteoporosis is a complex genetic disease^4,5 and no genetic markers for either low peak bone mass or high later losses are yet being measured routinely in clinical settings; however, family history, especially of hip fracture, is an important predictor of fractures, as is advancing age.⁶ Lifestyle factors also affect bone loss. For example, cigarette smoking and excessive alcohol consumption, as well as non–cancer-specific medications (eg, glucocorticoids) promote bone loss (Table 1).

TABLE 1. Osteoporotic Fracture Risk Factors

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In patients with nonmetastatic cancer, both the disease itself, through an association with increased local and systemic inflammation, and its treatment can pose challenges to skeletal integrity. Chronic inflammation can promote increased bone loss through altered systemic bone remodeling, increased bone resorption, and impaired bone formation.⁸ This is a result of the effect of inflammatory mediators on the differentiation and activity of osteoclasts and osteoblasts.⁸ Osteoclastogenesis and osteoclasts’ activity can be influenced by proinflammatory cytokines, such as tumor necrosis factor, interleukin-1, interleukin-6, macrophage colony-stimulating factor, and RANK ligand (RANK-L).⁷

THE BOTTOM LINE

Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic Disease: ASCO Clinical Practice Guideline

Guideline Questions

Which patients with nonmetastatic cancer are at increased risk for developing osteoporotic fractures?
How should patients with nonmetastatic cancer who are at an elevated risk for osteoporotic fractures be screened?
Which patients with nonmetastatic cancer should be treated and which interventions are effective in reducing the risk of osteoporotic fractures?

Target Population

Adults with nonmetastatic cancer, including patients in active treatment (eg, receiving aromatase inhibitors, antiandrogens, or gonadotropin-releasing hormone (GnRH) agonists or chemotherapy-induced ovarian failure [CIOF]) and long-term cancer survivors.

Target Audience

Oncologists, endocrinologists, specialists in rehabilitation, orthopedics, primary care physicians, and any other relevant member of a comprehensive multidisciplinary cancer care team, as well as patients and their caregivers.

Methods

An Expert Panel was convened to develop clinical practice guideline recommendations based on a systematic review of the medical literature.

Recommendations

CLINICAL QUESTION 1

Risk: Which patients with nonmetastatic cancer are at increased risk for developing osteoporotic fractures?

Recommendation 1.1.

It is recommended that patients with nonmetastatic cancer who meet any of the following criteria be considered to be at increased risk for developing osteoporotic fractures:

Advanced age
Current cigarette smoking
Excessive alcohol consumption
History of prior nontraumatic fractures in adulthood
Hypogonadism
Impaired mobility
Increased risks for falls
Long-term exposure to glucocorticoids
Low body weight
Parental history of hip fracture
Postmenopausal status

(Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate)

Qualifying statement.

Cutoffs used to define advanced age, excessive alcohol consumption, long-term glucocorticoid exposure, and low body weight vary across studies and populations. The specifics around these continuous predictors and the thresholds most often associated with increased risk are described further within the supporting text.

Recommendation 1.2.

Clinicians should be aware that the patient’s anticancer therapy (eg, aromatase inhibitors, antiandrogens, or GnRH agonists, or CIOF) may result in short- or long-term increased risk of osteoporotic fracture and should take anticancer therapy into account as potentially adding to baseline risk (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).

Recommendation 1.3.

Clinicians may use a risk assessment tool (eg, the WHO Fracture Risk Assessment Tool [FRAX]) to quantify the risk estimates for osteoporotic fracture in adult patients with nonmetastatic cancer. To date, existing risk assessment tools have not been validated in patients with cancer and clinical judgment is necessary in interpreting results from these tools (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).

Qualifying statement.

Note that several medical conditions that are known to cause bone loss are included in risk assessment tools, such as FRAX. Clinicians who are attempting to quantify the risk of osteoporosis or osteoporotic fracture should also consider additional evaluation or referral if there is a history or clinical suspicion of rarer high-risk conditions, such as endocrine or metabolic causes of secondary osteoporosis (eg, hypercortisolism, hyperparathyroidism, or acromegaly), disorders of collagen metabolism, and high-risk medications (or multiple moderate-risk medications) as described in the text.

CLINICAL QUESTION 2

Screening: How should patients with nonmetastatic cancer who are at an increased risk for osteoporotic fractures be screened?

Recommendation 2.1.

Patients with nonmetastatic cancer with one or more risk factors for osteoporotic fracture, as per Recommendation 1, should be offered bone mineral density (BMD) testing with central/axial dual-energy x-ray absorptiometry (DXA). In settings in which DXA is not available or technically feasible, other BMD testing (eg, quantitative ultrasound or calcaneal DXA) should be offered (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).

Recommendation 2.2.

Patients with nonmetastatic cancer who are prescribed a drug that causes bone loss or whose baseline or subsequent BMD is near the threshold of treatment using FRAX should be offered BMD testing every 2 years, or more frequently if deemed medically necessary, based on the results of BMD testing and expected bone loss. Testing should generally not be conducted more than annually (Type: expert panel consensus, relative balance of benefits and harms; Evidence quality: insufficient).

CLINICAL QUESTION 3

Treatment: Which patients with nonmetastatic cancer should be treated and which interventions are effective in reducing the risk of osteoporotic fractures?

Nonpharmacologic Intervention

Recommendation 3.1.

Clinicians should encourage patients to consume a diet with adequate calcium and vitamin D. If intake of calcium (1,000 to 1,200 mg/d) and vitamin D (at least 800 to 1,000 IU/d) is not being consumed, then supplements to reach those levels are recommended (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).

Recommendation 3.2.

Clinicians should actively encourage patients to engage in a combination of exercise types, including balance training, flexibility or stretching exercises, endurance exercise, and resistance and/or progressive strengthening exercises, to reduce the risk of fractures caused by falls. Whenever possible, exercise should be tailored according to the needs and abilities of the individual patient. Patients with an impairment hindering their gait or balance should be offered medical rehabilitation (Type: evidence based, benefits outweigh harms; Evidence quality: low; Strength of recommendation: moderate).

Recommendation 3.3.

Clinicians should actively encourage patients to stop smoking and to limit alcohol consumption, as smoking and alcohol consumption are risk factors for osteoporosis (Type: evidence based, benefits outweigh harms; Evidence quality: low; Strength of recommendation: moderate).

Pharmacologic Intervention

Recommendation 3.4.

For patients with nonmetastatic cancer with osteoporosis (T scores of −2.5 or less in the femoral neck, total hip, or lumbar spine) or who are at increased risk of osteoporotic fractures based on clinical assessment or risk assessment tools (10-year probability of ≥ 20% for major osteoporotic fractures or ≥ 3% for hip fractures based on the US-adapted FRAX tool), bone-modifying agents, such as oral bisphosphonates, intravenous (IV) bisphosphonates or subcutaneous denosumab at the osteoporosis-indicated dosage, may be offered to reduce the risk of fracture. Hormonal therapies for osteoporosis management (eg, estrogens) are generally avoided in patients with hormonal-responsive cancers. For patients without hormonally responsive cancers, estrogens may be offered along with other bone-modifying agents when clinically appropriate (Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong).

Qualifying statement.

Current evidence suggests that oral bisphosphonates, IV bisphosphonates, and subcutaneous denosumab are each efficacious options. The choice of which bone-modifying agent to offer should be based on several important considerations, including patient preference, potential adverse effects, quality-of-life considerations, adherence, safety for that population, cost, and availability.

Recommendation 3.5.

Provided that T score and/or risk assessment (eg, FRAX-estimated fracture risk) exceed threshold values for fractures (as described in Recommendation 3.4), the following specific populations may be considered appropriate candidate for bone-modifying agents:

Premenopausal women receiving GnRH therapies causing ovarian suppression or with CIOF or who have undergone an oophorectomy
Postmenopausal women who are receiving aromatase inhibitors
Men who have received or are receiving androgen deprivation therapy
Patients undergoing or with a history of bone marrow transplantation
Patients with chronic (> 3 to 6 months) glucocorticoid use

(Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong)

Qualifying statement.

The short-term bone loss associated with these conditions can be rapid. Because of this, clinicians could consider treatment at higher bone density or T score than recommended using FRAX or similar tools, with decision making further guided by anticipated losses as reviewed in the text (ie, the bulleted conditions above should be included as having secondary osteoporosis in the FRAX assessment tool).

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.

A number of cancer treatments also cause bone loss (Table 1). Estrogens and androgens maintain bone mass and mitigate bone loss.⁸ Cancer treatments, such as gonadotropin-releasing hormone (GnRH) agonists and chemotherapy-induced ovarian failure (CIOF) in premenopausal women, aromatase inhibitors (AIs) in postmenopausal women, and antiandrogens in men with NMPC, cause cancer-treatment induced bone loss.⁹ The estimated magnitude of bone loss due to cancer treatments is described in Table 2. Bone loss that occurs with cancer therapy is more rapid and severe than postmenopausal bone loss in women or normal age-related osteoporosis in men.⁹ Rates of bone loss occurring with cancer therapy can be more than seven-fold higher than that of normal aging.

TABLE 2. Bone Loss Associated With Various Cancer Therapies⁹

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The purposes of this systematic review and evidence-based guideline are to evaluate randomized controlled trials (RCTs) and other fundamental studies reported in the literature regarding osteoporosis in survivors of cancer, compare outcomes among trials, and provide guidance to clinicians on the management of osteoporosis in survivors of adult-onset cancers.

GUIDELINE QUESTIONS

Section:

This clinical practice guideline addresses three overarching Clinical Questions:

Which patients with nonmetastatic cancer are at increased risk for developing osteoporotic fractures?
How should patients with nonmetastatic cancer who are at an elevated risk for osteoporotic fractures be screened?
Which patients with nonmetastatic cancer should be treated and which interventions are effective in reducing the risk of osteoporotic fractures?

METHODS

Section:

Guideline Development Process

This systematic review-based guideline product was developed by a multidisciplinary Expert Panel (Appendix Table A1, online only) that included a patient representative and an ASCO guidelines staff member with health research methodology expertise. The Expert Panel met via teleconference and/or webinar and corresponded through e-mail. Based upon the consideration of the evidence, the authors were asked to contribute to the development of the guideline, provide critical review, and finalize guideline recommendations. Guideline recommendations were sent for an open comment period of 2 weeks, allowing the public to review and comment on the recommendations after submitting a confidentiality agreement. These comments were taken into consideration while finalizing the recommendations. Members of the Expert Panel were responsible for reviewing and approving the penultimate version of guideline, which was then circulated for external review and submitted to Journal of Clinical Oncology for editorial review and consideration for publication. All ASCO guidelines are ultimately reviewed and approved by the Expert Panel and the ASCO Clinical Practice Guideline Committee before publication. All funding for the administration of the project was provided by ASCO.

This evidentiary base was developed using a planned two-stage method that included an initial search and evaluation of existing guidelines and systematic reviews. Any relevant existing guideline or systematic review that addressed the research questions and was of reasonable quality would be included and form the core of the evidentiary base. As a second step, a systematic review of the primary literature would be conducted to focus on any areas not covered by existing reviews.

For this guideline, the literature search of the systematic review conducted by the US Preventive Services Task Force (USPSTF)¹⁰ in the noncancer population was used as the evidentiary base upon which the Expert Panel based many of its recommendations due to the paucity of evidence for fracture prevention outcomes in survivors of cancer. Supplementary literature searches were also conducted in PubMed (from January 2000 to December 4, 2018) to identify topics and populations not covered in the USPSTF review. The reference lists of included studies along with the personal reference lists of the Expert Panel were searched for additional studies.

A priori decision rules were established that specified that only comprehensive systematic reviews with relevance to at least one of the three clinical questions posed would receive formal quality assessments. Identified systematic reviews that required additional consideration based on the criteria above were assessed using the AMSTAR 2 tool.¹¹ Results of the AMSTAR 2 assessment were used to determine whether an existing review could be incorporated as part of the evidentiary base. Any identified reviews that did not meet the above criteria, that had important deficiencies in quality as indicted by AMSTAR 2 assessment, or that were otherwise not incorporated as part of the evidence base would be reported in the reference list but not further described or discussed. Any identified article not already included in the USPSTF review were selected for inclusion in the systematic review of the evidence based on the following criteria:

Clinical question 1: Increased risk.

Comparative studies that included bone health outcomes and considered therapeutic exposures and other factors related to bone morbidity.

Clinical question 2: Screening for osteoporosis.

Comparative studies that evaluated the utility and accuracy of screening in patients who are at risk for osteoporosis or fractures, including clinical exams, risk assessment tools, dual-energy x-ray absorptiometry (DXA), and other imaging techniques.

Clinical question 3: Interventions.

RCTs that investigated interventions for reducing the risk of osteoporosis and fractures, including bisphosphonates, RANK-L inhibitors, calcium and vitamin D, and lifestyle modifications.

Articles were excluded from the systematic review if they were (1) meeting abstracts not subsequently published in peer-reviewed journals; (2) editorials, commentaries, letters, news articles, case reports, or narrative reviews; or (3) published in a non-English language. Patients with cancer with metastatic disease are not included in this guideline, nor are survival outcomes, both of which are addressed in a recent American Society of Clinical Oncology/Cancer Care Ontario guideline.¹² Guideline recommendations are crafted, in part, using the Guidelines Into Decision Support methodology.¹³ In addition, a guideline implementability review was conducted. Based on the implementability review, revisions were made to the draft to clarify recommended actions for clinical practice. Ratings for the type and strength of recommendation, evidence, and potential bias are provided with each recommendation. The Methodology Manual (available at www.asco.org/guideline-methodology) provides additional information about the methods used to develop this guideline.

The ASCO Expert Panel and guidelines staff will work with co-chairs to keep abreast of any substantive updates to the guideline. Based on formal review of the emerging literature, ASCO will determine the need to update. This is the most recent information as of the publication date. Visit www.asco.org/survivorship-guidelines to submit new evidence.

Guideline Disclaimer

The Clinical Practice Guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (ASCO) to assist providers in clinical decision making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among patients. Recommendations reflect high, moderate, or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like “must,” “must not,” “should,” and “should not” indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an “as is” basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information, or for any errors or omissions.

Guideline and Conflicts of Interest

The Expert Panel was assembled in accordance with ASCO’s Conflict of Interest Policy Implementation for Clinical Practice Guidelines (“Policy,” found at www.asco.org/rwc). All members of the Expert Panel completed ASCO’s disclosure form, which requires disclosure of financial and other interests, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include employment; leadership; stock or other ownership; honoraria, consulting or advisory role; speaker's bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships. In accordance with the Policy, the majority of the members of the Expert Panel did not disclose any relationships constituting a conflict under the Policy.

RESULTS

Section:

The USPSTF 2018 systematic review included 168 studies that ranged in quality from good to fair and included systematic reviews, RCTs, and other comparative study designs.¹⁰ The supplemental systematic review identified a total of 2,191 new, unique citations published between 2000 and 2018, of which 362 were pulled for full-text review. Ultimately, 61 studies (23 risk and 38 intervention studies) were included (the Data Supplement provides a flow diagram of search results). Included studies are heterogeneous with respect to patient populations, sample size, methodologic quality, testing, treatment duration, and outcome measures. This diversity precluded a quantitative analysis and, as such, only a qualitative review was performed.

Study Quality Assessment

Study quality was formally assessed for the USPSTF systematic review and an additional 38 intervention studies were identified. Systematic reviews and meta-analyses were assessed for quality using the AMSTAR tool. Design elements, such as blinding, allocation concealment, sufficient sample size, intention to treat, funding sources, and so on, were assessed for RCTs. In general, most identified studies exhibited a low-to-intermediate potential risk of bias. AMSTAR scores ranged from 1 to 11 of a possible 11 points. Overall, the included systematic reviews were conducted in a rigorous fashion; however, some primary studies included in these reviews and other primary RCTs identified for inclusion in this analysis suffered from industry sponsorship, lack of blinding, and lack of reporting of intention-to-treat analyses. Additional RCTs that were identified and included ranged from low-to-intermediate overall risk of bias. Cohort studies were assessed for design elements, such as prospective design and data collection, consecutive sampling method, and the use of objective outcomes. Only one cohort study was included and deemed to have an overall low risk of bias. Refer to the Data Supplement for quality rating scores and the Methodology Manual (www.asco.org/guideline-methodology) for definitions of ratings for overall potential risk of bias.

