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Bisphosphonate Safety Evaluation Shows General Safety: Presented at IBCEF

By Chris Berrie

VIENNA, AUSTRIA -- February 21, 2006 -- While oral ibandronate (Bondronat(R)) provides decreased incidence of skeletal-related effects, rapid and sustained relief from metastatic bone pain, and improved mobility and function for patients with metastatic breast cancer, there is still the need to carefully monitor the safety profile of ibandronate and the other bisphosphonates.

These findings, from an overview by Ingo Diel, MD, Professor of Medicine, CGG-Klinik GmbH, Mannheim, Germany, were presented here on February 11^th at the International Breast Cancer Expert Forum: Milestones in Management, Confidence and Care (IBCEF).

Dr. Diel stressed the need to ensure optimal tolerability of bisphosphonate therapy in the palliative setting while monitoring for the common adverse effects, such as infusion-related events (acute phase reaction), renal toxicity/deterioration, gastrointestinal effects (gastritis, diarrhoea) and osteonecrosis of the jaw (ONJ).

Although it is known that oral ibandronate is at least as effective as zoledronic acid, he said, it is important to compare their safety profiles.

He discussed the findings of a multicentre, open-label, 12-week bone-marker study of patients with breast cancer. The results of this study showed a slightly improved safety profile for oral ibandronate 50 mg/day (n = 137) over intravenous zoledronic acid 4 mg in 15-minute infusions every 4 weeks (n = 137), in terms of any adverse events (65% vs. 76%, respectively), serious adverse events (6% vs. 8%) and treatment-related adverse events (22% vs. 51%).

For the aminobisphosphonates, Dr. Diel said the acute-phase reactions generally relate to interleukin-mediated pyrexia with bone and/or joint pain and leucocytosis, and flu-like symptoms that typically occur about 10 hours after the first infusion and last for 1 to 2 days. However, he noted that the same bone-marker study of breast cancer or multiple myeloma showed that the pyrexia and flu-like symptoms are not a concern when using intravenous ibandronate.

Similarly, the potential gastrointestinal effects of oral ibandronate have been shown to be manageable. Patients who continued oral ibandronate for 2 years beyond this study (for a total drug exposure of 4 years) had no treatment-related adverse events that were serious or led to withdrawal, and the adverse effects in these patients were similar manageable compared to those seen during the main study.

Dr. Diel then stressed that ONJ is a rare but serious adverse effect of the aminobisphosphonates, the clinical aspect of which typically involves exposure of the bone of the maxilla and spontaneous loss of teeth after chronic peridontitis and long-term use of the bisphosphonates.

While ONJ is being monitored with ibandronate use, Dr. Diel said he believes there are still too few reports to be able to draw any fixed conclusions, with around 680,000 patients having been treated with ibandronate since 1996, and only 11 reports of ONJ.

Another concern with bisphosphonate agents is renal toxicity, although as the renal toxicity profiles differ between the bisphosphonates, these effects need to be assessed individually, he said. It is important not to overload the kidney mechanisms for bisphosphonate excretion, otherwise they can accumulate in and damage the kidney tubular cells, he explained.

For ibandronate, it has been shown that for its standard dosing, it is well tolerated with few renal adverse events. In the above extension of oral ibandronate use to 4 years, no renal adverse events or serum creatinine changes of clinical relevance were seen. Similarly, the use of an ibandronate loading dose does not have any additional tolerability concerns or effects on serum creatinine as compared with the standard dosing.

On the basis that reduced infusion times of ibandronate loading have not shown effects on renal function, Dr. Diel indicated an ongoing phase 2 comparative study of a 60-minutes infusion (n = 25) and a 15-minute infusion (n = 105), with the primary endpoint of serum creatinine levels. Although the results are yet to be released, it is expected that this study will confirm the safety of a 15-minutes infusion seen in clinical practice.

From the trial data available to date for patients with metastatic bone disease, the safety profile of ibandronate appears to be manageable, and does not specifically include renal adverse events, thus allowing the initial intravenous loading of ibandronate in a rapid 15-minutes infusion. This provides reduced hospital visits and risk of bisphosphonate or chemotherapy discontinuation, while minimising the interactions with concomitant medications that have renal elimination or toxicity.

The conference was sponsored by Roche.


[Study title: Bisphosphonate Safety Matters.]

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