Clodronate

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Abstract
Clodronate (clodronate disodium, Bonefos®) is a non-nitrogen-containing bisphosphonate that inhibits osteoclast activity, and thereby inhibits bone resorption. Clodronate has been extensively used in patients with advanced breast cancer, and is generally well tolerated. In patients with primary breast cancer, clodronate is currently the only bisphosphonate shown to improve survival rates and to reduce the incidence of bone metastases in randomised controlled trials. Further trials in patients with early breast cancer are warranted to confirm results to date and to determine the optimal duration of treatment, as well as the efficacy of the drug compared with other bisphosphonates. In the meantime, clodronate is a well established bisphosphonate which has shown beneficial effects in the prevention of bone metastases and on survival in patients with primary breast cancer. Clodronate is a non-nitrogen-containing bisphosphonate that inhibits bone resorption by impairing osteoclast activity, although the exact molecular mechanism by which it does this is not fully understood. Clodronate may also act directly on tumour cells. Oral clodronate is rapidly absorbed, with the maximum serum concentration (Cmax) reached within ≈30 minutes of a single dose. The mean absolute bioavailability of oral clodronate was ≈2%. The drug is mainly eliminated by the kidneys and ≈80% of the absorbed dose is excreted within 48 hours, the remainder is bound to bone and eliminated slowly over time. Following a single oral dose, the mean terminal half-life of clodronate was 14.7 hours. Absorption of oral clodronate is best under fasting conditions when breakfast is consumed 2 hours after administration of the drug. When clodronate was administered with breakfast or 2 hours after breakfast, the Cmax of, and systemic exposure to, the drug were significantly reduced. Primary Breast Cancer: The clinical efficacy of 2 or 3 years of treatment with oral clodronate in reducing the incidence of bone metastases in patients with primary breast cancer has been investigated in three randomised, controlled trials (one large [n >1000], double-blind, placebo-controlled trial and two smaller, open-label trials [n ≈300]). Oral clodronate 1600 mg/day for 2 years significantly reduced the development of bone metastases over a 2- to 5-year period, compared with placebo in the large study and with no treatment in one of the smaller trials. In the third trial, after follow-up of 5 and 10 years, the number of patients with bone metastases did not differ significantly between the clodronate and control groups; however, in this trial there was a significant between-group imbalance in baseline prognostic factors. The effect of 2 or 3 years of clodronate therapy on the development of visceral metastases in the short- or long-term varied across studies. Clodronate, compared with placebo or no additional treatment, had beneficial effects on survival at all timepoints (up to 10.5 years) in two of three trials. Notably, in the largest trial, clodronate also significantly improved survival in patients with stage II or III breast cancer. Five-year survival rates were significantly lower with clodronate than no additional treatment in the third trial; however, there was no significant between-group difference when these results were adjusted for a baseline imbalance in progesterone receptor status. Advanced Breast Cancer: In two trials in patients with metastatic breast cancer, clodronate significantly reduced the cumulative incidence of all skeletal events (including fractures, hypercalcaemia and the need for radiotherapy for bone pain) per 100 patient-years compared with placebo. In two other trials, clodronate significantly delayed the time to first skeletal event compared with placebo or no additional treatment (primary endpoint in one trial). Clodronate significantly reduced the incidence of fractures compared with no treatment in one trial, significantly reduced the rate of vertebral fractures per 100 patient-years (primary endpoint) versus placebo in another, and in a third trial, the severity score for vertebral fractures was significantly reduced by clodronate versus placebo. However, these effects were not observed consistently across all clinical trials. In patients who did not have bone metastases at baseline, clodronate significantly reduced the rate of bone metastases per 100 patient-years and the total number of bone metastases. However, in this trial and another trial, there were no significant between-group differences in the proportion of patients who developed new bone metastases. Clodronate had beneficial effects on hypercalcaemia or pain reduction in some studies; however, these effects have not been observed consistently. Oral clodronate is generally well tolerated, with gastrointestinal symptoms being the most commonly observed adverse events. In several randomised trials comparing clodronate with placebo in patients with advanced breast cancer, there were no significant between-group differences in the incidence of any adverse events. In a large randomised trial in patients with primary breast cancer, in which patients received clodronate or placebo (1600 mg/day) for 2 years, only gastrointestinal system disorders occurred more frequently in clodronate recipients after a median of 5.5 years. Diarrhoea was the only individual adverse event which occurred in significantly more clodronate recipients than placebo recipients. Based on the very limited data available, clodronate appears to be cost effective (compared with placebo) for prolonging survival in patients with primary operable breast cancer and cost neutral (compared with pamidronic acid) for the prevention of skeletal events in patients with metastatic breast cancer.

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