Bone is a living and dynamic tissue that develops and remodels to. Clinical Management of Osteoporosis in Women with a History of Breast Carcinoma

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1 443 Clinical Management of Osteoporosis in Women with a History of Breast Carcinoma Catherine Van Poznak, M.D. 1 Nicholas P. Sauter, M.D. 2 1 Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, New York. 2 Endocrinology Service, Memorial Sloan-Kettering Cancer Center, New York, New York. Osteoporosis is a skeletal disorder that is characterized by low bone mass and compromised bone strength. Fractures are the clinically important consequence of osteoporosis and result not only in disability but also in excess mortality. Women who have a history of breast carcinoma may represent a unique population for whom screening and treatment for osteoporosis should be modified. A review of the English literature was performed that included original, review, consensus, and statement articles that were identified through Medline or National Institutes of Health-related links. According to the literature, osteoporosis constitutes a major public health problem. Approximately 55% of the U.S. population 50 years of age has low bone mass (osteopenia or osteoporosis). Annually, 200,000 women in the U.S. are diagnosed with breast carcinoma. Due to the high prevalence rates of both low bone mass and breast carcinoma in women, these two diseases commonly coexist in the same individuals. Women with a history of breast carcinoma may be at increased risk of developing bone loss and fragility fractures as a consequence of antineoplastic therapies. The majority of women treated for earlystage breast carcinoma do not develop recurrences, as a result of recent advances in therapy. Ensuring the diagnosis, prevention, and treatment of long-term toxicities and comorbid conditions like osteoporosis in breast carcinoma survivors is a serious concern and is of increasing importance. In this article, the authors address the evaluation and treatment of osteoporosis in women who have a history of early-stage breast carcinoma. Cancer 2005;104: American Cancer Society. Address for reprints: Catherine Van Poznak, M.D., Breast Cancer Medicine Service, Memorial Sloan- Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; Fax: (212) ; vanpoznc@mskcc.org Received December 2, 2004; revision received March 3, 2005; accepted March 16, Dr. Van Poznak received support from Novartis, AstraZeneca, Aventis/Proctor & Gamble, and Amgen. Dr. Sauter has been a member of the Speakers Bureau and acted as a consultant for Novartis and has been a member of the Speakers Bureau for Glaxo-SmithKline. KEYWORDS: osteoporosis, breast carcinoma, osteopenia, adjuvant breast carcinoma survivorship. Bone is a living and dynamic tissue that develops and remodels to accommodate changing conditions throughout life (Fig. 1). Bone strength reflects the integration of two main properties: bone mineral density (BMD) and bone quality. In women, bone mass is accumulated during youth, followed by a plateau during middle age until menopause, which marks a period of rapid bone loss that is followed by more gradual bone loss through the balance of life. 1 Bone Structure and Bone Remodeling To understand osteoporosis, it is helpful to consider the key features of bone structure, bone cells, and the remodeling process. Trabecular bone is located in the vertebral bodies and the inner portion of long bones and flat bones. The microarchitecture of trabecular bone consists of a network of vertical and horizontal struts arranged in perpendicular plates. Cortical bone is located in the outer portion of long bones and flat bones. The microarchitecture is composed of densely packed, cylindrical osteons. Cortical bone provides more mechanical 2005 American Cancer Society DOI /cncr Published online 20 June 2005 in Wiley InterScience (

2 444 CANCER August 1, 2005 / Volume 104 / Number 3 FIGURE 1. Normal bone remodeling is a balanced process. The bone resorption rate is equal to the bone formation rate. FIGURE 2. Osteoporosis is an unbalanced process. A bone resorption rate greater than a bone formation rate yields a net loss of bone. strength but is less active metabolically compared with trabecular bone. 2 Microscopically, bone tissue is composed of bone cells and the bone matrix. The matrix consists of organic (protein) and inorganic (hydroxyapatite crystal) components. Osteoclasts are bone-resorbing, multinucleated giant cells derived from the monocyte/macrophage lineage. 3 Osteoclasts resorb bone first by attaching firmly to the bone surface, with a ruffled border facing the area of resorption. The ruffled border secretes both hydrogen ions and proteases into the resorption space. The acid environment dissolves bone mineral, whereas proteolytic enzymes digest the protein portion of the bone matrix. 3 Osteoblasts are bone-forming cells derived from mesenchymal stem cells in the bone marrow. 4 Osteoblasts synthesize Type I collagen, alkaline phosphatase, and other proteins and secrete them into the bone matrix. Type I collagen is a triple -helical protein that constitutes the main structural protein of bone. Fibers of this protein are deposited in layers. The matrix proteins later become mineralized to form mature bone. 2 Bone remodeling is the process whereby bone is renewed continually during adulthood. Remodeling has four distinct phases: resorption, reversal, formation, and resting. Osteoblast and osteoclast activities are coupled tightly during adulthood. 2 Bone cell activity is regulated by several factors, including systemic hormones, such as parathyroid hormone, vitamin D, estrogen, testosterone, and others; local regulators that are produced in the bone microenvironment, such as growth factors, cytokines, and prostaglandins; nutrition; and mechanical forces. Two molecules produced by stromal cells/osteoblasts are required for the normal maturation and activation of osteoclasts: macrophage-colony stimulating factor (M-CSF), a paracrine soluble factor, and receptor activator of nuclear factor B ligand (RANKL), a molecule that is expressed on the surface of stromal cells/osteoblasts. 3,5,6 The receptor for M-CSF is c-fms, and the receptor for RANKL is receptor activator of nuclear factor B (RANK), both of which are present on the surface of osteoclast precursors. 3 The binding of RANKL to RANK is primarily mediated by direct cell-to-cell contact. Osteoprotegerin, which is a soluble decoy receptor that is secreted by osteoblasts, functions as a negative autocrine regulatory factor that inhibits the binding of RANKL to RANK. 2,3 The Pathogenesis of Osteoporosis Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility. The essential basis for the development of osteoporosis is an imbalance in bone remodeling, in which the bone resorption rate exceeds the bone formation rate. This results in a net loss of bone (Fig. 2). The loss of connectivity within trabecular bone and increased porosity of cortical bone reduces both the quality and the quantity of bone. 7 Bone mass is influenced by a variety of factors, including genes, hormones, nutrition, and physical activity. Low bone mass during late adulthood in women may result from bone loss not only due to estrogen deficiency and aging but also due to inadequate achievement of peak bone mass during young adulthood. Some risk factors for low bone mass can be modified, such as diet, exercise, alcohol use, and tobacco use, whereas others are nonmodifiable, for example age, gender, and genetic background (Table 1).

