Bone Health in Adult Cancer Survivorship Maryam B. Lustberg, Raquel E. Reinbolt, and Charles L. Shapiro

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1 VOLUME 30 NUMBER 30 OCTOBER JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E Bone Health in Adult Cancer Survivorship Maryam B. Lustberg, Raquel E. Reinbolt, and Charles L. Shapiro All authors: Ohio State University, Columbus, OH. Submitted February 3, 2012; accepted June 13, 2012; published online ahead of print at on September 24, Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Charles L. Shapiro, MD, Starling-Loving Hall, Rm B405, 320 West 10th Ave, Columbus, OH ; charles.shapiro@osumc.edu by American Society of Clinical Oncology X/12/ /$20.00 DOI: /JCO A B S T R A C T Optimizing health outcomes, including prevention of osteoporotic fractures, is essential for promoting the well-being of the growing number of cancer survivors. Medical providers who participate in the care of cancer survivors should be aware that various cancer treatments may cause bone loss, which can increase the risk of subsequent of osteoporosis. Healthy bone remodeling is a balanced and dynamic equation between new bone formation and bone resorption. Aging, natural menopause, and cancer treatments such as surgical oophorectomy, gonadotropin-releasing hormone agonists, chemotherapy-induced ovarian failure, androgen deprivation therapy, and aromatase inhibitors can all promote bone loss. The WHO Fracture Assessment Tool can be used as a clinical aid to assess an individual s osteoporotic fracture risk, with or without bone mineral density measurements obtained from dual-energy x-ray absorptiometry. Preventative strategies include adequate calcium and vitamin D supplementation and modifying risk factors such as alcohol intake, tobacco use, and lack of exercise. Bisphosphonate therapy and rank-ligand monoclonal antibody therapy are the most commonly used agents for management of bone loss resulting from cancer treatment. This review will summarize the mechanisms by which cancer treatments cause bone loss as well provide screening and treatment recommendations for the management of bone loss. J Clin Oncol 30: by American Society of Clinical Oncology INTRODUCTION Health promotion, including maintenance of bone health, is important in cancer survivors. Aging, natural menopause, and cancer treatments all cause bone loss, potentially increasing risks of osteoporosis and subsequent bone fractures. This review will summarize the mechanisms by which cancer treatments cause bone loss as well provide screening and treatment recommendations for the management of bone loss. Many of the recommendations for bone health in cancer survivors are extrapolated from noncancer populations, where there are evidence-based guidelines for osteoporosis screening and treatment. Although these guidelines are generally relevant for most cancer survivors, there are gaps in knowledge in special populations, and these will be discussed. BIOLOGY OF NORMAL BONE REMODELING Normal bone remodeling is a dynamic process between new bone formation, mediated by osteoblasts, and bone resorption, mediated by osteoclasts. Osteoclasts are of hematopoietic origin and differentiate to multinucleated giant cells by a variety of signaling pathways including cytokines, growth factors, and hormones. 1 Activated osteoclasts then undergo apoptosis after bone resorption has taken place, allowing the formation of new bone mediated by osteoblasts. Normal bone remodeling is regulated primarily by the receptor activator factor kappa B ligand (RANKL) pathway. RANKL, a member of the tumor necrosis factor ligand family, is produced by osteoblasts and binds to the RANK receptor on osteoclasts. Osteoprotegerin (OPG), secreted by osteoblasts, acts as a decoy receptor for RANKL and thereby inhibits osteoclast activation. The balance between RANKL and OPG is the foundation of normal bone remodeling, as illustrated in Figure 1. Multiple factors influence the ratio of RANKL to OPG. For example, estrogen (and androgen) increases OPG secretion from osteoblasts, decreases the ratio of RANKL to OPG, downregulates the expression of RANKL on osteoclasts, and decreases overall bone resorption. 2,3 Conversely, when estrogen or androgen levels decrease as a consequence of normal menopause and aging, or because of the effects of cancer treatments such as chemotherapy, gonadotropin-releasing agonists, oophorectomy, aromatase inhibitors (AIs), and androgen-deprivation therapy (ADT), the ratio of RANKL to OPG increases and causes net bone resorption. Other factors that affect the ratio between RANKL and OPG include parathyroid hormone (PTH), insulin-like growth factor 1, and proinflammatory cytokines by American Society of Clinical Oncology 3665

