The Use of Bisphosphonates in Patients With Breast Cancer

Catherine H. Van Poznak, MD

Disclosures

Cancer Control. 2002;9(6) 

In This Article

Treatment of Bone Metastases

Both antineoplastic therapy and bone supportive therapy may be used in the treatment of bone metastases. Antineoplastic interventions include hormonal therapy or chemotherapy for systemic treatment and radiation therapy or surgery for site-specific treatment. Supportive therapies include analgesics and bisphosphonates. Bisphosphonate therapy has demonstrated the ability to reduce the incidence of skeletal complications,[10,11,12,13,14,15] and novel therapeutics, including small molecules and monoclonal antibodies, are being developed to target bone and tumor signaling pathways.

Bisphosphonate therapy alters the "vicious cycle" by changing the bone microenvironment. Bisphosphonates decrease the number of osteoclasts by inhibiting the recruitment of osteoclasts, inhibiting osteoclast activity, and activating osteoclast apoptosis. Both the non-nitrogen-containing and the nitrogen-containing bisphosphonates act by inhibiting cell function and by inducing apoptosis. The non-nitrogen-containing bisphosphonates can be incorporated into adenosine triphosphate-containing compounds.[16] The nitrogen-containing bisphosphonates can inhibit the mevalonate pathway and thereby inhibit the prenylation of guano-sine triphosphate-binding proteins that control cytoskeletal reorganization, vesicular fusion, and apoptosis, thereby effecting processes involved in osteoclast activation and function ( Table 1 ).[17,18]

Preclinical data have shown that bisphosphates enhance apoptosis in breast cancer cells[19] and bisphosphonates can inhibit the attachment of breast and prostate cancer cells to bone matrix.[20] Preclinical data have also suggested that bisphosphonates may decrease tumor cell proliferation and increase the efficacy of anti-neoplastic therapy with paclitaxel.[21] In addition to a direct effect on tumor cells, bisphosphonates may also affect angiogenesis[22] and immunomodulation.[23] The inducement of apoptosis in tumor cells by the bisphosphonates may be a result of direct antitumor effect or indirect antitumor effect secondary to changes produced in the bone microenvironment. Although bisphosphonates have been shown to exert an apoptotic effect preclinically,[19] it is unclear whether bisphosphonates can clinically alter the volume of a patient's tumor burden.

The addition of bisphosphonates to standard chemotherapy or hormonal therapy has been shown to produce a reduction in skeletal complications in breast cancer patients. Presently within the United States, two bisphosphonates -- pamidronate and zoledronic acid -- are approved for the treatment of skeletal metastases from breast cancer. Three large randomized clinical trials have directed the use of bisphosphonates for metastatic breast cancer patients in the United States.[12,13,14,15] These studies investigated the effect of intra-venous bisphosphonates on skeletal-related events, an aggregate of bony complications that include pathologic fractures, spinal cord compression or collapse, radiation for pain relief or treatment of pathologic fracture, surgery to bone, and hypercalcemia. Two randomized, placebo-controlled studies investigated pamidronate 90 mg infused over 2 hours every 3 to 4 weeks in patients with lytic metastases greater than 1 cm in size and demonstrated the ability of pamidronate to reduce the risk of skeletal-related events. The third study investigated zoledronic acid in a randomized clinical trial where zoledronic acid was shown to be not inferior to pamidronate ( Table 2 and Table 3 ).

Three hundred eighty-two women with stage IV breast cancer and at least one osteolytic metastatic lesion who were receiving chemotherapy were randomized to receive either a 2-hour infusion of pamidronate 90 mg every 3 to 4 weeks or placebo.[12,13] The study drug was administered 12 times. Patients were evaluated for skeletal complications, including pathologic fractures, spinal cord compression with vertebral compression fracture, the need for surgery to treat or prevent pathologic fractures or spinal cord compression, or the need for radiation therapy to bone. Patients were also assessed for hypercalcemia. The pamidronate group demonstrated a significantly longer median time to the first skeletal complication than the placebo group (13.1 vs 7.0 months, P=.005) with the time to first non-vertebral pathologic fracture, first radiation therapy, first bone surgery, and first episode of hypercalcemia showing statistical significance. The pamidronate arm also demonstrated a decrease from baseline in bone pain and marker of bone metabolism. The incidence of adverse clinical side effects and toxic effects was similar in the two study groups. Overall survival was not statistically different between the two study groups, with a median estimate of survival of 14.8 months in the pamidronate group and 14.2 months in the placebo group.

To assess the long-term tolerability and safety, effects on survival and durability of the skeletal protection, the above study was continued for a second year.[13] All patients who entered the second year of the trial had received 12 doses of study drug (pamidronate or placebo) and remained on the same treatment. The proportion of patients with any skeletal complication was less in the pamidronate arm than in the placebo group (odds ratio 2.3, 95% confidence interval [CI], 1.5 to 3.5). Laboratory findings with anemia, thrombocytopenia, and hyperphosphatemia were slightly more common in the pamidronate group than in the placebo group. The requirements for treatment of hematologic and mineral disturbances were similar for placebo and pamidronate. Symptoms of myalgias, arthralgias, and influenza-like symptoms were slightly more common in the pamidronate arm. There was no difference in survival between the two treatment groups.