Key Outcomes of Interest

Table 3 outlines the studies that were particularly pertinent to the development of the recommendations.

TABLE 3. Outcomes of Interest Summary

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RECOMMENDATIONS

Section:

CLINICAL QUESTION 1

Which patients with nonmetastatic cancer are at increased risk for developing osteoporotic fractures?

Recommendation 1.1

It is recommended that patients with nonmetastatic cancer who meet any of the following criteria should be considered to be at increased risk for developing osteoporotic fractures:

Advanced age
Current cigarette smoking
Excessive alcohol consumption
History of prior nontraumatic fractures in adulthood
Hypogonadism
Impaired mobility
Increased risk for falls
Long-term exposure to glucocorticoids
Low body weight
Parental history of hip fracture
Postmenopausal status

(Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate)

Qualifying statement.

Cutoffs used to define advanced age, excessive alcohol consumption, long-term glucocorticoid exposure, and low body weight vary across studies and populations. The specifics around these continuous predictors and the thresholds that are most often associated with increased risk are described further within the supporting text.

Recommendation 1.2

Clinicians should be aware that the patient’s anticancer therapy (eg, AIs, androgen-deprivation therapy [ADT], GnRH agonists, or CIOF) may result in short- or long-term increased risk of osteoporotic fracture and should take anticancer therapy into account as potentially adding to baseline risk (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).

Recommendation 1.3

Clinicians may use a risk assessment tool (eg, the WHO Fracture Risk Assessment Tool [FRAX]) to quantify the risk estimates for osteoporotic fracture in adult patients with nonmetastatic cancer. To date, existing risk assessment tools have not been validated in patients with cancer and clinical judgment is necessary when interpreting results from these tools (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).

Qualifying statement.

Literature review and analysis.

The USPSTF review outlined common general risk factors for osteoporotic fractures, including advanced age, current smoking, excessive alcohol consumption, low body weight, parental history of hip fracture, and postmenopausal status in women.¹⁰ Advancing age, defined as age 65 years or older in women and 70 years or older in men, has been reported to be a more critical determinant of fracture than bone mass.¹⁰ A systematic review in men reports advancing age to be a statistically significant risk factor when evaluated as a continuous variable compared in 5- or 10-year increments or when used as a defined variable of age older than 70 years.⁴⁸ Increasing alcohol intake to greater than 10 servings per week was also a statistically significant risk factor, as were current smoking and history of chronic glucocorticoid use, although there was variability in how chronic was defined within the included studies.¹⁵ Body weight less than 58 kg (127 lbs) can also increase clinical risk.¹¹ History of a prior fracture in adulthood is another important risk factor, although some sites, such as the hip, the vertebra, and the humerus, are associated with a higher risk of subsequent fracture than others.^49,50

The connection between treatment with endocrine therapy in patients with cancer and bone loss is thought to be related to the downregulation of estrogen and/or testosterone, which can alter physiologic bone turnover and osteoblastic activity.^51,52 In women with breast cancer receiving AI therapy, there is a two- to four-fold increase in bone loss compared with physiologic postmenopausal bone mineral density (BMD) loss.^33,53-55 A patient-level meta-analysis of 31,920 postmenopausal women with estrogen receptor–positive early breast cancer suggests that the risk of fracture with 5 years of AI treatment is 8.2% versus 5.5% for tamoxifen (absolute excess 2.7%; 95% CI, 1.7 to 3.7).⁵⁶ Data from other study designs, which are believed to be more in line with a real-world setting, suggest that the fracture incidence in women with breast cancer receiving an AI is as high as 20% after 5 years of follow up.^33,57-63 With recent guidelines⁶⁴ recommending an increased duration of AI treatment in higher-risk patients for up to 10 years, fracture risk is believed to increase by 2% to 3% per annum.³³ In men with prostate cancer, treatment with ADT leads to an accelerated and disrupted bone turnover process and BMD loss in the range of 5% to 10% in the first year of ADT.^51,54,55 One study showed that, in 390 patients with prostate cancer, age 54 to 89 years, the prevalence of osteoporosis was 35% in hormone-naïve patients, 43% after 2 years of ADT, and 81% after 10 years of ADT.^33,65

Treatment with radiation therapy can also have a direct effect on bone in the treated field which leads to bone atrophy. It can also indirectly effect bone through vascular changes.⁶⁶ Insufficiency fractures are a common complication after radiation therapy and generally affect bones that are under the most physiologic stress⁶⁷—for example, pelvic or rib fractures with pelvic or chest irradiation, respectively.

A variety of physical, metabolic, and psychosocial changes in patients with cancer, such as malnourishment due to nausea, weight loss, and cancer-related fatigue, can also lead to bone loss. Nutritional deterioration can occur at any point in the timeline of cancer diagnosis, treatment, or support.⁶⁸ Whereas the etiology of cancer cachexia is multifactorial and complex, it is characterized by the loss of skeletal muscle even in the presence of adequate food intake, which can consequently lead to diminishing muscle strength and bone mass.^68,69 Cancer-related fatigue also often leads to reduced physical activity, which, in turn, can contribute to mechanical unloading, sarcopenia, and bone loss.⁶⁸

As reported by the USPSTF,¹¹ the discriminative ability of FRAX (available at https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9) to predict future fracture varied by sex, site of fracture prediction, and whether BMD was used in the risk prediction. Specifically, in women, pooling area under the curves (AUCs) identified in 10 to 17 studies by the USPSTF yielded estimates that ranged from 0.66 to 0.79. In cohorts of men, pooled estimates from three to 44 studies ranged from 0.62 to 0.76. The predictive accuracy of FRAX was found to be greater for hip fractures compared with major osteoporotic fractures, and pooled AUC estimates were higher when BMD was included in the model. In studies of both men and women combined, pooled estimates for the prediction of major osteoporotic fracture was 0.67 without BMD and 0.69 with BMD. USPSTF also reported on the Garvan Fracture Risk Calculator and found that the pooled AUC estimate for risk assessment with BMD was 0.68 (95% CI, 0.64 to 0.71) for predicting major osteoporotic fracture in women and 0.73 (95% CI, 0.66 to 0.79) for predicting hip fracture.

Clinical interpretation.

The 2006 report by the Institute of Medicine, Cancer Patient to Cancer Survivor: Lost in Transition,⁷⁰ highlights the impact of cancer and its treatments on potential burdens in cancer survivorship. This includes the risk of bone loss, osteoporosis, and fractures. In 2016, there were 15.5 million survivors of cancer in the United States, with more than 60% of survivors being age 65 years or older.⁷¹ Many of those affected by cancer may be at increased risk for osteoporosis and fracture, either as a consequence of their cancer and/or cancer therapy or as a concurrent comorbid condition. Identifying late effects of cancer therapy is a clinically important part of oncology care and, as the data illustrate, also a public health concern.

Clinical question 1 identifies risks that are associated with osteoporotic fractures in nonmetastatic disease and specifically does not speak to pathologic fractures as seen in bone metastases. The majority of the bone health data in nonmetastatic cancer addresses bone loss due to hormonal changes with limited data on risk of fracture. However, there is considerable data on bone health and fracture in the general population, although there is a lack of awareness of these data among the public and health care professionals, as noted in the Surgeon General’s report on bone health and osteoporosis.⁷² The three recommendations that fall under clinical question 1 identify known risk factors and risk assessment tools for osteoporotic fractures in the general population and overlay the cancer-associated factors that may accelerate the baseline risk. Given the limited osteoporotic fracture data available in cancer-specific populations, the Expert Panel extrapolates the existing data from the established osteoporosis field and provides recommendations on how to stratify osteoporotic fracture risk in patients with nonmetastatic cancer.

CLINICAL QUESTION 2

How should patients with nonmetastatic cancer who are at an elevated risk for osteoporotic fractures be screened?

Recommendation 2.1

Patients with nonmetastatic cancer with one or more risk factors for osteoporotic fracture, as per Recommendation 1, should be offered BMD testing with central/axial DXA. In settings in which DXA is not available or technically feasible, other BMD testing—for example, quantitative ultrasound (QUS) or calcaneal DXA—should be offered (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).

Recommendation 2.2

Patients with nonmetastatic cancer who are prescribed a drug that causes bone loss or whose baseline or subsequent BMD is near the threshold of treatment using FRAX should be offered BMD testing every 2 years or more frequently if deemed medically necessary based on the results of BMD testing and expected bone loss. Testing should generally not be conducted more than annually. (Type: Expert Panel consensus; relative balance of benefits and harms; Evidence quality: insufficient)

Literature review and analysis.

The USPSTF systematic review¹⁰ identified 11 studies that evaluated the accuracy of QUS, peripheral DXA, digital x-ray absorptiometry, and radiographic absorptiometry in screening for low bone mass or osteoporosis in noncancer populations. The AUC for calcaneal QUS in identifying central DXA-measured osteoporosis ranged from 0.69 to 0.90 in female populations, with a pooled AUC estimate of 0.77 (95% CI, 0.72 to 0.82). Additional studies in women reported AUCs that ranged from 0.67 to 0.80 for peripheral DXA, 0.84 (95% CI, 0.79 to 0.89) for digital x-ray absorptiometry, and 0.80 (95% CI, 0.74 to 0.85) for radiographic absorptiometry. Studies that focused solely on a male population evaluated calcaneal QUS in comparison with a centrally measured DXA BMD T-score cutoff of −2.5 or less and reported AUCs that ranged from 0.70 to 0.93, with a pooled AUC estimate of 0.80 (95% CI, 0.67 to 0.94).

The USPSTF systematic review also collected studies that evaluated the accuracy of various bone measurement tests in predicting fractures.¹⁰ A total of 23 studies were identified and the USPSTF reported that, ultimately, there were no appreciable differences in accuracy according to imaging test administered or by the gender of the population. AUC estimates for fracture prediction based on central DXA with or without trabecular bone score ranged from 0.63 to 0.74 for any osteoporotic fracture, 0.61 to 0.75 for vertebral or spine fracture, and 0.64 to 0.85 for hip fractures.¹⁰ QUS had similar accuracy, with the AUC for prediction of osteoporotic fracture of 0.64 to 0.72. One study of QUS in an exclusively male population reported an AUC of 0.84 for hip fracture. DXA demonstrated an AUC of 0.61. For both genders, testing was associated with predictions of future fractures of the hip, whereas AUC estimates for prediction of fractures at other sites was low.

Looking exclusively at female participants, central DXA resulted in AUC estimates that ranged from 0.64 to 0.82 in postmenopausal women and QUS AUC estimates that ranged from 0.66 to 0.72.¹⁰ Of interest, combining two tests, such as DXA and QUS, did not seem to significantly increase AUC, which ranged from 0.72 to 0.81.¹⁰ Fracture prediction in exclusively male participants found that DXA resulted in AUC estimates that ranged from 0.64 to 0.85, QUS that ranged from 0.64 to 0.84, and a combination of DXA and QUS that ranged from 0.69 to 0.85.¹⁰

Harms reported by the USPSTF systematic review form the evidentiary base for adverse events of screening.¹⁰ A qualitative study of 50 patients found that many patients could not name harms associated with screening, and, when they did name harms, the focus was only on the harms of the screening test itself and rarely on harms further along the screening cascade.⁷³ Other factors, such as clinicians’ recommendations, their age, family or friends’ experiences with disease, and insurance coverage, played a role in their screening decisions.⁷³ The USPSTF reported on one study that evaluated the harms of screening for osteoporosis and found no difference in rates of anxiety or quality-of-life scores in participants screened versus those undergoing usual care. The USPSTF acknowledged that additional harms may include radiation exposure from DXA and an increase in opportunity costs to both the patient and health care system. However, radiation exposure is very low with DXA and is equivalent to approximately one tenth of the radiation dose of one chest x-ray or 0.01 mSV. Approximately 3 mSV is the radiation exposure from ambient and cosmic sources in an average person per year.⁷⁴

Clinical interpretation.

There has only been one RCT of screening for osteoporosis in the noncancer population.⁷⁵ This study enrolled women age 70 to 85 years and randomly assigned them to a two-step procedure of FRAX-based evaluation, followed by bone density testing for those at higher risk. Those with bone density results meeting the United Kingdom’s age-based hip fracture risk thresholds were then treated with prescription medications. This study reported a significant reduction in hip fractures with a hazard ratio (HR) of 0.72, and even though it did not reduce nonhip fractures, it was highly cost effective.⁷⁶ Given that the trial-based evidence is limited to this single recent study, evidence on the usefulness of screening outside of cancer has also come from two groups of studies. The first group has assessed how well bone density or clinical risk assessment tools identify osteoporosis or predict fractures. Results of these studies, as reviewed here, show that these have, at best, only moderate accuracy and that there has been considerable heterogeneity in the populations studied. A second group of studies that included multiple RCTs examined the efficacy of medications and other interventions among patients who were identified through such screening. In cancer settings, several similar medication studies were also performed in high-risk populations as reviewed in Clinical Question 3.

Given this evidence, we advise initial clinical evaluation of all patients with cancer with assessment of potential risk factors, then additional assessment with bone density measurement with DXA (or other technologies) for those at high risk. Although there is some evidence from cohort studies in some cancers regarding the importance of specific baseline fracture risk factors,⁷⁷ data for risk factors listed in Recommendation 1.1 is robust outside of cancer. We therefore specifically recommend bone density testing for patients with baseline risk factors as outlined in Recommendation 1.1. We particularly emphasize the importance of bone density measurement in previously untested women age 65 years or older, for whom all major noncancer guidelines recommend universal BMD testing. Many patients with the other risk factors listed in Recommendation 1.1 should also be tested, although, as always, clinical judgment should also be used. For example, clinicians may vary in their recommendations for baseline testing for younger male patients who have only one of the listed risk factors (eg, smoking) and who have a cancer treatment regimen that confers low risk for bone loss. It also should be noted that other factors could be considered, including if a patient is at risk for a less common secondary cause of osteoporosis and low long-term intake of calcium and vitamin D is expected. Our recommendations and the evidence for calcium and vitamin D dietary and supplement discussions are addressed in key Clinical Question 3 at length.

For patients who do not have any of the high-risk conditions or treatments, the Expert Panel recommends consideration of clinical risk prediction tools to guide bone density testing. The accuracy of these tools, including simple ones that use only a few risk factors, has been judged to be moderate for predicting osteoporosis for patients without cancer. Although no study has yet validated any of the tools in cancer populations, the panel believes that they offer a valuable way to quantify risk for counseling and decision making about additional testing.

We also note the importance of incorporating cancer treatments into initial and follow-up assessments of osteoporosis and fracture risk. A number of studies have reported particularly rapid bone losses with cancer treatments that induce hypogonadism or early menopause, or directly block estrogen or testosterone effects on bone.⁷⁸ Although many of these studies have not been large enough to assess fractures directly, it is clear that cumulative bone losses after several years can be very large, as summarized in Table 3, and all patients receiving these treatments should receive baseline testing and close follow up. Glucocorticoid effects on bone are also large, but a number of studies suggest that the effects of short-term regimens used in most cancer treatments are small or rapidly reversible. Long-term use (eg, 3 or more months) of glucocorticoid doses equivalent to prednisone greater than 2.5 mg per day or higher confer high fracture risk, however, and evaluation and treatment of such patients should follow guidelines that are specifically focused on them.⁷⁹

Data are particularly limited regarding the appropriate interval between bone density evaluations among patients with cancer. Guidelines outside of cancer, such as that from the International Society for Clinical Densitometry,⁸⁰ emphasize using both baseline bone density and expected losses to make recommendations for intervals between tests. Data such as that in Table 3 can be used to estimate expected losses and guide individualized recommendations for testing intervals. For patients who are treated with one of the agents listed in Recommendation 3, many clinicians also use repeat testing at 1 to 2 years to evaluate whether expected responses are occurring.