2 Lustberg, Reinbolt, and Shapiro OPG + RANKL binding: increased bone formation Osteoclast precursor OPG RANKL RANK RANK + RANKL binding: increased resorption Osteoblasts Osteoclast Bone formation Bone resorption Fig 1. Normal bone remodeling is a dynamic process between new bone formation mediated by osteoblasts and bone resorption mediated by osteoclasts. Normal bone remodeling is governed by the balance between receptor activator factor kappa B ligand (RANKL) and osteoprotegerin (OPG). PATHOGENESIS OF OSTEOPOROSIS Imbalances in normal bone remodeling promote osteoporosis. Osteoporosis is a chronic bone disease characterized by decreased bone mineral density (BMD), leading to increased fracture risk, a condition that affects more than 10 million individuals in the United States. 7 Nontraumatic hip fractures are associated with increased mortality and morbidity and more than double the risk of future fractures. 8 Risk factors for osteoporosis are listed in Table 1. Steroids inhibit OPG production and stimulate RANKL production in osteoblastic cells. 9 Steroids also decrease androgen and estrogen secretion, ultimately resulting in bone resorption. 10,11 A dose-dependent relationship between chronic glucocorticoid use and fracture risk was identified in a retrospective cohort study of 244,235 oral glucocorticoid users in the United Kingdom General Practice Research Database. 12 Individuals receiving high-dose prednisolone ( 7.5 mg per day) were at the greatest risk for fracture development; however, lower doses (2.5 to 7.5 mg per day) were also associated with increased fracture risk. Both calcium and vitamin D play a role in skeletal homeostasis. Furthermore, vitamin D augments the intestinal absorption of calcium. In the setting of vitamin D deficiency, excessive bone resorption may result because of the inverse relationship between serum concentrations of PTH and 25-hydroxyvitamin D. 13 Vitamin D receptor, Table 1. Risk Factors for Osteoporosis Endocrine Genetic Lifestyle Nutritional Oophorectomy Family history Smoking Low calcium GnRH agonists Race Alcohol Low vitamin D Hypoestrogenic states Sex Sedentary lifestyle Androgen deprivation Low body Chronic corticosteroids weight Early menopause Prolonged immobilization Hypogonadism Abbreviation: GnRH, gonadotropin-releasing hormone. Denotes secondary osteoporosis FRAX risk factor. Denotes primary FRAX risk factor by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

3 Bone Health in Adult Cancer Survivorship Change in LS-Spine BMD at 12 Months (%) Normal menopause Tamoxifen ADT AI CIOF GnRH agonist Fig 2. Change in bone mineral density (BMD) in first 12 months of therapy with various cancer treatments. BMD loss occurs with various cancer therapies at higher rates than those seen in normal aging in men and women. 16 Tamoxifen causes a small amount of bone loss in premenopausal women and preserves bone in postmenopausal women. 17,18 Androgen-deprivation therapy (ADT), 19,20,21 aromatase inhibitors (AIs), chemotherapy-induced ovarian failure (CIOF), 17,26-30 and gonadotropin-releasing hormone (GnRH) agonist therapy 31,32 all promote bone loss to varying degrees. LS, lumbar spine. estrogen receptor, and OPG/RANK/RANKL pathway polymorphisms may also predispose to increased fracture risk. 14,15 Some cancer survivors are at an increased risk of osteoporosis and subsequent fractures related to the type of cancer treatment received along with modifiable lifestyle factors and genetic predispositions. The magnitude of effects on BMD of various cancer treatments is illustrated in Figure 2. Although normal aging in both men and women, lowered estrogen levels in postmenopausal women, and effects of cancer treatments all lead to bone loss, not all individuals develop osteoporosis or fractures. CHEMOTHERAPY-INDUCED OVARIAN FAILURE Chemotherapy-induced ovarian failure (CIOF) is defined as cessation of ovarian function in premenopausal women. Exposure to adjuvant chemotherapy leads to rapid bone loss, 25,33,34 which occurs as early as 6 months after the initiation of adjuvant chemotherapy and further increases at 12 months. 