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Journal of Cancer Research and Therapeutics, Vol. 7, No. 3, July-September, 2011, pp. 256-263 Review Article Bone health in breast cancer survivors Hikmat Abdel-Razeq1, Abdulla Awidi2 1 Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan PMID: 22044804 DOI: 10.4103/0973-1482.87006 Keywords: Bisphosphonates, bone health, breast cancer, denosumab, osteopenia, osteoporosis
Introduction Accounting for more than 25% of new cancer cases and 15% of cancer deaths, breast cancer continues to be the most common malignancy affecting women in developed countries. [1] Due to the widespread use of screening mammography and early detection programs, breast cancer patients are diagnosed at a much earlier stage. Additionally, the recent introduction of more effective adjuvant therapy has resulted in a higher percentage of women surviving their disease. [2] In curable cancers like breast cancer, more attention should be given to the long-term complications related to the treatment given or the cancer itself. Among the issues faced by clinicians caring for women with breast cancer are those related to bone health as many of these women survive their disease but continue to suffer from osteopenia and osteoporosis. In this review, we will discuss the contribution of anticancer treatment, both chemotherapy and hormonal therapy, in inducing or aggravating osteopenia or osteoporosis in women with breast cancer. Utilizing the most recently published research and guidelines, preventive measures and treatment options will also be addressed. Breast Cancer Treatment Most early-stage breast cancer patients are offered chemotherapy, the nature of which varies according to many clinical and pathological variables like disease stage and axillary lymph node status. [3] Chemotherapy is usually given in a combination that may include anthracyclines, taxanes and alkylating agents, like cyclophosphamide. [4] The majority of breast cancers expresses estrogen (ER) and/or progesterone receptors (PR) and thus receives hormonal therapy. Postmenopausal women are generally offered third-generation aromatase inhibitors (AI), while premenopausal women are usually treated with tamoxifen to which gonadotropin-releasing hormone (GnRH) agonists are added for high-risk premenopausal patients. [5],[6] Treatment of breast cancer can thus affect bone health in many ways:
Estrogen and Bone Health Estrogen deficiency plays a central role in the pathogenesis of osteoporosis in postmenopausal women. Estrogen inhibits bone resorption; so when deficient, it results in increased bone resorption and rapid bone loss. Though this role has been recognized for many years, the mechanisms by which estrogen regulates bone remodeling are not fully understood. [7] Estrogen is thought to affect osteoclast generation and function through its effects on local factors, produced by either bone or bone marrow cells. [8] Estrogen also decreases the depth of the erosion cavity caused by the osteoclast. [9] Additional indirect mechanisms involving other cells in the marrow have also been implicated. [10],[11] The Value of Endocrine Therapy for Breast Cancer In breast cancer patients whose tumor cells express ER or PR, adjuvant endocrine therapy prevents estrogen from stimulating the growth and proliferation of cancer cells. In such patients, endocrine therapy can be accomplished by tamoxifen, GnRH analogs (goserelin, leuprolide) or AI. Until recently, tamoxifen was the adjuvant endocrine therapy of choice for all women with hormone receptor-positive breast cancer. The most recent overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG) concluded that five years of tamoxifen was associated with a 41% reduction in the annual risk of breast cancer recurrence and a 34% reduction in the annual risk of death. [3] Tamoxifen has different effects on body organs and tissues; a fact that explains its unique side-effect profile. It has antiestrogenic properties in breast cancer cells, but its effects are estrogenic in other tissues like the endometrium where it increases the rate of uterine tumors. Its effect on bone is age-specific and will be detailed below. Aromatase inhibitors, on the other hand, are also effective for adjuvant endocrine therapy of postmenopausal women with breast cancer. Many trials have suggested that AI are superior to tamoxifen, in terms of prolonging time to recurrence and decreasing the incidence of contralateral breast cancers. [12],[13] The American Society of Clinical Oncology (ASCO) recently