3 Osteoporosis in Breast Ca Patients/Van Poznak and Sauter 445 TABLE 1 Risk Factors Associated with Osteoporosis Modifiable risk factors Diet: Age-appropriate calcium and vitamin D intake is critical to obtaining and maintaining bone mineral density Exercise: Weight-bearing exercise is recommended Medications: Certain medications that have adverse effects on bone may be substituted with appropriate, efficacious alternative medications Endocrine dysfunction: Depending on the clinical scenario, hormones may or may not be replaced safely Tobacco and excessive alcohol: To be avoided Risk factors that cannot be modified Gender: Women have less bone tissue and lose bone more rapidly than men because of the changes involved in menopause Age: Increased age is associated with increased loss of bone mass Body size: Individuals with small, thin-boned habitus have a greater risk Ethnicity: White and Asian women are at highest risk; African-American and Latina women have a lower but significant risk Family history: First-degree relative with lowtrauma fracture may indicate an increased risk Medications: Certain medications that have adverse effects on bone or increase the risk of falls may not be avoidable due to comorbid conditions; these include glucocorticoids and drugs that cause sedation or other neurologic impairments Comorbid conditions: Examples include chronic renal failure, chronic liver disease, advanced malignancy, and dementia The Epidemiology of Osteoporosis and Breast Carcinoma Of the estimated 10 million Americans who have osteoporosis, 8 million are women. 8 Osteoporosis is associated with an increased risk of fracture. 9 Difficulty in performing the activities of daily living can be a consequence of such fractures. For example, only onethird of hip fracture patients regain their prefracture level of function, and one-third require nursing home placement. 10,11 The effect of fractures on survival is dependent on the fracture type, 12 with hip fractures the most serious. 13 Annually, 200,000 women in the U.S. are diagnosed with breast carcinoma. 14 Both low bone mass and breast carcinoma are highly prevalent in postmenopausal women in the U.S. Consequently, these two disease states commonly coexist in the same individuals. In 1 study, although breast carcinoma survivors (mean age, 78.7 years) were more likely to have bone mineral density (BMD) testing than the control population, 10% of the study population actually had bone densitometry performed. 15 Current practice guidelines recommend consideration of screening for osteoporosis in all women age 65 years. 8 Clearly, there is a need to improve the screening practices of physicians who care for survivors of breast carcinoma and to consider the potential effects of treatment for each disease on the other. The Impact of Estrogen on BMD Estrogens act through direct and indirect mechanisms to restrain bone resorption and maintain BMD. The fall in estrogen levels associated with menopause results in an increase in osteoclast formation and survival. Compensatory increases in bone formation also occur in estrogen deficiency but are insufficient to maintain stable bone mass. 16 Thus, menopause triggers an initial period of rapid loss of bone. Several years after menopause, bone loss continues, at a slower rate, through the remaining years of a woman s life. The Women s Health Initiative (WHI) demonstrated that postmenopausal hormone therapy (hormone replacement therapy will be referred to herein as postmenopausal hormone therapy) with conjugated equine estrogen (CEE) plus progestin reduces the risk of osteoporotic fracture. 17 However, the same study was terminated early because of a significant increase in the risk of breast carcinoma. The Impact of Estrogen on Breast Carcinoma Risk Approximately 70% of breast tumors express the estrogen receptor. 18 Both endogenous and exogenous estrogen have been implicated in the pathogenesis of breast carcinoma. 19 Long-term estrogen deficiency has been associated with a reduced risk of developing breast carcinoma. 20 Because bone contains estrogen receptors and is highly sensitive to circulating estrogen levels, BMD may be a surrogate marker for longterm exposure to endogenous estrogen. A relation between body mass index, endogenous estrogen levels, and the risk of breast carcinoma has been reported Findings from the Study of Osteoporotic Fractures suggested that women with the highest BMD had a fold increase in the risk of breast carcinoma compared with women with the lowest BMD. 25,26 Similar results were obtained from the Framingham data. 27 The correlation between the risk of osteoporosis and breast carcinoma continues to be investigated. Postmenopausal hormone therapy, in the form of CEE plus progestin, as it has been used for the prevention of osteoporosis, is associated with an increased risk of breast carcinoma. 17 In July 2002, one component of the WHI, which studied the use of CEE plus progestin in postmenopausal women with an intact uterus, was terminated early, because a predetermined stop threshold for the excess risk of invasive breast carcinoma and global index of health risk was reached. 17 The incidence of breast carcinoma was increased by 26% in the treatment group compared with the control group in that study. The risk of hip fracture was reduced by 34% in the hormone therapy arm. 17 In