CLINICAL QUESTION 3

Which patients with nonmetastatic cancer should be treated and which interventions are effective in reducing the risk of osteoporotic fractures?

NONPHARMACOLOGIC INTERVENTION

Recommendation 3.1

Recommendation 3.2

Clinicians should actively encourage patients to engage in a combination of exercise types, including balance training, flexibility or stretching exercises, endurance exercise, and resistance and/or progressive strengthening exercises, to reduce the risk of fractures caused by falls. Whenever possible, exercise should be tailored according to the needs and abilities of the individual patient. Patients with an impairment that hinders their gait or balance should be offered medical rehabilitation (Type: evidence based, benefits outweigh harms; Evidence quality: low; Strength of recommendation: moderate).

Recommendation 3.3

Clinicians should actively encourage patients to stop smoking and to limit alcohol consumption as smoking and alcohol consumption are risk factors for osteoporosis (Type: evidence based, benefits outweigh harms; Evidence quality: low; Strength of recommendation: moderate).

Literature review and analysis.

Whereas there are specific studies in the cancer survivor population regarding bone health, there are more and larger studies, including systemic reviews, meta-analyses, and the recommendations of the USPSTF, on bone health in noncancer populations. To the extent possible and when appropriate, the Expert Panel considered both and extrapolations from noncancer populations to cancer populations are made. Although this approach introduces indirectness into the quality of the evidence, it is reassuring that the reported treatment effects are similar, which suggests that the assumption of generalizability is reasonable.⁸¹

Calcium and vitamin D: Noncancer populations.

A systematic review and meta-analysis¹⁴ that included 59 RCTs in noncancer patients age older than 50 years found that increasing calcium intake from dietary sources increased BMD by 0.6% to 1.0% at the total hip and total body at 1 year, and by 0.7% to 1.8% at total hip and body in addition to the lumbar spine and femoral neck at 2 years. Increases in BMD were similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus coadministration with vitamin D, and in trials with varying calcium doses.^14,15 However, these increases in BMD have not necessarily translated into a reduction in fracture risk as described in a systemic review of 26 RCTs.¹⁶ For dietary calcium, most studies reported no association between dietary calcium intake and fracture; however, calcium supplements did reduce the risk of total fracture (20 studies, N = 58,573; relative risk, 0.89; 95% CI, 0.81 to 0.96) and vertebral fracture (12 studies, N = 48,967; relative risk, 0.86; 95% CI, 0.74 to 1.00), but not hip (13 studies, N = 56,648; relative risk, 0.95; 95% CI, 0.76 to 1.18) or forearm fracture (eight studies, N = 51,775; relative risk, 0.96; 95% CI, 0.85 to 1.09). Yet when considering data only from high-quality trials with low risk of bias (four studies, N = 44,505), there was no effect of supplementation on the risk of fracture at any site.¹⁶

As trials of vitamin D supplementation on bone health also tend to include calcium, it is difficult to isolate the effects of each nutrient; however, a Cochrane review¹⁸ of 53 randomized trials with a total of 91,791 participants without cancer reports that there is high-quality evidence that vitamin D alone, in the formats and doses tested, is unlikely to be effective in preventing hip fracture (11 trials, 27,693 participants; relative risk [RR], 1.12; 95% CI, 0.98 to 1.29) or any new fracture (15 trials, 28,271 participants; RR, 1.03; 95% CI, 0.96 to 1.11). These results are supported by evidence gathered by other systematic reviews.¹⁷ Yet Avenell and colleagues¹⁸ report that there is high-quality evidence that vitamin D plus calcium results in a small reduction in hip fracture risk (nine trials, 49,853 participants; RR, 0.84; 95% CI, 0.74 to 0.96; P = .01) and a reduction in the incidence of new nonvertebral fractures. Evidence also suggests that vitamin D plus calcium supplementation reduces the risk of any type of fracture (10 trials, 49,976 participants; RR, 0.95; 95% CI, 0.90 to 0.99). These results are supported by a more recent meta-analysis.²⁰

Pooled patient-level data from 11 RCTs of oral vitamin D supplementation, with or without calcium, in persons age 65 years or older suggest that high-dose vitamin D supplementation (≥ 800 IU/d) reduces hip fracture and any nonvertebral fracture in persons age 65 years or older.⁸² The pooled data of 31,022 persons (mean age, 76 years; 91% women) showed that, by quartiles of actual intake, reduction in the risk of fracture was demonstrated only at the highest intake level (median, 800 IU/d; range, 792 to 2,000 IU/d), with a 30% reduction in the risk of hip fracture (HR, 0.70; 95% CI, 0.58 to 0.86) and a 14% reduction in the risk of any nonvertebral fracture (HR, 0.86; 95% CI, 0.76 to 0.96).⁸²

The Agency for Healthcare Research and Quality⁸³ identified and reported that a meta-analysis of 15 placebo-controlled trials of calcium demonstrated a small but statistically significant increase in the risk for myocardial infarction; however, serious concerns have been raised about methodologic issues and bias in these studies. Despite the uncertainty, it is recommended that patients figure out the calcium content that they get from their dietary sources and then only use supplements to get a total calcium dose of 1,000 to 1,200 mg per day.

Cancer population.

A review of calcium and vitamin D supplementation specifically in men with prostate cancer undergoing ADT found that the doses commonly recommended are inadequate to prevent the loss of BMD.²¹ In women receiving AIs for early breast cancer, the B-ABLE study (NCT03811509), which supplemented patients with 800 IU or more of vitamin D per day depending on baseline vitamin D levels, demonstrated significantly decreased AI-associated bone density loss after 1 year of AI treatment in women with serum vitamin D levels of40 ng/mL or more compared with those with levels less than 30 ng/mL.¹⁹ This may suggest that the standard dosing may not be adequate in the oncology setting, especially for women receiving AI. Because the prevalence of vitamin D deficiency in noncancer and cancer populations is high,^84,85 checking levels of 25-OH vitamin D is strongly recommended, either before starting AI or ADT and any cancer therapy that is associated with bone loss or when the first DXA scan shows osteopenia or osteoporosis.

Excercise: Noncancer population.

A Cochrane review considered the effectiveness of exercise interventions in preventing bone loss and fractures in postmenopausal women without cancer.²² Inclusion of 43 RCTs with 4,320 participants showed that high-force exercise, such as progressive resistance strength training for the lower limbs, seems to be ineffective in improving BMD in the femoral neck (mean difference, 1.03; 95% CI, 0.24 to 1.82). The most effective intervention for BMD at the spine was combination exercise programs (mean difference 3.22; 95% CI, 1.80 to 4.64); however, exercise did not statistically significantly reduce the numbers of fractures (odds ratio, 0.61; 95% CI, 0.23 to 1.64), a finding that was supported by another meta-analysis.²³

Cancer population.

A meta-analysis that included 12 RCTs of at least a 6-month duration investigating the effects of exercise on BMD compared with a control group in survivors of adult cancer found no significant benefit of exercise compared with controls on BMD at the lumbar spine (P = .057), femoral neck (P = .077), or total hip (P = .443).²⁴ However, subgroup analysis revealed a positive effect on lumbar spine BMD in three studies that implemented a combined resistance and impact exercise intervention (P = .019). The authors concluded that exercise may not be sufficient to improve bone health in survivors of cancer, but given the heterogeneity in the participant characteristics and several exercise programs that may not have been designed to specifically optimize bone health, the findings should be interpreted with caution.²⁴ One RCT not included in the meta-analysis evaluated a commercially available Web-based lifestyle modification program in survivors of breast cancer and found that the intervention group demonstrated enhanced whole-body bone area (P = .04) compared with the control group that lost whole-body bone area.²⁸ Cortical bone density also increased in the intervention group compared with the control group (P = .02).²⁸ Another meta-analysis in women who were treated for breast cancer supports the findings of preserved bone health among premenopausal but not postmenopausal women.²⁵

Meta-analyses and trials investigating aerobic and/or resistance exercise in men with NMPC receiving ADT demonstrated that, although exercise is an effective and safe intervention to improve muscular strength and performance as well as quality of life, it did not show a statistically significant difference in BMD.^26,27 However, recreational soccer training in elderly European men with advanced or locally advanced PC managed with ADT was associated with increases in bone formation markers and preserved bone mass compared with a control group at 12 weeks,⁸⁶ 32 weeks,⁸⁷ and 5 years of follow up.²⁹

Lifestyle factors.

Studies also show that many lifestyle factors can affect the reduction of BMD and osteoporosis. Cigarette smoking negatively affects bone quality and increases fracture risk.^88-90 Data examined from the Nurses’ Health Study on alcohol consumption and health outcomes found that chronic alcohol use is associated with low bone density and a high risk of fracture.⁹¹ Even moderate alcohol consumption—defined in the study as up to an average of one drink per day—can lead to poor balance and falls and higher risks of forearm and hip fractures.⁹¹ This information might be important to identify patients who are at risk for osteoporosis and emphasizes the importance of smoking cessation and moderate alcohol consumption in all patients.

Clinical interpretation.

From a nutritional standpoint, combination therapy of calcium and vitamin D seem to be more effective at improving BMD than monotherapy of either nutrient. Trials of bone-modifying agents (BMAs) have also used the combination of calcium and vitamin D in both placebo and active treatment groups. Studies that did not show a fracture reduction risk with nutritional supplementation may have underdosed vitamin D, and nutrient supplementation may be most effective in those with existing deficiencies, fractures, and/or osteoporosis. Although threshold values for prescribing vitamin D are not well defined, doses greater than 800 IU per day may be necessary in many populations, particularly in those with risk factors for BMD loss, including premenopausal women receiving tamoxifen (tamoxifen preserves BMD in postmenopausal patients) or AI therapy in postmenopausal women, patients using chronic glucocorticoids, older adults with cancer history, and patients with hematologic malignancies. There is no evidence that calcium and vitamin D supplementation preserves BMD in patients with NMPC.

Data for exercise in survivors of cancer are conflicting as to the preservation of BMD. Nonetheless, exercise is recommended by the panel because of its known benefits in the maintenance of overall health, including improved sleep, mood, fitness, and a reduction in the risk of cancer recurrence and/or certain new cancers. It is important to discuss and counsel survivors on this point.

For survivors of cancer who are at greater risk of falls (eg, a person with chemotherapy-induced peripheral neuropathy affecting balance) an exercise program should be individually tailored to the patient and supervised until the patient can safely and effectively perform their program individually. Survivors should have an exercise program prescribed by a clinician who can evaluate fracture and fall risk based on a patient’s physical and cognitive function and diagnostic studies, and who can recommend a program that is safe, incorporates resistance and weight-bearing exercise, and that potentially reduces falls via targeted strengthening interventions. Geriatric survivors of cancer older than age 65 years, which represents the most rapidly growing cohort,⁹² who are at greater risk of falling than younger survivors, should also receive special consideration when an exercise program is being designed.

PHARMACOLOGIC INTERVENTION

Recommendation 3.4

For patients with nonmetastatic cancer with osteoporosis (T scores of −2.5 or less in the femoral neck, total hip, or lumbar spine) or those who are at increased risk of osteoporotic fractures based on clinical assessment or risk assessment tools (10-year probability of ≥ 20% for major osteoporotic fractures or ≥ 3% for hip fractures based on the US-adapted FRAX tool), BMAs such as oral bisphosphonates, intravenous (IV) bisphosphonates or subcutaneous denosumab at the osteoporosis-indicated dosage may be offered to reduce the risk of fracture. Hormonal therapies for osteoporosis management (eg, estrogens) are generally avoided in patients with hormonal-responsive cancers. For patients without hormonally responsive cancers, estrogens may be offered along with other BMAs when clinically appropriate (Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong).

Qualifying statement.

Current evidence suggests that oral bisphosphonates, IV bisphosphonates, and subcutaneous denosumab are each an efficacious option. The choice of which BMA to offer should be based on several important considerations, including patient preference, potential adverse effects, quality of life considerations, adherence, safety for that population, cost, and availability.

Literature review and analysis.

Bisphosphonates. Noncancer populations.

The USPSTF review identified and included 15 studies that examined fracture outcomes in patients without cancer without prior fracture receiving alendronate, zoledronic acid (ZA), risedronate, or etidronate in addition to calcium with or without vitamin D compared with placebo and calcium with or without vitamin D.¹⁰ Three additional trials not included in the USPSTF systematic review that randomly assigned patients both with and without fractures were also identified.^30,93,94 The HORIZON trial (NCT00049829) included postmenopausal women with a BMD T score of −2.5 or less at the femoral neck with or without evidence of existing vertebral fracture, or a T score of −1.5 or less with radiologic evidence of at least two mild vertebral fractures or one moderate vertebral fracture.⁹³ FIT (Fracture Intervention Trial) enrolled women with existing vertebral fracture and those without but who had osteoporosis.³⁰ Most recently, a large trial randomly assigned 2,000 women age 65 years or older with osteopenia to receive ZA or placebo.⁹⁴

Vertebral fracture.

An analysis conducted by the USPSTF, which included five trials in women without cancer reported that oral bisphosphonates reduced clinical vertebral fractures compared with placebo (2.1% v 3.8%; RR, 0.57; 95% CI, 0.41 to 0.78; N = 5,433). The HORIZON trial demonstrated that a single yearly 15-minute infusion of ZA 5 mg reduced the risk of morphometric vertebral fracture by 70% during a 3-year period compared with placebo (3.3% in the ZA group v 10.9% in the placebo group; RR, 0.30; 95% CI, 0.24 to 0.38).⁹³ In the FIT trial, the risk reduction point estimates for vertebral fractures were consistent in those with and without baseline vertebral fractures (0.53 and 0.51, respectively). Pooling the two subgroups of women to obtain a more precise estimate of the effect of alendronate 5 to 10 mg on the relative risk of fracture, the investigators reported a statistically significant reduction in radiographic vertebral (RR, 0.52; 95% CI, 0.42 to 0.66) and clinical vertebral (RR, 0.55; 95% CI, 0.36 to 0.82) fractures.³⁰ Reid et al⁹⁴ also reported that, compared with the placebo group, women who received ZA at a dose of 5 mg over the course of 6 years had a lower risk of vertebral fractures (odds ratio, 0.45; P = .002).

A systematic review and meta-analysis of RCTs evaluating bisphosphonates for the treatment of osteoporosis or low BMD in adult males found a significantly reduced risk of vertebral fractures with alendronate (RR, 0.328; 95% CI, 0.155 to 0.692) and risedronate (RR, 0.428; 95% CI, 0.245 to 0.746).³¹ When considering bisphosphonates as an overall treatment category, meta-analyses demonstrate statistically significantly reduced risk of vertebral fractures (RR, 0.368; 95% CI, 0.252 to 0.537).³¹

Nonvertebral fractures.

A pooled analysis by the USPSTF of eight trials assessing nonvertebral fractures found a reduced risk of fractures among women in the treatment arm (8.9% v 10.6%; RR, 0.84; 95% CI, 0.76 to 0.92; N = 16,438). Nonvertebral fractures in the HORIZON trial were reduced by 25% (P < .001).⁹³ Similarly, in the FIT trial, the risk of nonvertebral fractures was reduced by 27% (RR, 0.73; 95% CI, 0.61 to 0.87; P < .001) in the pooled population.³⁰ In the subgroup of women with a baseline fracture, the relative risk was 0.81 (95% CI, 0.64 to 1.03). Reid et al⁹⁴ reported a lower risk of nonvertebral fragility fractures compared with those who received placebo (hazard ratio, 0.66; P = .001). Meta-analysis by Nayak et al³¹ found that bisphosphonates statistically significantly reduced the risk of nonvertebral fractures in men (RR, 0.6; 95% CI, 0.4 to 0.9).

