The Use of Bisphosphonates in Patients With Breast Cancer

Catherine H. Van Poznak, MD


Cancer Control. 2002;9(6) 

In This Article

Hypercalcemia of Malignancy

Hypercalcemia of malignancy is the most common metabolic complication of breast cancer. The bone destruction occurring in the osseous metastatic lesions can result in elevated serum calcium levels and the associated symptoms of hypercalcemia: fatigue, nausea, vomiting, dehydration, and mental status changes. Hypercalcemia of malignancy is also associated with an increase in renal tubular resorption and a decrease urinary calcium excretion that further increases the serum calcium level. The mechanism of hypercalcemia of malignancy involves production of tumoral parathyroid hormone-related protein (PTHrP) as well as bone-resorbing cytokines, vitamin D metabolites, and prostaglandins.[38] The key to long-term control of hypercalcemia of malignancy is to treat the underlying malignancy. In patients with moderate to severe hypercalcemia of malignancy, aggressive hydration, and anti-resorptive therapy with intravenous bisphosphonates are instrumental in regaining normocalcemia. The bisphosphonate reduces osteoclast activity, thereby decreasing the osteolytic process and the associated release of calcium from bone.

Two identical, concurrent, randomized, double-blind, parallel clinical trials were conducted to study hypercalcemia of malignancy in Europe and North America, and the results were pooled for analysis.[24] A total of 287 patients were enrolled to compare the efficacy and tolerability of a single dose of zoledronic acid, 4 or 8 mg, given as a 5-minute infusion vs a single 90-mg dose of pamidronate as a 2-hour infusion. The primary endpoint was complete response, defined as corrected serum calcium level <10.8 mg/dL by day 10, and the secondary endpoints included time to relapse and duration of complete response. Patients refractory to the initial treatment were eligible for a second phase of the trial and treatment with a single dose of 8 mg of zoledronic acid. Two hundred seventy-five patients were eligible for efficacy analysis. Patients treated with zoledronic acid had a significantly faster normalization of corrected serum calcium compared with the pamidronate group. The 4-mg zoledronic acid arm demonstrated a significantly longer therapeutic effect than the pamidronate arm, with a single dose of 4-mg zoledronic acid normalizing the corrected serum calcium level for 30 days vs 17 days for the 90-mg pamidronate arm. The complete response rate at day 10 was greater for the 4-mg zoledronic acid arm, with 88% of patients obtaining a complete response vs 70% of patients in the pamidronate group. Although the 8-mg zoledronic acid dosage appeared to be as effective as the 4-mg dose, the higher dosage is not recommended due to associated increased risk of renal toxicities. The 4-mg zoledronic acid dose demonstrated an improved efficacy over pamidronate in treating hypercalcemia of malignancy, has received FDA approval for hypercalcemia of malignancy, and may be considered as first-line therapy for this condition when intravenous bisphosphonates are indicated.


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