Less Frequent Zoledronic Acid Dosing ‘May Be Acceptable’ In Patients With Bone Metastases

Treatment with the bisphosphonate zoledronic acid once every 12 weeks is noninferior to the standard schedule of once every 4 weeks

medwireNews: Zoledronic acid could be given every 12 weeks rather than every 4 weeks in patients with cancer that has metastasised to the bone, say US researchers who found that increasing the dosing interval did not raise the risk of skeletal-related events over a 2-year period.

They found that the 12-week schedule was noninferior to the standard 4-week schedule, and say that the “longer interval may be an acceptable treatment option” for patients with metastatic breast or prostate cancer or multiple myeloma who have at least one site of bone involvement.

During a 2-year period, 28.6% of the 884 individuals randomly assigned to receive zoledronic acid once every 12 weeks experienced at least one skeletal-related event, defined as a clinical fracture, spinal cord compression, radiation to the bone or surgery involving bone.

This was comparable to the 29.5% rate for their 882 counterparts who received the third-generation aminobisphosphonate once every 4 weeks. And the noninferiority criteria were met in both the intention-to-treat and sensitivity analyses.

The treatment groups were also comparable with respect to average pain scores at any timepoint, as assessed by the Brief Pain Inventory questionnaire, and the ECOG performance status scores during the course of the study.

The team led by Andrew Himelstein, from the Helen F Graham Cancer Center & Research Institute in Newark, Delaware, notes that the incidence of adverse events of interest – namely, osteonecrosis of the jaw and kidney dysfunction – also did not vary significantly between study arms, even though patients in the 12-week group received a lower cumulative dose of the drug.

As reported in JAMA, bone turnover was suppressed to a lesser degree in the 12-week than the 4-week group, as shown by higher levels of C-terminal telopeptide in the former group, but the investigators do not believe this difference to be “clinically significant” in light of the comparable primary and secondary outcomes.

They add that their findings have broad applicability as the study included not just individuals with breast or prostate cancer, but also those with multiple myeloma, and especially given the lack of a significant difference between dosing schedules within each tumour subgroup.


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. A randomized clinical trial. JAMA 2017; 317: 48–58, first published online 03 January doi:10.1001/jama.2016.19425

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