25 The effects of chemotherapy on ovarian function depend on the age at treatment, the specific class of drugs, and the cumulative doses. The risk of CIOF increases with age, likely because of diminished ovarian reserve related to the reduced number and quality of follicles Likewise, the effect of age at treatment is seen in other malignancies such as Hodgkin s lymphoma 39 and in adult survivors of childhood malignancies (eg, acute lymphoblastic leukemia [ALL]) where treatment before puberty reduces the likelihood of ovarian failure. 40 Alkylating agents, such as cyclophosphamide, 25,34 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 incidence of CIOF. 41,42 In women who retain menstrual function after chemotherapy, natural menopause can occur at earlier ages than in those who did not receive chemotherapy. 43,44 It is important to distinguish between transient amenorrhea that often occurs in premenopausal women who receive adjuvant chemotherapy and permanent ovarian failure. This is not only for assessment of risk of bone loss in the future but, more importantly, for the selection of appropriate adjuvant antiestrogen treatment in women with estrogen receptor (ER) positive breast cancers as well. Illustrating this point, tamoxifen is effective irrespective of menopausal status, whereas AIs are only effective in postmenopausal women. Because of the difficulty in determining menopausal status in premenopausal women with ER-positive cancers who develop amenorrhea after adjuvant chemotherapy, it is common practice to treat these women with 5 years of tamoxifen and, if indicated, treat them with an AI only after establishing postmenopausal status. HIGH-DOSE CHEMOTHERAPY AND BONE HEALTH IN PATIENTS UNDERGOING TRANSPLANTATION A higher incidence of osteopenia and osteoporosis is observed in long-term survivors of Hodgkin s and non-hodgkin s lymphoma treated with autologous hematopoietic cell transplantation. 37,38 Intensive chemotherapy, total-body irradiation, and exposure to glucocorticoids can cause osteoporosis, which is observed in approximately 50% of survivors of allogeneic hematopoietic cell transplant recipients. 45 ADULT SURVIVORS OF CHILDHOOD MALIGNANCIES AND BONE HEALTH The growing number of adult survivors of childhood malignancies highlights the late-term adverse health consequences of curative therapies for pediatric malignancies. ALL is the most common pediatric malignancy. Glucocorticoids used with chemotherapy for childhood ALL reduce BMD. 46,47 Other agents that affect bone health include methotrexate, which is cytotoxic to osteoblasts and decreases new bone formation, 48,49 radiation to reproductive organs or the neuroendocrine axis, and high cumulative doses of alkylators that lower circulating levels of estrogen and testosterone and promote bone loss. 50 Osteoporosis is present in up to 25% of adult survivors of childhood ALL and up to 42% of adult survivors of pediatric hematopoietic transplantation. 51 The correlation of osteoporosis with long-term fracture risk is unclear in this population, although higher rates of fractures are seen during and immediately after treatment in children with ALL. 47,52 In addition to hypogonadism, growth hormone deficiency is a risk factor for low BMD in this population. 53 HORMONAL THERAPY AND BONE HEALTH Selective ER Modulators Both tamoxifen and raloxifene are selective ER modulators (SERMS). SERMS bind to the ER and, depending on the target tissue, act as estrogen agonists or antagonists. 54 In preclinical models, tamoxifen is an estrogen agonist in bone tissue. However, in the clinic, tamoxifen causes a small amount of bone loss in premenopausal women and preserves bone in postmenopausal women (Fig 2). 17,18 The bone-protecting properties of tamoxifen are relatively weak based on the finding across several trials that fragility fractures are not less by American Society of Clinical Oncology 3667

