Less Frequent Zoledronic Acid Not Linked to Increased Skeletal Events for Patients With Bone Metastases

January 8, 2017

Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, those who used zoledronic acid every 12 weeks, compared with the standard dosing interval of every 4 weeks, did not experience an increased risk of skeletal-related events over 2 years.

Andrew L. Himelstein, MD

“The findings are significant for a couple of reasons,” explained study author Andrew L. Himelstein, MD, a hematologist/oncologist, specializing in hospice and palliative medicine at Christiana Care Health System, in an interview with OncLive. “Our patients would not have to spend as much time at their hematologist's or oncologist's office. They would require fewer IV infusions to get the same benefit from the medication. Also, there would be lower costs with fewer infusions and fewer visits without any loss of effectiveness.”

Zoledronic acid is a third-generation aminobisphosphonate that reduces the incidence of SREs and pain in patients with bone metastases. However, the optimal dosing interval for zoledronic acid is still uncertain.

To evaluate what frequency of zoledronic acid administration works best for patients, this randomized study compared the 4-week standard regimen with a less frequent 12-week one. Adjusted for calculated creatinine clearance using each patient’s body weight, the dosing given to patients every 12 weeks was no different than if they were treated with the drug every 4 weeks.

Patients with metastatic breast cancer (n = 855), metastatic prostate cancer (n = 689), or multiple myeloma (n = 278) who had at least 1 site of bone involvement were eligible for the study, and the median age was 65 years. These 1822 participants were evenly randomized to intravenous zoledronic acid every 4 weeks or every 12 weeks over a 2-year period.

The study’s primary endpoint was to determine superiority of the less frequent regiment by evaluating the proportion of patients who experienced at least 1 SRE, defined as a clinical fracture, spinal cord compression, radiation to the bone, or surgery involving bone.

Researchers also looked at the following: how many patients experienced at least 1 SRE event by disease type, pain levels using the Brief Pain Inventory 1-10 rating scale; Eastern Cooperative Oncology Group performance status; incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (average number of SREs per year) and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels).

By the end of the study, 795 patients had completed the 2 years required for evaluation. Of those participants, 260 patients (29.5%) in the zoledronic acid every 4-weeks dosing group and 253 patients (28.6%) in the every 12-weeks dosing group experienced at least 1 SRE, and thus the results did not differ greatly between the groups.

Additionally, there were no significant differences between the groups in pain or performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction. Skeletal morbidity rates were the same in both groups; however, based on their higher C-terminal telopeptide levels, bone turnover was increased in patients on the every12 weeks-regimen.

According to Himelstein, it is currently up to the clinician whether they will recommend zoledronic acid dosing at every 12 weeks to their patients. Since this study only included patients with metastatic breast or prostate cancer or multiple myeloma, it is at the clinician’s discretion to recommend the approach to patients with other types of cancer.

As of now, there is no plan for further research on zoledronic acid dosing. “We have to see where things go with denosumab, which is an alternative way of increasing bone strength and reducing fracture risk,” Himelstein said.

“We are in the process of doing a cost-effectiveness analysis looking at denosumab versus zoledronic acid. We also are in the process of doing some genetic analyses to see if there are specific genetic characteristics that make patients more or less likely to benefit from the medication.”

He added that, “Denosumab appears to be slightly more effective than zoledronic acid. It's also a lot more expensive. At the time, dosing requires monthly visits to the doctor with injections under the skin. At some point, future research could look at less frequent zoledronic acid directly compared to denosumab.”

Himelstein AL, Foster JC, Khatcheressian L, 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.