Hip fractures.

Among women, the USPSTF pooled analysis of three trials of alendronate or risedronate suggested a lower risk, but this was not statistically significant (0.7% v 0.96%; RR, 0.70; 95% CI, 0.44 to 1.11; I², 0%; three trials, N = 8,988).¹⁰ In contrast, the HORIZON trial found that ZA statistically significantly reduced the risk of hip fracture in postmenopausal women with and without existing fractures by 41% (1.4% in the ZA group v 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83).⁹³ Similarly, the FIT trial found that the risk of hip fracture was reduced by 53% (P < .005) in the pooled analysis of women with and without baseline vertebral fractures.³⁰ In those women with existing baseline fractures, risk of hip fracture was reduced by 51% (RR, 0.49; 95% CI, 0.23 to 0.99), which was consistent with the reduction in women without baseline fractures (RR, 0.44; 95% CI, 0.18 to 0.97).³⁰ No studies reported on hip fractures in men.

Overall adverse events.

Both oral and IV bisphosphonates are associated with adverse events (Table 4), but the safety profile can vary depending on the route of administration.⁹⁵ IV administration has been associated with mild-to-moderate flu-like symptoms, including myalgias, arthralgias, fevers, and headaches, within the first 3 days after therapy that generally resolve within 3 to 4 days, but may persist for up to 14 days after initial infusions.⁹⁶ Oral administration has been associated with esophagitis, dysphagia, and gastric ulcers.⁹⁵ The USPSTF updated analysis of up to 20 trials and 17,369 participants found that the pooled risk of discontinuations due to adverse events (RR, 0.99; 95% CI, 0.91 to 1.07) or risk of serious adverse events (RR, 0.98; 95% CI, 0.92 to 1.04) were not significantly different for any individual drug (alendronate, ibandronate, etidronate, risedronate, or ZA at osteoporosis-indicated doses) or overall as a class.¹⁰ Upper GI events pooled from 13 trials with 20,485 participants demonstrated no significant differences for any individual drug (alendronate, risedronate, or ibandronate) or overall as a class (RR, 1.01; 95% CI, 0.98 to 1.05), although the AHRQ systematic review reported that, in a comparison of alendronate and denosumab and alendronate and placebo, alendronate was also more strongly associated with mild upper GI events than denosumab or placebo.⁸³ Serious adverse events, such as medication-related osteonecrosis of the jaw (MRONJ), bone pain, atrial fibrillation, and esophageal cancer, have been reported; however, incidence is rare.⁹⁶ Atypical femoral fractures are less poorly understood, but the incidence reported in a recent systematic review ranged from 3.0 to 9.8 cases per 100,000 patient-years.⁹⁷ Data on cardiovascular events or MRONJ were not pooled, but the USPSTF noted that there was no clear evidence of an association between bisphosphonate use and atrial fibrillation or MRONJ. AHRQ confirmed that the evidence is insufficient for the risk for atrial fibrillation and did estimate that the incidence of MRONJ associated with bisphosphonate use for osteoporosis ranged from less than one to 28 cases per 100,000 person-years of treatment.⁸³ AHRQ systematic review deemed the evidence insufficient to establish an increased risk of esophageal cancer with bisphosphonate use but did acknowledge a small increase in the risk of atypical fractures of the femur with long-term bisphosphonate use.⁸³

TABLE 4. Commonly Used Bone-Modifying Agents for the Prevention and Treatment of Osteoporosis in Nonmetastatic Cancer

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Cancer populations.

Systemic reviews of patients with nonmetastatic prostate cancer have reported a statistically significant increase in GI toxicities and fever with bisphosphonates compared with placebo.⁹⁸ No statistically significant difference was reported in other systematic reviews between bisphosphonates and placebo in terms of fatigue, anemia, flushing, arthralgia, constipation, musculoskeletal pain, limb pain, hypertension, upper respiratory infection or influenza syndrome, or urinary frequency.⁹⁸ Among trials of ZA, adverse effects in renal function were rare, as were atrial fibrillation and hypocalcemia.⁹⁸ Two trials that compared ZA with no ZA reported osteonecrosis of the jaw, but incidence was low.

Prevention and management of MRONJ in patients with cancer is the subject of a recent consensus-based guideline.⁹⁹ The schedule of dosing and duration of BMA use also influences the incidence of MRONJ. The incidence of MRONJ increases with extended durations of monthly IV bisphosphonates or subcutaneous RANK-L inhibitor, especially that exceeding 2 years. In contrast, schedules for osteoporosis prevention or treatment—for example, every 6 months—are associated with a much lower incidence (0% to 1%). With oral bisphosphonates, incidence on MRONJ is even less (0% to 0.5%).

Clinical interpretation.

Although oral bisphosphonates are generally well tolerated, treatment adherence is reported to be poor, with up to 70% of patients discontinuing treatment in the first year.^100,101 There are several factors that have been reported to influence adherence, including socioeconomic and cultural factors and patient–physician communication.¹⁰² Evidence suggests that optimal adherence in the first year is highly predictive of optimal adherence in the subsequent 1 to 2 years.¹⁰² Clinicians should take into account all possible factors affecting adherence and offer differing levels of support and monitoring to maximize treatment benefit, especially based on early patterns of use.¹⁰²

Whereas IV bisphosphonates may not have as severe issues with adherence, there are surprisingly high numbers of patients who do not return for subsequent yearly doses. In addition, they are associated with acute phase reactions and renal dysfunction¹⁰³ that often require renal monitoring.¹⁰⁰ MRONJ is the most important adverse event associated with prolonged administration of potent inhibitors of bone resorption, but is rare with osteoporosis-indicated schedules of IV bisphosphonates or with oral bisphosphonates that are administered for the preservation of bone mass.^100,109 Whereas meta-analyses show an increased risk of atypical femoral fractures with bisphosphonate use, these are rare events and their risk is likely to be outweighed by bisphosphonate’s reduction of typical osteoporotic fractures in most patients¹⁰⁵

As MRONJ has been observed in patients receiving either bisphosphonates or denosumab, all patients should receive an oral exam before therapy initiation with bisphosphonates or denosumab and maintain good oral hygiene while on treatment. Invasive dental surgical procedures, such as extractions or implant placement, should be avoided.^96,100

RANK-L binder: Denosumab.

The ABCSG-18 (NCT00556374) RCT⁴⁷ of 3,420 postmenopausal patients with early hormone receptor–positive breast cancer receiving treatment with AIs randomly assigned women to receive either denosumab (60 mg) or placebo. Patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio, 0.50; 95% CI, 0.39 to 0.65; P < .001). The overall lower number of fractures in the denosumab group (n = 92) than in the placebo group (n = 176) was similar in all patient subgroups, including in patients with a BMD T score of −1 or higher at baseline (n = 1,872; HR, 0.44; 95% CI, 0.31 to 0.64; P < .001) and in those with a BMD T score of less than −1 already at baseline (n = 1,548; HR, 0.57; 95% CI, 0.40 to 0.82; P = .002).

A trial in 1,468 men receiving ADT for nonmetastatic prostate cancer¹⁴², found BMD of the lumbar spine had increased by 5.6% in patients who were randomly assigned to denosumab (60 mg) compared with a loss of 1.0% in those randomly assigned to placebo (P < .001). Denosumab therapy was also associated with significant increases in BMD at the total hip, femoral neck, and distal third of the radius. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5% v 3.9% with placebo; relative risk, 0.38; 95% CI, 0.19 to 0.78; P = .006).

The FREEDOM trial (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months; NCT00089791) enrolled women between the ages of 60 and 90 years who had a BMD T score of less than −2.5 but not less than −4.0 at the lumbar spine or total hip and randomly assigned them to denosumab 60 mg or placebo subcutaneously every 6 months for 36 months. A statistically significant difference in new radiographic vertebral fractures (2.3% v 7.2%; RR, 0.32; 95% CI, 0.26 to 0.41), nonvertebral fractures (6.1% v 7.5%; RR, 0.80; 95% CI, 0.67 to 0.95), and hip fractures (0.7% v 1.1%; RR, 0.60; 95% CI, 0.37 to 0.97) were reported.⁴⁵ The study also reported a reduction in new clinical vertebral fractures and multiple new vertebral fractures. A long-term extension of the FREEDOM trial, which observed patients for up to 10 years of denosumab (60 mg every 6 months), estimated the relative risk of new vertebral fractures to be 0.62 (95% CI, 0.47 to 0.80) and nonvertebral fractures to be 0.54 (95% CI, 0.43 to 0.68).⁴⁶

Overall adverse events.

The most common adverse effects of denosumab identified in initial studies of postmenopausal women include arthralgia, nasopharyngitis, headache, extremity pain, upper respiratory infection, constipation, urinary tract infection, rash, and asymptomatic hypocalcemia⁹⁶ (Table 4). The USPSTF pooled estimates of adverse effects from three trials that included 8,451 participants suggested no differences compared with placebo in rates of discontinuation due to adverse events (2.4% v 2.1%; RR, 1.14; 95% CI, 0.85 to 1.52), serious adverse events (23.8% v 23.9%; RR, 1.12; 95% CI, 0.88 to 1.44), or serious infections (4.0% v 3.3%; RR, 1.89; 95% CI, 0.61 to 5.91).¹⁰ An AHRQ pooled analysis of four trials found an increased rate of rash but no increase in the rate of injection site reactions for denosumab compared with placebo.⁸³

Analyses of MRONJ cases in the US Food and Drug Administration’s adverse event reporting system found that the odds ratio for MRONJ with denosumab use in patients with osteoporosis was 0.63 (95% CI, 0.56 to 0.70^105a). Indeed, data from the large postmenopausal osteoporosis FREEDOM trial, the ABCSG-18 trial in patients with breast cancer, and trial evidence in men with NMPC on ADT suggest there were no significant differences in the total incidence of adverse events or serious adverse events in patients receiving denosumab at osteoporosis dosing or placebo. No statistically greater risks of cancer, infection, delayed fracture union, hypocalcemia, or MRONJ were detected in the first 3 years of the FREEDOM trial,⁴⁵ and adverse events and serious adverse events did not increase with time in the 10-year FREEDOM Extension.^46,106

Recommendation 3.5

Premenopausal women receiving GnRH therapies causing ovarian suppression
Premenopausal women with CIOF or who have undergone an oophorectomy
Postmenopausal women who are receiving aromatase inhibitors
Men who have received or are receiving ADT
Patients undergoing or with a history of bone marrow transplantation
Patients with chronic (> 3 to 6 months) glucocorticoid use

(Type: evidence based, benefits outweigh harms; quality: high; recommendations: strong)

Qualifying statement.

The short-term bone loss associated with these conditions can be rapid. Because of this, clinicians could consider treatment at higher bone density or T score than that recommended using FRAX or similar tools, with decision making further guided by anticipated losses as reviewed in the text (ie, the bulleted conditions above in Recommendation 3.5 should be included as having secondary osteoporosis in the FRAX assessment tool).

Literature review and analysis.

Ovarian suppression/failure.

The ABCSG-12 trial (NCT00295646) investigated the effect of adding ZA 4 mg every 6 months in premenopausal patients with early breast cancer treated with ovarian suppression plus anastrozole or tamoxifen.³⁹ Ovarian suppression with goserelin plus tamoxifen or anastrozole for 3 years without concomitant ZA caused significant bone loss. Whereas a partial recovery of BMD was observed in these patients 2 years after completing treatment, the recovery level was lower than their baseline BMD. Addition of ZA prevented bone loss in both the lumbar spine and hip at 36 months and increased lumbar spine BMD at 60 months.³⁹ Similarly, in a small pilot study, 11 premenopausal women were randomly assigned to receive alendronate 10 mg or placebo by mouth per day during 6 months of GnRH use.³² Patients who received alendronate experienced a mean gain of 1.0% (P = .35) in lumbar BMD compared with a significant mean loss in the control group of 3.8% (P = .01). Patients in the placebo group experienced a significant reduction in mean femur BMD of 3.4% (P = .02), whereas alendronate-exposed patients had a loss of 0.4% (P = .65).

Seven additional trials published in eight reports^{35,36,40-43,107} investigated the use of bisphosphonates in premenopausal women who develop ovarian failure due to adjuvant chemotherapy. All trials found that ZA, pamidronate, and oral bisphosphonates prevent bone loss in premenopausal women receiving adjuvant chemotherapy, with the exception of one RCT that found no significant difference in BMD measured at 1 year in the lumbar spine (LS) between oral risedronate and placebo groups.³⁵ One trial in patients who were randomly assigned to receive treatment with either ZA 4 mg IV every 3 months or placebo found that ZA significantly prevented bone loss during the first year of chemotherapy.⁴² Moreover, BMD remained stable in the ZA-treated cohort (P < .001 v placebo), whereas the LS BMD decreased from baseline by 5.5% at 12 months and 6.3% at 24 months in patients receiving placebo. Similarly, by 24 months, total hip and femoral neck BMD declined by 2.6% and 2.4%, respectively, in the placebo group.⁴³

The Cancer and Leukemia Group B (CALGB) 79809 (NCT00022087) study randomly assigned 469 premenopausal women beginning adjuvant chemotherapy to ZA 4 mg IV every 3 months or ZA administered 1 year after adjuvant chemotherapy.⁴⁰ Primary end point was change in BMD in the LS. Bone density was preserved in patients who were treated with early ZA at 12 months compared with a 6.6% loss of BMD in the LS at 1 year reported in the delayed group.

The ProBONE II study (NCT00375505) also investigated the effect of adjuvant ZA on BMD and bone turnover markers in premenopausal women with early-stage hormone receptor breast cancer treated with adjuvant chemotherapy and/or endocrine therapy plus ZA 4 mg IV every 3 months or placebo for 24 months.⁴¹ Women who were randomly assigned to ZA had their LS BMD increased by 3.14% from baseline to 24 months compared with a 6.43% decrease in placebo-treated participants (P < .001). Mean changes in T and Z scores and femoral neck and total femoral BMD showed similar results. In addition, the ProBONE II substudy¹⁰⁸ found a statistically significant change at 24 months in trabecular bone score, a gray-level texture measurement related to the bone microarchitecture and considered to be independent of the BMD in women who were treated with IV ZA compared with placebo.

Clinical interpretation.

Oophorectomy, GnRH agonist.

In healthy individuals, peak bone mass occurs at age 30 years.¹⁰⁹ After age 30 years, the two sources of bone loss are age related, which happens throughout the remainder of life, and hormonally related. In women and men, the estrogen deprivation of menopause and the more gradual decreasing of androgens, respectively, also contributes to bone loss. Almeida et al¹¹⁰ describe a review of the mechanisms by which estrogens and androgens are protective against bone loss.

Cancer treatments cause bone loss via hypogonadism.^{92, 111} Bone loss is caused by orchiectomy,¹¹² oophorectomy,^113,114 and GnRH agonists,^115-117 which cause reversible medical castration. These treatments form the basis endocrine therapies in men with prostate cancer and premenopausal women with breast cancer.

CIOF.

CIOF is the cessation of ovarian function in premenopausal women, and it causes rapid bone loss.^118,119 This bone loss occurs as early as 6 months after the initiation of adjuvant chemotherapy and further increases at 12 months.¹¹⁸ Effects of chemotherapy on ovarian function depend on the age at treatment, the specific class of drugs, and the cumulative doses. Risk of CIOF increases with age, likely because of a diminished ovarian reserve related to the reduced number and quality of follicles.¹²⁰ Alkylating agents, such as cyclophosphamide, are associated with the highest risk of CIOF, followed by platinum agents, anthracyclines, and taxanes. Higher cumulative doses of cyclophosphamide are associated with a higher rate of CIOF.¹²¹ In women who retain menstrual function after chemotherapy, natural menopause can occur at an earlier age than in those who did not receive chemotherapy.¹²²

It is essential to distinguish between transient amenorrhea, which often occurs in younger premenopausal women who receive adjuvant chemotherapy, and permanent ovarian failure. Women who experience transient amenorrhea with a loss of bone mass at 6 months tend to recover their bone density by 12 months.¹¹⁸ In addition, it has implications for the choice of endocrine therapy and fertility.