4 Lustberg, Reinbolt, and Shapiro frequent in women treated with tamoxifen. 55,56 Raloxifene increases BMD and decreases spine fractures but has no impact on nonspinal fractures. 9 Raloxifene is not associated with estrogen agonist activity in the endometrium and does not increase the risk of endometrial cancer. However, because of the lack of data in treating breast cancer and the potential for cross-reactivity with tamoxifen based on preclinical models, 57 raloxifene should not be prescribed for osteoporosis after tamoxifen treatment in breast cancer survivors. AIs AIs are approved for treatment of hormone receptor positive postmenopausal breast cancer, and current guidelines recommend AIs as the initial treatment or AIs used sequentially after 2 to 3 years of tamoxifen. The source of estrogens in postmenopausal women is androgens produced by the adrenal glands that are converted to estrogens by aromatase. AIs decrease circulating estrogen levels by selectively inhibiting aromatase. Relative to tamoxifen, AIs are associated with an increased risk of bone loss and fractures. All the major trials of AIs in the adjuvant setting show an increased rate of fractures, except MA-17, as shown in Table 2. When AIs are used for 5 years without sequencing with prior tamoxifen, fracture rates are higher, which is likely because of bone protective properties of tamoxifen in postmenopausal women. The ATAC (Arimidex, Tamoxifen Alone or in Combination) study has shown the highest fracture rates, in large part because of longer follow-up time, and this increased fracture rate seems to decrease after stopping AIs. 58,65 The rate and magnitude of bone loss caused by AIs are lower than those observed after oophorectomy or CIOF (Fig 2). Although AI use is considered a risk factor for osteoporosis, and careful monitoring of BMD is recommended, a majority of women who have normal BMD or who were mildly osteopenic before starting AI therapy will not develop osteopenia or osteoporosis while being treated with these drugs. For example, after 5 years of treatment with an AI, only 25% of control patients in the Z-Fast study received zoledronic acid, because their T-scores decreased to less than ADT and Bone Loss ADT consisting of gonadotropin-releasing hormone agonist and antiandrogens is used in management of prostate cancer. Men with Table 2. Summary of Fractures in Breast Cancer Adjuvant Studies With AIs Trial No. of Patients Median Duration of Follow-Up (months) Fractures (%) AI TAM AI v TAM ATAC 58 6, ATAC post-treatment 58 6, BIG , AI after 2-3 years of TAM IES 60 4, ABCSG8/ARNO 61 3, AI after 5 yrs of TAM MA , Abbreviations: ABCSG, Austrian Breast and Colorectal Cancer Study Group; AI, aromatase inhibitor; ARNO, Arimidex-Nolvadex; ATAC, Arimidex, Tamoxifen Alone or in Combination; BIG, Breast International Group; IES, Inter-Group Exemestane Study; TAM, tamoxifen. After 60 months of AI use, fracture rates decrease after stopping AI. P prostate cancer receiving ADT lose bone and have increased fracture rates. 65 The mechanism for bone loss is likely a result of the combination of testosterone deficiency as well decreased aromatization of testosterone to estrogen. 66 Gonadotropin-releasing hormone agonists also increase PTH-mediated osteoclast activation and increase bone turnover. 67 Similar to CIOF, the highest magnitude of bone loss occurs during the first year of ADT and continues with long-term treatment. 68 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. 65 Bisphosphonate therapy and RANKL monoclonal antibody therapy are the most commonly used agents for management of bone loss during ADT. Toremifene, a SERM used for treating metastatic breast cancer, resulted in a statistically significant decrease in new vertebral fractures and improved BMD at the lumbar spine, hip, and femoral neck when used in men with prostate cancer receiving ADT. 69 SCREENING, DIAGNOSIS, AND TREATMENT OF OSTEOPOROSIS Dual-energy x-ray absorptiometry (DEXA) scanning is routinely used to screen for osteoporosis and measure BMD. The number of standard deviations (SDs) above or below the mean of the difference between a patient s BMD compared with that of a reference population of normal adults age 30 years of the same sex is defined as the T score. 7 In contrast, the Z score is the number of SDs above or below the mean of the difference in the patient s BMD relative to the expected BMD for the patient s age and sex. In postmenopausal women and men older than age 50 years, the WHO defines normal bone density as a T score 1, osteopenia as a T score of 1 and 2.5, and osteoporosis as a T score 2.5 or one or more nontraumatic fractures. In men younger than age 50 years or in premenopausal women and children, Z scores are preferred. 