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Clodronate

A Review of its Use in Breast Cancer

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Summary

Abstract

Like other members of its class, the bisphosphonate clodronate (clodronic acid) inhibits bone resorption. The efficacy of oral clodronate 1600 mg/day in reducing the incidence of skeletal complications and metastasis development has been assessed in several clinical trials in patients with breast cancer.

Long term use of oral clodronate significantly reduced the total cumulative incidence of skeletal events (including fractures, hypercalcaemia, and the need for radiotherapy for bone pain) compared with that in placebo recipients in 2 randomised double-blind placebo-controlled studies, each involving >100 patients. Significant differences in favour of clodronate were also seen in the frequency of some individual skeletal events in 1 trial.

A nonblind trial in 302 patients considered to be at high risk of developing metastases found that, at a 3-year follow-up, significantly fewer patients who received clodronate for 2 years developed skeletal metastases than those in a control group. Clodronate recipients were also significantly less likely than controls to develop visceral metastases, and had significantly higher survival rates. A smaller double-blind placebo-controlled study in women with recurrent breast cancer found that clodronate significantly decreased the total number of new skeletal metastases, but not the number of patients who developed them.

In a nonblind trial in 299 patients with node-positive breast cancer, however, the incidence of skeletal metastases did not differ significantly between patients who received clodronate for 3 years and those in a control group. In addition, clodronate recipients had a significantly greater incidence of nonskeletal metastases (local and visceral), and significantly lower survival rates.

Intravenous or oral clodronate has been well tolerated in clinical trials. The most common adverse effects reported were mild gastrointestinal disturbances such as nausea, vomiting and diarrhoea. All these events were transient, and usually resolved without stopping treatment.

Conclusions: Clodronate is a well tolerated bisphosphonate, available in both oral and intravenous forms, that significantly reduces the incidence of skeletal complications associated with breast cancer. Further research is needed to establish more clearly its efficacy in reducing metastasis development, to assess its efficacy compared with other bisphosphonates, and to determine which patients will benefit most from treatment. Currently, clodronate is probably most effective in the treatment and prevention of general skeletal complications in patients with breast cancer.

Pharmacodynamic Properties

Clodronate has a strong affinity for calcium phosphate, and can therefore bind to hydroxyapatite crystals in the bone matrix. In vitro and in vivo animal studies confirm that clodronate can inhibit bone resorption induced by a number of agents [including parathyroid hormone (PTH) and breast cancer cells] in a dose-dependent manner. Clodronate is thought to inhibit bone resorption by impairing osteoclast function and inducing osteoclast apoptosis, although further confirmation of the exact mechanism of action is required. Unlike etidronate, it does not appear to impair the mineralisation of bone.

In 3 randomised studies, oral clodronate 1600mg daily for 2 years significantly reduced the loss of bone mineral density (BMD) at the hip and lumbar spine in patients receiving systemic treatment with chemotherapy and/or antiestrogens. The effect was evident whether or not the women involved had experienced menopause. One of these analyses (a subgroup analysis from a larger trial) showed that the mean reduction from baseline BMD in the lumbar spine in 156 pre-, peri- and postmenopausal women who received clodronate was 0.16% after 2 years, compared with 1.88% in the 155 placebo recipients (p = 0.04).

Pharmacokinetics

Clodronate, like all bisphosphonates, is poorly absorbed from the gastrointestinal tract with a bioavailability of 1 to 2%. This is further reduced if clodronate is taken with food or calcium. Because plasma concentrations of clodronate are low after oral administration, most available pharmacokinetic data relate to parenteral administration.

In 6 women with breast cancer and skeletal metastases who received radioactively labelled intravenous clodronate 200mg, the area under the plasma concentration-time curve (AUC) was 35.1 mg/L • h, and the plasma elimination half-life (t½β) was 2.3 hours. The volume of distribution (Vd) averaged 16.3L at steady state (roughly equivalent to the volume of extracellular water). Average total plasma clearance was 6.4 L/h, with a renal clearance of 4.8 L/h. Clodronate was largely excreted unchanged by the kidney, with 75% of the dose being recovered from the urine over the 3 days following administration. 5% of the dose was recovered from faeces, and the remaining 20% retained in the body. These pharmacokinetic values were similar to those from studies in healthy volunteers.

Urinary excretion data from some studies indicated that the elimination of clodronate involved a terminal elimination phase with a mean half-life of 12.8 hours, consistent with a 3-compartment model. This phase is thought to be due to the delayed release of clodronate from bone.

In a study in patients with tumour-mediated bone disease (including breast cancer), total body clearance of intravenous clodronate 300mg was significantly lower in patients with marked renal impairment (creatinine clearance < 2.4 L/h) than in those with normal or moderately impaired renal function. The authors recommended reducing doses of clodronate during long term treatment in this group of patients. However, t½β was not significantly affected by renal impairment, and changes in dosage interval were not considered necessary.

Clinical Efficacy

Two randomised double-blind placebo-controlled studies (n = 133 and n = 173) in patients with breast cancer with or without pre-existing skeletal metastases have shown that, compared with placebo, long term use of oral clodronate 1600mg daily significantly reduced the total cumulative incidence of morbid skeletal events. Only 1 of the studies found that clodronate significantly reduced the frequencies of individual skeletal events.