updated their guidelines recommending that AI should be considered as a component of adjuvant endocrine therapy in all postmenopausal women with hormone receptor-positive breast cancer. [14] Aromatase inhibitors have only antiestrogenic effects; the increased rate of osteoporosis and fractures associated with their use is well-documented in many clinical trials as outlined below. Tamoxifen and Bone Health Though the positive effect of tamoxifen on bone health of postmenopausal women is well-known, [15] its negative effect on bone in premenopausal women is often under-recognized; such detrimental effect was demonstrated in several clinical studies. In one study, bone mineral density (BMD) was measured in 179 premenopausal and postmenopausal healthy women who participated in a placebo-controlled tamoxifen chemoprevention trial. In the premenopausal women, BMD decreased progressively in the lumbar spine (P<0.001) and in the hip (P<0.05) for women on tamoxifen, but not those on placebo. The mean annual loss in lumbar BMD over the three-year study period in tamoxifen-treated women who remained premenopausal throughout the study period was 1.88%, compared with a small gain of 0.24% for women on placebo (P<0.001). Tamoxifen had the opposite effect in postmenopausal women; the mean annual increase in BMD for women on tamoxifen was 1.17% in the spine (P<0.005) and 1.71% in the hip (P<0.001) compared with no significant loss in the placebo group. [16] In another trial, 111 premenopausal women with early breast cancer were treated with adjuvant chemotherapy. Following the completion of chemotherapy, patients with hormone receptor-positive tumors were put on five years of adjuvant tamoxifen treatment, while those with hormone receptor-negative tumors received no further therapy. A significant bone loss (P<0.0001) was noted in tamoxifen-treated patients who continued to menstruate after chemotherapy. At three years of follow-up, menstruating patients on tamoxifen had lost 4.6% of their baseline BMD values, while a modest gain of 0.6% was noted in the control group. [17] Aromatase Inhibitors and Bone Health Aromatase inhibitors prevent conversion of androgens produced by the adrenal gland, the primary source of estrogen in postmenopausal women, resulting in a relatively rapid decline in circulating estrogens. [18],[19] Two groups of AI are widely used; steroidal (exemestane) and nonsteroidal inhibitors (letrozole and anastrozole). Owing to its androgenic structure, some preclinical studies suggested that exemestane may be more bone-sparing than letrozole. [20] However, there are no clinical trials showing a differential effect of the individual AIs on bone. The MA-27 trial is a comparative trial of exemestane versus anastrozole as adjuvant therapy in postmenopausal women. It includes end-points such as BMD and fractures. The initial results were presented at the 2010 San Antonio Breast Cancer Symposium. Clinical fracture rates were similar in both study arms (10% versus 9%, P=0.91), although exemestane caused lower rates of osteoporosis (31% versus 35%, P=0.001). [21] The effects of AI on BMD and bone turnover markers were evaluated in several of the AI trials; BMD of the lumbar spine and total hip were significantly reduced in postmenopausal women receiving AI versus tamoxifen or placebo. A prospective substudy of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial assessed BMD changes in postmenopausal women with invasive primary breast cancer receiving anastrozole or tamoxifen as adjuvant therapy for five years. Lumbar spine and total hip BMD were assessed at baseline and after one, two, and five years. One hundred ninety-seven women from the monotherapy arms of the ATAC trial were recruited into this bone substudy, and 108 were included in the primary analysis. Among anastrozole-treated patients, there was a decrease in median BMD from baseline to five years in lumbar spine (-6.08%) and total hip (-7.24%) compared with the tamoxifen group (lumbar spine, +2.77%; total hip, +0.74%). [22] The negative effect of anastrozole on BMD was also reflected clinically in a higher incidence of fractures; the annual incidence of fractures was higher in women receiving anastrozole (11% versus 7.7%) throughout the five years of treatment. [23] However, this study suggested that AI-related fracture rates will decrease upon cessation of the drug. [24] Another large randomized trial, the Intergroup Exemestane Study (IES), compared the switch to the steroidal AI exemestane with continuation of tamoxifen in the adjuvant