Bone loss in patients with breast cancer receiving aromatase inhibitors and associated treatment strategies

Hormone-receptor-positive breast cancer in postmenopausal women is treated increasingly with aromatase inhibitors because of increased efficacy and reduced incidence of endometrial cancer compared with tamoxifen. However, aromatase inhibitor therapy increases bone turnover as a result of nearly complete oestrogen depletion, leading to increases in bone loss and fragility fractures that erode patients' functional independence and quality of life. Management of patients with aromatase inhibitor-associated bone loss (AIBL) is currently evolving and intervention strategies are under investigation. Although no treatments are specifically approved for AIBL, bisphosphonates are currently the intervention of choice for patients with low bone mineral density or evidence of rapid bone turnover, along with adequate calcium and vitamin D supplementation and a healthy lifestyle. In this setting, the majority of information available regarding bisphosphonate efficacy is from studies of intravenous zoledronic acid (4 mg) every 6 months. Data from four large international studies (three of identical design in postmenopausal women and one in premenopausal women) indicate that zoledronic acid is effective in the management of AIBL. Treatment algorithms based on risk factors and bone mineral density are under development, and the results of ongoing studies should help define optimal bone health management for patients undergoing aromatase inhibitor treatment for early breast cancer.     

Management of bone loss induced by aromatase inhibitors

Aromatase inhibitors are quickly becoming standard adjuvant endocrine therapy for hormone-receptor positive breast cancer, either upfront or in sequence after tamoxifen. As other means of estrogen-depleting therapy, decreasing bone mineral density is the major side effect of this treatment. As increase in fracture incidence have already been reported in most major trials of aromatase inhibitors. Bisphosphonates are used to treat this cancer-treatment induced bone loss, the available data is reviewed here.     

Aromatase and aromatase inhibitors

Aromatase inhibition provides both paracrine/intracrine and endocrine treatment. Recent accumulated data clarified that 3rd generation aromatase inhibitors potently suppress intratumoral estrogen synthesis particularly in postmenopausal patients. In the 2nd-line treatment for metastatic breast cancer patients, aromatase inhibitors achieved results antitumor activity at least equal to and sometimes better than that of tamoxifen. In the first-line treatment for metastatic breast cancer patients, a recent pivotal study clearly demonstrated that aromatase inhibitor was superior to tamoxifen. Based upon these results, various adjuvant trials which compare aromatase inhibitors with tamoxifen and attempt to determine optimal combination therapies and treatment periods with aromatase inhibitors are currently being conducted. In addition, preliminary studies conducted in neoadjuvant setting indicated that aromatase inhibitors showed an extremely high response rate, which predicts a future paradigm, that neoadjuvant therapy using aromatase inhibitors singly or in combination may become standard for hormone-responsive and post-menopausal breast cancer patients.     

Combining Src inhibitors and aromatase inhibitors: A novel strategy for overcoming endocrine resistance and bone loss

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes.     

Bone health issues in women with early-stage breast cancer receiving aromatase inhibitors

Bone health is an important issue for women with all stages of breast cancer, but especially those with early-stage breast cancer receiving aromatase inhibitors (AIs). AIs have been shown to reduce bone mineral density and are associated with an increased incidence of fractures. Although AIs significantly improve survival times in early-stage breast cancer patients, many of these patients eventually develop metastatic bone disease. Therefore, identifying effective strategies for preventing bone metastases is needed. Results of preclinical studies with bisphosphonates show increased tumor cell kill in several breast cancer cell lines, but study results evaluating this class of drugs for prevention of bone metastases in women with early-stage breast cancer receiving adjuvant therapies have been inconsistent. However, several large studies to clarify the role of bisphosphonates in maintaining or improving bone health in these women are under way.     

