Osteoclast Inhibitors: A Multifaceted Tool in the Management of Breast Cancer

Many adjuvant breast cancer treatments are associated with loss of bone mineral density. Aromatase inhibitors are the most recognized in this regard.[1] However, chemotherapy-induced ovarian dysfunction is also associated with bone loss.[2,3] Hence, bone-modifying agents (bisphosphonates and denosumab, which are potent inhibitors of osteoclast activity) have been routinely used for the management of therapy-related bone loss in patients with early breast cancer. In patients with metastatic breast cancer, these same osteoclast inhibitors have been shown to reduce the risk of bone-associated complications (skeletal-related events [SREs]) and are an integral part of palliative supportive therapy. Current guidelines and recommendations support the use of osteoclast inhibitors for these purposes.[4-6]

In this issue of ONCOLOGY, Dr. Blanchette and Dr. Pritchard summarize the evidence behind such recommendations for the use of bisphosphonates in both the adjuvant and metastatic settings.[7] Moreover, the authors insightfully point out the need for more research to define how best to preserve bone health and how best to prescribe osteoclast inhibitors. More important, the authors address the somewhat controversial use of bisphosphonates as an anticancer treatment in patients with early breast cancer. Their review provides an excellent overview of key studies and the meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) reported at the San Antonio Breast Cancer Symposium in 2013.[8]

Optimal use of osteoclast inhibitors for bone health in early-stage breast cancer

Low bone mass is a public health concern because it affects more than 40 million people in the United States and is associated with fragility fractures, which carry significant morbidity and mortality.[9] In general, the recommendations for screening for and treating low bone mass in women with early-stage breast cancer parallel those for women of a similar age without cancer who may have either primary or secondary low bone mass. Many similarities exist, but unlike in the general population, in women with a history of breast cancer the use of exogenous estrogens is generally to be avoided and is not considered an option for maintaining bone in this population.[6,9-11]

Optimal use of osteoclast inhibitors in metastatic breast cancer for the prevention and treatment of SREs

Although osteoclast inhibitors are commonly used for patients with metastatic breast cancer who have bone metastases, a few fundamental questions still remain. Dr. Blanchette and Dr. Pritchard address many of these concerns, including the dosing interval for long-term zoledronic acid therapy; we will expand on additional points.

When and in whom should osteoclast inhibitor therapy be initiated? To date, any osseous metastasis may trigger the start of therapy, yet the ideal time to start has not been formally studied. It is also unknown whether all patients benefit equally.

Which osteoclast inhibitor to choose? The data have yielded some suggestions regarding the preferred choice of agents, as Dr. Blanchette and Dr. Pritchard point out. Denosumab is often considered a favored therapy because it has demonstrated superior efficacy in delaying time to the first SRE and time to a subsequent SRE,[12] and because it does not require intravenous access for administration. However, denosumab does not provide a survival benefit, and its generic formulation is not available. Clinically important factors that influence prescribing patterns include the availability of specific drugs, the cost of therapy, the drug-toxicity profile in relationship to a particular patient, the route of administration, and the patient’s preferences.

When should osteoclast inhibitor therapy be stopped? There are insufficient data to guide the duration of therapy with an osteoclast inhibitor. A prior SRE is a risk factor for subsequent SREs. Indeed, in a study of patients with multiple myeloma, the occurrence of one SRE was associated with a twofold risk of subsequent SREs.[13] Given that the bone metastases and the risk of SREs will be present lifelong, it has been recommended that osteoclast inhibitor therapy be continued indefinitely.[4] Survey data suggest that medical oncologists typically continue osteoclast inhibitor therapy into the last 6 months of life,[14] and a limited number of reports have examined the use of bisphosphonates in the hospice setting and at the end of life.[15,16]