treatment of 206 postmenopausal women with breast cancer. Within six months of switching to exemestane, BMD was lowered by 2.7% (95% confidence intervals (CI) 2.0-3.4; P<0.0001) at the lumbar spine and by 1.4% (95% CI 0.8-1.9; P<0.0001) at the hip compared with baseline. BMD decreases were only 1.0% (0.4-1.7; P=0.002) and 0.8% (0.3-1.4; P = 0.003) in Year 2 at the lumbar spine and hip, respectively. With a median follow-up of 58 months in all IES participants (n = 4274), 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio (OR) 1.45 [1.13-1.87]; P=0.003). [25] Recently, the same group reported a partial reversal of BMD following cessation of AI therapy. [26] The effect of extended hormonal therapy with AI following a standard five years of tamoxifen was examined in the MA.17 trial. In this study, postmenopausal women completing five years of tamoxifen treatment were randomly assigned to five years of letrozole (n = 2593) or placebo (n = 2594). Among the women included, 256 had a clinical fracture (5.3% of patients assigned to letrozole compared with 4.6% assigned to placebo). [27],[28] This lower rate of fractures in this study can be attributed to the prior five-year use of tamoxifen. [29] The duration of tamoxifen use in other trials like IES was shorter (two to three years) than in the MA-17 trial, which could account for the difference in the findings. Treatment-Related Premature Ovarian Failure and Bone Health Breast cancer patients are at higher risk for premature ovarian failure. This is mainly due to the chemotherapy given, but sometimes is intentionally induced for high-risk early-stage premenopausal women utilizing GnRH agonists. The effect of cytotoxic chemotherapy agents on ovarian function varies widely; some having no effect while others causing permanent hypogonadism. Following, or even during chemotherapy, many women will be amenorrheic; often with high serum gonadotropin levels, but menstrual function and fertility often return several months to years after cessation of therapy. [30],[31] Cyclophosphamide, an alkylating agent commonly used in breast cancer patients, is the best documented drug and most potent at inducing ovarian failure. The effect is age and dose-dependent, with younger women affected less often than older women. [32] In a study of Bines et al., the average incidence of amenorrhea with a CMF (cyclophosphamide, methotrexate, and fluorouracil)-based regimen was 40% for patients younger than age 40 and 76% for older women. [33] Younger women who experience chemotherapy-induced ovarian failure (CIOF) have a greater chance of regaining menstrual function; approximately 50% of women younger than 40 years can be expected to return their regular menses compared with approximately 10% of older women. The adverse effects of premature menopause in women with CIOF are numerous, including osteoporosis. This risk may be increased further by the use of AI following five years of adjuvant tamoxifen, or if AI is given following CIOF or combined with GnRH agonists. This fact was clearly demonstrated in the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial, in which premenopausal women were randomly assigned to tamoxifen plus goserelin versus anastrozole plus goserelin. Half of each group received zoledronic acid. Among patients who did not receive zoledronic acid, BMD loss in the lumbar spine was more severe in the anastrozole group compared with the tamoxifen group (-13.6% vs. -9.0%). [34] Clinical Assessment Osteoporosis and related fracture are commonly encountered. According to the National Osteoporosis Foundation, nearly 50% of women over age 50 will experience an osteoporosis-related fracture during their remaining lifetime. [35] Because treatment offered for breast cancer is associated with a higher risk of osteopenia, osteoporosis or even fracture, other contributing risk factors should be carefully assessed [Table - 1]. In a recent study, the presence of at least one secondary cause of bone loss, excluding cancer-related therapies, was seen in 78% of breast cancer patients, with vitamin D deficiency being the commonest. [36] Following careful clinical evaluation, BMD measurement should be obtained in high-risk patients (low calcium levels, previous fracture, age over 65 years, family history of hip fracture, low body mass index (BMI), corticosteroid use for more than six months and smoking). Dual-energy X-ray absorptiometry (DEXA) is the gold standard for measuring BMD of the hip and spine. [37] The results of DEXA are reported as T scores, which represent the