Clodronate

Studies investigating the efficacy of oral clodronate (1,600mg/day) in patients with bone metastases from breast cancer have demonstrated significant clinical benefits compared with placebo or controls.^12,13 However,these studies are several years old, and patient populations and chemotherapeutic regimens have since changed, making comparisons to newer bisphosphonates difficult. In a study involving 173 patients, treatment with clodronate for 18 months significantly reduced the incidence of all skeletal events, as well as the incidence of vertebral fractures and the rate of vertebral deformity, compared with placebo (p<0.025).¹² However, the efficacy of oral clodronate was complicated by a lack of compliance during this trial. Of the 78% of complianceevaluable patients, 26% were completely non-compliant with the oral regimen. Similarly, in a randomized, openlabel trial involving 100 patients being treated with chemotherapy or endocrine therapy, treatment with concomitant clodronate for two years significantly prolonged the time to first skeletal event (p=0.015) and reduced the incidence of fractures (p=0.023) compared with patients who did not receive clodronate.¹³ However, the efficacy of clodronate was transient; after 15 months, the need for radiotherapy to treat bone pain increased in the clodronate group compared with the control group. Recent studies have also investigated the efficacy of oral clodronate for the prevention of bone metastases in patients with breast cancer.Although the study reported by Powles et al.²⁰ demonstrated positive results, this outcome has not been confirmed by other trials that did not show any clinical benefit of oral clodronate for this indication.^21,22

Pamidronate

Since the mid 1990s, IV pamidronate (90mg via twohour infusion) has been the standard of care for breast cancer patients with bone metastases. Pamidronate became the gold standard on the basis of evidence from two long-term, randomized, placebo-controlled trials that demonstrated that this agent significantly reduced the incidence and delayed the onset of skeletal-related events (SREs).^3,23,24 These studies defined an SRE as a pathologic fracture, spinal cord compression, or radiation or surgery to bone. Hypercalcemia was also included as an SRE for some assessments. In these trials, bone pain was also measured quantitatively using a scoring system that assessed both the severity and frequency of bone pain.

A pooled analysis of these two trials demonstrated that treatment with pamidronate resulted in statistically significant reductions in all types of skeletal complications and bone pain compared with placebo.³ In these trials, 751 patients were treated with pamidronate (90mg) or placebo every three to four weeks. After 24 months of therapy, pamidronate significantly reduced the percentage of patients who experienced at least one SRE excluding hypercalcemia (51% versus 64% for placebo; p<0.001; see Figure 2)^3,6,9 and the annual incidence of SREs (2.4 versus 3.7 SREs/year for placebo; p<0.001), and significantly delayed the median time to the first SRE by more than five months (12.7 versus seven months for placebo; p<0.001). At 24 months, pamidronate also significantly reduced mean pain scores (p=0.015 versus placebo) and analgesic scores (p<0.001 versus placebo) from baseline compared with increases from baseline in the placebo group.Moreover, these trials validated the composite SRE end-point and set a new standard for clinical evaluation of bisphosphonates for the treatment of malignant bone disease.

Ibandronate

Recently, IV ibandronate was approved in Europe for the treatment of bone metastases in patients with breast cancer, on the basis of a randomized trial comparing IV ibandronate (2mg or 6mg) with placebo.¹¹ This study defined bone events as vertebral fractures, pathologic non-vertebral fractures, and radiation or surgery to bone. In this trial involving 466 patients, IV ibandronate (6mg via one- to two-hour infusion) every three to four weeks for up to 96 weeks significantly reduced the skeletal morbidity period rate (SMPR)—defined as the number of 12-week periods with a new bone event divided by number of periods on study—compared with placebo (p=0.004) and significantly delayed the median time to first bone event (50.6 versus 33.1 weeks for placebo; p=0.018).¹¹ In contrast, the 2mg bolus IV dose was not effective. In addition, at last evaluation, IV ibandronate (6mg) significantly reduced mean pain scores (assessed on a 5-point scale) from baseline compared with increased pain scores in both the 2mg ibandronate and placebo groups (p<0.001 versus placebo).²⁵