Berry, S., Waldron, T., Winquist, E., & Lukka, H. (2006). The use of bisphosphonates in men with hormone-refractory prostate cancer: A systematic review of randomized trials. The Canadian Journal of Urology, 13(4), 3180–3188.

To review results of published randomized controlled trials (RCTs) and meta-analyses to determine the benefits that bisphosphonates provide to men with hormone-refractory prostate cancer

• Databases searched were MEDLINE, EMBASE, CANCERLIT, and the Cochrane Library. Investigators also retrieved selected conference proceedings. The date range searched, for all materials, was 1980–2004.
• Search keywords were text words and medical subject headings that were disease specific, treatment specific, and study-design specific.
• Studies were included in the review if they
  • Were RCTs or meta-analyses.
  • Involved a sample of men with hormone-refractory prostate cancer and compared bisphosphonate treatment with placebo, no treatment, or treatment with another bisphosphonate.
  • Reported outcomes regarding new bone metastases, skeleton-related events, symptom response, survival, or quality of life.

• Authors did not report total number of search results.
• Authors identified 17 reports as eligible.
• Authors stated quality characteristics of evaluated studies, but did not report quantitative grading.

The final sample of 17 reports included three systematic reviews and 12 RCTs. The sample included 1,446 patients. The range of sample size was 13–643. Eight trials supplied pain outcomes, and these eight trials involved 756 patients.

Variability of pain measurement across studies prevented statistical pooling. Overall, trials did not detect significant differences in pain outcomes between patients taking the study drug and patients taking placebo. However, over a relatively long period and among individuals with at least moderate pain severity at baseline, authors noted trends toward better pain relief with bisphosphonates than with placebo. Most trials were identified as underpowered, a fact that may have prevented investigators from detecting significant differences. In general, patients tolerated bisphosphonates well. Nausea was the most frequently reported adverse event; across trials 9%–33% of patients experienced nausea.

Overall, trials reviewed did not show significant differences in pain outcomes between those who received bisphosphonates and those who received placebo. However, at specific time points subgroups of bisphosphonate-using patients who had at least moderate pain showed trends toward improvement.

Findings suggest that bisphosphonates may be helpful in providing pain relief to men with hormone-refractory prostate cancer who have at least moderate pain levels. Clinicians should watch for nausea in bisphosphonate-using patients and be ready to provide relief. Further research, to define the most effective timing of bisphosphonate administration and the best way to use a bisphosphonate alone or in combination with other therapies, is warranted.