In a randomised nonblind 2-year trial, oral clodronate significantly reduced the development of new skeletal metastases in 302 patients considered to be at high risk of such events. Of those who received clodronate 1600mg daily, 8% had developed bony metastases at a median follow-up of 3 years, in contrast to 17% of the control group (p = 0.003). Patients receiving clodronate were also significantly less likely than those in the control group to develop visceral metastases (8 vs 19%, p = 0.003).

In a double-blind placebo-controlled trial in 133 women with recurrent breast cancer, the total number of new skeletal metastases observed was significantly lower in patients who received oral clodronate 1600mg daily for 3 years (32 vs 63, p < 0.005), but the number of patients who developed skeletal metastases did not differ significantly between groups.

In contrast, a nonblind trial (reported in abstract form; n = 299) found no significant difference in incidence of skeletal metastases at a minimum 5-year follow-up between high risk (node-positive) breast cancer patients who received oral clodronate 1600mg daily for 3 years and those in a control group. In addition, patients receiving clodronate had a significantly higher incidence of nonskeletal (visceral and local) metastases (45 vs 27%, p = 0.001).

Results from a randomised double-blind trial in nonselected patients with breast cancer without pre-existing skeletal metastases tended towards significance; 5.2% of patients who received oral clodronate for 2 years developed skeletal metastases, compared with 8.1% of placebo recipients (p = 0.054). Analysis of a subgroup of postmenopausal women indicated that clodronate significantly reduced the percentage who developed skeletal metastases (3.3 vs 7.3% with placebo, p = 0.041).

Although fewer patients with pre-existing skeletal metastases who received clodronate developed new skeletal metastases, data from available studies are limited by small patient numbers and short treatment duration (≤9 months).

In a small randomised double-blind trial, intravenous clodronate 300mg daily for up to 7 days was significantly more effective than placebo in the acute treatment of tumour-induced hypercalcaemia (TIH); significantly more patients became normocalcaemic (ionised serum calcium level below 1.4 mmol/L) during clodronate treatment, and the time to normocalcaemia was also significantly less than with placebo. All patients also received 12 to 24 hours of intravenous rehydration.

Oral and intravenous clodronate may have some benefit in the acute treatment of pain resulting from skeletal metastases, although available data are limited. The effects of clodronate on survival have been inconsistent across studies.

Tolerability

Pooled data from clinical studies involving 1930 patients with a range of conditions indicate that clodronate (oral and intravenous) was generally well tolerated, with few serious adverse events. The most commonly reported adverse events were transient hypocalcaemia (3% of patients), gastrointestinal (GI) disturbance (1.8%), transient increase in serum creatinine levels (0.7%), transient increase in parathyroid hormone levels (0.6%), and acute renal failure (0.5%). Another review of studies involving 916 patients (some trials were covered in both reviews) found a greater incidence of GI disturbance (2 to 10%). Almost all of the GI disturbances reported were limited and resolved without suspending treatment, often after dividing or reducing the total daily dose. Prolonged treatment with clodronate had no adverse effects on laboratory parameters.

Three large randomised double-blind trials in patients with breast cancer found that the incidence of individual adverse events reported by patients receiving oral clodronate 1600mg daily for up to 3 years was not significantly different from that reported by placebo recipients. In a subgroup of 311 women with breast cancer enrolled in a large randomised double-blind trial, diarrhoea was reported by significantly more patients receiving clodronate 1600mg daily for 2 years than placebo recipients (17 vs 5%, respectively, p < 0.0001).

In a placebo-controlled study, 4 of 25 patients (16%) with skeletal metastases due to breast cancer developed hypocalcaemia (level not stated) during 7 days of treatment with intravenous clodronate 300mg daily for TIH. Another small study found that 13% of patients who received intravenous clodronate 300 to 1500 mg/day for ≤7 days reported GI adverse effects.

Dosage and Administration

Intravenous administration of clodronate is indicated in the treatment of TIH or for short term control of pain from skeletal metastases. Recommendations are to give clodronate 300mg daily as a slow infusion over at least 2 hours until plasma calcium normalises (usually after 2 to 5 days). Single doses of clodronate 1500mg, infused over 4 hours, have been used successfully in 1 study.

The recommended standard dose of oral clodronate is 1600mg daily (maximum 3200 mg/day). While this is a once daily dose, patients experiencing adverse GI effects may prefer to receive 2 divided doses. Although duration of therapy has varied, most studies showing benefits in patients with breast cancer lasted for at least 2 years.

The oral absorption of clodronate is impaired by coadministration with food or calcium. Current recommendations are to take clodronate at least 1 hour before or 2 hours after a meal and not with milk products or calcium supplements.

Current recommendations are to reduce the dose by half in patients with marked renal impairment. Clodronate is contraindicated in patients with severe renal impairment.

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    Miriam Hurst & Stuart Noble

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Hurst, M., Noble, S. Clodronate. Drugs Aging 15, 143–167 (1999). https://doi.org/10.2165/00002512-199915020-00007

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