4 446 CANCER August 1, 2005 / Volume 104 / Number 3 March 2004, a second component of the WHI, which studied CEE (estrogen-only) therapy in women who had undergone hysterectomy, likewise was terminated early and concluded that the use of mg of CEE daily should not be recommended for chronic disease prevention in postmenopausal women. 28 The results from the estrogen-only WHI study did not show an increased risk for invasive breast carcinoma, and the risk of hip fracture was reduced by 39% in the estrogen-treated group. 28 Similar results were obtained in a European study (Hormonal Replacement Therapy after Breast Cancer Is it Safe? [HABITS]) of postmenopausal hormone therapy in women who had a history of breast carcinoma. In the HABITS study, among 345 women who were followed, 26 women in the hormone-treatment group and 8 women in the nonhormone-treatment group reportedly have experienced new breast carcinoma events, and the study was terminated early due to unacceptable risks. 29 The Effect on Bone of Antitumor Therapies for Breast Carcinoma The full extent to which adjuvant therapies for breast carcinoma may affect the risk of osteoporotic fracture remains to be determined. However, there are data to suggest that certain forms of adjuvant therapy for breast carcinoma may have a negative impact on bone and that women with a history of breast carcinoma represent a subpopulation of individuals who require special attention to bone health. 30 The use of adjuvant antiestrogen therapy to prevent recurrence of estrogen receptor-positive and/or progesterone receptor-positive breast carcinoma impacts BMD differently, depending on the class of antiestrogen therapy and the menopausal status of the woman. It has been shown that the selective estrogen receptor modulator (SERM) tamoxifen prevents bone loss in postmenopausal women, presumably by an agonist effect on estrogen receptors in bone 31 ; however, tamoxifen is not indicated for the prevention or treatment of osteoporosis. 31 In premenopausal women, it has been shown that both tamoxifen 32 and raloxifene 33 result in bone loss, as measured by BMD. The impact of the SERMs on bone loss in premenopausal women warrants additional investigation, because tamoxifen may counteract bone loss associated with the gonadotropin-releasing hormone agonist goserelin. 34 It also has been suggested that, in some subsets of women, tamoxifen may hasten slightly the onset of menopause. 35 The third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) not only are effective in treating advanced breast carcinoma but also have found an expanded role in the adjuvant setting. Anastrozole and letrozole have received approval from the U.S. Food and Drug Administration (FDA) for use in adjuvant breast carcinoma hormone therapy in postmenopausal women. Studies are ongoing in an attempt to identify the most efficacious means of using the antiestrogen therapies. The potential longterm toxicities of the new aromatase inhibitors on bone are of concern. In postmenopausal women, the aromatase inhibitors may accelerate bone loss due to their profound suppression of circulating and tissue levels of estrogen Current studies are investigating the magnitude of change in BMD and are evaluating interventions to preserve and/or improve BMD. Clinical trials are in progress to explore the utility of aromatase inhibitor therapy in conjunction with ovarian suppression in premenopausal women with breast carcinoma. Ovarian ablation, which is required before premenopausal women initiate an aromatase inhibitor, would be expected to cause a brisk loss of bone mass similar to that seen in surgical menopause. The Austrian Breast Cancer Study Group (ABCSG-012) is examining the BMD of premenopausal women with hormone receptor-positive breast carcinoma who are treated with goserelin for ovarian ablation and then randomized to receive either tamoxifen or anastrozole. Each antiestrogen treatment group will be randomized either to receive or not to receive zoledronic acid. Data at the 6-month mark from this study, as reported at the San Antonio Breast Cancer Symposium in 2004, demonstrated that zoledronic acid preserved BMD and that loss of BMD was most pronounced in the arm that received anastrozole and goserelin without zoledronic acid. 40 That study is ongoing, and follow-up data are awaited eagerly. A subprotocol of the large international study of adjuvant anastrozole, tamoxifen alone, or in combination revealed that patients who received tamoxifen alone experienced an increase in BMD at the spine ( 1.9%) and hip ( 1.2%), whereas patients who received anastrozole alone had a decrease in BMD at the spine ( 4.0%) and hip ( 3.2%) after 2 years of therapy. 38,41,42 It is probable that the tamoxifen arm experienced a weakly positive effect on bone, as has been reported with the use of this SERM in postmenopausal women. There also were increases in the rates of bone resorption and bone formation with anastrozole, leading to an overall increase in bone remodeling. 38 Anastrozole treatment was associated with a moderate but significant increase in fracture risk compared with tamoxifen treatment. 38,41,42 Data from a large, double-blind, randomized controlled trial in women with early-stage breast carcinoma comparing exemestane versus tamoxifen after

5 Osteoporosis in Breast Ca Patients/Van Poznak and Sauter 447 TABLE 2 Adjuvant Aromatase Inhibitor Trials and the Effect on None Mass or Fracture a Trial Design: Adjuvant No. of patients Fractures (P value) b ATAC Tamoxifen vs. anastrozole vs. the combination % vs. 4.4% ( 0.001) MA-17 Letrozole vs. placebo after completion of 5 yrs of tamoxifen % vs. 2.9% (0.24) IES Tamoxifen vs. exemestane after completion of 2 3 yrs of tamoxifen % vs. 2.3% (0.08) ATAC: anastrozole, tamoxifen alone, or in combination (see ATAC Trialists Group, and ); MA-17: a randomized trial of letrozole in postmenopausal women after 5 years of tamoxifen therapy for early-stage breast carcinoma (see Goss et al., ); IES: a randomized trial of exemestane after 2 3 years of tamoxifen therapy in postmenopausal women with primary breast carcinoma (see Coombes et al:, ). a See Winer et al., b All trials had numerically more fractures in the aromatase inhibitor arm. 2 3 years of adjuvant tamoxifen showed an increase in osteoporosis with exemestane 43 despite preclinical data and small trials that initially suggested a possible bone-sparing effect. 44 In a study of the sequential use of tamoxifen followed by letrozole versus placebo, again, a reduction in BMD was noted among those women who received the aromatase inhibitor; however, this change in BMD did not reach statistical significance. 45 The American Society of Clinical Oncology (ASCO) recently published a technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast carcinoma (Status Report, 2004). 