There are randomized trials of ZA in women receiving GnRH agonists with either tamoxifen or the AI anastrozole^123,124 and CIOF^40,42 These trials have BMD as the primary end point as opposed to trials in healthy populations that have prevention of fractures as a primary end point. BMD is a surrogate end point, however, and fracture risk is not only determined by bone loss, but also by bone mass before initiating treatment.

Literature review and analysis.

AI therapy.

The recent systematic review and position statement from a panel of bone experts representing multi-international societies suggest that denosumab and intravenous and oral bisphosphonates can effectively prevent AI-associated bone loss (AIBL) in patients with breast cancer.³³ Data collected as part of their review included clinical trials in more than 6,000 patients with breast cancer. The Adjuvant Denosumab in Breast Cancer Trial (ABCSG-18) found that postmenopausal women with hormone receptor–positive breast cancer who were treated with denosumab had a significant reduction in the risk of any clinical fracture (HR, 0.50; 95% CI, 0.39 to 0.65; P < .001). Treatment with denosumab also significantly decreased the number of incident morphometric vertebral fractures and worsening of prevalent vertebral fractures over 36 months (odds ratio, 0.54; 95% CI, 0.34 to 0.84; P = .007). Moreover, the reduction in fracture risk seemed to occur irrespective of age and baseline BMD.³³

Data collected by Hadji and colleagues supporting IV bisphosphonate therapy to prevent AIBL in postmenopausal women with early breast cancer comes predominantly from four independent studies with a total of more than 2,700 postmenopausal women with early breast cancer (Zometa-Femara Adjuvant Synergy Trials: ZO-FAST,¹²⁵ Z-FAST,¹²⁶ E-ZO-FAST,¹²⁷ and NO3CC ALLIANCE [NCT00107263]¹²⁸). When ZA was administered in conjunction with AI therapy, patients continued to gain BMD at the LS and total hip (TH) versus BMD losses at both sites in the delayed zoledronate group.³³

Hadji et al³³ identified eight RCTs that investigated the efficacy of oral bisphosphonates in preventing AIBL. Four trials found that oral risedronate compared with placebo or a no treatment control significantly increased LS BMD and TH BMD versus baseline and modestly increased LS BMD and TH BMD at 24 months and 36 months of follow up.³³ The 3-year results showed that risedronate could prevent bone loss over the 3 years at the spine, although the treatment was less effective at the hip. Monthly oral ibandronate was also effective at preventing bone loss in women with osteopenia or preexisting osteoporosis compared with placebo by increasing LS BMD by 5.01% and TH BMD by 1.19%. In the Bisphosphonate and Anastrozole Trial-Bone Maintenance Algorithm Assessment (BATMAN) study (NCT00122356), osteoporotic patients received weekly alendronate, whereas osteopenic patients received alendronate or placebo. Results showed that lumbar spine mean BMD significantly increased in the osteoporotic group and the osteopenic group with early intervention of alendronate; however, no significant change was observed in those with osteopenia without alendronate. Overall, the included studies of oral bisphosphonates demonstrated a substantial BMD loss during AI therapy in patients who did not receive a bisphosphonate.³³

Clinical interpretation.

The position statement by Hadji et al³³ recommended a BMD measurement upon starting AI and, if the T score was greater than −2, then lifestyle measures were to be implemented. BMD is then to be repeated after 1 to 2 years, as accelerated bone loss is an indication for starting antiresorptive treatments.³³ If the BMD T score is less than −2 or if the patient had major risk factors, such as prior fracture, then antiresorptive treatments should be administered³³ (algorithm; Fig 1)

FIG 1. Algorithm for maintaining bone health in individuals with nonmetastatic cancers.²⁰ BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; FRAX, WHO Fracture Risk Assessment Tool; GnRH, gonadotropin-releasing hormone; IV, intravenous. (*) Bone mineral density assessment should not be conducted more than annually.

The strongest evidence of benefit from antiresorptive drugs is for treatment with denosumab at the osteoporosis dose of 60 mg every 6 months. This has been demonstrated to reduce the risk of fracture; however, when denosumab is discontinued, there may be an increase in the risk of vertebral fractures. The European Calcified Tissue Society suggests the use of a bisphosphonate to reduce this risk upon stopping denosumab.¹²⁹

There is good evidence of benefit based on gain in BMD from treatment with ZA. In osteoporosis, the licensed dose is 5 mg administered once per year by IV infusion. For osteopenia, ZA is dosed 5 mg every 2 years. However, in the AI trials, it was usually administered as 4 mg twice per year by IV infusion. The treatment is highly effective in preventing bone loss and decreasing bone turnover, as well as building bone mass, but we have limited data on fracture risk reduction. ZA can result in an acute phase response within the first week of administration, in which case an antipyretic, such as acetaminophen or ibuprofen, may be useful. There is fairly good evidence of benefit from treatment with several oral bisphosphonates, including alendronate (70 mg once per week), risedronate (35 mg once per week), and ibandronate (150 mg once per month), and the clinical trials cited used these osteoporosis doses. The treatment prevents bone loss and decreases bone turnover, but again, we have no data on fracture risk reduction. The challenge with these treatments is to maintain good adherence as they have GI adverse effects.

Hadji et al³³ also point to the value of bisphosphonates to prevent breast cancer recurrence and to increase breast cancer survival, and so there may well be benefits of these antiresorptive treatments beyond bone. Although the anticancer effect of BMA is controversial, Cancer Care Ontario and ASCO have a joint guideline for the use of BMAs in the adjuvant setting.¹³⁰

Literature review and analysis.

ADT: BMD.

A recent network meta-analysis evaluated all available preventive BMAs for osteoporosis in men with NMPC and found that all treatments were effective in reducing the rate of bone loss compared with placebo. BMD change from baseline ranged from –1.2% to 6.0% in treated patients.³⁷ Denosumab and ZA at osteoporosis-indicated doses showed statistically significant improvement in BMD across all sites (approximately 3% at the TH and FN, and approximately 6% at LS sites).³⁷ The use of surface under the cumulative ranking curve (SUCRA), a numeric presentation of the overall ranking, with values ranging from 0% to 100% to determine treatment rank probability, demonstrated that ZA consistently ranked among the top two treatments at all sites.³⁷ Not included in the network meta-analysis was another trial investigating the use of denosumab versus alendronate for treatment of secondary osteoporosis related to ADT which found that denosumab and alendronate showed similar clinical efficacy.¹³¹ However, denosumab showed a statistically significant decrease in bone turnover markers and an increase in BMD (mean change in BMD at 24 months was 5.6% compared with alendronate [−1.1%]; P < .001).¹³¹

A meta-analysis for the change in BMD at 12 months included 15 trials and found a statistically significant differences between bisphosphonates and placebo at the LS, femoral neck, and TH favoring bisphosphonates.³⁸ Additional studies of bisphosphonate with 6-month, 24-month, or 36-month results were also identified. A statistically significant difference in BMD at 6 months at the LS, femoral neck, and TH for risedronate compared with placebo was reported¹³² and sustained at 24 months at the proximal femur¹³³ and at the LS, femoral neck, and TH with alendronate.³⁴ One trial showed greater improvement with ZA at 36 months compared with no ZA at the LS, left femoral neck, and left hip.¹³⁴

Osteoporosis.

The systematic review by Alibhai and colleagues³⁸ reported on four osteoporosis-indicated dose bisphosphonate trials that considered osteoporosis as an outcome in men with NMPC receiving ADT. One trial evaluating risedronate and estrogen, alone and in combination, showed no difference in the incidence of osteoporosis at 6 or 12 months across the four study arms.¹³⁵ Similarly, the incidence of osteoporosis did not significantly differ with alendronate at 24 months³⁴ or ZA at 12 months.^135a However, one study comparing clodronate or ZA with control showed a statistically significantly lower occurrence of osteoporosis with clodronate or ZA after 12 months (18% v 58%; P < .05; and 21% v 58%; P < .001, respectively^135b). In trials of men receiving ADT, rates between denosumab and placebo were similar for total adverse effects, grade 3 or greater effects, serious adverse effects, and cardiovascular events.⁹⁸ MRONJ developed in 33 denosumab patients (5%) compared with zero placebo patients; however, the majority of patients had oral risk factors, including tooth extraction, poor oral hygiene, and dental appliance use.⁹⁸

Fracture.

A network meta-analysis evaluating the effect of preventive therapy on fracture risk at 24 months found that denosumab and toremifene were both effective in reducing vertebral fracture risk, with denosumab ranking higher based on SUCRA.³⁷ The included trial found that, compared with placebo, denosumab prevented new vertebral fractures at 12 months (RR, 0.15; P = .004), 24 months (RR, 0.31; P = .004), and 36 months (RR, 0.38; P = .006). More than one fracture at any site occurred in fewer denosumab patients (0.7% v 2.5%; P = .006). Trials of alendronate or ZA found no statistically significant difference in the incidence of fractures in patients receiving active treatment compared with those receiving placebo.³⁷

Clinical interpretation.

ADT consists of GnRH agonist and antiandrogens in the management of prostate cancer. Men with prostate cancer receiving ADT lose bone and have increased fracture rates.¹³⁶ Mechanisms for bone loss are the result of testosterone deficiency as well as decreased aromatization of testosterone to estrogen.¹³⁷ GnRH agonists also increase parathyroid hormone–mediated osteoclast activation and increase bone turnover.¹³⁸ Similar to cancer therapy–induced bone loss, the highest magnitude of bone loss occurs during the first year of ADT, but losses continue with long-term treatment.¹³⁹ Within 6 months of diagnosis, men treated with ADT or those after bilateral orchiectomy have a 5-year fracture risk of 19% versus 12% in matched controls.¹³⁶ Bisphosphonate therapy and RANK-L monoclonal antibody therapy are the most commonly used agents for the management of bone loss during ADT.^140,141

Results of randomized trials of the antiresorptive drugs ZA or denosumab in men with NMPC receiving GnRH agonists^112,142 show mitigation of bone loss, increases bone mass, and a reduction in fractures with these drugs. There are also less potent oral bisphosphonates and other treatments that demonstrate similar results. Likewise, there are randomized trials of ZA in premenopausal women with early breast cancer on GnRH agonists and either tamoxifen or anastrozole.^120,121 ZA mitigates bone loss in this setting.

Literature review and analysis.

Bone marrow transplantation patients.

Several studies of high-dose chemotherapy with either autologous or allogeneic bone marrow support show rapid bone loss in the first few years after transplantation.¹⁴³ In of itself, standard doses of adjuvant chemotherapy cause small amounts of bone loss independent of CIOF causing hypogonadism.¹¹⁸ Direct and indirect effects of high-dose chemotherapy, in addition to hypogonadism, include factors that increase bone resorption (eg, renal dysfunction with decreases in 1,25[OH]₂ vitamin and secondary hyperparathyroidism, glucocorticoids) and decrease new bone formation (eg, malabsorption to as a result of graft-versus-host disease or mucositis with resultant decrease in vitamin D and calcium absorption, and the direct inhibitory effects of chemotherapy on osteoblasts).¹⁴⁴ There are several randomized studies of oral or IV bisphosphates at osteoporosis treatment dosing showing BMD increases in patients who have received allogenic transplantation.¹¹¹ There are no fracture prevention data in this population.

Patients with chronic (> 6 months) glucocorticoid use.

Treatment with glucocorticoids over a long-term period can lead to drug-induced osteoporosis, which has been associated with rapid and significant bone loss.¹⁴⁵ As such, the resulting increased vertebral fracture risk occurs at higher BMD thresholds in glucocorticoid-induced osteoporosis.¹⁴⁵ The American College of Rheumatology recently released a guideline on the assessment, prevention, and treatment of glucocorticoid-induced osteoporosis in patients taking prednisone at doses > 2.5 mg per day for 3 or more months.⁷⁹ Based on a systematic review of the literature, recommendations are made for treating only with calcium and vitamin D in adults who are at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred, when appropriate) in adults at moderate-to-high fracture risk, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive glucocorticoid treatment. The ASCO Expert Panel did not further update the American College of Rheumatology’s systematic review and supports their recommendations for the management of patients on long-term glucocorticoids.

DISCUSSION

Section:

Increasing physical activity, strength training, training to prevent falls, smoking cessation, decreasing alcohol consumption, and adequate intake of calcium and vitamin D are the cornerstones of overall and bone health in survivors of cancer. The Expert Panel cannot overstate the importance of these factors. DXA screening should occur at least every 2 years and once per year in some cases, if clinically indicated. The decision to treat with BMA should be guided by the estimated fracture risk using a guide such as FRAX calculator. FRAX may underestimate the true fracture risk for those beginning high-risk treatment, so those survivors of cancer receiving ADT, AI, GnRH agonists, or chronic glucocorticoids or undergoing allogenic transplantation, or those who develop CIOF should be deemed to have secondary osteoporosis when using FRAX. (algorithm; Fig 1)

If a survivor of nonmetastatic cancer has an estimated 10-year fracture that exceeds 3% and/or 20% nonhip major osteoporotic fracture risk, then BMAs are indicated. The choice of either oral or IV bisphosphonate or subcutaneous RANK-L inhibitor should be based on patient preference, adherence, and cost (Table 5). Before initiating a BMA, a dental screening exam should be performed. Invasive dental work undertaken as one of the prime risk factors of MRONJ is dental work during BMA administration, and elective procedures are recommended to be done before the initiation of BMA. Survivors of cancer should be encouraged to undergo routine dental exams, including periodic dental cleanings, during BMA treatment. When T scores improve, one can consider discontinuation of the BMA and follow up with periodic DXA scans.

TABLE 5. Estimated Drug Costs for Bone-Modifying Agents

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Treatment of patients with a history of cancer who are at risk for osteoporosis will often be under the purview of the primary oncology treatment team during active treatment. However, early in the course of follow up and as the survivor transitions to primary care (timing determined individually) the primary care physician may take over the management of osteoporosis and/or assessment of fracture risk. Ultimately, coordination of care is imperative and should be discussed among the clinical teams and the patient. A treatment summary and individualized care plan mandated by the American College of Surgeons Commission on Cancer (https://www.facs.org/~/media/files/quality%20programs/cancer/coc/omh%20manual.ashx) should contain the identified health care provider responsible for bone health.

PATIENT AND CLINICIAN COMMUNICATION

Section:

Osteoporosis is a serious and debilitating disease that can have a major impact on the quality of a patient’s life. Loss of bone can occur without symptoms until the first fracture occurs. Moreover, the risk of fracture associated with commonly prescribed cancer treatments can occur both during treatment or after treatment has been completed, so it is important for clinicians to initiate discussion about the risks of developing osteopenia or osteoporosis as part of the treatment decision-making process and to revisit it after treatment has ended.

Management of bone health should be part of an overall survival plan, given the long period of risk for fracture. Providers may include oncologists, primary care physicians, gynecologists, endocrinologists, and other relevant members of the care team. Clear communication combined with an intentional strategy of shared decision making can result in effective monitoring of bone loss through appropriate screening and effective strategies for maintaining healthy bone to minimize the risk of fracture.

As the risks of fracture vary depending on a number of elements, such as age, treatment, mobility, body weight, and other elements, it is important for providers to personalize their recommended screening strategy. The choice of risk assessment tools, such as FRAX, could be discussed with patients. Although most patients who are at risk should be offered BMD with DXA, in settings in which DXA is not available providers and patients should discuss alternatives. The frequency of screening should be personalized according to the risk of bone loss, results of the baseline screening test, and patient preference.