70 Z scores of 2.0 are defined as below the expected range for age, and Z scores of 2.0 are within the expected range for age. Guidelines for screening and treating osteoporosis in noncancer patients are described in Table 3. Although DEXA measurement is considered the gold standard, it has a number of limitations, including variability in calibration if different machines are used or, in the case of certain health conditions (eg, osteoarthritis and calcification of the aorta), false elevation of BMD. In noncancer populations, a T score of 2.5 is frequently used as the threshold for initiating osteoporosis treatment, when in fact, a majority of osteoporotic fractures occur in individuals with T scores above the osteoporosis threshold, 77 and over 50% of women and 70% of men with fragility fractures did not have a BMD in the osteoporotic range. 78 Guidelines for cancer populations are summarized in Table 3. Most of these address postmenopausal women receiving AIs, and they differ in recommendations of DEXA screening intervals, incorporation of risk factors, and when to initiate treatment. The WHO Fracture Assessment Tool (FRAX; was developed as a clinical aid to assess an individual s osteoporotic fracture risk, with or without BMD measurements. 79 FRAX evaluates the 10-year probability for osteoporotic fracture risk, taking into account both modifiable and nonmodifiable risk factors (Table 1) to guide treatment decisions. FRAX is optimized for postmenopausal women and men age 50 years or older who have not been previously treated for bone loss. FRAX may underestimate the bone by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

5 Bone Health in Adult Cancer Survivorship Table 3. Guidelines for Osteoporosis Screening and Treatment in General Population and Cancer Survivors Group Population Screening Interval Indications for Osteoporosis Treatment General population USPSTF 71 Women: DEXA every 2 years T score 2.5 All age 65 years 10-year fracture risk in age 65 years Men: Not enough evidence NOF 7 Women: DEXA every 2 years Any of the following: All age 65 years Prior hip or vertebral fracture Men: T score 2.5 in femoral neck or spine All age 70 years T score between 1.0 and 2.5 High risk populations: FRAX 10-year probability for hip fracture 3% or FRAX Low BMI major osteoporotic fracture 20% Prior nontrauma fracture High-risk medication Fracture after age 50 years ISCD 70 Women: Not specified Not specified All age 65 years Postmenopausal women age 65 years with clinical risk factors for fracture Women during menopausal transition with clinical risk factors Men: All age 70 years Age 70 years with clinical risk factors for fracture High risk populations: Fragility fractures Conditions associated with bone loss High-risk medications Cancer population ASCO 72 High-risk women: Annual DEXA T score 2.5 Age 65 years Age 60 to 64 years at high risk for osteoporosis Initiating AI therapy Premenopausal with ovarian suppression NCCN 73 Women initiating AI therapy DEXA every 2 years Any of the following: Men receiving ADT T score 2.0 FRAX 10-year probability for hip fracture 3% FRAX 10-year probability for major osteoporotic fracture 20% International Expert Women initiating AI therapy DEXA every 1 to 2 Panel 74 years ESCEO 75 Any woman initiating AI therapy Not specified Any of the following: Belgian Bone Club 76 Premenopausal women with ovarian suppression Any woman initiating AI therapy or GnRH agonist therapy Any man initiating ADT DEXA every 1 to 2 years Any of the following: T score 2.0 T score 2.0 with two additional clinical factors Age 75 years irrespective of BMD Personal fragility fracture 50 T score 2.5 T score 1.5 plus one clinical risk factor T score 1.0 plus two clinical risk factors FRAX 10-year hip fracture 3% T score of 2.5 History of fragility fracture T score 1.0 plus clinical risk factors Abbreviations: ADT, androgen-deprivation therapy; AI, aromatase inhibitor; ASCO, American Society of Clinical Oncology; BMD, bone mineral density; BMI, body mass index; DEXA, dual-energy x-ray absorptiometry; ESCEO, European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis; GnRH, gonadotropin-releasing hormone; ISCD, International Society for Clinical Densitometry; NCCN, National Comprehensive Cancer Network; NOF, National Osteoporosis Foundation; USPSTF, US Preventative Services Task Force. T score 1.5, age 65 years, BMI 20 kg/m 2, family history of hip fracture, personal history of fragility fracture after age 50 years, steroid use 6 months, or smoking history. Age 65 years, BMI 20 kg/m 2, family history of hip fracture, steroid use, smoking history, tendency for falls, inadequate nutritional intake, or other conditions associated with osteoporosis by American Society of Clinical Oncology 3669