46 In this document, ASCO recommends that the optimal adjuvant hormone therapy for postmenopausal women with hormone-receptor positive breast carcinoma should include an aromatase inhibitor. Of course, it also is recommended that the risks and benefits be considered for each individual before initiating therapy. Because the aromatase inhibitors play an expanded role in the treatment of patients with early-stage, hormone receptor-positive breast carcinoma, medical oncologists will be challenged with monitoring and managing bone-related toxicities, either directly or through collaboration with other health care providers (Table 2). Systemic adjuvant polychemotherapy is used commonly in the treatment of breast carcinoma 47,48 based on data that show reduced rates of recurrence. Retrospective studies suggest that adjuvant therapies for breast carcinoma may affect BMD. 49,50 After adjuvant therapy for breast carcinoma, women may have an increased risk for fracture. 51 Several effective adjuvant chemotherapy regimens for breast carcinoma include one or more of the following agents: doxorubicin, cyclophosphamide, and methotrexate. In animal models, it has been shown that these drugs have negative effects on bone In addition, supportive therapy with glucocorticoids exposes patients to the risk of rapid bone loss independent of the potential insult to bone caused by chemotherapy. The actual effects and clinical significance of adjunctive chemotherapy and supportive medications on the bones of women with breast carcinoma remain to be determined. In premenopausal women undergoing adjuvant chemotherapy, there is a well established risk of chemotherapy-induced, premature ovarian failure. 35,55 58 Surgically induced ovarian ablation is associated with a significant increase in fracture risk, even in postmenopausal women. 60 Several studies have shown that reductions in BMD due to treatment-induced ovarian failure can be prevented by the use of bisphosphonates, such as clodronate, risedronate, and zoledronic acid. 40,56,57 The objectives of ongoing clinical trials in premenopausal women seek to identify risk factors for chemotherapy-induced ovarian failure and to develop methods for prevention of premature menopause and preservation of bone mass. The Cancer and Leukemia Group B study is exploring the use of the bisphosphonate zoledronic acid in this setting. In addition to the aforementioned ABCSG-012 trial, another study, the Suppression of Ovarian Function Trial (SOFT), is examining the use of ovarian ablation with oral antiestrogen agents. A subset of women in SOFT will undergo BMD assessment. Screening and Diagnosis of Osteoporosis Physicians should be alert to the possibility of decreased BMD and increased fracture risk in both premenopausal and postmenopausal women with breast carcinoma. The World Health Organization defines osteoporosis as a BMD T-score lower than 2.5 standard deviations (SD) below the mean for a reference population of healthy, young adult women (matched for weight, height, and ethnic background), and osteopenia is defined as a BMD T-score between 1.0 and 2.5 SD below the young-adult mean 8 (Table 3). The risk for fracture increases steadily as bone density

6 448 CANCER August 1, 2005 / Volume 104 / Number 3 TABLE 3 World Health Organization Definition of Osteoporosis a Diagnosis Normal Osteopenia Osteoporosis BMD criteria BMD: bone mineral density; SD: standard deviation. a See Dawson-Hughes et al., BMD value within 1 SD of the young adult mean (T-score 1.0) BMD value between 1.0 and 2.5 SD below the young adult mean S cores between 1.0 and 2.5) BMD values lower than 2.5 SD below the young adult mean (T-score 2.5) declines, but no clear threshold exists. Clinical signs of severe osteoporosis include loss of height, increased kyphosis of the thoracic spine, reduction in the distance between the rib cage and the pelvis, and tenderness on palpation of the vertebral column. In the absence of screening asymptomatic patients who are at risk, low bone mass would not be recognized until fractures or skeletal deformities have occurred. Pathologic fracture from metastatic disease should be included in the differential diagnosis when fracture occurs in a woman with breast carcinoma. BMD frequently is used as a proxy estimate of overall bone strength. BMD can be assessed using a variety of techniques; however, dual-energy X-ray absorptiometry (DEXA) of the axial skeleton (lumbar spine and hip) is the most widely used method and has many advantages. 2 BMD, as measured by DEXA, is expressed both as an areal density, in grams of mineral per square centimeter (g/cm 2 ), and statistically, in SD from the mean in relation to a reference population. 2 BMD provides an important contribution to the assessment of fracture risk. Serial BMD measurements over time measure the rate of change in BMD and can be used to monitor either disease progression or the effect of treatment. One of the limitations of DEXA is that changes in BMD due to disease or treatment are relatively small compared with the variability of the measurement. 60 Clinical practice guidelines have been developed by various committees to address screening and treatment of osteopenia and osteoporosis. Examples of such guidelines are those of the National Osteoporosis Foundation 8 and the American Association of Clinical Endocrinologists. 