difference in the number of standard deviations between the patient′s BMD and the mean value from a comparison group of young adults of the same sex. [38] Recently, a T score value of ≤-2.5 at the femoral neck has been proposed as a defining criterion for osteoporosis. Osteopenia, on the other hand, is defined as a T score between -1.0 and -2.5. [39] The relationship between BMD and fracture risk is well-established and has been addressed in many clinical studies. There is an exponential relationship between BMD and fracture risk such that small changes in BMD can be expected to have very significant effects on fracture risk. [40],[41],[42] Several professional groups have published recommendations for the evaluation of fracture risk in women with breast cancer. [43],[44] The American Society of Clinical Oncology recommends BMD testing with a DEXA scan for postmenopausal women taking AI and for premenopausal women who develop treatment-related premature ovarian failure. [45] Despite this known risk and the published recommendations, the issue of bone health in breast cancer patients is not well-addressed by oncologists. [46],[47] In a survey done by Lester et al., 32% of UK oncologists had not requested a BMD assessment for any indication in their patients and 76% were not assessing bone health status in breast cancer patients on AI. The majority of the physicians was not even confident on how to interpret BMD results. [48] Prevention and Treatment Nonpharmacologic interventions are extremely important in preventing and treating cancer therapy-related bone loss. Lifestyle changes that include smoking cessation and weight-bearing exercises should be encouraged. Calcium and vitamin D supplements lead to a positive calcium balance and potentially reduce the rate of bone loss. [49],[50] Many clinical guidelines recommend supplementation with calcium and vitamin D; [45],[51] a total of 1200 mg of elemental calcium and 800 international units of vitamin D daily are reasonable doses. It is extremely important that women with vitamin D deficiency get enough supplements of vitamin D prior to bisphosphonate therapy to decrease the risk of hypocalcemia. In addition to its importance for bone health, the association between vitamin D and breast cancer is the subject of intensive research. This association was addressed in relation to the risk of developing breast cancer, the aggressiveness of the disease and was recently related to survival following the development of breast cancer. [52] Bisphosphonates, specific inhibitors of osteoclast-mediated bone resorption, are considered first-line pharmacologic therapy for postmenopausal women with osteoporosis. [53] Given the low incidence of observed fractures, clinical trials used the decline in BMD as a primary endpoint. However, fracture data were reported as adverse events in the original studies. This point was well-illustrated in a meta-analysis of six trials evaluating bisphosphonates in women with breast cancer receiving AI. Despite the significant improvement in BMD, bisphosphonates did not significantly decrease the number of fractures compared with placebo or no treatment (OR 0.79, 95% CI 0.53-1.17). [54] The two largest randomized trials addressing the use of bisphosphonates in this setting were the Zometa-Femara Adjuvant Synergy Trials (Z-FAST and ZO-FAST). [55],[56],[57] In the ZO-FAST trial, a total of 1065 patients on adjuvant letrozole were randomized to immediate-start or delayed-start zoledronic acid (4 mg intravenously every six months for five years). The delayed group received zoledronic acid if lumbar spine or total hip T-score decreased below -2.0 or when a non-traumatic fracture occurred. At Month 12, lumbar spine BMD increased from baseline in the immediate arm, while it decreased from baseline in delayed-arm patients. The difference between the groups in lumbar spine BMD was 5.7% (P<0.0001; 95% CI, 5.2% to 6.1%), and 3.6% in total hip (P<0.0001; 95% CI, 3.3 to 4.0%), respectively. Although this study was not designed to show anti-fracture efficacy, the incidence of fractures was slightly higher in the delayed group (upfront, 17 [5.7%] vs. delayed, 19 [6.3%]), but not statistically significant (P=0.8638). Both regimens were well-tolerated with few serious adverse events. [55] This study was recently updated and showed at 36 months a mean change in lumbar BMD of +4.4% for immediate versus -4.9% for delayed zoledronic acid group (P<0.0001). The between-group differences were 7.94% at 24 months, and 9.29% at 36 months (P<0.0001 for all). [56] The