6 Lustberg, Reinbolt, and Shapiro loss attributed to cancer therapies such as AIs. 74 Large prospective studies evaluating whether the FRAX calculator can accurately estimate fracture risk in cancer survivors are not available. Despite these limitations, FRAX permits a more individualized assessment of risk, and the National Comprehensive Cancer Network Bone Health Task Force incorporates FRAX into its guidelines (Table 3). 73 MANAGING OSTEOPENIA AND OSTEOPOROSIS IN ADULT CANCER SURVIVORS A summary of the major randomized trials in cancer populations is provided in Table 4. Modifiable risk factors should always be addressed, with recommendations for regular weight-bearing exercises, physical activity, and supplemental calcium and vitamin D. 7 These not only contribute to the maintenance of bone health but also promote overall health. The Institute of Medicine issued a consensus statement in 2010 on calcium and vitamin D, and the recommendations for healthy adults were 1,000 mg calcium per day and 600 IU vitamin D per day. 89 For women older than age 50 years and for men older than age 70 years, intake of 1,200 mg calcium per day is recommended. For adults older than age 70 years, 800 IU vitamin D per day is recommended. The applicability of these recommendations to adult cancer survivors who experience treatment-related bone loss is unclear. An algorithm based on several guidelines is illustrated in Figure 3. Osteoporosis is treated when certain criteria are met, such as T score 2.5, FRAX 10-year probability for hip fracture 3% or for major osteoporotic fracture 20%, or history of personal fragility fracture. These criteria are well accepted in both the general and cancer populations. The majority of fractures occur in women with a T scores 2.5, 90 and the FRAX calculator can assist in further stratifying the Table 4. Selected Randomized Trials of Pharmacologic Treatments for Osteoporosis Noncancer Populations and Cancer Survivors Population Trial No. of Patients Treatment Arm Duration (years) Outcomes Noncancer population Postmenopausal women with osteoporosis Postmenopausal women with osteoporosis BC Pre-BC treated with adjuvant chemotherapy Pre-BC treated with ovarian suppression plus AI or TAM HORIZON 80 3,889 ZA 5 mg annually v placebo 3 Vertebral fractures 3.3% with ZA v 10.9% with placebo (RR, 0.30; 95% CI, 0.24 to 0.38) Hip fractures 1.4% with ZA v 2.5% with placebo (HR, 0.59; 95% CI, 0.42 to 0.83) FREEDOM 81 7,868 DMAB 60 mg once every 6 months v placebo CALGB ZA 4 mg once every 3 months v control Hershman ZA 4 mg once every 3 months v control ABCSG (bone substudy) ZA 4 mg once every 6 months v control Post-BC treated with AI Z-FAST ZA 4 mg once every 6 months v delayed ZA Post-BC treated with AI ZO-FAST 23 1,065 ZA 4 mg once every 6 months v delayed ZA Post-BC treated with DMAB HALT-BC DMAB 60 mg SC once every 6 months v placebo Prostate cancer with ADT ZA ZA 4 mg once every 6 months v placebo Alendronate Alendronate 70 mg once per week v placebo Toremifene 1,389 Toremifene 80 mg once G per day v placebo DMAB HALT ,468 DMAB 60 mg SC once every 6 months v placebo Allogeneic transplantation Risedronate Risedronate 5 mg once per day v placebo ZA ZA 4 mg once every 3 months v risedronate v HRT 3 Vertebral fractures 2.3% with DMAB v 7.2% with placebo (RR, 0.32; 95% CI, 0.26 to 0.41) Hip fractures 0.7% with DMAB v 1.2% with placebo (HR, 0.60; 95% CI, 0.42 to 0.83) 2 LS BMD 1.2% increase with ZA v 6.7% decrease in control at 1 year (P.001) 1 LS BMD 0% with ZA v 3.0% decrease with placebo at 1 year (P.001) 3 LS BMD 4.0% increase in ZA v baseline (P.02); 6.3% decrease in control v baseline in (P.001) at 5 years 5 LS BMD 4.4% decrease in upfront ZA group v delayed group at 1 year (P.001) 5 LS BMD 5.7% increase in upfront ZA group v delayed group at 1 year (P.001) 2 LS BMD 5.5% increase with DMAB v placebo at 1 year (P.001) 1 LS BMD 5.6% increase with ZA v 2.2% decrease with placebo (P.001) 1 LS BMD 3.7% increase with alendronate v 1.4% decrease with placebo (P.001) 2 Toremifene decrease in new vertebral fractures (2.5% v 4.9%; P.05) 2 LS BMD 5.6% increase with DMAB v 1.0% decrease with placebo (P.001) Vertebral fractures 1.5% v 3.9% (P.006) with DMAB v placebo 1 LS BMD 5.9% increase with risedronate (P.05) 1 HRT did not prevent bone loss; LS BMD increase with risedronate; both LS and femoral neck BMD increase with ZA PA PA 90 mg v control 1 LS BMD 2% increase with PA v 3% decrease in control at 1 year (P.003) Abbreviations: ABCSG, Austrian Breast and Colorectal Cancer Study Group; ADT, androgen-deprivation therapy; AI, aromatase inhibitor; BC, breast cancer; BMD, bone mineral density; CALGB, Cancer and Leukemia Group B; DMAB, denosumab; HR, hazard ratio; HRT, hormone replacement therapy; LS, lumbar spine; PA, pamidronate; RR, relative risk; SC, subcutaneously; TAM, tamoxifen; ZA, zoledronic acid; Z-FAST, Zometa-Femara Adjuvant Synergy Trial; ZO-FAST, Zometa-Femara Adjuvant Synergy Trial by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

