An increasing amount of clinical evidence confirms the value of bisphosphonates in metastatic bone disease.

Long-term studies have shown that bisphosphonates can reduce skeletal morbidity, pain and improve the quality of life in patients with multiple myeloma and bone metastases due to breast cancer. With metastatic prostate cancer, short-term studies have demonstrated improved symptoms with oral etidronate, clodronate and intravenous pamidronate. Pamidronate has been shown to prevent androgen deprivation-related osteoporosis in patients with locally-advanced but pre-metastatic prostate cancer as shown by changes in BMD after 48 weeks of leuprolide treatment. Currently though, there is no long term evidence demonstrating that clodronate or pamidronate can prevent  skeletal complications or improve survival. Currently, the outcome is awaited for two large, placebo-controlled studies investigating the value of initiating long term clodronate therapy in patients with prostate cancer to prevent

• Skeletal complications in patients commencing hormone therapy because of bone metastases, and
• Progression to bone metastatic disease in patients with only localized tumours

Trials

Several clinical trials have been reported using the relatively low potency oral bisphosphonate, clodronate. In the largest study, 1,079 women with primary operable breast cancer were randomized to either clodronate 1600mg daily or placebo for two years in addition to standard adjuvant systemic treatment. Recent data presented with a median follow-up time of 5 years revealed a non-significant reduction in the frequency of bone metastases in the clodronate treated patients (63 (12%) v 80 (15%) patients, p=0.127).

During the two years on active treatment there was a reduction in bone metastases but this disappeared on discontinuation of the study drug, suggesting that adjuvant bisphosphonate treatment trials in the future should test a longer duration of treatment. There was no effect on non-bone recurrence (112 (21%) v 128 (24%) patients, p=0.26) but, despite little effect on the primary endpoint (bone recurrence), patients randomized to the clodronate arm had a better survival (p=0.047).

In a second study, Diel et al. studied 302 breast cancer patients randomly allocated to either oral clodronate 1600mg daily (n=157) for 3 years or a control group (n=145). These women had no overt evidence of metastatic disease, but were selected for the trial on the basis of immunocytochemical detection of tumor cells in the bone marrow, a known risk factor for the subsequent development of distant metastases⁴⁰. Patients received appropriate adjuvant chemotherapy and endocrine treatment. There were no discernable prognostic or treatment imbalances between the two groups and the follow-up schedules were similar. The median observation period was 36 months.  The incidence of osseous metastases was significantly lower in the clodronate group (11 (7%) versus 25 (17%) patients, p < 0.002). There was also an unexpected large reduction in the incidence of visceral metastases in the clodronate group (19 (13%) versus 42 (29%) patients, p < 0.001).  These results have subsequently been updated⁴¹ and show similar results although the striking effect on extraskeletal visceral relapse seen in the earlier report is less and no longer statistically significant.

The exciting findings of the Diel study must, however, be viewed in the light of a further trial which produced conflicting results. Saarto et al⁴² randomized 299 women with primary node-positive breast cancer to oral clodronate 1600mg daily (n=149) or a control group (n=150). The median follow-up was 5 years. Treatment with clodronate in this study did not lead to a reduction in the development of bone metastases (29 (19%) v 24 (16%) patients, p=0.27 for the clodronate and control groups respectively). Additionally the development of non-skeletal recurrence was significantly higher in the clodronate group (60 (40%) versus 36 (24%) patients, p = .0007) and, most importantly, the overall five year survival was significantly lower in the clodronate group (70% versus 83%, p = .009). It is possible that there were some prognostic imbalances favoring the control group but the safest assumption is to consider that the Diel and Saarto studies cancel each other out and probably reflect the usual heterogeneity of results seen in relatively small adjuvant studies. 

In patients with locally advanced breast cancer (n=33) or with extraskeletal metastases (n=91) no preventive efficacy of supportive oral pamidronate treatment (300 mg daily) could be demonstrated with respect to the incidence of bone metastases when compared to a control group with freely allowed tumor therapy. Radiologic evidence of bone metastases was detected in 36% of patients on pamidronate and in 27% of patients in the control group.

Interpretation of these results has to consider that an oral dose of 300 mg daily pamidronate seems to be too low to effectively reduce the incidence of bone metastases since oral bioavailability is only 1%. Furthermore, breast cancer patients of the pamidronate study were in an advanced cancer stage. Therefore, differences in study populations might have contributed to controversial results of the oral bisphosphonate prevention studies. 

The zoledronic acid preclinical and preliminary clinical data favor this new bisphosphonate over clodronate and pamidronate, and intravenous infusion therapy with zoledronic acid appears promising in the prevention of bone metastases and shall therefore be investigated in the present study.

This protocol contains a substudy measuring bone mineral density in men with high risk prostate cancer starting with hormone therapy. In a recently completed trial (Zometa Protocol 705), Zometa^® 4 mg given as a 15-minute intravenous infusion every 12 weeks for one year (5 treatments) significantly increased lumbar spine and hip bone mineral density compared to placebo in 106 men with prostate cancer who were beginning androgen deprivation therapy.⁴⁴ Men who received the Zometa^® infusions had an increase in lumbar spine bone mineral density (BMD) of 5.16% (p<0.001 vs. placebo). BMD increased by 1.08% in the total hip, 1.64% at the femoral neck, 2.37% at the trochanteric region, and 3.39% at Wardâ