Zoledronic acid in treating bone metastases

Zoledronic acid has been shown in clinical trials to be a highly efficacious bisphosphonate that significantly reduces skeletal complications across all tumour and lesion types.

Bone metastases are common in cancers, with myeloma, breast cancer and prostate cancer being the malignancies most commonly associated with bone involvement. As one of the treatment modalities of metastatic bone disease, bisphosphonates have been used with the goal of treating hypercalcaemia, treating bone metastases, preventing skeletal-related events and potentially achieving anti-tumour effect.Bisphosphonates act by inhibiting osteoclast formation and migration and thereby osteolytic activity, as well as causing osteoclast apoptosis. Zoledronic acid is a highly potent third generation bisphosphonate approved in more than 80 countries. It is indicated in the treatment of hypercalcaemia of malignancy and bone lesions or metastases from multiple myeloma, breast cancer, prostate cancer, lung cancer and other solid tumours. It is on the grounds of clinical trial evidence that zoledronic is said to be a potent bisphosphonate in reducing skeletal-related events of bone metastases. The United States Food and Drug Administration (FDA) accepts composite endpoints based on skeletal related events (SREs) to evaluate bisphosphonate benefit, SREs being defined as radiation to bone for bone pain or to treat or prevent pathologic fractures or spinal cord compression, pathologic fracture, spinal cord compression, and surgery to bone. In Coleman’s review of metastatic bone disease, zoledronic acid was reported to be the most potent bisphosphonate as determined by in vitro and in vivo animal models.¹ While pamidronate, ibandronate and clodronate have been compared with placebo and only pamidronate showed superiority versus placebo in all endpoints, zoledronic acid is the only bisphosphonate that has been compared with pamidronate, and the results were promising. “Long-term follow-up data confirmed that zoledronic acid was more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast carcinoma,” Rosen et al. reported in their randomised multicentre trial of 24 months involving 1648 patients.²An additional 20% risk reduction was achieved by zoledronic acid compared to pamidronate in patients with breast carcinoma. Also concluded in the same study was that zoledronic acid was of similar efficacy with pamidronate in patients with multiple myeloma. When it comes to prostate cancer, treatment of bone metastases with 1st and 2nd generation bisphosphonates has only achieved transient palliation of bone pain but no objective clinical benefits. Clodronate and pamidronate have not shown any significant difference when compared to placebo in reducing symptomatic bone progression or SREs. Zoledronic acid, on the other hand, produced a 22% relative reduction of SREs compared to placebo in prostate cancer patients, as reported by Saad et al.³ Consistent reduction was shown across all types of SREs. The time to first SRE was extended by 5 months with the use of zoledronic acid. In terms of pain control, zoledronic acid has also done well by producing consistently lower pain scores. For patients with renal cell carcinoma, non-small cell lung carcinoma, and other solid tumours, zoledronic acid, too, has been proven effective in delaying the onset of SREs. This further proves the efficacy of zoledronic acid in reducing skeletal complications across a wide range of tumour types. References:[1] Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001; 27: 165–76.[2] Rosen LS et al. Cancer 2003; 98: 1735-44. [3] Saad F et al. J Natl Cancer Inst 2004; 96(11): 879-82.