7 Bone Health in Adult Cancer Survivorship Cancer survivors Individualized assessment of fracture risk Screen for osteoporosis risk factors FRAX algorithm DEXA screening for BMD Address lifestyle and modifiable risk factors Adequate calcium and vitamin D intake* Physical activity Monitor annually for osteoporosis risk factors Repeat DEXA every 1-2 years as appropriate Consider therapy with approved osteoporotic therapy if: T score < -1.5 and ongoing cancer therapy plus 1-2 additional clinical risk factors Strongly consider therapy with approved osteoporotic therapy if: T score < -2.0 and ongoing cancer therapy Begin therapy with approved osteoporotic therapy if: T score < -2.5, or High FRAX risk or Personal fragility fracture > age 50 Fig 3. Algorithm for management of bone loss in cancer survivors. All cancer survivors benefit from individualized fracture risk assessment and bone health management. This algorithm summarizes guidelines for osteoporosis screening and treatment in cancer survivors from various organizations listed in Table 3. (*) Per Institute of Medicine, for all healthy adults, 1,000 mg calcium per day and 600 IU vitamin D per day are recommended. For women age 50 years and men age 70 years, 1,200 mg calcium per day is recommended. For adults age 70 years, 800 IU vitamin D per day is recommended. For individuals at risk for ongoing bone loss, higher calcium and vitamin D intake may be needed. ( ) Aromatase inhibitor, androgen-deprivation, and gonadotropin-releasing hormone agonist therapies. ( ) Age 65 years, body mass index 20 kg/m 2, family history of hip fracture, steroid use 6 months, or smoking history. ( ) FRAX (WHO Fracture Assessment Tool) 10-year probability for hip fracture 3% or FRAX 10-year probability for major osteoporotic fracture 20%. FRAX may underestimate risk of fractures during ongoing cancer therapy. BMD, bone mineral density; DEXA, dual-energy x-ray absorptiometry. risk of fractures. Bone loss resulting from cancer treatment has led several organizations to recommended initiating therapy for osteoporosis if T score 2.0, irrespective of the FRAX score, 73-75,77 or if T score 1.5, with clinical risk factors for bone loss such as older than age 65 years or BMI less than 20, based on guidelines from an international expert panel, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and the Belgian Bone Club It is important to remember that most of the recommendations described here for the initiation of antiresorptive therapy using T scores with or without risk factor incorporation have been based on trials of postmenopausal women receiving AIs, and none have been prospectively validated in patients with cancer. Beyond the specific recommendations, which vary, the following are important: awareness of the potential for cancer treatment related bone loss, the availability of DEXA scan screening, and the recognition that maintaining optimal bone health is a priority, especially for long-term survivors. There are several different classes of pharmacologic agents approved for the prevention or treatment of osteoporosis including bisphosphonates, denusomab, SERMs, and teriparatide. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption, and several oral (alendronate, risedronate, and ibandronate) and intravenous (IV) bisphosphonates (pamidronate and zoledronic acid) are approved for prevention and/or treatment of osteoporosis. The most frequent toxicity of oral bisphosphonates is esophagitis, and the compliance rate with oral bisphosphonates is lower than that with IV administration. 91 The efficacy of oral bisphosphonates in treating bone loss associated with AIs and ADT has been demonstrated in a few small trials. 