Bone-Modifying Agents in Metastatic Breast Cancer: Time to De-escalate Dosing Intervals

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Julie R. Gralow, MD, FASCO

Julie R. Gralow, MD, FASCO

AS REVIEWED in this issue of The ASCO Post, ASCO and Cancer Care Ontario (CCO) have issued an updated guideline on the role of bone-modifying agents in metastatic breast cancer.1 The updated guideline supports a change in clinical practice for our patients with breast cancer and bone metastasis. After reviewing data from recently published phase III studies evaluating dosing intervals for zoledronic acid in patients with bone metastases, the ASCO/CCO update now includes the option of every-12-week dosing of zoledronic acid (4 mg over 15 minutes), in addition to the prior standard interval of every 3 to 4 weeks. 

Recent phase III noninferiority trials of zoledronic acid dosing intervals include two trials with patients who had received approximately 1 year of prior bisphosphonate therapy (both restricted to metastatic breast cancer) and one trial in patients with no prior bisphosphonate treatment for bone metastases (including patients with prostate cancer and multiple myeloma, as well as breast cancer). All three trials showed similar rates of skeletal complications whether zoledronic acid was dosed every 12 weeks or every 4 weeks, with at least trends seen in some studies for fewer serum creatinine elevations and lower rates of osteonecrosis of the jaw with the less-frequent dosing interval. 

Dr. Gralow is Professor of Breast Medical Oncology and Professor of Global Health at the University of Washington School of Medicine; Director of Breast Medical Oncology at Seattle Cancer Care Alliance; and Member of the Clinical Research Division at Fred Hutchinson Cancer Research Center, Seattle.

Key Comparisons Among Agents 

THE GUIDELINE continues to strongly support the initiation of bone-modifying agents in all patients with breast cancer and bone metastases but still does not recommend one bone-modifying agent over another. Pamidronate, zoledronic acid, and denosumab (Xgeva) continue to be recommended equally in this update, as they were in the 2011 guideline. 

Although the ASCO/CCO update supports dosing intervals of every 12 weeks and every 3 to 4 weeks for zoledronic acid, there is not an identifiable population of breast cancer patients with bone metastases who appear to be harmed by using the less-frequent dosing interval, either after prior exposure to bisphosphonates or in the first-line setting. Additionally, with ASCO/CCO support for longer dosing intervals of zoledronic acid and the availability of generic versions of the drug that have dropped the price considerably, it is hard to any longer imagine a role for pamidronate. The mandatory 2-hour infusion for pamidronate and lack of data supporting extended dosing intervals beyond every 3 to 4 weeks make this a less convenient and now more costly option. 

As for denosumab, there is no current evidence to support lengthening dosing intervals in metastatic patients. Based on differences in the mechanism of action, drug distribution, and half-life between bisphosphonates and RANK ligand inhibitors, one cannot extrapolate findings in the zoledronic acid trials to denosumab. The head-to-head comparison of denosumab and zoledronic acid in breast cancer patients with bone metastasis did show a longer time to first skeletal-related event with denosumab, although overall survival, progression-free survival, and adverse events were similar between the arms. 

In a cost analysis included in the ASCO/CCO guideline update, every-4-week denosumab is estimated to have an annual cost of more than 100 times that of every-12-week zoledronic acid (taking into account only drug pricing). A recently published non–industry-funded cost-effectiveness analysis took into account costs associated with the drug, drug administration, and treatment of a skeletal-related event; it concluded that every-3-month zoledronic acid was more cost-effective than denosumab (with a mean ninefold higher cost) and that quality-adjusted life-years were virtually identical.2 With several remaining years of patent protection for denosumab before biosimilars are expected to become available, denosumab prices are not expected to drop in the near future. There may be some patients for whom denosumab is a superior agent, including possibly those with the highest risk of skeletal-related events or those for whom the subcutaneous delivery route represents a major convenience, but for the average breast cancer patient with newly diagnosed bone metastases, it is hard to justify the considerably higher cost of denosumab. 

“When initiating and choosing between bone-modifying agents, discussion of expected benefits, toxicities, and costs, including out-of-pocket expenses and deductibles, are an important part of shared decision-making.”
— Julie R. Gralow, MD, FASCO

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The ASCO/CCO guideline update recommends sticking to the U.S. Food and Drug Administration–approved package insert dosing for denosumab (120 mg at 4-week intervals) at present, while we await the results of ongoing studies evaluating the extension of denosumab dosing intervals in patients with bone metastases. 

Additional Considerations 

THE UPDATED ASCO/CCO guideline on the role of bone-modifying agents in metastatic breast cancer emphasizes the importance of a comprehensive and multidisciplinary supportive care and pain management strategy. That said, these guidelines specifically do not address the treatment of hypercalcemia of malignancy with bone-modifying agents, and they are restricted to breast cancer. Evaluation of longer zoledronic acid dosing intervals for tumor types other than breast cancer was not within the scope of this update, although one of the trials leading to the change in the ASCO/CCO guideline included patients with prostate cancer and myeloma. 

We still have not determined the optimal duration of treatment with bone-modifying agents once initiated, and ASCO/CCO is maintaining a recommendation for “indefinite use” in the metastatic breast cancer population, although reiterating the importance of weighing potential benefits and harms of long-term therapy. Obtaining data on the long-term effects of bone-modifying agents is important, especially in our patients with metastatic breast cancer who have a long life expectancy. 

Can we stop bone-modifying agents when the cancer is quiescent and restart them at disease progression without causing harm? Is there a definable group, possibly those with very active bone disease, who still benefit from shorter dosing intervals? Is there a patient population for whom RANK ligand inhibition is preferred? How do we help those who continue to have skeletal-related events despite treatment with bone-modifying agents? We still have work to do to optimally support our patients with bone metastases. 

When initiating and choosing between bone-modifying agents, discussion of expected benefits, toxicities, and costs, including out-of-pocket expenses and deductibles, is an important part of shared decision-making. De-escalation of the zoledronic acid dosing interval to every 12 weeks should be considered a new standard of care—and should lead to decreased costs, fewer visits to the infusion room, and decreased toxicity for our patients with metastatic breast cancer. ■

DISCLOSURE: Dr. Gralow has served in a consulting or advisory role for Novartis, Genentech, Pfizer, Merck, Puma, Sandoz, and AstraZeneca. 


1. Van Poznak C, Somerfield MR, Barlow WE, et al: Role of bone-modifying agents in metastatic breast cancer: An American Society of Clinical Oncology–Cancer Care Ontario focused guideline update. J Clin Oncol 35:3978- 3986, 2017. 

2. Shapiro CL, Moriarty JP, Dusetzina S, et al: Cost-effectiveness analysis of monthly zoledronic acid, zoledronic acid every 3 months, and monthly denosumab in women with breast cancer and skeletal metastases: CALGB 70604 (Alliance). J Clin Oncol 35:3949-3955, 2017. 

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