Wong, R., & Wiffen, P.J. (2009). Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database of Systematic Reviews 2009(4).

To determine the effectiveness of bisphosphonates as a treatment for pain in patients with bone metastases

• Databases searched were MEDLINE, CANCERLIT, the Cochrane Library, and the Oxford Pain Relief Database.
• Keywords searched were bisphosphonates, diphosphonates, multiple myeloma, and bone neoplasm.
• Studies were included if they
  • Reported on patients with bone metastasis.
  • Were randomized controlled trials (RCTs).
  • Were reports of bisphosphonate use.
  • Were full research reports (no abstracts).
  • Included pain or analgesic use as an outcome measure.

The initial search identified 85 studies, of which 30 met inclusion criteria. Study quality was evaluated using the Jadad scale. Five studies included pain as a primary endpoint.

The final sample of 30 studies included 3,582 patients. Types of diagnoses included breast and prostate cancer, multiple myeloma, and other types of primary tumors.

• Drugs studied included etidronate, clodronate, and pamidronate. In 22 of the 30 studies, additional hormone therapy or chemotherapy was used.
• Proportion of patients with pain relief: Across eight studies, pooled data showed significant pain relief with treatment (OR = 2.37, 95% CI 1.61–3.5).
• Average pain score effects: Seven studies showed a general trend in favor of treatment, though data were insufficient to allow pooled analysis. Differences between treatment and control groups ranged from –0.037 through –0.53. Most studies used a visual analog scale measurement.
• Analgesic consumption:
  • Three studies showed no differences between groups.
  • Three studies showed less increase in analgesic consumption with treatment.
• Adverse effects:
  • Twenty-four studies reported nonsignificant increases in nausea and vomiting.
  • Three studies reported an adverse effect that necessitated discontinuation of therapy.
  • Other effects reported were abdominal pain, allergic response, and hypocalcemia.

Results of this review suggest that one of six patients treated with a bisphosphonate will receive modest pain relief. Results suggest that 1 of 11 patients treated with a bisphosphonate will experience side effects severe enough to justify discontinuing bisphosphonate treatment. Overall, data were insufficient to allow investigators to recommend the use of a bisphosphonate to achieve an immediate effect. Findings show that the maximum response to bisphosphonate-related pain management can be observed by four weeks.

• Study results do not provide information about effects beyond 12 weeks.
• Most studies used insufficient, unvalidated pain outcome measures.

Bisphosphonates appear to help reduce the pain of bone metastases in some patients. Long-term efficacy is unclear. The effects of bisphosphonates on pain appear to be at the maximum at four weeks of use. Effects appear to be stable up to 12 weeks. Efficacy after 12 weeks has not been studied. Studies reviewed in this investigation reported little data; the result is the inability to analyze results quantitatively across studies. Future research should incorporate valid pain measures and report results.