Anticancer effect of osteoclast inhibition in early breast cancer

Most recently, a subgroup analysis in postmenopausal women from the EBCTCG meta-analysis reported the benefits of bisphosphonates in reducing rates of distant recurrence at 10 years (3.5%), risk of bone metastasis (34%), and risk of death (relative, 17%; absolute, 3%).[8] The EBCTCG study results are not yet published. However, several previously published meta-analyses evaluated the impact of bisphosphonates as adjuvant therapy. The results and conclusions from these published reports vary and are inconsistent with regard to reduction of the risk of bone metastases and improvements in disease-free survival and overall survival.[17-19] We must keep in mind that meta-analysis is a statistical analysis method that can be affected by various techniques, assumptions (such as individual data–based vs non-individual data–based), and biases (such as publication, availability, and selection biases), and the reliability of its conclusions depends on the quality of the data.[20,21] Most of all, meta-analysis is no replacement for a well-designed, large randomized clinical trial addressing an a priori hypothesis. With these caveats in mind, we eagerly await the publication of the EBCTCG meta-analysis, as well as the reports of the remaining phase III studies that are ongoing, and of biologic studies seeking to define the mechanism by which the efficacy of adjuvant bisphosphonates seems to vary by menopausal status.

In determining whether bisphosphonates should become a standard of care, as suggested by Dr. Blanchette and Dr. Pritchard, one must consider the therapeutic ratio and cost-benefit of adding such drugs to the regimens of thousands of patients with early breast cancer. For this, it is important to evaluate the incidence of side effects and treatment acceptability by our patients. At the 2014 American Society of Clinical Oncology Annual Meeting, the Southwest Oncology Group (SWOG) investigators reported the toxicities and patient-stated preference for bisphosphonates as adjuvant therapy in primary breast cancer from the SWOG S0307 phase III trial.[22] In this study, patients with stage I–III disease were randomized to receive 3 years of oral clodronate daily; 3 years of oral ibandronate daily; or intravenous zoledronic acid monthly for 6 months, then every 3 months for a total of 3 years. The most frequently reported adverse events were musculoskeletal complaints, pain, gastrointestinal toxicity, metabolic/laboratory changes, and acute-phase reactions. At the time of abstract reporting, osteonecrosis of the jaw (40 cases) was reported more frequently in the zoledronic acid group (1.15%) than in the oral drug groups (0.28% for clodronate and 0.66% for ibandronate), with a statistically significant difference (P = .03); the incidence of fracture was similar among the drug groups (4.1%–4.8%). Patients reported a preference for the oral drugs over the IV drug (76% vs 24%), assuming equal efficacy.

At the same meeting, Reeder-Hayes et al[23] presented a cost-effectiveness analysis of bisphosphonate use in the adjuvant setting. The results showed that cost-effectiveness differed with the regimen, even for the same drug. For example, alendronate at 70 mg per week and low-dose ibandronate at 150 mg per month (but not high-dose ibandronate at 50 mg daily) were cost-saving compared with placebo.

In addition, the same questions from the metastatic setting (which agent and what duration/dose?) apply to this setting as well. The choice of bisphosphonate agents, duration, and dosing schedules differ among the clinical trials included in published and not-yet published meta-analyses. For example, should we administer zoledronic acid for 5 years (ZO-FAST and AZURE trials) or for 3 years (Austrian Breast and Colorectal Cancer Study Group Trial 12), and would the difference in duration make any difference-such as it has shown for adjuvant endocrine therapy?[24-26] Moreover, it is unclear whether denosumab will have an adjuvant anticancer effect, and if so, whether menopausal status will influence efficacy. Currently, denosumab is being compared with placebo in the D-CARE study, where the primary outcome measure is bone metastasis–free survival (ClinicalTrials.gov identifier: NCT01077154). The study has fully accrued, but the results have not yet been reported.

In summary, there are still questions to be answered about the use of osteoclast inhibitors in the care of patients with breast cancer. The optimal duration and dosing schedule and how to improve treatment compliance are important issues to address. We believe that there is a promising benefit of bisphosphonates as an adjuvant therapy in postmenopausal patients with early breast cancer. However, routine use of bisphosphonates as a standard of care for such a purpose in patients with early breast cancer warrants closer examination. As the data continue to evolve, consideration needs to be given to defining the therapeutic ratio and to cost-benefit analysis in a wide array of settings.

Financial Disclosure:Dr. Van Poznak serves (uncompensated) on the steering committee for a phase III trial being conducted by Novartis. Dr. Morikawa has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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