Managing bone loss in women with early-stage breast cancer receiving aromatase inhibitors

Third-generation aromatase inhibitors (AIs; anastrozole, letrozole, exemestane) have replaced tamoxifen as the adjuvant treatment of choice for postmenopausal women with hormone receptor-positive early-stage breast cancer. Because bone loss is a predictable adverse event of AI therapy, early recognition, prevention, and/or treatment of AI-induced bone loss is needed. One to 5 years of AI therapy causes a bone mineral density (BMD) loss of up to 7.2% in postmenopausal women; however, current clinical guidelines do not recommend initiating bisphosphonate therapy for the treatment of BMD loss until fragility fractures or frank osteoporosis occur. Results of recent trials evaluating the use of intravenous (I.V.) zoledronic acid as prevention and treatment of AI-induced bone loss in women with early-stage breast cancer receiving letrozole suggest a potential benefit to the concurrent use of zoledronic acid and letrozole. To our knowledge, clinical trials assessing oral or other I.V. bisphosphonates for these indications have not been published. Recently, concerns of bisphosphonate-induced renal safety and osteonecrosis of the jaw have emerged. Studies evaluating bisphosphonates in women with breast cancer have reported lower rates of renal dysfunction than those reported in patients with metastatic cancer receiving bisphosphonates, and no cases of jaw osteonecrosis. The use of bisphosphonates in this population requires further study to more clearly define the most appropriate timing and length of therapy as well as the long-term efficacy and safety of these drugs. Until these data become available, balancing the safety concerns with the potential benefits of I.V. bisphosphonates to minimize or prevent AI-induced bone loss in women with early-stage breast cancer is required.     

Sequencing of aromatase inhibitors

Since the development of the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, these agents have been the subject of intensive research to determine their optimal use in advanced breast cancer. Not only have they replaced progestins in second-line therapy and challenged the role of tamoxifen in first-line, but there is also evidence for a lack of cross-resistance between the steroidal and nonsteroidal AIs, meaning that they may be used in sequence to obtain prolonged clinical benefit. Many questions remain, however, as to the best sequence of the two types of AIs and of the other available agents, including tamoxifen and fulvestrant, in different patient groups.     

Toxicity of aromatase inhibitors

Adjuvant hormonal therapy in hormone receptor-positive breast cancer is used for the prevention of disease recurrence and prolongation of survival. Aromatase inhibitors are increasingly being used for this purpose. Numerous studies now reveal their benefits over tamoxifen while demonstrating a markedly different toxicity profile. With greater use, a better understanding of the long-term effects of aromatase inhibitors on the prevention of cancer recurrence and on their long-term effects on chronic comorbid conditions will develop. Recognizing and understanding these toxicities, as well as the differences among the various aromatase inhibitors, will be crucial for all clinicians. When choosing the type of adjuvant hormonal therapy for each individual patient, comorbidities and quality-of-life parameters must be considered. In addition, ongoing studies evaluating these agents directly should reveal differences among them that may aid in determining the principal agent for use in this setting. In this article, we review the known toxicity profile of aromatase inhibitors and the current guidelines that exist in the diagnoses and management of these toxicities.     

Safety of aromatase inhibitors in the adjuvant setting

The third-generation aromatase inhibitors (AIs) letrozole, anastrozole, and exemestane are replacing tamoxifen as adjuvant therapy in most postmenopausal women with early breast cancer. Although AIs have demonstrated superior efficacy and better overall safety compared with tamoxifen in randomized controlled trials, they may not provide the cardioprotective effects of tamoxifen, and bone loss may be a concern with their long-term adjuvant use. Patients require regular bone mineral density monitoring, and prophylactic bisphosphonates are being evaluated to determine whether they may protect long-term bone health. AIs decrease the risks of thromboembolic and cerebrovascular events compared with tamoxifen, and the overall rate of cardiovascular events in patients treated with AIs is within the range seen in age-matched, non-breast-cancer populations. AIs are also associated with a lower incidence of endometrial cancer and fewer vaginal bleeding/discharge events than tamoxifen. Compared with tamoxifen, the incidence of hot flashes is lower with anastrozole and letrozole but may be higher with exemestane. Generally, adverse events with AIs are predictable and manageable, whereas tamoxifen may be associated with life-threatening events in a minority of patients. Overall, the benefits of AIs over tamoxifen are achieved without compromising overall quality of life.     

