Reducing Zoledronic Acid Frequency Did Not Raise Risk of Skeletal Events

Among cancer patients with bone metastases, administration of zoledronic acid every 12 weeks did not increase the risk of skeletal events over 2 years compared with the standard dosing of every 4 weeks, according to a new study.

“Zoledronic acid administered every 3 to 4 weeks reduces pain and the incidence of skeletal-related events, including clinical fracture, spinal cord compression, radiation to bone, and surgery to bone by 25% to 40%,” wrote study authors led by Andrew L. Himelstein, MD, of the Helen F. Graham Cancer Center & Research Institute in Newark, Delaware. That dosing schedule, though, was not based on comparative studies or “compelling pharmacodynamic data,” and thus the optimal dosing remained unknown.

The new study was a randomized, open-label trial conducted across 269 sites in the United States. A total of 1,822 patients were included, with metastatic breast cancer (855 patients), prostate cancer (689 patients), or multiple myeloma (278 patients); they received zoledronic acid intravenous infusion either every 4 weeks or every 12 weeks. Of those, 795 completed the study at 2 years; the results were published online ahead of print in JAMA.

In the 4-week group, 260 patients (29.5%) experienced at least one skeletal-related event within 2 years of randomization; in the 12-week group, 253 patients (28.6%) experienced at least one such event. The most common event was due to radiation to bone, followed by clinical fracture, spinal cord compression, and surgery involving bone.

A stratified test showed that the risk difference to bone between the two dosing schedules was –0.3% (P < .001 for noninferiority). A 2-year risk analysis showed the two doses were nearly identical; the odds ratio for the 12-week dose was 1.02 (95% CI, 0.84–1.24; P = .85 for superiority).

There were no differences between the schedules as well when the researchers divided the cohort by primary cancer type. Mean pain scores were also no different between the groups, including pain within the last 24 hours and other pain measures.

Nine patients in the 12-week group had osteonecrosis of the jaw, compared with 18 patients in the 4-week group (P = .08). Kidney dysfunction occurred in 4 patients in the 12-week group and 10 patients in the 4-week group (P = .10). Notably, treatment delays were less frequent in the 12-week group (63% had no such delays) than in the 4-week group (38% had no delays).

The researchers noted that the open-label design does limit the result, given the potential for biased reporting of skeletal-related events and toxic effects. Still, they wrote that “this longer interval may be an acceptable treatment option.”