Healthy lifestyle behaviors for preventing bone loss should be discussed with all patients and adjusted to their personal circumstances. Patients can be reminded that there are often local resources, support, and advice for maintaining an active lifestyle and there may already be cancer survivor programs in place. Adequate levels of calcium and vitamin D are ideally reached through a healthy diet but may be supplemented by vitamins. Some patients might benefit from a referral to a nutritionist. A combination of exercise types can reduce fracture, but specific combinations should be tailored to the patient. Evidence for potentially modifiable risk factors, such as diet, smoking, and alcohol consumption, is important to share with patients, as well as the strength of evidence upon which they are based.

Pharmacologic interventions for patients who are at increased risk of bone fracture can include a choice of BMAs to reduce the risk of fracture. Discussing the potential benefits, adverse effects, cost, availability, method of administration, and patient preferences around risk and convenience should all be included in the discussion. Duration of treatment should be a part of this conversation, including the strength of evidence behind the recommended length of time. Such resources as the US Food and Drug Administration’s Risk Evaluation and Mitigation Strategy (www.fda.gov/media/78868/download) can help inform health care providers and patients about the risks associated with denosumab. As the evidence base for the prevention and treatment of osteoporosis in survivors of cancer is still evolving, patients and their providers should plan to review their risk reduction or treatment strategies at regular intervals to align them with the most recent evidence. When available, participation in clinical trials should be considered.

For recommendations and strategies to optimize patient–clinician communication, see Patient-Clinician Communication: American Society of Clinical Oncology Consensus Guideline.¹⁴⁶

HEALTH DISPARITIES

Section:

Although ASCO Clinical Practice Guidelines represent expert recommendations on the best practices in disease management to provide the highest level of cancer care, it is important to note that many patients have limited access to medical care. Racial and ethnic disparities in health care contribute significantly to this problem in the United States. Patients with cancer who are members of racial/ethnic minorities suffer disproportionately from comorbidities, experience more substantial obstacles to receiving care, are more likely to be uninsured, and are at greater risk of receiving care of poor quality than other Americans.^147-150 Many other patients lack access to care because of their geographic location and distance from appropriate treatment facilities. Awareness of these disparities in access to care should be considered in the context of this clinical practice guideline, and health care providers should strive to deliver the highest level of cancer care to these vulnerable populations.

There are multiple, complex factors associated with health disparities in osteoporosis. Evidence suggests that most osteoporosis treatment candidates remained untreated and that men, black patients, patients with noncommercial insurance, and patients with fracture or chronic comorbidities are less likely to receive treatment, representing disparity in the recognition, screening, and treatment of osteoporosis.^151-153 Additional research is needed to investigate new strategies for increasing guideline-concordant screening and treatment patterns in these patients.

MULTIPLE CHRONIC CONDITIONS

Section:

Creating evidence-based recommendations to inform the treatment of patients with additional chronic conditions, a situation in which the patient may have two or more such conditions—referred to as multiple chronic conditions (MCCs) —is challenging. Patients with MCCs are a complex and heterogeneous population, making it difficult to account for all possible permutations to develop specific recommendations for care. In addition, the best available evidence for treating index conditions, such as cancer, is often from clinical trials whose study selection criteria may exclude these patients to avoid potential interaction effects or confounding of results associated with MCCs. As a result, the reliability of outcome data from these studies may be limited, thereby creating constraints for expert groups to make recommendations for care in this heterogeneous patient population.

As many patients for whom guideline recommendations apply present with MCCs, any treatment plan needs to take into account the complexity and uncertainty created by the presence of MCCs and highlight the importance of shared decision making regarding guideline use and implementation. Therefore, in consideration of recommended care for the target index condition, clinicians should review all other chronic conditions present in the patient and take those conditions into account when formulating the treatment and follow-up plan.

In light of the above considerations, practice guidelines should provide information on how to apply the recommendations for patients with MCCs, perhaps as a qualifying statement for recommended care. This may mean that some or all of the recommended care options are modified or not applied, as determined by best practice in consideration of any MCC.

COST IMPLICATIONS

Section:

Increasingly, individuals with cancer are required to pay a larger proportion of their treatment costs through deductibles and coinsurance.^154,155 Higher patient out-of-pocket costs have been shown to be a barrier to initiating and adhering to recommended cancer treatments.^156,157

Discussion of cost can be an important part of shared decision making.¹⁵⁸ Clinicians should discuss with patients the use of less expensive alternatives when it is practical and feasible for treatment of the patient’s disease and there are two or more treatment options that are comparable in terms of benefits and harms.¹⁵⁸

Table 5 lists estimated prices for the available treatment options addressed in this guideline. Of note, medication prices may vary markedly, depending on negotiated discounts and rebates.

Patient out-of-pocket costs may vary depending on insurance coverage. Coverage may originate in the medical or pharmacy benefit, which may have different cost-sharing arrangements. Patients should be aware that different products may be preferred or covered by their particular insurance plan. Even with the same insurance plan, the price may vary between different pharmacies. When discussing financial issues and concerns, patients should be made aware of any financial counseling services that are available to address this complex and heterogeneous landscape.¹⁵⁸

As part of the guideline development process, ASCO may opt to search the literature for published cost-effectiveness analyses that might inform the relative value of available treatment options. Excluded from consideration are cost-effectiveness analyses that lack contemporary cost data and agents that are not currently available in either the United States or Canada and/or are industry sponsored.

In metastatic bone disease, there is one independent (non–pharmaceutical industry sponsored) cost-effectiveness analysis comparing generic every 3-month ZA with monthly denosumab.¹⁵⁹ The analysis found that mean 2015 costs of the denosumab treatment strategy were nine-fold higher than those of generic ZA every 3 months. As quality-adjusted life-years were virtually identical in all three treatment arms, the optimal treatment would be ZA every 3 months because it was the least costly treatment. The sensitivity analyses showed that, relative to ZA every 3 months, the incremental costs per mean skeletal-related event avoided for denosumab over ZA ranged from $162,918 to $347,655.¹⁵⁹

EXTERNAL REVIEW AND OPEN COMMENT

Section:

Draft recommendations were released to the public for open comment from February 7, 2019, through February 21, 2019. Response categories of “Agree as written”, “Agree with suggested modifications”, and “Disagree. See comments” were captured for every proposed recommendation. A total of eight respondents, who had not previously reviewed the recommendations, either agreed or agreed with slight modifications to all but one recommendation, for which two respondents disagreed and provided comments. Expert Panel members reviewed comments from all sources and determined whether to maintain original draft recommendations, revise with minor language changes, or consider major recommendation revisions. All changes were incorporated before clinical practice guidelines committee review and approval.

GUIDELINE IMPLEMENTATION

Section:

ASCO guidelines are developed for implementation across health settings. Barriers to implementation include the need to increase awareness of the guideline recommendations among front-line practitioners and survivors of cancer and caregivers, and also to provide adequate services in the face of limited resources. The guideline Bottom Line Box was designed to facilitate implementation of recommendations. This guideline will be distributed widely through the ASCO Practice Guideline Implementation Network. ASCO guidelines are posted on the ASCO Web site and most often published in Journal of Clinical Oncology and Journal of Oncology Practice.

LIMITATION OF THE RESEARCH AND FUTURE RESEARCH

Section:

As with other survivorship intervention studies (ie, cardiac monitoring and thresholds for instituting cardiac medications) extrapolations from studies in noncancer populations occurs. This is particularly apt for osteoporosis management. In most cases, screening for osteoporosis with DXA scans and approach to treatment with BMAs is essentially the same for cancer and noncancer populations. The difference is that cancer treatments often cause bone loss, which, in some patients, leads to an increased risk of osteoporotic fractures. Newer BMAs are being evaluated in noncancer populations. For example, romosozumab is an antibody that blocks the substance sclerostin, which slows the new formation of bone.^160,161 Romosozumab was approved by the US Food and Drug Administration in April 2019 for the treatment of osteoporosis in postmenopausal women who are at high risk for fracture, defined as a history of osteoporotic fracture or multiple risk factors for fracture, or for patients who have experienced failure with or are intolerant to other available osteoporosis therapy. Data, as available, on romosozumab and other novel agents will be addressed in guideline updates.

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.

ADDITIONAL RESOURCES

Section:

More information, including a supplement, slide sets, and clinical tools and resources, is available at www.asco.org/survivorship-guidelines. Patient information is available at www.cancer.net.

Related ASCO Guidelines

Role of Bone-Modifying Agents in Multiple Myeloma¹⁶² (https://ascopubs.org/doi/10.1200/JCO.2017.76.6402)
Role of Bone-Modifying Agents in Metastatic Breast Cancer¹² (https://ascopubs.org/doi/10.1200/JCO.2017.75.4614)
Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer¹³⁰ (https://ascopubs.org/doi/10.1200/JCO.2016.70.7257)
Patient-Clinician Communication¹⁴⁶ (https://ascopubs.org/doi/10.1200/JCO.2017.75.2311)

C.L.S. and J.N. were Expert Panel co-chairs.

Clinical Practice Guidelines Committee approval: June 18, 2019

Reprint Requests: 2318 Mill Rd, Suite 800, Alexandria, VA 22314; [email protected]

This American Society of Clinical Oncology (ASCO) Clinical Practice Guideline provides recommendations, with comprehensive review and analyses of the relevant literature for each recommendation. Additional information, including a supplement with additional evidence tables, slide sets, clinical tools and resources, and links to patient information at www.cancer.net, is available at www.asco.org/survivorship-guidelines.

AUTHOR CONTRIBUTIONS

Conception and design: Charles L. Shapiro, Catherine Van Poznak, Jeffrey Kirshner, Robert Gagel, Sean Smith, Beatrice J. Edwards, Gary H. Lyman, Matthew R. Smith, Tara Henderson

Administrative support: Charles L. Shapiro

Provision of study materials or patients: Beatrice J. Edwards

Collection and assembly of data: Catherine Van Poznak, Christina Lacchetti, Beatrice J. Edwards

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic Disease: ASCO Clinical Practice Guideline

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Catherine Van Poznak

Research Funding: Bayer (Inst)

Patents, Royalties, Other Intellectual Property: UpToDate

Richard Eastell

Honoraria: Alexion Pharmaceuticals, Eli Lilly, Immunodiagnostic Systems, Roche Diagnostics, GSK Nutrition, Mereo, Sandoz-Novartis, Nittobo Medical, AbbVie, Samsung Bioepis

Consulting or Advisory Role: Amgen (Inst), GlaxoSmithKline (Inst), Immunodiagnostic Systems (Inst), Roche Diagnostics (Inst), Alexion Pharmaceuticals (Inst), AbbVie (Inst), Eli Lilly (Inst), Nittobo Medical (Inst), Sandoz-Novartis (Inst)

Research Funding: Alexion Pharmaceuticals (Inst), Immunodiagnostics Systems (Inst), Roche Diagnostics (Inst), Amgen (Inst), Nittobo Medical (Inst)

Travel, Accommodations, Expenses: Amgen, Alexion Pharmaceuticals

Robert Gagel

Stock and Other Ownership Interests: Varian Medical Systems, Epic Sciences

Consulting or Advisory Role: Novo Nordisk

Travel, Accommodations, Expenses: Novo Nordisk

Other Relationship: National Osteoporosis Foundation

Elizabeth Frank

Travel, Accommodations, Expenses: Roche

Gary H. Lyman

Stock and Other Ownership Interests: Generex Biotechnology

Consulting or Advisory Role: G1 Therapeutics, Halozyme, Partners Healthcare, Amgen, Pfizer, Agendia, Helsinn Therapeutics, Celldex (I), Janssen (I), Genomic Health, Mylan, Samsung Bioepis, Spectrum Pharmaceuticals

Research Funding: Hexal

Matthew R. Smith

Consulting or Advisory Role: Bayer, Janssen Oncology, Amgen, Pfizer, Eli Lilly, Novartis, Astellas Pharma

Research Funding: Janssen Oncology (Inst), Gilead Sciences (Inst), Bayer (Inst), Eli Lilly (Inst)

Travel, Accommodations, Expenses: Amgen, Bayer, Janssen, Eli Lilly

Tara Henderson

Research Funding: Seattle Genetics

Other Relationship: Seattle Genetics

No other potential conflicts of interest were reported.

Appendix

TABLE A1. Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic Disease: ASCO Clinical Practice Guideline Expert Panel Membership

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ACKNOWLEDGMENT

The Expert Panel thanks Tracey Weisberg, MD, and Bruno Ferrari, MD, and the Clinical Practice Guidelines Committee for thoughtful reviews and insightful comments on this guideline.

REFERENCES

Section:

1.	American Cancer Society: Cancer Facts & Figures 2019. Atlanta, GA, American Cancer Society, 2019 Google Scholar
2.	International Osteoporosis Foundation: What is osteoporosis? Epidemiology, 2019. https://www.iofbonehealth.org/epidemiology Google Scholar
3.	Ramaswamy B, Shapiro CL: Osteopenia and osteoporosis in women with breast cancer. Semin Oncol 30:763-775, 2003 Crossref, Medline, Google Scholar
4.	Morris JA, Kemp JP, Youlten SE, et al: An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet 51:258-266, 2019 [Erratum: Nat Genet 51:920, 2019] Crossref, Medline, Google Scholar
5.	Zhu D-L, Chen X-F, Hu W-X, et al: Multiple functional variants at 13q14 risk locus for osteoporosis regulate RANKL expression through long-range super-enhancer. J Bone Miner Res 33:1335-1346, 2018 Crossref, Medline, Google Scholar
6.	Wright NC, Looker AC, Saag KG, et al: The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res 29:2520-2526, 2014 Crossref, Medline, Google Scholar
7.	Briot K, Geusens P, Em Bultink I, et al: Inflammatory diseases and bone fragility. Osteoporos Int 28:3301-3314, 2017 Crossref, Medline, Google Scholar
8.	Manolagas SC, O’Brien CA, Almeida M: The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol 9:699-712, 2013 Crossref, Medline, Google Scholar
9.	Guise TA: Bone loss and fracture risk associated with cancer therapy. Oncologist 11:1121-1131, 2006 Crossref, Medline, Google Scholar
10.	Viswanathan M, Reddy S, Berkman N, et al: Screening to Prevent Osteoporotic Fractures: An Evidence Review for the U.S. Preventive Services Task Force. Rockville, MD, Agency for Healthcare Research and Quality, Evidence Synthesis No. 162, 2018 Crossref, Google Scholar
11.	Shea BJ, Reeves BC, Wells G, et al: AMSTAR 2: A critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 358:j4008, 2017 Crossref, Medline, Google Scholar
12.	Van Poznak C, Somerfield MR, Barlow WE, et al: Role of bone-modifying agents in metastatic breast cancer: An American Society of Clinical Oncology-Cancer Care Ontario focused guideline update. J Clin Oncol 35:3978-3986, 2017 Link, Google Scholar
13.	Shiffman RN MG, Michel G, Rosenfeld RM, et al: Building better guidelines with BRIDGE-Wiz: Development and evaluation of a software assistant to promote clarity, transparency, and implementability. J Am Med Inform Assoc 19:94-101, 2012 Crossref, Medline, Google Scholar
14.	Tai V, Leung W, Grey A, et al: Calcium intake and bone mineral density: Systematic review and meta-analysis. BMJ 351:h4183, 2015 Crossref, Google Scholar
15.	Shea B, Wells G, Cranney A, et al: Meta-analyses of therapies for postmenopausal osteoporosis. VII. Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis. Endocr Rev 23:552-559, 2002 Crossref, Google Scholar
16.	Bolland MJ, Leung W, Tai V, et al: Calcium intake and risk of fracture: Systematic review. BMJ 351:h4580, 2015 Crossref, Google Scholar
17.	Kahwati LC, Weber RP, Pan H, et al: Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: Evidence report and systematic review for the US Preventive Services Task Force. JAMA 319:1600-1612, 2018 Crossref, Google Scholar
18.	Avenell A, Mak JC, O’Connell D: Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev 2014:CD000227, 2014 Google Scholar
19.	Prieto-Alhambra D, Servitja S, Javaid MK, et al: Vitamin D threshold to prevent aromatase inhibitor-related bone loss: The B-ABLE prospective cohort study. Breast Cancer Res Treat 133:1159-1167, 2012 Crossref, Google Scholar
20.	Weaver CM, Alexander DD, Boushey CJ, et al: Calcium plus vitamin D supplementation and risk of fractures: An updated meta-analysis from the National Osteoporosis Foundation. Osteoporos Int 27:367-376, 2016 [Erratum: Osteoporos Int 27:2643-2646, 2016] Crossref, Google Scholar
21.	Datta M, Schwartz GG: Calcium and vitamin D supplementation during androgen deprivation therapy for prostate cancer: A critical review. Oncologist 17:1171-1179, 2012 Crossref, Medline, Google Scholar
22.	Howe TE, Shea B, Dawson LJ, et al: Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev 2011:CD000333, 2011 Google Scholar
23.	Kemmler W, Häberle L, von Stengel S: Effects of exercise on fracture reduction in older adults: A systematic review and meta-analysis. Osteoporos Int 24:1937-1950, 2013 Crossref, Google Scholar
24.	Dalla Via J, Daly RM, Fraser SF: The effect of exercise on bone mineral density in adult cancer survivors: A systematic review and meta-analysis. Osteoporos Int 29:287-303, 2018 Crossref, Google Scholar
25.	Fornusek CP, Kilbreath SL: Exercise for improving bone health in women treated for stages I-III breast cancer: A systematic review and meta-analyses. J Cancer Surviv 11:525-541, 2017 Crossref, Google Scholar
26.	Yunfeng G, Weiyang H, Xueyang H, et al: Exercise overcome adverse effects among prostate cancer patients receiving androgen deprivation therapy: An update meta-analysis. Medicine (Baltimore) 96:e7368, 2017 Crossref, Medline, Google Scholar
27.	Hasenoehrl T, Keilani M, Sedghi Komanadj T, et al: The effects of resistance exercise on physical performance and health-related quality of life in prostate cancer patients: A systematic review. Support Care Cancer 23:2479-2497, 2015 Crossref, Google Scholar
28.	Sturgeon KM, Dean LT, Heroux M, et al: Commercially available lifestyle modification program: Randomized controlled trial addressing heart and bone health in BRCA1/2⁺ breast cancer survivors after risk-reducing salpingo-oophorectomy. J Cancer Surviv 11:246-255, 2017 Crossref, Google Scholar
29.	Uth J, Fristrup B, Haahr RD, et al: Football training over 5 years is associated with preserved femoral bone mineral density in men with prostate cancer. Scand J Med Sci Sports 28:61-73, 2018 (suppl 1) Crossref, Google Scholar
30.	Black DM, Thompson DE, Bauer DC, et al: Fracture risk reduction with alendronate in women with osteoporosis: The Fracture Intervention Trial. J Clin Endocrinol Metab 85:4118-4124, 2000 Crossref, Google Scholar
31.	Nayak S, Greenspan SL: Osteoporosis treatment efficacy for men: A systematic review and meta-analysis. J Am Geriatr Soc 65:490-495, 2017 Crossref, Google Scholar
32.	Ripps BA, VanGilder K, Minhas B, et al: Alendronate for the prevention of bone mineral loss during gonadotropin-releasing hormone agonist therapy. J Reprod Med 48:761-766, 2003 Medline, Google Scholar
33.	Hadji P, Aapro MS, Body JJ, et al: Management of aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol 7:1-12, 2017 Crossref, Medline, Google Scholar
33a.	Van Poznak C, Hannon RA, Mackey JR, et al: Prevention of aromatase inhibitor-induced bone loss using risedronate: The SABRE trial. J Clin Oncol 28:967-975, 2010 Link, Google Scholar
34.	Greenspan SL, Nelson JB, Trump DL, et al. Skeletal health after continuation, withdrawal, or delay of alendronate in men with prostate cancer undergoing androgen-deprivation therapy. J Clin Oncol 26:4426-4434, 2008 Link, Google Scholar
34a.	Sestak I, Singh S, Cuzick J, et al: Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: An international, double-blind, randomised, placebo-controlled trial. Lancet Oncol 15:1460-1468, 2014 Crossref, Google Scholar
35.	Hines SL, Mincey BA, Sloan JA, et al: Phase III randomized, placebo-controlled, double-blind trial of risedronate for the prevention of bone loss in premenopausal women undergoing chemotherapy for primary breast cancer. J Clin Oncol 27:1047-1053, 2009 Link, Google Scholar
36.	Saarto T, Vehmanen L, Blomqvist C, et al: Ten-year follow-up of 3 years of oral adjuvant clodronate therapy shows significant prevention of osteoporosis in early-stage breast cancer. J Clin Oncol 26:4289-4295, 2008 Link, Google Scholar
36a.	Lester JE, Dodwell D, Purohit OP, et al: Prevention of anastrozole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer. Clin Cancer Res 14:6336-6342, 2008 Crossref, Medline, Google Scholar
37.	Poon Y, Pechlivanoglou P, Alibhai SMH, et al: Systematic review and network meta-analysis on the relative efficacy of osteoporotic medications: Men with prostate cancer on continuous androgen-deprivation therapy to reduce risk of fragility fractures. BJU Int 121:17-28, 2018 Crossref, Google Scholar
38.	Alibhai SMH, Zukotynski K, Walker-Dilks C, et al: Bone health and bone-targeted therapies for nonmetastatic prostate cancer: A systematic review and meta-analysis. Ann Intern Med 167:341-350, 2017 Crossref, Medline, Google Scholar
38a.	Doria C, Mosele GR, Solla F, et al: Treatment of osteoporosis secondary to hypogonadism in prostate cancer patients: A prospective randomized multicenter international study with denosumab vs. alendronate. Minerva Urol Nefrol 69:271-277, 2017 Google Scholar
39.	Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al: Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol 9:840-849, 2008 Crossref, Medline, Google Scholar
40.	Shapiro CL, Halabi S, Hars V, et al: Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: Final results from CALGB trial 79809. Eur J Cancer 47:683-689, 2011 Crossref, Medline, Google Scholar
41.	Hadji P, Kauka A, Ziller M, et al: Effect of adjuvant endocrine therapy on hormonal levels in premenopausal women with breast cancer: The ProBONE II study. Breast Cancer Res Treat 144:343-351, 2014 Crossref, Medline, Google Scholar
42.	Hershman DL, McMahon DJ, Crew KD, et al: Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 26:4739-4745, 2008 Link, Google Scholar
43.	Hershman DL, McMahon DJ, Crew KD, et al: Prevention of bone loss by zoledronic acid in premenopausal women undergoing adjuvant chemotherapy persist up to one year following discontinuing treatment. J Clin Endocrinol Metab 95:559-566, 2010 Crossref, Google Scholar
44.	Fuleihan G-H, Salamoun M, Mourad YA, et al: Pamidronate in the prevention of chemotherapy-induced bone loss in premenopausal women with breast cancer: A randomized controlled trial. J Clin Endocrinol Metab 90:3209-3214, 2005 Crossref, Google Scholar
45.	Cummings SR, San Martin J, McClung MR, et al: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756-765, 2009 Crossref, Medline, Google Scholar
46.	Bone HG, Wagman RB, Brandi ML, et al: 10 years of denosumab treatment in postmenopausal women with osteoporosis: Results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 5:513-523, 2017 Crossref, Medline, Google Scholar
47.	Gnant M, Pfeiler G, Dubsky PC, et al: Adjuvant denosumab in breast cancer (ABCSG-18): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433-443, 2015 Crossref, Medline, Google Scholar
48.	Drake MT, Murad MH, Mauck KF, et al: Clinical review. Risk factors for low bone mass-related fractures in men: A systematic review and meta-analysis. J Clin Endocrinol Metab 97:1861-1870, 2012 Crossref, Google Scholar
49.	Kanis JA, Johnell O, De Laet C, et al: A meta-analysis of previous fracture and subsequent fracture risk. Bone 35:375-382, 2004 Crossref, Medline, Google Scholar
50.	Morin SN, Lix LM, Leslie WD: The importance of previous fracture site on osteoporosis diagnosis and incident fractures in women. J Bone Miner Res 29:1675-1680, 2014 Crossref, Google Scholar
51.	Handforth C, D’Oronzo S, Coleman R, et al: Cancer treatment and bone health. Calcif Tissue Int 102:251-264, 2018 Crossref, Google Scholar
52.	Bae DC, Leocádio DE, Stein BS: A comparison of dual energy X-ray absorptiometry of the hip and accuDEXA of the finger for the diagnosis of osteoporosis in men on androgen deprivation therapy for advanced prostate cancer. Prostate Cancer Prostatic Dis 10:94-96, 2007 Crossref, Google Scholar
53.	Coleman RE, Banks LM, Girgis SI, et al: Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): A randomised controlled study. Lancet Oncol 8:119-127, 2007 Crossref, Medline, Google Scholar
54.	Rabaglio M, Sun Z, Price KN, et al: Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol 20:1489-1498, 2009 Crossref, Medline, Google Scholar
55.	Amir E, Seruga B, Niraula S, et al: Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: A systematic review and meta-analysis. J Natl Cancer Inst 103:1299-1309, 2011 Crossref, Medline, Google Scholar
56.	Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Aromatase inhibitors versus tamoxifen in early breast cancer: Patient-level meta-analysis of the randomised trials. Lancet 386:1341-1352, 2015 Crossref, Medline, Google Scholar
57.	Edwards BJ, Gradishar WJ, Smith ME, et al: Elevated incidence of fractures in women with invasive breast cancer. Osteoporos Int 27:499-507, 2016 Crossref, Google Scholar
58.	Melton LJ III, Hartmann LC, Achenbach SJ, et al: Fracture risk in women with breast cancer: A population-based study. J Bone Miner Res 27:1196-1205, 2012 Crossref, Google Scholar
59.	Edwards BJ, Raisch DW, Shankaran V, et al: Cancer therapy associated bone loss: Implications for hip fractures in mid-life women with breast cancer. Clin Cancer Res 17:560-568, 2011 Crossref, Google Scholar
60.	Schmidt N, Jacob L, Coleman R, et al: The impact of treatment compliance on fracture risk in women with breast cancer treated with aromatase inhibitors in the United Kingdom. Breast Cancer Res Treat 155:151-157, 2016 [Erratum: Breast Cancer Res Treat 157:401, 2016] Crossref, Google Scholar
61.	Villa P, Lassandro AP, Amar ID, et al: Impact of aromatase inhibitor treatment on vertebral morphology and bone mineral density in postmenopausal women with breast cancer. Menopause 23:33-39, 2016 Crossref, Google Scholar
62.	Chang CH, Chen SJ, Liu CY: Fracture risk and adjuvant therapies in young breast cancer patients: A population-based study. PLoS One 10:e0130725, 2015 Google Scholar
63.	Brufsky AM, Bosserman LD, Caradonna RR, et al: Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results. Clin Breast Cancer 9:77-85, 2009 Crossref, Medline, Google Scholar
64.	Burstein HJ, Lacchetti C, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO Clinical Practice Guideline focused update. J Clin Oncol 37:423-438, 2019 Link, Google Scholar
65.	Morote J, Morin JP, Orsola A, et al: Prevalence of osteoporosis during long-term androgen deprivation therapy in patients with prostate cancer. Urology 69:500-504, 2007 Crossref, Medline, Google Scholar
66.	Howland WJ, Loeffler RK, Starchman DE, et al: Postirradiation atrophic changes of bone and related complications. Radiology 117:677-685, 1975 Crossref, Google Scholar
67.	Pacheco R, Stock H: Effects of radiation on bone. Curr Osteoporos Rep 11:299-304, 2013 Crossref, Google Scholar
68.	Ryan AM, Power DG, Daly L, et al: Cancer-associated malnutrition, cachexia and sarcopenia: The skeleton in the hospital closet 40 years later. Proc Nutr Soc 75:199-211, 2016 Crossref, Google Scholar
69.	Rizzoli R, Bonjour J-P: Undernutrition and Osteoporosis. Malnutrition in the Elderly. Heidelberg, Germany, Steinkopff, 1999, pp 49-58 Crossref, Google Scholar
70.	Institute of Medicine National Research Council: From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, DC, National Academies Press, 2006 Google Scholar
71.	Bluethmann SM, Mariotto AB, Rowland JH: Anticipating the “silver tsunami”: Prevalence trajectories and comorbidity burden among older cancer survivors in the United States. Cancer Epidemiol Biomarkers Prev 25:1029-1036, 2016 Crossref, Medline, Google Scholar
72.	Office of the Surgeon General: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD, Reports of the Surgeon General, 2004 Google Scholar
73.	Sutkowi-Hemstreet A, Vu M, Harris R, et al: Adult patients’ perspectives on the benefits and harms of overused screening tests: A qualitative study. J Gen Intern Med 30:1618-1626, 2015 Crossref, Google Scholar
74.	RadiologyInfo.org: Radiation Dose in X-Ray and CT Exams. https://www.radiologyinfo.org/en/pdf/safety-xray.pdf Google Scholar
75.	Shepstone L, Lenaghan E, Cooper C, et al: Screening in the community to reduce fractures in older women (SCOOP): A randomised controlled trial. Lancet 391:741-747, 2018 Crossref, Google Scholar
76.	Turner DA, Khioe RFS, Shepstone L, et al: The cost-effectiveness of screening in the community to reduce osteoporotic fractures in older women in the UK: Economic evaluation of the SCOOP study. J Bone Miner Res 33:845-851, 2018 Crossref, Google Scholar
77.	Neuner JM, Yen TW, Sparapani RA, et al: Fracture risk and adjuvant hormonal therapy among a population-based cohort of older female breast cancer patients. Osteoporos Int 22:2847-2855, 2011 Crossref, Google Scholar
78.	Mohamad N-V, Soelaiman I-N, Chin K-Y: A concise review of testosterone and bone health. Clin Interv Aging 11:1317-1324, 2016 Crossref, Google Scholar
79.	Buckley L, Guyatt G, Fink HA, et al: 2017 American College of Rheumatology Guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol 69:1521-1537, 2017 Crossref, Google Scholar
80.	International Society for Clinical Densitometry (ISCD): ISCD Official Positions—Adult, 2015. https://www.iscd.org/official-positions/2015-iscd-official-positions-adult/ Google Scholar
