Less Frequent Dosing of Bisphosphonate in Patients With Bone Metastases

Bone metastases
Bone metastases
Less frequent dosing with zoledronic acid does not increase fracture risk in patients with bone metastases.

Less frequent dosing of the bisphosphonate zoledronic acid may not increase the risk for skeletal events in patients with cancer who have bone metastases, researchers reported in JAMA.

Although zoledronic acid administered intravenously (IV) decreases pain and skeletal-related events, bisphosphonates have been linked to toxic effects, including osteonecrosis of the jaw, toxicity of the kidneys, and abnormally low levels of calcium in the blood, the researchers wrote, noting that the optimal dosing interval for zoledronic acid has not been established.

In this study (Zoledronic Acid in Treating Patients With Metastatic Breast Cancer, Metastatic Prostate Cancer, or Multiple Myeloma With Bone Involvement; ClinicalTrials.gov identifier: NCT00869206), 1822 patients (median age: 65 years) with metastatic breast cancer (n = 855), metastatic prostate cancer (n = 689), or multiple myeloma (n = 278) and at least 1 site of bone involvement were randomly assigned to receive IV zoledronic acid every 4 weeks (n = 911) or every 12 weeks (n = 911) for 2 years.

The study’s primary end point was having at least 1 skeletal-related event, which was defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone. A total of 795 patients completed the study.

Within 2 years, 260 patients (29.5%) in the 4-week dosing group and 253 patients (28.6%) in the 12-week dosing group experienced at least 1 skeletal-related event (risk difference: –0.3%; 1-sided 95% CI, –4 to ∞; P <.001 for noninferiority). No significant difference was found in the percentage of skeletal-related events between groups.

Additionally, the researchers noted no significant differences in pain scores, performance status scores, incidence of osteonecrosis of the jaw, or kidney dysfunction between the 4-week dosing and the 12-week dosing groups.

Despite similar rates of skeletal morbidity between treatment groups, C-terminal telopeptide levels were higher in patients receiving zoledronic acid every 12 weeks vs every 4 weeks, indicating greater bone turnover in this treatment group.

“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,” the researchers concluded. “This longer interval may be an acceptable treatment option.”

Study Limitations

  • A higher-than-expected percentage of patients did not complete 2 years of treatment
  • The study’s open-label design
  • The assessment of noninferiority instead of superiority
  • Survival or risks and benefits of administering zoledronic acid for longer than 2 years were not addressed

Disclosures: Dr Qin reported owning stock in Regeneron, UnitedHealth Group, and Gilead Sciences. Dr O’Mara reported owning stock in Pfizer. 

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  1. Himelstein A, Foster JC, Khatcheressian JL, et al. Effect of longer- interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: a randomized clinical trial. JAMA. 2017;317(1):48-58. doi:10.1001/jama.2016.19425