Longer Dosing Interval of Zoledronic Acid May Be Acceptable for Bone Metastases

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The optimal dosing interval for zoledronic acid remains uncertain.
The optimal dosing interval for zoledronic acid remains uncertain.

The use of zoledronic acid every 12 weeks, as opposed to the standard 4-week interval, did not increase the risk of skeletal events over 2 years among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, a study published in JAMA has shown.1

Zoledronic acid is a third-generation aminobisphosphonate used to lower the incidence of skeletal-related events and pain in patients with metastases to the bone. Although it is approved to be administered every 3 to 4 weeks, the optimal dosing interval for zoledronic acid remains unclear.

Therefore, researchers designed a, multicenter, open-label, phase 3 trial (ClinicalTrials.gov Identifier: NCT00869206) to evaluate whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid given every 4 weeks.

For the study, researchers enrolled 1822 patients with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement. Participants were randomly assigned 1:1 to receive zoledronic acid intravenously every 4 weeks or 12 weeks for 2 years. 

Results showed that 29.5% of patients in the zoledronic acid every 4-week dosing group who completed the study and 28.6% of those in the every 12-week dosing group experienced at least 1 skeletal-related event, defined as a clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone, within 2 years of randomization.

The between-group absolute difference in risk of skeletal-related events was −0.3% (95% CI, −4 to ∞), below the 7% predefined noninferiority margin threshold (P <.001 for noninferiority).

Researchers also found no significant difference in the proportions of skeletal-related events between the 2 groups 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 every 4-week dosing group and the every 12-week dosing group.

Although the study demonstrated identical rates of skeletal morbidity between the 2 treatment arms, bone turnover was greater among those given the bisphosphonate every 12 weeks.

The findings ultimately suggest that among patients with breast cancer, prostate cancer, or multiple myeloma with bone involvement, zoledronic acid administered every 12 weeks may be an acceptable treatment option that could potentially reduce health care costs without negatively impacting efficacy or quality of life.


1. Himelstein AL, Foster JC, Khatcheressian JL, et al. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases. JAMA. 2017;317(1):48-58.
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