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Zoledronic acid more cost-effective than denosumab for bone metastases

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October 30, 2017

Charles L. Shapiro

Administering generic zoledronic acid every 3 months appeared more cost-effective than monthly denosumab in reducing the risk for skeletal-related events among women with breast cancer and bone metastases, according to a study published in Journal of Clinical Oncology.

“The trend now is to consider the value of care — what a patient gains from a drug vs. what it costs,” Charles L. Shapiro, MD, FASCO, professor of medicine at Icahn School of Medicine and a HemOnc Today Editorial Board Member, told HemOnc Today. “From a payer’s point of view, denosumab [Xgeva/Prolia, Amgen] is more expensive and I’m not convinced it’s so superior.”

Skeletal metastases occur in up to 75% of women with metastatic breast cancer and cause morbidity, including pain, pathologic fracture, spinal cord compression and hypercalcemia.

When given monthly, zoledronic acid — a third-generation amino-bisphosphonate that became available as a generic drug in 2013 — reduces the risk for pain and skeletal related events by up to 40%. Denosumab — a human monoclonal antibody that inhibits osteoclasts by binding to receptor activator of nuclear factor kappa-B ligand — delays the onset of first and subsequent skeletal related events.

Both drugs can cause osteonecrosis of the jaw and hypocalcemia. Zoledronic acid can cause renal toxicity depending upon dose and duration of infusion, among other factors.

In an analysis from the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology 70604 trial —published in January in JAMA — Himelstein and colleagues reported that zoledronic acid administered every 3 months appeared noninferior to monthly doses. That study included 833 women with breast cancer, 674 men with prostate cancer and 270 patients with myeloma.

“We know zoledronic acid can be taken every 3 months because it stays in the bone,” Shapiro said. “Its half-life is years, but denosumab’s half-life is 25 days. There have been retrospective studies that say giving denosumab every 2 or 3 months is not as good as every month.”

Shapiro and colleagues used a Markov model to compare the cost-effectiveness of 4 mg IV zoledronic acid monthly, 4 mg IV zoledronic acid every 3 months and 120 mg subcutaneous denosumab monthly for women with breast cancer and skeletal metastases.

Researchers defined the average cost of a treatment strategy as the average of the drug cost, its administration cost and the cost associated with having a skeletal-related event. Costs per skeletal-related event included costs of bone surgery, fracture and spinal cord compression.


Based on CMS reimbursement data, the average cost of zoledronic acid — including IV administration — is $140 per dose and $74 for administration. Subcutaneous denosumab costs $1,828 per dose and $78 for administration.

Base-case results showed mean costs of monthly denosumab treatments ($57,200) appeared more than nine times higher than zoledronic acid every 3 months ($5,667) or every month ($9,290). This analysis also showed the mean number of skeletal-related events was 0.22 with zoledronic acid every 3 months, 0.23 with monthly zoledronic acid, and 0.8 with denosumab.

Average quality-adjusted life years appeared virtually identical for all three treatments (year 1; monthly zoledronic, 0.9; every 3 months zoledronic acid, 0.91; denosumab, 0.88).

Researchers performed sensitivity analyses with denosumab skeletal-related event probabilities assumed to be 50%, 75% and 90% lower than probabilities for zoledronic acid.

These analyses showed that, relative to zoledronic acid every month, the incremental costs per mean skeletal-related event avoided for denosumab ranged from $162,918 to $283,109. When compared with zoledronic acid taken every 3 months, the mean incremental costs per mean skeletal related event avoided for denosumab ranged from $162,918 to $347,655.

“Our study is free of pharma bias and, any way you slice the pie, denosumab is about ninefold more expensive than zoledronic acid,” Shapiro said. “Even if denosumab reduced skeletal events by 90%, it still would not be as cost effective as zoledronic acid.”

Limitations of the study included a lack of patients’ preference for subcutaneous or IV injections, a short timeline of 2 years, and a lack of differentiation between a vertebral and nonvertebral (hip) fracture. Costs of osteonecrosis and atypical femoral fractures also were not considered, researchers noted.

With an increased emphasis on value-based care, Shapiro said he expects to see more studies that assess alternative dosing schedules, thus reducing the costs of cancer care.

“Right now, it’s empiric,” Shapiro said. “Drug companies just decide on dosing schedules and we need more studies like this that show there can be substantial cost savings. I think we’ve been reluctant to confront this issue about how these very expensive drugs have marginal benefit.

“As it stands now, every drug is available to every patient, no matter how much it costs,” Shapiro added. “That’s our system, but we can’t sustain that system because new generations of drugs are very expensive. We really have to think of the value we’re getting compared [with] what we’re paying.” – by Chuck Gormley


Himelstein AL, et al. JAMA. 2017;doi:10.1001/jama.2016.19425.

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Charles L. Shapiro, MD, FASCO, can be reached at

Disclosures: NCI funded this study. Shapiro reports no relative financial disclosures. One author reports research funding from HalioDx.