19,92 The majority of trials in cancer populations used IV bisphosphonates dosed every 3 to 6 months for 1 to 5 years, initiated with the treatment (Table 4). These drugs are well tolerated and increase BMD. However, because of limited sample size and duration of follow-up in most of these trials, the question of whether fracture risk is significantly reduced cannot be answered. Additionally, the optimal dosing, frequency, and duration of therapy are unknown. The main adverse effects of IV bisphosphonates are transient fevers, arthralgias, renal insufficiency necessitating standard labeldefined dose reductions, and osteonecrosis (ONJ). ONJ is a rare but serious complication of primarily IV bisphosphonate therapy. The most common risk factors for ONJ include monthly dosing of IV bisphosphonates and therapy duration longer than 2 years. 93 Dental procedures are possible predisposing factors for ONJ, and a screening dental examination and completion of major dental procedures before initiation of IV bisphosphonates is advisable. The incidence of ONJ is low with the infrequent dosing schedule of IV bisphosphonate therapy used for osteopenia/osteoporosis, compared with that used for bone metastases. Recent reports of rare atypical femoral fractures with long-term cumulative oral and IV bisphosphonate dose are under investigation. 94 Denusomab is a human monoclonal antibody to RANKL that blocks osteoclast formation and activation. At a dose of 60 mg subcutaneously every 6 months, it is approved for the management of postmenopausal osteoporosis 81 and AI-induced bone loss. 84 This drug has a higher incidence of asymptomatic hypocalcaemia relative to IV bisphosphonate treatment, but it has fewer infusion reactions and decreased risk of renal insufficiency. The risk of ONJ is similar to that with bisphosphonates. In men with prostate cancer undergoing ADT, denosumab increased BMD in all sites and reduced vertebral fractures. 85 Additional studies are under way to investigate denosumab in preventing skeletal metastases by American Society of Clinical Oncology 3671

8 Lustberg, Reinbolt, and Shapiro Recombinant parathyroid hormone (teriparatide) is approved for the treatment of postmenopausal osteoporosis. Increased risks of osteosarcoma were observed in animal models but not in long-term studies in humans. 95 Teriparatide is generally not used in the cancer population, because some cancers have PTH receptors, and there is theoretic risk of stimulating cancer growth. Optimization of serum vitamin D levels is important to successful treatment of bone loss. Vitamin D deficiency or insufficiency, with or without secondary hyperparathyroidism, is common in the general population and in patients with cancer Although the definitions of 25-OH D deficiency levels are controversial, 99 the recent Institute of Medicine report defined 20 ng/ml (50 nmol/l) as adequate, corresponding to 600 IU/d. 89 Several studies have demonstrated improved response to bisphosphonate therapy when vitamin D levels are optimized. 100 In conclusion, many individuals diagnosed with cancer will be long-term survivors. Optimizing bone health and preventing osteoporotic fractures are high priorities in this group. Although data show using bisphosphonates and RANKL inhibitors can effectively mitigate bone loss, there are several unanswered questions related to the optimal duration and schedule of these drugs, with most studies in noncancer populations showing that at least 1 to 2 years of bisphosphonate therapy are needed to achieve a significant reduction in fracture risk. 101 In treating AI-induced bone loss, some have advocated the use bisphosphonates for the entire duration of AI treatment. 74,75 What limits the majority of trials in cancer populations is their exclusive use of BMD as a surrogate end point for fractures. Unlike noncancer osteoporosis trials, where reduction in fractures is the primary end point, the sample sizes in the largest trials in cancer populations are often too small and/or the follow-up too short to detect differences in fracture rates. In addition, the results of studies with anti bone resorptive therapies for the prevention of bone metastases and improvement of overall survival are conflicting. 26, Additional trials are ongoing, which will help answer this question. Finally, it is important to define which health care provider is going to take responsibility for bone health (eg, the medical oncologist, primary physician, gynecologist, or endocrinologist) based on regional expertise and practice patterns. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation. Nature 423: , Bord S, Ireland DC, Beavan SR, et al: The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts. 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