Bisphosphonates in metastatic breast cancer

Bone is the most common site of metastatic involvement in breast cancer. About 20-30% of patients with breast cancer have osseous metastases as the first site of metastatic disease and about 60-70% of patients will develop metastases to the bone during the course of their disease. Although bone metastases have usually only limited impact on overall survival, they cause significant morbidity due to pain, pathological fractures, hypercalcemic episodes or spinal cord compression. Bisphosphonates are a class of agents that can effectively reduce the number and activity of osteoclasts and therefore reduce bone complications in breast cancer. Bisphosphonates are the current standard of care in patients with tumour-induced hypercalcemia (TIH) since they achieve rapid normalisation of serum calcium levels in the majority of patients. Zoledronic acid, a third generation bisphosphonate, has recently been shown to be significantly more effective than the previous standard, pamidronate, in the treatment of TIH. In patients with bone metastases, large randomised clinical trials have shown the efficacy of bisphosphonates in addition to hormone therapy or chemotherapy in reducing and delaying skeletal complications and associated pain and in improving quality of life. A clear positive impact on overall survival, however, has not been observed. The optimal duration of treatment is currently unclear. Therefore, treatment with bisphosphonate should be continued until evidence of substantial decline in patient's general performance status. Until recently, best results were obtained with intermittent intravenous therapy with aminobisphosphonates resulting in a risk reduction of developing skeletal complications of at least 13%. There is evidence for a dose effect with pamidronate resulting in higher efficacy at doses of 90 mg compared to 45 or 60 mg. New data indicate a potential benefit of zoledronic acid over pamidronate in patients with osteolytic metastases. Oral bisphosphonates can also effectively reduce the risk of skeletal events. Treatment with oral aminobisphosphonate pamidronate was limited by gastrointestinal toxicity, however, oral ibandronate has recently been shown to be tolerable and highly effective. These data might increase the role of oral bisphosphonates in the treatment of metastatic breast cancer. In patients without evidence of bone involvement, three randomised trials have failed to show a clear benefit for bisphosphonates. Thus, bisphosphonate treatment cannot be recommended in this setting outside clinical trials. In conclusion bisphosphonates (intravenous or oral) are an effective treatment in patients with advanced breast cancer and clinically evidence bone metastases. They can reduce skeletal events and improve quality of life and are therefore recommended in all patients with bone metastases.