Nonsteroidal and steroidal aromatase inhibitors in breast cancer

Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the hormonal therapy of choice in estrogen-receptor-positive, postmenopausal, metastatic breast cancer. This article will review the role of aromatase in the pathogenesis of breast cancer and the results of recent studies that have established the role of its inhibitors in estrogen-receptor-positive breast cancer. We will also briefly outline the rationale and design of ongoing studies.     

First generation aromatase inhibitors — aminoglutethimide and testololactone

Summary Aminoglutethimide and testololactone may be considered the first generation aromatase inhibitors for the endocrine treatment of breast carcinoma. Initially, both of these agents were designed and used clinically based on different concepts of their mechanisms of action. Only later were they both demonstrated to inhibit aromatase.Curiously, testololactone was earlier and more widely used than aminoglutethimide in treating advanced breast carcinoma. The discovery of the peripheral aromatase inhibition as the proper mechanism of action was delayed for both the agents but was relatively more timely for aminoglutethimide. Paradoxically, the clinical use of testololactone has become already obsolete since its true mechanism of action was discovered.Aminoglutethimide is still the most widely used aromatase inhibitor in treating advanced breast carcinoma. Due to the initial misinterpretation of its mechanism of action, aminoglutethimide was used for a long time at a relative high daily dose, always combined with hydrocortisone. Subsequent phase II and then randomized phase III studies demonstrated an equivalent efficacy using half (500 mg) of the previous conventional daily dose (1000 mg), with hydrocortisone. Very recently, a randomized clinical trial demonstrated that administering this lower dose without hydrocortisone did not significantly decrease the clinical efficacy.By decreasing the dose of aminoglutethimide, the incidence of side effects has been reduced. So, the last paradoxical aspect of the aminoglutethimide story is that this agent seemed initially very toxic but finally, with the new schedules, shows a very low toxicity profile, especially after the first few weeks of treatment.     

Development of aromatase inhibitors and their pharmacologic profile

Major advances have been recently made in the treatment of postmenopausal women with hormone-sensitive breast cancer. It is widely accepted that estrogen is associated with the progression of hormone-sensitive breast cancer. Whereas previous therapy was based on surgical ablation (ovariectomy, adrenalectomy, and hypophysectomy) or additive treatment (estrogens, androgens), more recently antiestrogens (in premenopausal as well as postmenopausal women), medical ovarian ablation, and aromatase inhibition have replaced these procedures. The current focus of clinical research efforts is to maximize efficacy with these agents and determine an effective treatment strategy for these patients. This article reviews the development of aromatase inhibitors and inactivators (AIs), with particular emphasis on the potent third-generation agents now available. Also provided is information on the relative potency and efficiency of estrogen synthesis inhibition with these agents. Results from in vitro and in vivo studies of AIs suggest that there is variability in efficacy among agents in this class, and the potential clinical implications of these variations are discussed.     

Role of aromatase inhibitors in breast cancer

Primarily, the role of the aromatase inhibitors has been investigated in postmenopausal women with breast cancer, although it is also now being assessed in premenopausal patients following ovarian ablation/suppression. Aromatase inhibitors markedly suppress endogenous oestrogens without directly interacting with oestrogen receptors, and thus have a different mechanism of action to the antioestrogen, tamoxifen. The inhibitors may be divided into subgroups according to their structure (steroidal and nonsteroidal), and there appears to be a lack of cross-resistance between the classes of aromatase inhibitors enabling them to be used sequentially and potentially to prolong endocrine hormone therapy. In addition, with increased efficacy and favourable safety and tolerability profiles, the aromatase inhibitors are starting to challenge tamoxifen as first choice endocrine treatment in a number of settings. Potential differences in side-effect profiles may appear between the steroidal and nonsteroidal aromatase inhibitors when used in long-term settings. Thus, it has been suggested that the steroidal agents have favourable end organ effects; for example, the steroidal inhibitor, exemestane, has minimal negative effects on bone and lipid metabolism in animal and clinical studies. This paper provides an overview of the current and future roles of aromatase inhibitors for breast cancer treatment.     

