Bisphosphonates in Oncology
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- Body, JJ. Am J Cancer (2005) 4: 293. doi:10.2165/00024669-200504050-00002
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Pamidronate (pamidronic acid) is an aminobisphosphonate that interferes with the mevalonate pathway inducing osteoclast-apoptotic cell death. A 90mg dose of pamidronate administered in a 2- to 24-hour infusion achieves normocalcemia in >90% of unselected patients. Zoledronate (zoledronic acid) is more effective than pamidronate in normalising calcium levels in patients with tumor-induced hypercalcemia, at least in patients without bone metastases; however, zoledronate should be used with caution in patients with renal insufficiency. Pamidronate can be safely administered in hypercalcemic patients with renal insufficiency. Clinically meaningful bone pain relief occurs in about half of patients treated with pamidronate.
Pamidronate also achieved significantly better pain control than placebo in patients with breast cancer (bone metastases) or myeloma, in 2-year placebo-controlled trials. Pamidronate 90mg administered over 2 hours every 3–4 weeks for 2 years has been shown to reduce the frequency of skeletal-related events in patients with bone metastases from breast cancer by up to 40% and in patients with multiple myeloma by nearly 50%. In the largest randomized double-blind trial that compared zoledronate 4 or 8mg with pamidronate 90mg every 3–4 weeks in patients with breast cancer or myeloma, the primary efficacy endpoint (proportion of patients experiencing at least one skeletal-related event) was similar in all three treatment groups. The 8mg dose of zoledronate had to be lowered to 4mg during the trial because of renal toxicity. Indeed, concern about the renal toxicity of zoledronate has led authorities to recommend controlling serum creatinine levels before each infusion. When the data were analyzed by a complex multiple-event analysis, the hazard ratio for developing a bone complication was reduced by about 16% in patients treated with zoledronate compared with pamidronate after 2 years of therapy. This superiority of zoledronate was observed in the breast cancer subgroup but not in myeloma patients. However, multiple-event analyses rely on assumptions that are not unanimously accepted. The short duration of zoledronate infusion (15 minutes compared with 1.5–2 hours for pamidronate) is its most evident advantage, but cost savings have not been confirmed so far in limited micro-costing analyses.
Positive effects of pamidronate therapy on bone mass have been shown in patients with prostate cancer who are undergoing androgen-blockade therapy; antineoplastic therapy-induced bone loss was prevented. Studies with bisphosphonates are ongoing in breast cancer patients receiving aromatase inhibitors for the prevention of cancer treatment-induced bone loss. Zoledronate appears to be more potent than pamidronate for the prevention of endocrine therapy-induced bone loss.