1 Treatment should be considered for the following groups: women with established postmenopausal osteoporosis (BMD T-scores 2.5), women with a history of low-trauma fracture and low BMD, women with moderate-to-severe osteopenia (e.g., T-scores from 1.5 to 2.5) when additional risk factors for fracture are present, and women in whom nonpharmacologic preventive measures have been ineffective (bone loss continues or low-trauma fractures occur). It is reasonable to apply these recommendations to patients with breast carcinoma, although there are limited data specific to this population. The ASCO published an updated guideline 61 to address bone health in women with breast carcinoma. This guideline is similar to those developed for the general population of postmenopausal women. However, ASCO draws specific attention to postmenopausal women of any age who are receiving aromatase inhibitors and premenopausal women with therapyassociated, early menopause (Table 4). Unfortunately, there is little information to guide the frequency with which premenopausal women with a history of breast carcinoma should have BMD monitoring. Clinicians need to practice best clinical judgment and actively participate in research to define the bone health needs of this younger subset of patients with breast carcinoma. The use of urine and serum as assessment markers of bone turnover is an evolving field. Serum markers of bone formation include bone-specific alkaline phosphatase and osteocalcin. Bone resorption markers include collagen-degradation products (such as pyridinoline and deoxypyridinoline) and Type I collagen telopeptides (e.g., N-terminal and C-terminal cross-linked telopeptides) in serum or urine. The level of these markers may identify changes in bone remodeling within a short period. Bone turnover markers may predict fracture risk independent of BMD. 62 The combination of bone resorption markers and BMD is a more powerful predictor of fracture risk than either test alone. 63 A variety of medical conditions can predispose individuals to reduced bone mass. 2,8 Laboratory testing for possible secondary causes of osteoporosis (Table 5), therefore, should be considered when osteoporosis is diagnosed. Treatments for secondary causes of osteoporosis are disease-specific. Nutritional and Behavioral Influences on Bone Health Adequate intake of calcium and vitamin D throughout life is required to obtain optimal bone mass and bone strength. Good sources of calcium include low-fat dairy products, dark-green leafy vegetables, bony fish (such as sardines and salmon), and fortified foods. Calcium intake requirements vary over different stages of life, and supplementation of calcium and vitamin D often is necessary to maintain optimal bone health. For older adults, calcium intake should be maintained at mg per day, yet only approximately 50 60% of this population meets this recom-

7 Osteoporosis in Breast Ca Patients/Van Poznak and Sauter 449 TABLE 4 Comparison of Osteoporosis Screening Guidelines NOF recommendations for postmenopausal women U.S. PSTF guidelines for postmenopausal women ASCO guidelines for women with breast carcinoma AACE guidelines for postmenopausal women All women age 65 yrs, regardless of risk factors Younger postmenopausal women with 1 risk factors (other than being white, postmenopausal and female) Postmenopausal women who presented with fractures (to confirm the diagnosis and determine disease severity) Estrogen-deficient women at clinical risk for osteoporosis Individuals with vertebral abnormalities Individuals receiving or planning to receive long-term glucocorticoid (steroid) therapy Individuals with primary hyperparathyroidism Individuals being monitored to assess the response or efficacy of an approved osteoporosis drug therapy Women age 65 yrs who were screened routinely Routine screening begin at age 60 yrs for women at increased risk for osteoporotic fractures No recommendation for or against routine osteoporosis screening in postmenopausal women age 60 yrs or in women ages yrs who were not at increased risk for osteoporotic fractures All women 65 yrs Women ages yrs with a family history, weight 70.0 kg, and prior nontraumatic fracture Premenopausal women with therapyassociated early menopause; postmenopausal women of any age receiving aromatase inhibitors All women age 65 yrs Younger postmenopausal women with a clinical risk for fractures who had low body weight ( 57.6 kg) and a family history of spine or hip fractures Adult women with a history of fracture not caused by severe trauma NOF: National Osteoporosis Foundation (see Dawson-Hughes et al., ); U.S. PSTF: United States Preventive Services Task Force (see Nelson et al., ); ASCO: American Society of Clinical Oncology (see Hillner et al., ); AACE: American Association of Clinical Endocrinologists (see AACE, ). TABLE 5 Causes of Generalized Secondary Osteoporosis in Adults Endocrine disease or metabolic causes Nutritional conditions Drugs Disorders of collagen metabolism Other Hypogonadism Malabsorption syndromes and malnutrition Hyperadrenocorticism Chronic liver disease Phenytoin Homocystinuria due to cystathionine deficiency Vitamin D toxicity Osteogenesis imperfecta Rheumatoid arthritis Myeloma and some carcinomas Thyrotoxicosis Gastric operations Glucocorticoids Ehlers Danlos syndrome Immobilization Anorexia nervosa Vitamin D deficiency Phenobarbital Marfan syndrome Renal tubular acidosis Hyperprolactinemia Calcium deficiency Excessive thyroid medication Hypercalciuria Porphyria Alcoholism Heparin Chronic obstructive pulmonary disease Hypophosphatasia in adults Gonadotrophin-releasing hormone Organ transplantation antagonists Diabetes mellitus, Type 1 Cholestatic liver disease Pregnancy Mastocytosis Hyperparathyriodism Thalassemia Acromegaly

8 450 CANCER August 1, 2005 / Volume 104 / Number 3 mendation. 10 In addition, older adults also are more likely to have chronic medical problems and to use medications that impair calcium absorption. Vitamin D is required for adequate bone health. Elderly individuals, in particular, may require vitamin D supplementation to ensure a daily intake of IU of vitamin D. 64 Calcium is absorbed best through dietary intake. Vitamin D is required to maximize calcium absorption. Individuals who are lactose intolerant may use lactase to permit intake of dairy products. Vitamin D can be obtained through sun exposure, dietary sources, or supplementation. Many Americans do not consume adequate quantities of calcium or vitamin D in their diet; therefore, supplements often are required to meet recommended requirements. The required dose of supplemental calcium is determined by subtracting the amount contained in the diet from the recommended total daily intake. Postmenopausal American women typically consume 600 mg per day of calcium in their diets 8 and, thus, would require mg of supplemental calcium. Calcium supplements are absorbed best when they are taken in small ( 500 mg) and