81.	Guyatt GH, Oxman AD, Kunz R, et al: GRADE guidelines: 8. Rating the quality of evidence--Indirectness. J Clin Epidemiol 64:1303-1310, 2011 Crossref, Google Scholar
82.	Bischoff-Ferrari HA, Willett WC, Orav EJ, et al: A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 367:40-49, 2012 [Erratum: N Engl J Med 367:481, 2012] Crossref, Medline, Google Scholar
83.	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. https://effectivehealthcare.ahrq.gov/topics/osteoporosis-bone-fracture/research Google Scholar
84.	Hassannia T, GhaznaviRad E, Vakili R, et al: High prevalence of vitamin D deficiency and associated risk factors among employed women in a sunny industrial city. Int J Vitam Nutr Res 85:119-128, 2015 Crossref, Google Scholar
85.	Gupta D, Vashi PG, Trukova K, et al: Prevalence of serum vitamin D deficiency and insufficiency in cancer: Review of the epidemiological literature. Exp Ther Med 2:181-193, 2011 Crossref, Google Scholar
86.	Uth J, Hornstrup T, Christensen JF, et al: Football training in men with prostate cancer undergoing androgen deprivation therapy: Activity profile and short-term skeletal and postural balance adaptations. Eur J Appl Physiol 116:471-480, 2016 Crossref, Google Scholar
87.	Uth J, Hornstrup T, Christensen JF, et al: Efficacy of recreational football on bone health, body composition, and physical functioning in men with prostate cancer undergoing androgen deprivation therapy: 32-week follow-up of the FC prostate randomised controlled trial. Osteoporos Int 27:1507-1518, 2016 Crossref, Google Scholar
88.	Bijelic R, Milicevic S, Balaban J: Risk factors for osteoporosis in postmenopausal women. Med Arh 71:25-28, 2017 Crossref, Google Scholar
89.	Pompe E, Bartstra J, Verhaar HJ, et al: Bone density loss on computed tomography at 3-year follow-up in current compared to former male smokers. Eur J Radiol 89:177-181, 2017 Crossref, Google Scholar
90.	de Jong WU, de Jong PA, Vliegenthart R, et al: Association of chronic obstructive pulmonary disease and smoking status with bone density and vertebral fractures in male lung cancer screening participants. J Bone Miner Res 29:2224-2229, 2014 Crossref, Google Scholar
91.	Mostofsky E, Mukamal KJ, Giovannucci EL, et al: Key findings on alcohol consumption and a variety of health outcomes from the Nurses’ Health Study. Am J Public Health 106:1586-1591, 2016 Crossref, Google Scholar
92.	Shapiro CL: Cancer survivorship. N Engl J Med 379:2438-2450, 2018 Crossref, Medline, Google Scholar
93.	Black DM, Delmas PD, Eastell R, et al: Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809-1822, 2007 Crossref, Medline, Google Scholar
94.	Reid IR, Horne AM, Mihov B, et al: Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med 379:2407-2416, 2018 Crossref, Google Scholar
95.	Conte P, Guarneri V: Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. Oncologist 9(Suppl 4):28-37, 2004 Crossref, Medline, Google Scholar
96.	Gehret C: Denosumab: A New Therapy for Osteoporosis. https://www.clevelandclinicmeded.com/medicalpubs/pharmacy/pdf/Pharmacotherapy_XIII-1.pdf Google Scholar
97.	Khow KSF, Shibu P, Yu SCY, et al: Epidemiology and postoperative outcomes of atypical femoral fractures in older adults: A systematic review. J Nutr Health Aging 21:83-91, 2017 Crossref, Google Scholar
98.	Alibhai SMH, Zukotynski K, Walker-Dilks C, et al: Bone health and bone-targeted therapies for prostate cancer: A Programme in Evidence-based Care - Cancer Care Ontario Clinical Practice Guideline. Clin Oncol (R Coll Radiol) 29:348-355, 2017 Crossref, Google Scholar
99.	Yarom N, Shapiro C, Peterson D, et al: Medication-related osteonecrosis of the jaw: MASCC/ISOO/ASCO Clinical Practice Guideline. J Clin Oncol 37:2290-2310, 2019 Link, Google Scholar
100.	Hadji P, Coleman RE, Wilson C, et al: Adjuvant bisphosphonates in early breast cancer: Consensus guidance for clinical practice from a European Panel. Ann Oncol 27:379-390, 2016 Crossref, Medline, Google Scholar
101.	Hui RL, Adams AL, Niu F, et al: Predicting adherence and persistence with oral bisphosphonate therapy in an integrated health care delivery system. J Manag Care Spec Pharm 23:503-512, 2017 Google Scholar
102.	Vieira HP, Leite IA, Araújo Sampaio TM, et al: Bisphosphonates adherence for treatment of osteoporosis. Int Arch Med 6:24, 2013 Crossref, Google Scholar
103.	Wilson C, Coleman RE: Adjuvant therapy with bone-targeted agents. Curr Opin Support Palliat Care 5:241-250, 2011 Crossref, Google Scholar
104.	Migliorati CA, Epstein JB, Abt E, et al: Osteonecrosis of the jaw and bisphosphonates in cancer: A narrative review. Nat Rev Endocrinol 7:34-42, 2011 Crossref, Medline, Google Scholar
105.	Gedmintas L, Solomon DH, Kim SC: Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: A systematic review and meta-analysis. J Bone Miner Res 28:1729-1737, 2013 Crossref, Google Scholar
105a.	Zhang X, Hamadeh IS, Song S, et al: Osteonecrosis of the jaw in the United States Food and Drug Administration’s Adverse Event Reporting System (FAERS). J Bone Miner Res 31:336-340, 2016 Crossref, Google Scholar
106.	Papapoulos S, Lippuner K, Roux C, et al: The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: Results from the FREEDOM Extension study. Osteoporos Int 26:2773-2783, 2015 Crossref, Google Scholar
107.	Powles TJ, McCloskey E, Paterson AH, et al: Oral clodronate and reduction in loss of bone mineral density in women with operable primary breast cancer. J Natl Cancer Inst 90:704-708, 1998 Crossref, Medline, Google Scholar
108.	Kalder M, Kyvernitakis I, Albert US, et al: Effects of zoledronic acid versus placebo on bone mineral density and bone texture analysis assessed by the trabecular bone score in premenopausal women with breast cancer treatment-induced bone loss: Results of the ProBONE II substudy. Osteoporos Int 26:353-360, 2015 Crossref, Google Scholar
109.	Weaver CM, Gordon CM, Janz KF, et al: The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: A systematic review and implementation recommendations. Osteoporos Int 27:1281-1386, 2016 [Erratum: Osteoporos Int 27:1387, 2016] Crossref, Google Scholar
110.	Almeida M, Laurent MR, Dubois V, et al: Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev 97:135-187, 2017 Crossref, Google Scholar
111.	Lustberg MB, Reinbolt RE, Shapiro CL: Bone health in adult cancer survivorship. J Clin Oncol 30:3665-3674, 2012 Link, Google Scholar
112.	Smith MR: Osteoporosis during androgen deprivation therapy for prostate cancer. Urology 60:79-85, discussion 86, 2002 (suppl 1) Crossref, Google Scholar
113.	Hibler EA, Kauderer J, Greene MH, et al: Bone loss after oophorectomy among high-risk women: An NRG oncology/gynecologic oncology group study. Menopause 23:1228-1232, 2016 Crossref, Google Scholar
114.	Stĕpán JJ, Pospíchal J, Presl J, et al: Bone loss and biochemical indices of bone remodeling in surgically induced postmenopausal women. Bone 8:279-284, 1987 Crossref, Google Scholar
115.	Michaelson MD, Kaufman DS, Lee H, et al: Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol 25:1038-1042, 2007 Link, Google Scholar
116.	Smith MR: Therapy Insight: Osteoporosis during hormone therapy for prostate cancer. Nat Clin Pract Urol 2:608-615, quiz 628, 2005 Crossref, Google Scholar
117.	Sverrisdóttir A, Fornander T, Jacobsson H, et al: Bone mineral density among premenopausal women with early breast cancer in a randomized trial of adjuvant endocrine therapy. J Clin Oncol 22:3694-3699, 2004 Link, Google Scholar
118.	Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19:3306-3311, 2001 Link, Google Scholar
119.	Fogelman I, Blake GM, Blamey R, et al: Bone mineral density in premenopausal women treated for node-positive early breast cancer with 2 years of goserelin or 6 months of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Osteoporos Int 14:1001-1006, 2003 Crossref, Medline, Google Scholar
120.	Gracia CR, Sammel MD, Freeman E, et al: Impact of cancer therapies on ovarian reserve. Fertil Steril 97:134-140.e1, 2012 Crossref, Medline, Google Scholar
121.	Bines J, Oleske DM, Cobleigh MA: Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 14:1718-1729, 1996 Link, Google Scholar
122.	Partridge A, Gelber S, Gelber RD, et al: Age of menopause among women who remain premenopausal following treatment for early breast cancer: Long-term results from International Breast Cancer Study Group Trials V and VI. Eur J Cancer 43:1646-1653, 2007 Crossref, Medline, Google Scholar
123.	Gnant MF, Mlineritsch B, Luschin-Ebengreuth G, et al: Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: A report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 25:820-828, 2007 Link, Google Scholar
124.	Gnant M, Mlineritsch B, Stoeger H, et al: Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 12:631-641, 2011 Crossref, Medline, Google Scholar
125.	Coleman R, de Boer R, Eidtmann H, et al: Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): Final 60-month results. Ann Oncol 24:398-405, 2013 Crossref, Medline, Google Scholar
126.	Brufsky AM, Harker WG, Beck JT, et al: Final 5-year results of Z-FAST trial: Adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer 118:1192-1201, 2012 Crossref, Medline, Google Scholar
127.	Llombart A FA, Paija O, et al: Zoledronic acid prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: E-ZO-FAST 36-month follow-up. American Society of Clinical Oncology 2009 Breast Cancer Symposium, San Francisco, CA, October 8-10, 2009 Google Scholar
128.	Hines SL, Mincey B, Dentchev T, et al: Immediate versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen-N03CC. Breast Cancer Res Treat 117:603-609, 2009 Crossref, Medline, Google Scholar
129.	Tsourdi E, Langdahl B, Cohen-Solal M, et al: Discontinuation of denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone 105:11-17, 2017 Crossref, Google Scholar
130.	Dhesy-Thind S, Fletcher GG, Blanchette PS, et al: Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 35:2062-2081, 2017 Link, Google Scholar
131.	Doria C, Mosele GR, Solla F, et al: Treatment of osteoporosis secondary to hypogonadism in prostate cancer patients: A prospective randomized multicenter international study with denosumab vs. alendronate. Minerva Urol Nefrol 69:271-277, 2017 Google Scholar
132.	Taxel P, Dowsett R, Richter L, et al: Risedronate prevents early bone loss and increased bone turnover in the first 6 months of luteinizing hormone-releasing hormone-agonist therapy for prostate cancer. BJU Int 106:1473-1476, 2010 Crossref, Google Scholar
133.	Choo R, Lukka H, Cheung P, et al: Randomized, double-blinded, placebo-controlled, trial of risedronate for the prevention of bone mineral density loss in nonmetastatic prostate cancer patients receiving radiation therapy plus androgen deprivation therapy. Int J Radiat Oncol Biol Phys 85:1239-1245, 2013 Crossref, Google Scholar
134.	Kachnic LA, Pugh SL, Tai P, et al: RTOG 0518: Randomized phase III trial to evaluate zoledronic acid for prevention of osteoporosis and associated fractures in prostate cancer patients. Prostate Cancer Prostatic Dis 16:382-386, 2013 Crossref, Google Scholar
135.	Kearns AE, Northfelt DW, Dueck AC, et al: Osteoporosis prevention in prostate cancer patients receiving androgen ablation therapy: Placebo-controlled double-blind study of estradiol and risedronate—N01C8. Support Care Cancer 18:321-328, 2010 Crossref, Google Scholar
135a.	Israeli RS, Rosenberg SJ, Saltzstein DR, et al: The effect of zoledronic acid on bone mineral density in patients undergoing androgen deprivation therapy. Clin Genitourin Cancer 5:271-277, 2007 Crossref, Medline, Google Scholar
135b.	Rodrigues P, Hering FO, Bruna P, et al: Comparative study of the protective effect of different intravenous bisphosphonates on the decrease in bone mineral density in patients submitted to radical prostatectomy undergoing androgen deprivation therapy. A prospective open-label controlled study. Int J Urol 14:317-320, 2007 Crossref, Google Scholar
136.	Shahinian VB, Kuo YF, Freeman JL, et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154-164, 2005 Crossref, Medline, Google Scholar
137.	Fink HA, Ewing SK, Ensrud KE, et al: Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab 91:3908-3915, 2006 Crossref, Medline, Google Scholar
138.	Leder BZ, Smith MR, Fallon MA, et al: Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men. J Clin Endocrinol Metab 86:511-516, 2001 Medline, Google Scholar
139.	Lee H, McGovern K, Finkelstein JS, et al: Changes in bone mineral density and body composition during initial and long-term gonadotropin-releasing hormone agonist treatment for prostate carcinoma. Cancer 104:1633-1637, 2005 Crossref, Medline, Google Scholar
140.	Briot K, Paccou J, Beuzeboc P, et al: French recommendations for osteoporosis prevention and treatment in patients with prostate cancer treated by androgen deprivation. Joint Bone Spine 86:21-28, 2019 Crossref, Google Scholar
141.	Saad F, Sternberg CN, Mulders PFA, et al: The role of bisphosphonates or denosumab in light of the availability of new therapies for prostate cancer. Cancer Treat Rev 68:25-37, 2018 Crossref, Medline, Google Scholar
142.	Smith MR, Egerdie B, Hernández Toriz N, et al: Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361:745-755, 2009 Crossref, Medline, Google Scholar
143.	Kendler DL, Body JJ, Brandi ML, et al: Bone management in hematologic stem cell transplant recipients. Osteoporos Int 29:2597-2610, 2018 Crossref, Google Scholar
144.	McClune BL, Polgreen LE, Burmeister LA, et al: Screening, prevention and management of osteoporosis and bone loss in adult and pediatric hematopoietic cell transplant recipients. Bone Marrow Transplant 46:1-9, 2011 Crossref, Google Scholar
145.	Edwards BJ, Desai A, Tsai J, et al: Elevated incidence of fractures in solid-organ transplant recipients on glucocorticoid-sparing immunosuppressive regimens. J Osteoporos 2011:591793, 2011 Crossref, Medline, Google Scholar
146.	Gilligan T, Coyle N, Frankel RM, et al: Patient-clinician communication: American Society of Clinical Oncology Consensus Guideline. J Clin Oncol 35:3618-3632, 2017 Link, Google Scholar
147.	American Cancer Society: Cancer facts and figures for African Americans 2016-2018. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-047403.pdf Google Scholar
148.	National Cancer Institute: SEER cancer statistics review, 1975-2013. http://seer.cancer.gov/csr/1975_2013/ Google Scholar
149.	US Cancer Statistics Working Group: United States cancer statistics: 1999–2012 incidence and mortality web-based report. http://www.cdc.gov/uscs Google Scholar
150.	Mead H, Cartwright-Smith L, Jones K, et al: Racial and Ethnic Disparities in US Health Care: A Chartbook. New York, NY, The Commonwealth Fund, 2008 Google Scholar
151.	Liu Z, Weaver J, de Papp A, et al: Disparities in osteoporosis treatments. Osteoporos Int 27:509-519, 2016 Crossref, Google Scholar
152.	Cram P, Saag KG, Lou Y, et al: Racial differences and disparities in osteoporosis-related bone health: Results from the PAADRN randomized controlled trial. Med Care 55:561-568, 2017 Crossref, Google Scholar
153.	Hamrick I, Cao Q, Agbafe-Mosley D, et al: Osteoporosis healthcare disparities in postmenopausal women. J Womens Health (Larchmt) 21:1232-1236, 2012 Crossref, Google Scholar
154.	Schnipper LE, Davidson NE, Wollins DS, et al: Updating the American Society of Clinical Oncology value framework: Revisions and reflections in response to comments received. J Clin Oncol 34:2925-2934, 2016 Link, Google Scholar
155.	Schnipper LE, Davidson NE, Wollins DS, et al: American Society of Clinical Oncology statement: A conceptual framework to assess the value of cancer treatment options. J Clin Oncol 33:2563-2577, 2015 Link, Google Scholar
156.	Streeter SB, Schwartzberg L, Husain N, et al: Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract 7:46s-51s, 2011 (suppl) Link, Google Scholar
157.	Dusetzina SB, Winn AN, Abel GA, et al: Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol 32:306-311, 2014 Link, Google Scholar
158.	Meropol NJ, Schrag D, Smith TJ, et al: American Society of Clinical Oncology guidance statement: The cost of cancer care. J Clin Oncol 27:3868-3874, 2009 Link, Google Scholar
159.	Shapiro CL, Moriarty JP, Dusetzina S, et al: Cost-effectiveness analysis of monthly zoledronic acid, zoledronic acid every 3 months, and monthly denosumab in women with breast cancer and skeletal metastases: CALGB 70604 (Alliance). J Clin Oncol 35:3949-3955, 2017 Link, Google Scholar
160.	Saag KG, Petersen J, Brandi ML, et al: Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 377:1417-1427, 2017 Crossref, Google Scholar
161.	Ferrari SL: Osteoporosis: Romosozumab to rebuild the foundations of bone strength. Nat Rev Rheumatol 14:128, 2018 Crossref, Google Scholar
162.	Anderson K, Ismaila N, Flynn PJ, et al: Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 36:812-818, 2018 Link, Google Scholar

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