Yuen, K.K., Shelley, M., Sze, W.M., Wilt, T., & Mason, M.D. (2010). Bisphosphonates for advanced prostate cancer. Cochrane Database of Systematic Reviews 2010(2).

To determine the effectiveness of bisphosphonates in relieving the bone pain of patients with bone metastases from prostate cancer

• Databases searched were MEDLINE, EMBASE, LILACS, the Database of Abstracts of Reviews of Effects (DARE), Allied and Complementary Medicine Database (AMED), and the Cochrane Central Register of Controlled Trials (CENTRAL). Investigators performed manual searches of reference lists and proceedings of the American Society of Clinical Oncology.
• Search keywords included bone neoplasms, osseous metastasis, cancer or carcinoma and bisphosphonates or diphosphonates. Authors included an extensive list of search terms in their review.
• Studies were included if they
  • Were randomized controlled trials that assessed the effect of bisphosphonates in prostate cancer patients with bone metastases
  • Measured pain as one of the outcome variables
• Studies were excluded if the primary site of the cancer was not the prostate, if the treatment assessed was a radioactive bisphosphonate, or if the study was an abstract or unpublished.

• The search identified 23 studies. After exclusions, the set of studies to be investigated included 10 studies.
• The sample size of the 10 studies was 1,955 patients. 
• Range of sample size across studies was 55–378 patients.
• Investigators evaluated study quality by using the Jadad scale.

The final sample of 10 studies included placebo-controlled and active controlled studies of patients with prostate cancer and confirmed bone metastases.

• Four studies analyzed pain response. There was no significant heterogeneity. The overall odds ratio (OR) was in favor of bisphosphonates over placebo (OR = 1.64, 95% CI 1.02–2.61, p = 0.07).
• Four studies assessed mean pain change. Because the four studies were extremely heterogeneous, investigators could perform no meaningful analysis.
• In regard to analgestic consumption, investigators noted no significant heterogeneity. The overall OR showed no difference between bisphosphonates and placebo in terms of reduced analgesic consumption.
• In regard to skeletal events, investigators noted a marginally significant difference: Incidence of skeletal effects was lower for patients using bisphosphonates than for patients using placebo (OR = 0.79, 95% CI 0.62–1.0, p = 0.05).
• In terms of adverse events, the analysis showed a significant increase in nausea with bisphosphonates.
• Authors also analyzed findings related to quality of life, survival, disease progression, and prostate-specific antigen.
• No study compared different types of bisphosphonates.

Compared to patients receiving placebo, a higher proportion of patients receiving bisphosphonates reported a decrease in skeletal events. Use of bisphosphonates was associated with increased nausea. Findings supported the use bisphosphonates for reduction of the bone pain associated with prostate cancer. However, findings did not show that bisphosphonates made any difference in analgesic use or consumption.

This review was limited to prostate cancer patients with bone metastases. Authors noted that findings were influenced by the way in which studies were analyzed. In general, analysis of the number of evaluable patients favored bisphosphonates, but intention-to-treat analysis revealed no difference between treatments. Invesigators also saw that results differed according to how data from active study arms were handled. In one key study, when data from study arms were analyzed individually, meta-analysis was significant; however when data from active arms were combined, investigators noted no statistical difference relating to bisphosphonate use.

Bisphosphonate appears to have a role in decreasing pain and skeletal complications in patients with metastatic prostate cancer. Nausea appears to be the most frequent side effect associated with bisphosphate use. Data are insufficient to allow researchers to determine the most appropriate bisphosphonate choice, dose, or route of administration. More research is needed to determine the most effective treatment schedules and cost-effectiveness.