other trial, the Z-FAST, enrolled similar patients and used the same treatment plan. At Month 12, lumbar spine BMD was 4.4% higher in the upfront group than in the delayed group (95% CI, 3.7% to 5.0%; P<0.0001), and total hip BMD was 3.3% higher (95% CI, 2.8% to 3.8%; P<0.0001). [57] This trial was also recently updated with 36 months′ follow-up results. The between-group differences in lumbar spine and total hip BMD were 6.7 and 5.2%, respectively [Figure - 1]a. At this time point, 15% of women in the delayed group required zoledronic acid for a T-score decrease to <-2.0. However, there was no difference in the incidence of fractures between the two groups (5.7% vs. 6.3%). [58] Zoledronic acid also prevents significant bone loss associated with use of AI in combination with GnRH agonists in premenopausal women. A five-year update was recently reported from the previously discussed ABCSG-12 study. [59] In this sub-study, 404 patients were included, with 199 randomized to endocrine therapy alone and 205 randomized to endocrine therapy plus zoledronic acid. After three years of treatment, there was a significant loss in both lumbar spine and trochanter BMD among patients treated with endocrine therapy alone. By contrast, BMD values were comparable to baseline in zoledronic acid-treated patients, at both the lumbar spine (+0.4%) and trochanter (+0.8%). In fact, patients who received zoledronic acid actually experienced an increased BMD at 60 months for both sites compared with baseline. Oral bisphosphonates were also tested for the same indication. The study of anastrozole with the bisphosphonate risedronate (SABRE) trial was designed to evaluate the effect of weekly oral risedronate on bone loss in postmenopausal women receiving anastrozole. [60] In this trial, postmenopausal women with hormone receptor-positive early breast cancer were assigned to one of three risk strata. Patients with the highest risk (T-score <-2) received anastrozole plus risedronate 35 mg/week orally while patients with moderate risk (T-score between -1.0 and -2.0) were randomly assigned in a double-blind manner to anastrozole and risedronate or to anastrozole and placebo. Patients with lower risk (T-score of ≥-1.0) received anastrozole alone. Calcium and vitamin D were offered to all patients. At 24 months, patients in the moderate risk group treated with risedronate had a significant increase in lumbar spine and total hip BMD compared with placebo (2.2% vs. -1.8%; P<.0001; and 1.8% vs. -1.1%; P<.0001, respectively) [Figure - 1]b. In the high-risk stratum, lumbar spine and total hip BMD increased significantly (3.0%; P=.0006; and 2.0%; P=.0104, respectively). Patients in the low-risk stratum showed a significant decrease in lumbar spine BMD (-2.1%; P = 0109), but not in total hip BMD (-0.4%; P=.5988). Similar conclusions were reached in a smaller trial using the same bisphosphonates for postmenopausal women with breast cancer taking AI. [61] Another oral bisphosphonate, ibandronate, was also tested in 131 postmenopausal early breast cancer patients treated with AI. [62] Of these, 50 patients had osteopenia (T-score -1.0 to -2.5) at either the hip or lumbar spine. All patients were treated with anastrozole, calcium and vitamin D supplementation. In addition, osteopenic patients were randomized to receive either treatment with ibandronate 150 mg orally every month or placebo. After two years, osteopenic patients treated with ibandronate gained +2.98% and +0.60% in BMD at the lumbar spine and hip, respectively. Patients treated with placebo, however, lost -3.22% at the lumbar spine and -3.90% at the hip. The differences between the two treatment arms were statistically significant at both sites (P<0.01) [Figure - 1]c. Current ASCO guidelines [Figure - 2] suggest pharmacologic therapy (bisphosphonates) in those with a BMD T-score ≤-2.5. In patients with BMD T-scores above -2.5, annual BMD testing is recommended with initiation of bisphosphonates when BMD T-score falls to <-2.5. [45] However, we need to emphasize that these guidelines are relatively old (2003) and due for update. Given the recent publications of new studies and introduction of new agents, the recommendations for annual DEXA scans and the threshold for treatment based on T-scores may change. On the other hand, the UK Expert Group recommends bisphosphonate therapy for elderly women (>75 years) who have one or more risk factors for osteoporotic fracture, regardless of BMD. [36] In addition, they recommend bisphosphonates for postmenopausal women <75 years of age