Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial

Abstract

Importance: Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain.

Objective: To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks.

Design, setting, participants: Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014.

Interventions: Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years.

Main outcomes and measures: The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels).

Results: Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks.

Conclusions and relevance: Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option.

Trial registration: clinicaltrials.gov Identifier: NCT00869206.

Figure 1. Flow Diagram of Progress Through Phases of a Randomized Trial Comparing Standard Dosing vs Longer Dosing of Zoledronic Acid Among Patients with Metastatic Cancer

^aData on the number of patients screened for the study and excluded prior to enrollment were not collected. ^bSkeletal-related event forms detailing if and when a clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone had occurred were collected every 4 weeks for all patients.

Figure 2. Cause-Specific Cumulative Incidence of Skeletal-Related Events

There were 256 patients with skeletal-related events in the zoledronic acid every 4-week dose group and 246 patients in the every 12-week dose group (hazard ratio, 0.96 [95%CI, 0.81–1.15]). The median follow-up was 15.7 months (interquartile range, 6.4–24.1 months) in the zoledronic acid every 4-week dose group and 16.8 months (interquartile range, 6.4–24.0 months) in the every 12-week dose group. There were 122 patients who died in the zoledronic acid every 4-week dose group and 118 in the every 12-week dose group.

Figure 3. Mean C-Telopeptide Levels by Treatment Group at Each Week

Error bars indicate 95%confidence intervals.