divided doses through the day. The safe upper limit for total calcium intake has been set at 2500 mg per day, and the safe upper limit for vitamin D intake is up to 2000 IU per day. 8 The prescribing physician should consider whether any comorbid disorders of calcium metabolism or concurrent medication would impact the decision to use calcium and vitamin D supplements. For example, patients with a history of nephrolithiasis or hyperparathyroidism and patients on diuretic therapy require special attention to their calcium and vitamin D needs. Patients on oral bisphosphonate therapy must wait at least 30 minutes after the bisphosphonate dose to take calcium or vitamin D supplements. Calcium carbonate and calcium citrate are the most commonly used forms of calcium supplements. Calcium carbonate is absorbed best when it is taken with meals. Some may prefer to use calcium citrate over calcium carbonate formulations due to variations in symptoms, such as bloating or constipation. Such symptoms often are relieved by increasing the amount water and fiber in the diet. Calcium citrate is absorbed best if it is taken before meals. A variety of formulations and brands of calcium and vitamin D supplements are available. The best supplement is the one that the patient uses reliably. Concurrent use of calcium supplements and other medications needs to be considered. Calcium supplements may interfere with the absorption of some medications by forming chelating complexes or altering the gastric ph. Thiazide and thiazide-like diuretics may cause hypercalcemia by decreasing renal calcium excretion; therefore, a potential for inducing a milkalkali syndrome (hypercalcemia, metabolic alkalosis, renal failure) exists with thiazides and excessive calcium intake. Patients should review the optimal timing and coadministration of all of their medications with their physician and pharmacist. Behavioral factors that influence the maintenance of bone mass positively include weight-bearing exercise, such as walking; muscle-resistance training, such as weight-lifting; and avoidance of tobacco or excess alcohol consumption. Medications like glucocorticoids and anticonvulsants have been associated with bone loss 2,8,10 ; however, the use of such medications may be unavoidable. Medications that cause sedation or postural hypotension can increase the risk of falls and fractures in elderly patients 2 and should be avoided when possible. Treatments for Osteopenia and Osteoporosis in Patients with Breast Carcinoma The decision to begin therapy for the prevention or treatment of osteoporosis should take into account several factors, including BMD, the risk of fracture, life expectancy, and the benefits and side effects of treatment. The greatest potential impact on osteoporosis is likely to be achieved by primary and secondary prevention efforts that are initiated early, before a large loss of bone has occurred. 65 Once severe microarchitectural damage has occurred, currently available treatments that stimulate bone formation or inhibit bone resorption cannot restore completely the structural integrity and strength of bone. Treatment options for low bone mass in women with a history of breast carcinoma centers on nonhormonal manipulations A healthy lifestyle with a balanced diet and exercise is recommended. 8,61 Calcium and vitamin D from diet and/or supplements can increase spinal BMD and reduce vertebral and nonvertebral fractures. 66 The use of exercise and weight training is beneficial for reducing the risk of falls. 2,8 In frail women who have an increased risk of falling, it has been shown that hip protectors prevent hip fractures. 67 Pharmacologic therapy can be used to increase BMD and prevent fractures. An individual s risk for experiencing a fragility fracture is affected by many factors, including BMD, age, risk of falls, comorbid conditions, and family history. There is no clearly defined threshold for pharmacologic intervention; however, guidelines have been developed to aid in treatment decisions (Table 6). The causes, diagnostic approach, and treatment of low bone mass or risk of fracture in women with

9 Osteoporosis in Breast Ca Patients/Van Poznak and Sauter 451 TABLE 6 Comparison of Guideline Thresholds for Treatment Intervention NOF recommendations for postmenopausal women Canadian Clinical Practice Guidelines a ASCO guidelines for women with breast carcinoma AACE guidelines for postmenopausal women BMD T-scores 2.0 by hip DXA with no risk factors BMD T-scores 1.5 by hip DXA with 1 risk factors A prior vertebral or hip fracture Low BDM (T-score 2.5) T-score 1.5 and nontraumatic vertebral compression deformities, personal history of fragility fracture after age 40 yrs, or other clinical risk factors Those on long-term glucocorticoid therapy Women with a fragility fracturewomen with a BMD 2.5 Women without fractures but who have a borderline low BMD score ( 1.0) and other risk factors (controversial and should be decided on an individual basis) All postmenopausal women with low-trauma fractures All women with low BMD scores (T-scores ( 2.5) Women with borderline low BMD (T scores 1.5) if risk factors are present All women in whom prevention interventions are ineffective (bone loss continues or low trauma fractures occur) NOF: National Osteoporosis Foundation (see Dawson et al., ); ASCO: American Society of Clinical Oncology (see Hillner et al., ); AACE: American Association of Clinical Endocrinologists (see AACE, ); BMD: bone mineral density; DXA: dual-energy X- ray absorptiometry. a See Brown and Josse, early-stage breast carcinoma may differ from those in women with advanced disease. The current review focuses on the management of osteoporosis in women with a history of early-stage breast carcinoma without evidence of recurrent disease. The ASCO guidelines address the use of intravenous bisphosphonates in women with metastatic breast carcinoma. 