Emerging role of aromatase inhibitors in the adjuvant setting

Aromatase inhibitors (AIs) have been approved as second-line treatment for estrogen receptor-positive (ER+) metastatic breast cancer after first-line treatment with the selective estrogen receptor modulator (SERM) tamoxifen. Anastrozole and letrozole have also recently been widely approved as first-line endocrine therapy for postmenopausal women with hormone receptor-positive metastatic breast cancer. The three third-generation selective oral AIs approved for use in the United States include two nonsteroidal agents, anastrozole (Arimidex) and letrozole (Femara), and the irreversible steroidal inhibitor exemestane (Aromasin). Several major ongoing clinical trials with a variety of treatment regimens are comparing the relative efficacy of tamoxifen with the steroidal and nonsteroidal AIs in the adjuvant setting. The first strategy compares an AI against tamoxifen directly. Among these are the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (anastrozole), the BIG FEMTA (Femara-Tamoxifen Breast International Group) trial (letrozole), and the EXEM and TEAM (exemestane) trials. A second strategy is examining the use of an AI as an extension after the initial 5 years of tamoxifen. Examples of this trial design are the MA-17 (letrozole) and the National Surgical Adjuvant Breast and Bowel Project (NSABP B-33, exemestane) trials. A third approach is the use of these agents in sequence with tamoxifen as therapy within the initial 5 postoperative years. Examples of this approach are the International Collaboration Cancer Group trial (tamoxifen for 2-3 years followed by either tamoxifen or exemestane for the remainder of the 5-year period), the BIG FEMTA trial (patients are crossed over from tamoxifen to Ietrozole or letrozole to tamoxifen), and the Arimidex-Nolvadex (ARNO) trial (patients receiving tamoxifen are randomized either to continue with tamoxifen or to switch to anastrozole). A single trial is comparing tamoxifen and anastrozole as initial 5-year therapy, or a combination of the two. The study addressing this design is the ATAC trial. Finally, a small trial in Norway is comparing 2 years of an AI versus a placebo in very low-risk patients with receptor-positive breast tumors. Most adjuvant trials have companion studies associated with the main protocol. These are to determine the end-organ effects of the inhibitors and include measurements of quality of life, bone and lipid metabolism, and endometrial effects. This review addresses the clinical implications of these studies of AIs.     

Effects of third-generation aromatase inhibitors on bone

Low oestradiol levels in women are associated with decreased bone mineral density (BMD) and increased fracture risk. The third-generation aromatase inhibitors (AIs; anastrozole, letrozole, and exemestane) are used in the treatment of early and advanced breast cancer and act by substantially reducing oestrogen synthesis in postmenopausal women. However, due to their mechanism of action, there is concern regarding the long-term effects of these agents on bone, particularly when used in the adjuvant setting. In this paper, the currently available data on the effects of the third-generation AIs on markers of bone turnover, BMD, and fracture risk are reviewed, with the emphasis on results in the adjuvant treatment of early breast cancer. These data suggest that both the steroidal (exemestane) and non-steroidal (anastrozole and letrozole) AIs appear to affect bone turnover. Conclusions regarding any clinically relevant differences between these agents are difficult to make, and further data are awaited from long-term adjuvant use of these three agents in ongoing clinical studies. Postmenopausal women are at increased risk of osteoporosis and fracture, and the increasing use of AIs in the adjuvant treatment of postmenopausal breast cancer patients will require appropriate consideration of fracture risk, with the use of anti-osteoporotic therapies, if necessary.