Nick Mulcahy

December 13, 2012

SAN ANTONIO, Texas — Zoledronic acid (Zometa, Novartis) is effective at keeping skeletal-related events (SRE) at a low rate over the long term in women with breast cancer and bone metastases, according to 2 new studies — one from Belgium and the other from Japan.

However, both studies found that in women who had been on the drug for more than 2 years, the rate of osteonecrosis of the jaw (ONJ) ranged from 3.6% to 4.5%. In addition, the Belgian study, known as LOTUZ, found that the rate of ONJ rose to 11.1% after any invasive dental procedure.

These studies, which were presented as posters here at the 35th Annual San Antonio Breast Cancer Symposium, fill an information gap.

"Data on the effectiveness and safety of zoledronic acid beyond 2 years are scarce," write Tim Van den Wyngaert, MD, from the Antwerp University Hospital in Edegem Belgium, and his coauthors in their poster.

The prospective multicenter Belgian trial involved patients with metastatic bone disease from a solid tumor, including 108 women with breast cancer who were regularly treated with zoledronic acid and followed for 18 months.

In that study, 83.3% of the women were free of SREs during the 18-month study period. A total of 22 SREs occurred in 21 women.

Importantly, prior to enrollment, the 108 women had received at least 24 months of regular zoledronic acid therapy (infusion every 3 to 4 weeks); 21% had received at least 48 months of therapy.

In addition to SREs, the women were monitored for the safety measures of renal deterioration, hypocalcemia, and ONJ.

Renal deterioration occurred in 6 patients. The risk was numerically higher when the dose of zoledronic acid was not adjusted for renal function (hazard ratio [HR], 3.54; P = .14), as occurred in 11.5% of patients.

No symptomatic hypocalcemia was reported, even though adherence to supplemental calcium and vitamin D was only 15.9%.

ONJ developed in 7 patients (4.5%). Invasive dental procedures, such as oral surgery and tooth extraction, and dental trauma numerically increased ONJ risk (HR, 2.87; P = .3).

In the retrospective Japanese study, from investigators at the Tokai School of Medicine in Kanagawa, the frequency of ONJ was 3.6% (3 of 83 patients) in breast cancer patients with bone metastases who had been treated with zoledronic acid for at least 24 months (median, 33 months). This is higher than the 2.4% (5 of 209 patients) seen in similar patients who had been on the drug for shorter periods.

In other words, the rate of ONJ increased with a longer duration of therapy. The median time to ONJ was 1240 days, report Yasuhiro Suzuki, MD, and his colleagues.

As in the Belgian study, patients in the Japanese study were treated with zoledronic acid 4 mg as a 15-minute infusion every 3 to 4 weeks.

There were 36 SREs in 27 of the 83 Japanese patients who received zoledronic acid for at least 24 months.

There was also no hypocalcemia in the Japanese study. However, there were infusion reactions (6.7%), fatigue (2.6%), and creatinine increases (34.9%; 27% with stage G1 and 2% with stage G2) in the women treated with the bone drug for at least 24 months. "Prolonged treatment with zoledronic acid seems to be well tolerated," they conclude.

However, the Belgian team conclude their poster with a note of concern.

"While low in frequency, ONJ remains an issue with long-term zoledronic acid treatment and warrants prevention strategies to avoid dental trauma and extractions," they write.

The Belgian LOTUZ trial was supported by Novartis. Dr. Van den Wyngaert reports receiving lecture fees from Novartis. Some of his coauthors are employees of Novartis. Dr. Suzuki has disclosed no relevant financial relationships.

35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstracts P3-13-01 and P3-13-02. Presented December 7, 2012.