Should Bisphosphonates Be Used Routinely in Patients With Prostate Cancer Metastatic to Bone?
Authors: C. M. Canil, I. F. Tannock
Journal: JNCI Journal of the National Cancer Institute (2002)

Prostate cancer is a disease that is characterized by a high incidence of metastases to bone, which cause substantial morbidity, including pain, fractures, and spinal cord compression. The primary modality of treatment for patients with metastatic prostate cancer is hormonal therapy, which is designed to reduce the stimulatory effects of androgens on prostate cancer cells. However, long-term use of androgen blockade has been shown to result in osteoporosis, which further contributes to bone fragility (1). Hormonal therapy to suppress serum testosterone levels is usually continued in patients with prostate cancer, even those with hormone-resistant prostate cancers. Treatment of patients with hormone-resistant prostate cancer has focused on palliation of symptoms and quality of life. Management of bone pain includes treatments with narcotic and anti-inflammatory medications, external beam radiation, bone-seeking radioactive isotopes such as strontium-89, and chemotherapy. The role of bisphosphonates in the treatment of prostate cancer has been controversial. Patients with bone metastases resulting from breast cancer (2–4) and multiple myeloma (5) had improved pain and decreased risk of skeletal events (fractures, hypercalcemia, need for intervention with surgery or radiation therapy) with the use of bisphosphonates such as pamidronate. However, because bone metastases in patients with breast cancer or multiple myeloma are primarily osteolytic, the observations (2–5) are in concordance with the principal action of bisphosphonates: to inhibit bone-resorbing osteoclasts. By contrast, bone metastases in patients with prostate cancer are primarily osteoblastic, which results in the deposit of calcium in new bone. The rationale for the use of bisphosphonates in the treatment of patients with prostate cancer comes from studies showing that abnormal osteoblastic bone formation is associated with osteoclastic bone resorption and an elevation in osteoclastic markers (6,7). Fractures, and particularly hypercalcemia, are less common in patients with osteoblastic bone metastases than in patients with osteolytic lesions. Pamidronate has been shown to prevent bone loss in men with prostate cancer and no overt bone metastases who were treated with antiandrogen therapy (8), but the role of bisphosphonates in preventing or treating events relating to osteoblastic metastases remains uncertain. Although there have been three previous reports (9–11) of randomized, double-blind, placebo-controlled trials of the use of bisphosphonates in patients with metastatic prostate cancer, all used less potent drugs than those now available, and two have been presented only in abstract form. Smith (9) randomly assigned 57 patients to receive intravenous and/or oral sodium etidronate or placebo and found no difference in symptomatic response or analgesic requirements. A British study by Dearnaley et al. (10) randomly assigned 311 patients with hormonesensitive disease to oral clodronate or placebo and, in a preliminary report, found a delay in the time to symptomatic bone progression. Recently, a Canadian study by Ernst et al. (11) randomly assigned 208 patients with hormone-resistant disease and symptomatic bone metastases to receive intravenous clodronate or placebo in addition to palliative chemotherapy with mitoxantrone and prednisone. There were no differences in the primary endpoint of palliative response (defined by improvement in pain and/or decrease in analgesic intake), although a secondary analysis suggested that moderate or severe pain was improved in a small subset of patients who received clodronate. In this issue of the Journal, Saad and his colleagues (12) describe a study that attempts to define the role of the potent bisphosphonate zoledronic acid in patients with hormonerefractory prostate cancer with bone metastases. In this doubleblind, placebo-controlled study, 643 patients were randomly assigned to three arms in which they were to receive intravenous infusions of placebo or of zoledronic acid (4 mg or 8 mg) every 3 weeks for up to 15 months. The primary endpoint was the proportion of patients having at least one skeletal-related event (pathologic fracture, spinal cord compression, surgery to bone, radiation therapy to bone, or a change in antineoplastic therapy to treat bone pain). Because some patients receiving the 8-mg infusion dose of zoledronic acid had renal dysfunction, all patients on this arm subsequently received the 4-mg infusion dose of zoledronic acid. The statistical plan was amended to base the primary analysis on the comparison between those in the 4-mg zoledronic acid arm and the placebo arm. The results of the study show a difference in the primary endpoint of skeletal-related events between patients randomly assigned to the 4-mg zoledronic acid arm and the placebo arm (33.2% versus 44.2%, P .02). The percentage of patients with skeletal-related events who were randomly assigned to the 8/4-mg zoledronic acid arm was intermediate (38.5%) and was not statistically significantly different from the percentage of patients in the placebo arm. The median time to the first skeletal-related event was at least 420 days in patients in the 4-mg zoledronic acid arm compared with 321 days for those in the placebo arm (P .01) and 363 days for those in the 8/4-mg zoledronic arm (not statistically significantly different from that in the placebo arm). No differences were identified in disease progression, performance status, or quality-of-life scores in any of the arms. The authors conclude that zoledronic acid may reduce skeletal-related events in prostate cancer patients with bone metastases. The study by Saad et al. (12) was well designed and showed a statistically significant reduction in skeletal-related events for patients randomly assigned to receive 4-mg doses of zoledronic