with T-scores <-2.0 or if bone loss in women with preexisting osteopenia (T-score between -1.0 and -2.0) occurs at a rate ≥ to 4% per year. Due to the rapid bone loss that occurs in premenopausal women receiving ovarian suppression with a GnRH agonist and AI, some groups, like The UK Expert Group, recommend bisphosphonates for such women if the T-score is ≤-1.0. However, it is important to emphasize that both ASCO and UK recommendations are based on consensus and not on prospectively generated data. Prolonged therapy with bisphosphonates is generally well tolerated. However, patients should be periodically monitored for a number of complications, including renal insufficiency, hypocalcemia, and osteonecrosis of the jaw which is rarely encountered at this dose schedule in breast cancer patients. In October 2010, the US Food and Drug Administration (FDA) issued an updated report describing the risk of atypical fractures of the thigh, known as subtrochanteric and diaphyseal femur fractures, in patients who take bisphosphonates for osteoporosis. [63] This notice does not affect bisphosphonate drugs that are used for other indications like cancer-related hypercalcemia and prevention of osteoporosis. However, physicians should keep an eye on this evolving subject. Additionally, bisphosphonates also have anticancer activity in the adjuvant setting for breast cancer. At 36 months of follow-up in the ZO-FAST trial, the immediate therapy group had a significant 41% relative risk reduction for disease-free survival (DFS) events (P=0.0314). [56] Survival advantage of bisphosphonates in early-stage breast cancer was also addressed in many recent studies. Mature results from ABCSG-12 (with a median follow-up of 62 months) were presented at the 2010 American Society of Clinical Oncology annual meeting. A total of 183 DFS events and 65 deaths were reported. Overall, zoledronic acid reduced the risk of DFS events by 32% [Hazarad Ratio (HR = 0.68 [95% CI = 0.51, 0.91]; P=0.009)]. Additionally, zoledronic acid reduced the risk of death by 34% (HR = 0.66 [0.41, 1.09]; P= 0.10). [64] However, the results of the AZURE trial, which is one of the largest Phase III studies of adjuvant bisphosphonates, did not support the routine use of adjuvant zoledronic acid in the management of early breast cancer. In this study with a median follow-up of 59 months, there have been 752 DFS events (zoledronic acid 377; control 375-HR 0.98, 95% CI 0.85-1.13; P = 0.79). [65] Denosumab Osteoclast formation involves multiple cell types and proteins. RANKL (Receptor Activator of Nuclear factor Kappa-B Ligand) and its receptor RANK are key players in this process. RANKL is produced by osteoblasts and their immature stromal cell precursors, whereas the RANK receptor is expressed on the surface of osteoclasts and their precursors. [66] Binding of RANKL to RANK leads to osteoclast differentiation and activation and thus results in bone loss. The interaction of RANKL with RANK is inhibited by denosumab, a subcutaneously administered fully human monoclonal antibody. [67] In June 2010, denosumab was approved by the US FDA for the treatment of patients who have failed or are intolerant to other available osteoporosis therapy. In one study, 252 women with hormone receptor-positive nonmetastatic breast cancer treated with AI were randomized to receive placebo or subcutaneous denosumab 60 mg every six months. Both groups received supplemental calcium and vitamin D. At enrollment, all patients were required to have evidence of low bone mass but not osteoporosis. At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively in the denosumab group versus placebo (P<0.0001 at both time points). [68] There were no vertebral fractures, and nonvertebral fractures occurred in eight subjects in each group. The most common side-effects were arthralgia, back pain, and fatigue. Conclusions Compared to years ago, a higher percentage of women with breast cancer survive their cancer. As a complication of treatment given, osteopenia and osteoporosis are commonly encountered in this group of patients. Current guidelines call for early diagnosis, application of preventive measures and treatment of established cases. Bisphosphonates are currently the standard of care, while new agents like denosumab can be offered for patients who failed to respond to or are intolerant to other available drugs. Acknowledgment The authors would like to thank Ms. Haifa Al-Ahmad for her support in preparing this manuscript. References
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