61 It is noteworthy that, when evaluating fractures in women who have a history of breast carcinoma, the possibility of a pathologic fracture must be considered, because it may herald a recurrence. Bisphosphonates The oral bisphosphonates alendronate and risedronate have received FDA approval for the prevention and treatment of osteoporosis. It has been shown that these drugs not only increase BMD but also reduce the risk of fractures at vertebral and nonvertebral sites, including the hip. 68,69 Clodronate, a bisphosphonate with both oral and intravenous formulations, is available in Europe but has not been approved by the FDA. It has been shown that the intravenous bisphosphonates (etidronate, pamidronate, ibandronate, and zoledronic acid) also increase BMD However, the use of intravenous bisphosphonates for the prevention and treatment of osteoporosis has not received FDA approval at this time. Bisphosphonates currently are considered the treatment of choice for women with breast carcinoma who require pharmacologic intervention for low bone mass. 61 It has been shown that intravenous bisphosphonate therapy (pamidronate, zoledronic acid) reduces the incidence of skeletal complications in patients with bone metastases from breast carcinoma. The role of bisphsphonate therapy in metastatic breast carcinoma is summarized by Hillner et al. in the ASCO guidelines. 61 It has been shown that the bisphosphonates reduce osteoclast activity and that, theoretically, they reduce the release of bone-derived growth factors and cytokines associated with bone resorption. Growth factors and cytokines in the bone microenvironment may attract tumor cells to bone and facilitate tumor proliferation. To investigate the possibility that bisphosphonates may prevent the development of bone metastases, three randomized trials of adjuvant clodronate versus placebo in women with early-stage breast carcinoma have been conducted In the first trial reported, the incidence of overall metastases, bone metastases, and visceral metastases was more than halved in the group that received clodronate compared with the placebo group. 73 With longer follow-up (103 months 12 months), the incidence of bone and visceral metastases was similar in both groups, but there still was a significantly better overall survival for the clodronate-treated group. 76 A larger trial of 1069 women initially showed that the incidence of bone metastases was significantly lower in the clodronate group compared with the placebo group after 2 years of treatment. 75 An updated report of that study presented at the 2004 annual meeting of the ASCO 77 continued to show that oral clodronate significantly reduced the risk of bone metastases and improved survival rates during the medication and at 5-year study periods compared with placebo. In conflict with the results from those two studies are the results of another adjuvant clodronate trial in which both disease-free survival and overall survival were lower in the clodronate arm. 74 The updated data

10 452 CANCER August 1, 2005 / Volume 104 / Number 3 from that trial 78 demonstrated that, at 10 years, bone metastases were detected at the same frequency in the clodronate and control groups. The frequency of nonskeletal recurrences (visceral and local) was significantly higher in the clodronate group compared with the control group, and the 10-year disease-free survival rate remained significantly lower in the clodronate group, but without a difference in the overall survival. Because the results of the three trials described above were inconsistent, additional study will be necessary to resolve the question of whether or not adjuvant clodronate, or any bisphosphonate, can lower the risk of bone or visceral metastases or impact survival in women with breast carcinoma. One such trial is through the National Surgical Adjuvant Bowel and Breast Program (NSABP). The primary objective of the NSABP B-34 Phase III trial is to determine whether clodronate administered for 3 years, either alone or in addition to adjuvant chemotherapy and/or hormone therapy, in patients with early-stage breast carcinoma will improve disease-free survival. The B-34 trial has enrolled 3200 patients with early-stage breast carcinoma, randomized them to receive either clodronate or placebo, and is closed to accrual. A second, large, U.S. intergroup trial is planned and will compare oral and intravenous bisphosphonate use in the adjuvant setting (South West Oncology Group trial S0307). A third large trial is being performed in Europe (the Adjuvant Zoledronic Acid to Reduce Recurrence [AZURE] trial). The AZURE trial will assess disease-free survival and time to metastasis in patients who receive standard antitumor therapy alone and in patients who receive standard therapy plus zoledronic acid. The results of these trials may alter clinical practice significantly and are awaited eagerly. It is expected that adjuvant bisphosphonate therapy will have a positive impact on BMD and fracture risk. Hormonal agents The use of estrogens in patients who have a known diagnosis of breast carcinoma is controversial, even if the tumor is hormone receptor-negative. The SERM raloxifene has demonstrated efficacy in the treatment and prevention of postmenopausal osteoporosis and has been approved by the FDA for this use. However, the concurrent or sequential use of the SERMs, such as tamoxifen and raloxifene, raises concerns over possible adverse estrogen receptor modulation, 79 thereby restricting therapy options for osteoporosis in postmenopausal women with breast carcinoma. Tamoxifen can have a modestly protective effect on BMD in postmenopausal women; however, the effect on fracture risk is unclear. The positive effect of tamoxifen on the BMD of postmenopausal women 31 may be taken into consideration during the selection of adjuvant antiestrogen therapy. However, tamoxifen is not considered a treatment for low bone mass. Tamoxifen has both agonist and antagonist effects on the estrogen receptor. In premenopausal women, tamoxifen is associated with a lowering of BMD, as discussed above. It has been shown that intranasal salmon calcitonin increases BMD modestly and prevents vertebral fractures, but not nonvertebral fractures. The calcitonin data are less compelling than those for the bisphosphonates, 80 but calcitonin has received FDA approval for the treatment of postmenopausal osteoporosis in women 5 years postmenopause. Teriparatide (human recombinant parathyroid hormone [1-34]) has been approved by the FDA for the treatment of osteoporosis in postmenopausal women at high risk of fracture. Teriparatide is an anabolic agent that has been shown to prevent both vertebral and nonvertebral fractures in this population. 