Bisphosphonates for Breast Cancer: Questions Answered, Questions Remaining

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Bone is an important organ that is essential to adult hematopoiesis, electrolyte balance, and locomotion. Individuals who have metastatic breast cancer involving the bone are at increased risk for skeletal complications and those who have a history of early-stage breast cancer may be at increased risk for fragility fractures. Maintaining bone integrity is critical to control the morbidity and mortality associated with fractures and other skeletal complications. The bisphosphonates have been shown to be efficacious in decreasing the risk for skeletal complications in cancer and in osteoporosis. The article reviews the use of bisphosphonates in patients who have breast cancer.

Section snippets

Bone Biology

The skeleton is a dynamic structure in constant flux between bone resorption and deposition; its microenvironment is composed of a matrix and a cellular component. The bone matrix consists of organic and inorganic elements. The predominant bone matrix protein is type I collagen, and the inorganic component of crystalline mineral salts is largely composed of calcium and phosphorous in the form of hydroxyapatite crystals. Osteoblasts, derived from mesenchymal stem cells, are bone-forming cells

Bisphosphonates—Biology and Mechanism of Action

Bisphosphonates are bone-targeting agents used to treat low bone mass, hypercalcemia, Paget's disease of bone, multiple myeloma, and bony metastases from various solid malignancies. Bisphosphonates are synthetic analogs of inorganic pyrophosphate, an endogenous regulator of bone mineralization [4], and are composed of two phosphonate groups linked by a central carbon atom and two covalently bonded side chains (referred to as R1 and R2) (Fig. 2). The three-dimensional structure and the phosphate

Bone Metastasis in Breast Cancer

Bone metastases occur in approximately 70% of patients who have metastatic breast cancer and are associated with a median survival of approximately 24 months with an estimated 20% of patients living 5 years [11]. Patients who have bone metastases are at risk for skeletal-related complications, including bone pain, pathologic fractures, and spinal cord compression. In addition to localized skeletal symptoms, patients who have bone involvement may experience hypercalcemia or compromised

Osteoporosis and Osteopenia

Osteoporosis and osteopenia are common bone disorders characterized by decreased bone mass that leads to compromised bone strength and ultimately predisposes individuals to an increased risk for fracture. Women who have breast cancer may be at increased risk for low bone mass because of their adjuvant hormonal therapy or chemotherapy. This section focuses on bone loss in women who have a history of breast cancer and no known metastases.

Bisphosphonates—Concerns for Toxicity and Safety

Bisphosphonate therapy may be appropriate in managing lytic or blastic bone metastases and benign conditions, such as osteoporosis. With the widespread use of bisphosphonates, it is important for clinicians and their patients to be aware of potential bisphosphonate-associated toxicities (Table 4). Although both oral and intravenous bisphosphonates have proven efficacy in reducing the risk for SREs in cancer, the toxicity profiles vary between the nitrogen-containing and non–nitrogen-containing

Open Questions and Clinical Trials

Although the bisphosphonates have been instrumental in reducing the risk for skeletal complications, a paradigm for the optimal use of the bisphosphonates has yet to be defined [25], [113]. Approximately 65% to 75% of patients who have metastatic breast cancer have bone metastases [114]. There is a significant likelihood that the management of bone metastases will go hand in hand with management of the patient's advanced cancer. Although the life expectancy of patients who have metastatic

Discussion

In the United States, the bisphosphonates pamidronate and zoledronic acid have an important role in the treatment of patients who have metastatic breast cancer involving the bone [25]. The administration of bisphosphonates may reduce the frequency of SREs by approximately 25% to 50% [13], and therefore these agents have become incorporated into the routine treatment of osseous metastases. The oral bisphosphonates used to treat postmenopausal osteoporosis are often prescribed for maintaining

Key Points

  • Breast cancer frequently metastasizes to bone.

  • Bisphosphonate therapy decreases the risk for skeletal complications in individuals who have osseous metastases by approximately one third.

  • Although the bisphosphonates have a positive effect in the care of patients who have metastatic breast cancer, they carry associated toxicities, including acute phase reactions, renal toxicities, and ONJ.

  • The bone microenvironment seems to exert a dynamic influence on breast cancer metastases and the understanding

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    Catherine Van Poznak has funding from the Susan G. Komen Breast Cancer Foundation. Catherine Van Poznak has been a consultant for Amgen, Novartis, and Roche.

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