Patients with advanced breast cancer are at high risk for developing bone metastases and ensuing skeletal complications. Since the mid 1990s, intravenous (IV) pamidronate has been the international standard of care for breast cancer patients with bone metastases. Recently, a large, randomized, phase III trial in this patient population demonstrated that 4mg zoledronic acid, a new-generation bisphosphonate, was safe and significantly reduced the overall risk of skeletal complications compared with pamidronate. Zoledronic acid has also been shown to provide consistent, durable pain reduction in these patients compared with placebo. Based on these results, zoledronic acid is rapidly becoming the new international standard for patients with bone metastases from breast cancer.

Introduction

More than 200,000 women in the US are diagnosed with breast cancer each year1 and, among the approximate one-third of these patients who develop advanced disease, 65–75% will develop bone metastases.² These patients are at high risk for skeletal complications, including pathologic fractures, spinal cord compression, and debilitating bone pain. In fact, studies have demonstrated that in the absence of bisphosphonate therapy nearly 70% of breast cancer patients with bone metastases will experience a skeletal complication within two years, with an annual incidence of approximately four events per year (see Figure 1).^3,4 Moreover, breast cancer patients have a long median survival after diagnosis of bone metastases (in the range of two to three years), during which they often suffer from significant skeletal morbidity that can have a devastating effect on quality of life.^2,5

Traditional options for the treatment of patients with bone metastases from advanced breast cancer include standard anti-neoplastic therapies, surgery to treat or prevent fractures, and radiotherapy to stabilize bone lesions, prevent fractures, and palliate severe bone pain. In addition, these patients often receive systemic analgesic therapy with non-steroidal anti-inflammatory drugs (NSAIDS) or opioids. Recently, bisphosphonates have emerged as the standard for the prevention of skeletal complications in breast cancer patients with bone metastases. Bisphosphonates are potent inhibitors of bone resorption and have been shown to significantly reduce the percentage of patients with skeletal complications, delay the median time to first skeletal event, reduce the need for radiotherapy, and palliate bone pain compared with placebo in randomized, controlled trials.6 Currently, IV pamidronate (90mg) and zoledronic acid (4mg) are the only bisphosphonates recommended by the American Society of Clinical Oncology (ASCO) for the treatment of patients with multiple myeloma or breast cancer,^7,8 and zoledronic acid is quickly becoming the new standard of care for the treatment of bone metastases in patients with breast cancer.

The Role of Bisphosphonates in Breast Cancer

Both IV and oral bisphosphonates have been shown to provide significant clinical benefits in patients with bone metastases from breast cancer in randomized trials (see Table 1).^3,9–16 Conservative assessments of treatment effects include first-event analyses, such as percentage of patients with at least one skeletal complication or time to first skeletal complication, and are preferred end-points for regulatory approval by the US Food and Drug Administration (FDA).¹⁷ Treatment effect on incidence of pathologic fractures is particularly important. Oral bisphosphonates have not demonstrated consistent, statistically significant reductions in the percentage of patients with at least one skeletal complication. In addition, the use of oral bisphosphonates is complicated by poor bioavailability and gastrointestinal (GI) toxicity, as well as issues with patient compliance.¹⁸ Currently, these agents are only approved outside the US for the treatment of bone metastases from breast cancer.¹⁹ This section provides a brief review of the efficacy and safety of IV and oral bisphosphonates currently marketed for the treatment of patients with bone metastases from breast cancer.