Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies

Abstract

Although intravenous (i.v.) bisphosphonates are the standard of care for metastatic bone disease, they are less than ideal for many patients due to infusion-related adverse events (AEs), an increased risk of renal toxicity and the inconvenience of regular hospital visits. The use of oral bisphosphonate therapy is limited by concerns over efficacy and gastrointestinal (GI) side effects. There remains a clinical need for an oral bisphosphonate that offers equivalent efficacy to i.v. bisphosphonates, good tolerability and dosing convenience. Oral ibandronate, a highly potent, third-generation aminobisphosphonate, has been evaluated in phase III clinical trials of patients with bone metastases from breast cancer. In two pooled phase III studies, patients with breast cancer and bone metastases were randomised to receive oral ibandronate 50 mg (n ¼ 287) or placebo (n ¼ 277) once daily for up to 96 weeks. The primary end point was the skeletal morbidity period rate (SMPR), defined as the number of 12-week periods with new skeletal complications. Multivariate Poisson's regression analysis was used to assess the relative risk of skeletal-related events in each treatment group during the study period. Oral ibandronate 50 mg significantly reduced the mean SMPR compared with placebo (0.95 vs 1.18, P ¼ 0.004). There was a significant reduction in the mean number of events requiring radiotherapy (0.73 vs 0.98, Po0.001) and events requiring surgery (0.47 vs 0.53, P ¼ 0.037). Poisson's regression analysis confirmed that oral ibandronate significantly reduced the risk of a skeletal event compared with placebo (hazard ratio 0.62, 95% CI ¼ 0.48, 0.79; P ¼ 0.0001). The incidence of mild treatment-related upper GI AEs was slightly higher in the oral ibandronate 50 mg group compared with placebo, but very few serious drug-related AEs were reported. Oral ibandronate 50 mg is an effective, well-tolerated and convenient treatment for the prevention of skeletal complications of metastatic bone disease.

Safety of Intravenous and Oral Bisphosphonates and Compliance With Dosing Regimens

“…In the study cited above in 173 patients with breast cancer, 34% of patients in the clodronate group Data from Body et al [44]. [49].…”

“…Notably, one patient treated with the 20-mg ibandronate dose developed radiographically confirmed esophageal ulceration. Similarly, in a pooled analysis of two recent trials of oral ibandronate (50 mg/day for up to 96 weeks) in breast cancer patients with bone metastases (n = 564), 10% of patients receiving ibandronate withdrew from the study because of adverse events [44].…”

Medical Treatment of Breast Cancer Bone Metastasis: From Bisphosphonates to Targeted Drugs

“…In a pooled analysis of two randomized, placebo controlled studies, 50mg oral ibandronate daily reduced the risk of a SRE compared with placebo (HR 0.62, 95%CI:0.48, 0.79; p=0.0001). Need for radiotherapy (0.73 vs 0.98, p<0.001) and surgery (0.47 vs 0.53, p=0.037) was significantly less in ibandronate group and it was well tolerated except slight upper gastrointestinal adverse effects (Body et al, 2004). (Table 2.)…”

“…If renal function deterioration is encountered during therapy, drug should be withheld until renal function returns to within 10 percent baseline (Van Poznak et al, 2011). In ibandronate studies, intravenous and oral, renal adverse effects of treatment were similar with placebo and no one experienced renal failure (Body et al, 2003, Body et al, 2004. Denosumab is mostly cleared through the reticuloendothelial system.…”

The molecular mechanisms of breast cancer metastasis

“…At present, in the case of increased risk for bone metastasis, bisphosphonates are proved to be effective. They prevent or delay metastasis formation (Body et al, 2004). Bisphosphonates selectively attach to bone and trigger osteoblast apoptosis.…”