To investigate the use of intravenous pamidronate in women with osteolytic breast cancer metastases who were receiving hormonal therapy, a parallel study to the above-mentioned chemotherapy trial was preformed.[14] In this study, pamidronate 90 mg was administered intravenously over 2 hours vs placebo administered monthly for 24 cycles. The first 12 months of study focused on safety and efficacy. The second 12 months focused on the assessment of the safety of long-term administration of pamidronate. Double-blind administration of the study drug continued throughout the study. A total of 372 patients were randomized to pamidronate or control. The median time to first skeletal complication was 10.4 months for the pamidronate group vs 6.9 months for the placebo group (P=.049). At 24 cycles of treatment, the odds ratio of having a skeletal event on placebo to pamidronate was 1.6 (95% CI 1.1 to 2.5). Fatigue, vomiting, leukopenia, and injection site reactions were slightly more common in the pamidronate group. An exploratory subgroup analysis demonstrated that women 50 years of age or younger experienced a median survival of 26 months in the pamidronate group vs 18 months in the placebo group. However, for the entire study, the median estimate of survival was approximately 23 months for both groups, demonstrating no overall survival difference between the pamidronate and placebo groups.

Zoledronic acid is a new, high-potency, nitrogen-containing bisphosphonate developed on the hypothesis that a more potent inhibitor of osteoclast-mediated bone resorption would have greater clinical activity. A large international, randomized phase III clinical trial compared zoledronic acid (4 or 8 mg) to pamidronate 90 mg infused over 2 hours every 3 to 4 weeks in patients with multiple myeloma and metastatic breast cancer who had at least one bone lesion, which could be osteolytic or mixed.[15] The study was designed to directly compare the efficacy and safety of the two intravenous bisphosphonates in these two patient populations. A total of 1,648 patients were enrolled, 69% of whom had breast cancer. During the course of the study and other zoledronic acid studies, the data monitoring safety board noted evidence of renal toxicity in some patients receiving zoledronic acid. This renal impairment was related to the dose and infusion duration of zoledronic acid. To avoid excess renal toxicities, the protocol underwent two modifications. The initial zoledronic acid infusion rate of 5 minutes was extended to 15 minutes and the 8-mg dose was changed to a 4-mg dose, making this group the 8/4-mg arm. Approximately 60% of patients completed 12 months of therapy. Rosen et al[15] published the study with the three arms defined as 4-mg zoledronic acid, 8/4-mg zoledronic acid, and pamidronate.

The primary efficacy endpoint was the proportion of patients with at least one skeletal-related event (not including hypercalcemia of malignancy) during the 13-month trial. The proportion of patients experiencing at least one skeletal-related event (44% to 46%) was similar between treatment groups and disease process. The median time to first skeletal-related event was similar between treatment groups (range 353-373 days from study entry). In subgroup analysis the proportion of patients receiving radiation therapy to bone was statistically significantly lower overall in the 4-mg zoledronic acid group than the pamidronate group (15% vs 20%, P=.031) and among breast cancer patients receiving hormonal therapy (16% vs 25%, P=.022). In addition, the zoledronic acid group demonstrated a statistically significant decrease in the markers of bone metabolism. Analysis of skeletal morbidity rate (ie, the ratio of the number of skeletal complications experienced by a patient divided by the time on the trial by the end of the specified time period, for all skeletal-related events, including hypercalcemia of malignancy) was lower in the 4-mg zoledronic acid group than in the pamidronate group. No statistically significant difference among treatment groups was noted with respect to the secondary endpoints of change in pain score, analgesic score, and performance status. To date, there has been no statistically significant difference in bone lesion response, time to disease progression, or overall survival.

In all treatment groups, the most commonly reported adverse events were bone pain, fatigue, and fever. The frequency of renal impairment associated with zoledronic acid was related to the dose and infusion rate. The proportion of patients with renal toxicity in the 8/4-mg zoledronic acid arm (18% to 29%) was greater than that of the 4-mg zoledronic acid arm and the pamidronate arm. After the protocol amendments, the proportion of patients with deterioration of renal function in the 4-mg zoledronic acid group resembled that of the pamidronate group. In the 4-mg zoledronic acid group, 9% of patients with normal baseline serum creatinine levels experienced an increase in serum creatinine of 0.5 mg/dL or more compared with 8% in the pamidronate group. In patients with abnormal baseline serum creatinine values, 4% of patients in the 4-mg zoledronic acid group experienced a rise of 1.0 mg/dL or more from baseline serum creatinine compared with 9% in the pamidronate group. At a dose of 4 mg via a 15-minute infusion in 100 mL of infusate, zoledronic acid demonstrated a renal tolerability profile similar to pamidronate 90 mg via 2-hour infusion in 250 mL of infusate. Due to the risk of renal changes with intra-venous bisphosphonates, monitoring for changes in serum creatinine is to be performed as outlined in the packet inserts. For both pamidronate and zoledronic acid, the serum creatinine should be measured before each dose, and treatment should be withheld for renal deterioration. In the clinical study, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine and an increase of 1.0 mg/dL for patients with abnormal creatinine. In the clinical study, the intravenous bisphosphonate was resumed only when the creatinine returned to within 10% of the baseline value.

Zoledronic acid had demonstrated superiority over pamidronate in the treatment of hypercalcemia of malignancy.[24] The study by Rosen et al[15] demonstrated non-inferiority of 4-mg zoledronic acid infused over 15 minutes when compared with 90-mg pamidronate infused over 2 hours in the treatment of osteolytic or mixed bone metastases in patients with metastatic breast cancer or myeloma. The question of whether the high-potency nitrogen-containing bisphosphonates yield an increased efficacy in treating bone metastases warrants further exploration.

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