Zoledronic Acid

In a randomized study in women with bone metastases from breast cancer (N = 228), patients received 4 mg zoledronic acid or placebo via 15-minute infusions every 4 weeks for 1 year (7). For these analyses, hypercalcemia of malignancy was included as an SRE. Zoledronic acid significantly reduced the skeletal morbidity rate (SMR; 0.63 SRE/year for zoledronic acid versus 1.10 SREs/year for placebo; P = 0.016). Both the percentage of patients with an SRE (30.7% for zoledronic acid versus 52.2% for placebo; P = 0.001) and the proportion of patients experiencing each type of SRE were reduced (Figure 3) (7). The median time to SRE was not reached in patients treated with zoledronic acid versus 360 days in patients treated with placebo (P = 0.004). Zoledronic acid also significantly reduced the risk of SREs by 44% compared with placebo (P = 0.009). Moreover, zoledronic acid was well tolerated in this population, with a safety profile similar to that of placebo. Zoledronic acid also significantly reduced BPI composite pain scores and reduced the incidence of palliative radiation to bone compared with placebo.

Figure 3. Proportion of patients with bone metastases from breast cancer experiencing each type of skeletal-related event (SRE). Patients were randomized to receive either 4 mg zoledronic acid (N = 114) or placebo (N = 113). HCM = Hypercalcemia of malignancy. Adapted with permission from Kohno N, et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 2005, 23(15):3314—3321. Reprinted with permission from the American Society of Clinical Oncology (7).

Figure 3. Proportion of patients with bone metastases from breast cancer experiencing each type of skeletal-related event (SRE). Patients were randomized to receive either 4 mg zoledronic acid (N = 114) or placebo (N = 113). HCM = Hypercalcemia of malignancy. Adapted with permission from Kohno N, et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 2005, 23(15):3314—3321. Reprinted with permission from the American Society of Clinical Oncology (7).

3.1.5. Direct Comparison of Bisphosphonates in Patients With Bone Metastases From Breast Cancer

Zoledronic acid is the only bisphosphonate to be directly compared with pamidronate for efficacy and safety in patients with advanced breast cancer in a large-scale, randomized, phase III noninferiority trial (28,29). Patients with bone metastases from breast cancer or bone lesions from multiple myeloma (N = 1,648) were randomized to receive either zoledronic acid (4 mg via 15-minute infusion) or pamidronate (90 mg via 2-hour infusion) every 3-4 weeks for up to 2 years (29). Zoledronic acid was at least as effective as pamidronate in reducing the proportion of patients with an SRE and in reducing the SMR, and multiple event analysis showed that zoledronic acid reduced the risk of developing a skeletal complication by an additional 16% compared with pamidronate (risk ratio = 0.841; P = 0.030) (29).

In a subset analysis of patients with bone metastases from breast cancer (N = 766), 4 mg zoledronic was at least as effective as 90 mg pamidronate in reducing the proportion of patients with an SRE (43% versus 45%, respectively) (30). Zoledronic acid consistently reduced the proportion of patients experiencing each type of SRE compared with pamidronate and significantly reduced the percentage of patients requiring radiation to bone below that in the pamidronate group (19% versus 27%, respectively; P = 0.011) (31). Overall, zoledronic acid produced a 40% reduction beyond that produced by pamidronate in the SMR (0.90 SRE/year for zoledronic acid versus 1.49 SREs/year for pamidronate, P = 0.125) (31). Moreover, zoledronic acid significantly reduced the risk of developing an SRE (including hypercalcemia of malignancy) by 20% compared with pamidronate in patients with breast cancer (hazard ratio = 0.799; P = 0.025) (31). Notably, zoledronic acid reduced the requirement for radiation to bone significantly more than pamidronate, suggesting that patients treated with zoledronic acid may have had better pain relief versus patients treated with pamidronate.

In a post hoc analysis of this trial in patients with bone metastases from breast cancer and at least 1 primarily osteolytic bone lesion (N = 528), zoledronic acid reduced the proportion of patients with an SRE compared with pamidronate (48% versus 58%; P = 0.058) (30). Moreover, zoledronic acid significantly prolonged the time to first SRE by approximately 4.5 months compared with pamidronate (median, 310 days for zoledronic acid versus 174 days for pamidronate; P = 0.013) and significantly reduced the mean SMR (1.2 SREs/year for zoledronic acid versus 2.4 SREs/year for pamidronate; P = 0.008) (30). In addition, treatment with zoledronic acid produced a significant 30% reduction in the risk of SREs compared with pamidronate (hazard ratio = 0.704; P = 0.010) (30).

3.1.6. Independent Meta-Analysis of Bisphosphonates in Patients With Bone Metastases From Breast Cancer

An independent meta-analysis (18) of placebo-controlled trials of bisphosphonates in patients with bone metastases from breast cancer by the Cochrane Library concluded that bisphosphonates as a class reduce the risk of developing an SRE by 17% (risk ratio = 0.83, P < 0.00001). Although it was not based on a head-to-head analysis, zoledronic acid produced the greatest reduction in the risk of SREs versus placebo (41%) of all bisphosphonates assessed (pamidronate, IV or oral ibandronate, and oral clodronate; Figure 4) (18). Overall, bisphosphonates significantly delayed the median time to an SRE and significantly improved bone pain compared with placebo. The authors concluded that bisphosphonates may improve global QoL.

In a british economic analysis of the associated health-care costs and quality-adjusted survival associated with commonly used bisphosphonates versus no therapy, bisphosphonates were determined to be cost saving or cost-effective, with a cost per quality-adjusted life year of £6,126 (~$12,000) (32). Among the bisphosphonates, zoledronic acid was determined to be the most cost-effective, with a net monetary benefit greater than £750 compared with oral ibandronate, and greater than £2,500 compared with IV pamidronate or ibandronate.

Figure 4. Independent analysis indicates that zoledronic acid provides the greatest risk reduction in patients with breast cancer. SRE = Skeletal-related event. Adapted from Pavlakis N, et al. Bisphosphonates for breast cancer (review). Cochrane Database Syst Rev, Issue 4, 2005, Copyright Cochrane Collaboration, reproduced with permission (18).

Figure 4. Independent analysis indicates that zoledronic acid provides the greatest risk reduction in patients with breast cancer. SRE = Skeletal-related event. Adapted from Pavlakis N, et al. Bisphosphonates for breast cancer (review). Cochrane Database Syst Rev, Issue 4, 2005, Copyright Cochrane Collaboration, reproduced with permission (18).

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