Because bone is the most common site of metastatic breast cancer, orthopaedic surgeons should be aware of treatment options.

Breast cancer is the leading malignancy affecting women. Approximately 178,480 women will be newly diagnosed with breast cancer in 2007.¹ Bone is the most common site of distant metastasis and will be affected in up to 80 percent of cases.² In vitro studies have shown that breast cancer cells cause both matrix degradation and mineral release in devitalized bone. The primary mechanism of tumor-induced osteolysis in breast cancer, however, involves the release of factors from tumor cells activating osteoclastic bone resorption.

Tumor cells secrete factors, including parathyroid hormone-related protein (PTHrP), that indirectly stimulate osteoclasts to effect bone resorption. Their specific affinity to bone surfaces undergoing osteoclastic bone resorption makes bisphosphonates natural candidates to counteract tumor-induced osteolysis. In addition, various in vitro and in vivo animal studies have shown that amino-bisphosphonates have the capacity to interfere with tumor cell adhesion, inhibit tumor angiogenesis, and cause tumor cell apoptosis.^3-5

Treatment efficacy
Skeletal-related events (SRE)—such as hypercalcemia of malignancy (HCM), spinal cord compression (SCC), pathologic fracture (vertebral or nonvertebral), the need for radiotherapy (RT), or orthopaedic surgery—can be used as clinical measures of the debilitation imposed by bone metastases. Therapeutic trials use the occurrence, or the time to first occurrence, of SREs as a parameter of treatment efficacy.

A meta-analysis that included 12 randomized trials of bisphosphonate therapy for patients with bone metastases from various malignancies showed that the risks of nonvertebral fractures, vertebral fractures, RT requirement, and episodes of HCM were reduced to 65 percent, 69 percent, 67 percent, and 54 percent, respectively, in comparison to risks in placebo-treated controls.⁶ A temporal analysis found no significant reduction in skeletal morbidity until after 6 months of treatment, when both episodes of HCM and the need for RT were significantly reduced. After 12 months of treatment, significant reduction in vertebral fractures was noted. A progressive reduction in the need for orthopaedic surgery became significant at 24 months. This analysis suggests that bisphosphonate therapy should be started as soon as bone metastasis is diagnosed because treatment could delay the occurrence of a first SRE.

In a study of 382 women with lytic bone metastases, patients were randomized to receive 90 mg of intravenous (IV) pamidronate or a placebo infusion every 3 to 4 weeks. As an adjunct to standard chemotherapy, 24 months of pamidronate therapy reduced the proportion of patients with SREs by one third, delayed the occurrence of a first SRE by 7 months, and lowered pain scores and analgesic use.⁷

A large randomized trial comparing zoledronate and pamidronate over a 1-year treatment period found a similar proportion of patients with one or more SREs and no significant differences in pain reduction, median time to the first SRE, and survival. The proportion of patients requiring radiation therapy, however, was significantly lower with zoledronate.⁸ Zoledronate also requires a shorter infusion time (4 mg over 15 minutes, versus 90 mg over 2 hours for pamidronate).

Yet another study randomized women with breast cancer and bone metastases to receive either 2 mg of ibandronate, 6 mg of ibandronate, or placebo for 96 weeks.⁹ The treatments were administered by IV infusion at 3- or 4-weekly intervals to a maximum of 24 treatments. Treatment with 6 mg of ibandronate resulted in significantly better pain relief and improved quality of life.

Oral treatment options
Intravenously administered bisphosphonates have two obvious disadvantages: the patient must make regular visits to oncology facilities and the potential exists for IV infusion-related adverse reactions. Oral ibandronate has been studied for efficacy and safety. In international trials, 564 breast cancer patients with bone metastases were randomized to treatment with either oral ibandronate or placebo pills for 96 weeks. The proportion of 12-week periods with new SREs was significantly lower in patients treated with 50 mg of oral ibandronate. The median time to occurrence of a first SRE was delayed by 6 months, although this did not reach statistical significance.¹⁰

In addition, oral ibandronate rapidly alleviated bone pain, reducing and maintaining bone pain scores below baseline throughout the 2-year study period.¹¹ Patients treated with oral ibandronate also experienced a significantly slower decline in quality of life scores, although they had a slightly higher incidence of adverse events such as hypocalcemia, abdominal pain, dyspepsia, nausea, and esophagitis compared to patients treated with a placebo.

Use in nonmetastatic disease
The clinical efficacy of bisphosphonates in reducing skeletal morbidity among women with advanced (stage IV) breast cancer prompted studies on its effectiveness when given to women with nonmetastatic disease (stages I to III). One prospective study involved women with primary operable breast cancer (stages I to III) who had evidence of tumor cells on bone marrow aspirates. (The presence of tumor cells in bone marrow, though not used for cancer staging, has been linked to a higher risk of distant metastasis.)

Participants underwent standard surgical resection, received adjuvant systemic therapy, and were then randomized to receive clodronate therapy (1,600 mg of oral clodronate per day, taken as four 400 mg capsules every morning), or simply standard follow-up. At a median of 36 months, the clodronate group had a significantly lower incidence of bone metastasis, half the number of bone metastases, and unexpectedly, a lower incidence of visceral metastases, and higher survival rate.¹²

Another large, randomized, placebo-controlled study of 1,069 women with stages I to III breast cancer had similar findings. Women received either 1,600 mg of clodronate or a placebo orally each day for 2 years, in conjunction with standard therapy (surgery, radiation, chemotherapy, and immunotherapy). At 2 years, women who received clodronate had a significantly lower incidence of bone metastasis as well as a significantly higher survival rate.¹³ At 5 years, although the reduction in bone metastases continued to be significant, the survival advantage did not. The incidence of SREs among patients with confirmed bone metastases was lower in the clodronate group (57 percent) than in the placebo group (73 percent) at 5 years.¹⁴

In contrast, another randomized, controlled study of 299 women with primary node-positive breast cancer did not show any benefit for clodronate therapy in the prevention of bone metastasis.¹⁵ Furthermore, the overall survival rate and disease-free survival rates were worse with clodronate treatment. Thus, the evidence for the usefulness of bisphosphonates as an adjuvant treatment in early breast cancer remains equivocal.

ASCO guidelines
In its updated 2003 guidelines, the American Society of Clinical Oncologists (ASCO) advocated the initiation of bisphosphonate treatment with 90 mg of IV pamidronate or 4 mg of IV zoledronate every 3 to 4 weeks in a woman with breast cancer and lytic bone metastasis on radiographs, as an adjunct to systemic therapy. Currently, zoledronic acid (Zometa®) is the most commonly used bisphosphonate, followed by pamidronate. These IV formulations may be soon be replaced by the orally administered ibandronate.

Benjamin E. Tuy, MD is a fellow in musculoskeletal oncology at the University of Medicine and Dentistry-New Jersey Medical School in Newark, N.J. Joseph Benevenia, MD, is the director of the division of musculoskeletal oncology and professor of orthopaedics at the University of Medicine and Dentistry-New Jersey Medical School and a member of the AAOS Biological Implants Committee. He can be reached at benevejo@umdnj.edu.

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