81 However, the use of teriparatide may not be appropriate for women who have a history of breast carcinoma. Teriparatide is contraindicated in patients with prior radiation therapy, and there is also a theoretical concern that this anabolic hormone could activate micrometastatic disease in the bone marrow. The contraindication in patients with a prior history of radiation therapy is based on the finding of an increased risk of osteosarcoma in a rat toxicology study with the drug 82 and the increased baseline risk of osteosarcoma in patients with a prior history of radiation therapy. In patients with breast carcinoma, regardless of their disease stage, it is possible to identify micrometastatic tumor cells in the bone marrow using immunohistochemical techniques. 83,84 The clinical significance of these cells is being defined through clinical trials, including the American College of Surgeons Oncology Group prognostic study of sentinel lymph node and bone marrow metastases in women with Stage I or Stage IIA Breast carcinoma (ACOSOG- Z0011). These tumor-like cells in the bone marrow may represent occult bone metastases, and the use of teriparatide is contraindicated in the setting of bone metastases. Teriparatide, an anabolic agent, markedly increases bone turnover, 85 although bone formation generally exceeds bone resorption. In this high-turnover state, cytokines and growth factors may be released in higher than normal concentrations in the bone microenvironment. Such growth factors and cytokines, which have been shown to play an important role in the pathophysiology of clinically apparent bone metastases, 86,87 theoretically could support or enhance the growth of micrometastases. In summary, teriparatide may not be an appropriate intervention

11 Osteoporosis in Breast Ca Patients/Van Poznak and Sauter 453 for women who have a history of breast carcinoma due to the concerns of osteosarcoma after chest wall or breast radiotherapy and the potential for growth of occult bone marrow micrometastases. Combination therapy for postmenopausal osteoporosis has been explored in several studies. Fracture efficacy has not been evaluated in trials of combination therapy. A study of alendronate in combination with parathyroid hormone (1 84) in postmenopausal women with osteoporosis did not demonstrate any additive effect of the 2 medications, and alendronate reduced the anabolic effect of parathyroid hormone. 88 In another study, the combination of raloxifene and alendronate in postmenopausal women with osteoporosis showed an additive effect on BMD and bone resorption markers over 12 months of therapy compared with either therapy alone. 89 A randomized, controlled trial of menopausal hormone therapy in combination with alendronate showed that alendronate was superior to hormone therapy in increasing BMD, and the combination of alendronate with hormone therapy was better than either therapy alone. 90 In considering the specific needs of women with breast carcinoma, the combination of alendronate with raloxifene may be appropriate for some patients. The use of parathyroid hormone or estrogen in combination with other therapies is problematic because of the safety issues noted above. If monotherapy for the prevention or treatment of osteoporosis is not effective, and combination therapy is under consideration, then it may be appropriate for the medical oncologist and/or the patient to seek consultation with an endocrinologist or another osteoporosis specialist. Conclusions Osteoporosis is a skeletal disease characterized by reduced bone mass, compromised bone strength, and increased risk of fracture. Effective therapy for the prevention and treatment of osteoporosis is available. The optimal timing for osteoporosis intervention is early in the course of the disease. The ASCO guidelines for the role of bisphosphonates and bone health in women with breast carcinoma call for the medical oncologist to take an expanded role in the routine and regular assessment of patients bone health. 61 The selection of therapy for breast carcinoma should aim to optimize antitumor efficacy while weighing the risk of toxicities. It should be recognized that patients with breast carcinoma may be at increased risk for osteoporosis. Breast carcinoma therapies may contribute to bone loss through various mechanisms. Hypogonadism can be either a consequence or an objective of therapy for breast carcinoma; in either situation, the reduction in estrogen adversely affects the maintenance of bone mass and strength. The ASCO technology assessment of the use of aromatase inhibitors may well lead to increased utilization of these drugs in the adjuvant setting. 46 Chemotherapy and supportive medications, such as glucocorticoids, also may have an adverse impact on bone health. The recognition of patients who are at risk for osteoporosis, combined with appropriate screening and intervention, is an important aspect of the longterm care of patients who have survived breast carcinoma. Optimizing diet, exercise, and lifestyle should be part of care for all patients. If a patient with breast carcinoma is diagnosed with osteopenia or osteoporosis, then the decision to intervene to decrease the risk of fracture must be individualized through the appropriate application of existing guidelines or as part of a well designed clinical trial. Patients who would benefit from medication have treatment options, with bisphosphonates the favored choice for this patient population. 61 REFERENCES 1. American Association of Clinical Endocrinologists. AACE medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for Endocr Pract. 2003;9: Raisz, LG, Kream BE, Lorenzo JA. Metabolic bone disease. 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