Use of bisphosphonates in the treatment of prostate cancer.

Recently, there has been much controversy over whether patients with prostate cancer should be treated with bisphosphonates not only to decrease pain, but to prevent metastasis. This brief review summarizes the known data in this area. The main points made in the discussion are highlighted in previews appearing at the beginning of each section of the article. Preview: Bisphosphonates inhibit bone destruction by osteoclasts. They are not very effective in inhibiting osteoblasts, which build bone and are the main cause of metastatic prostate cancer lesions. Although tumor cells may directly destroy bone, most tumor-related bone destruction appears to be due to substances released by the tumor that stimulate osteoclasts. Bisphosphonates effectively inhibit bone resorption by interfering with osteoclast activity through multiple mechanisms, some of which are still not clearly understood. These drugs have a high affinity for calcium and, once administered, bind to hydroxyapatite in areas of exposed bone mineral where active bone remodeling is occurring, making the bone surfaces less available to osteoclastic resorption. Bisphosphonates prevent the migration of osteoclasts toward bone and inhibit the recruitment of osteoclastic precursors at the bone marrow level, thus decreasing osteoclast numbers. They may also induce osteoclastic apoptosis.[1,2] Several bisphosphonates have been used successfully to treat conditions associated with abnormal osteoclastic activity, such as hypercalcemia, Paget’s disease, and osteolytic skeletal metastases. In these populations, bisphosphonate treatment is associated with decreased pain scores, improved performance status, better quality of life, and a significant decrease in skeletal events, such as fractures, spinal cord compressions, and bony pain requiring palliative radiation.[1-4] Preview: In breast cancer patients, bisphosphonates have been shown to decrease pain at metastatic sites. One bisphosphonate, pamidronate (Aredia), reduced skeletal complications from 64% to 51% over 2 years when compared with placebo but showed no effect on survival or quality of life. Breast cancer patients often have both osteolytic and osteoblastic lesions. Several recent trials of bisphosphonates in breast cancer patients have shown statistically significant decreases in bone pain and skeletal complications (fractures, spinal cord compression, and the need for palliative external-beam radiation).[3,4] Long-term follow-up data were recently published from two large, multicenter, randomized, double-blind, placebo-controlled trials comparing the efficacy of pamidronate plus antineoplastic treatment with antineoplastic treatment alone in women with advanced breast cancer.[5] A total of 751 patients receiving either endocrine therapy (protocol 18) or chemotherapy (protocol 19) at study enrollment were randomized to receive either pamidronate, 90 mg IV every 3 to 4 weeks, or placebo in addition to their primary treatment. All patients were allowed to change their anticancer treatment at any time during the study. The primary end point was the skeletal morbidity rate, defined as the number of skeletal complications divided by the time on the trial. Secondary end points were bone pain scores, analgesic use, quality of life, and performance status. Both mean and individual skeletal morbidity rates were significantly better in the pamidronate group after 24 cycles: Mean skeletal morbidity rate (including hypercalcemia) was 2.5 skeletal complications per year in the pamidronate group vs 4.0 in the placebo group. Median times from study entry to first skeletal complication were 7.0 and 12.7 months in the placebo and pamidronate groups, respectively. Median time to new pathologic fracture was 12.8 months in the placebo group and 25.2 in the pamidronate group. Median time to palliative bone radiation was 16.0 months in the placebo group and had not yet been reached in the pamidronate group. Although mean pain and analgesia scores had declined by the last study visit in both groups, the