Bisphosphonates in multiple myeloma

Background: Bisphosphonates are specific inhibitors of osteoclastic activity and are currently used as supportive therapy for multiple myeloma (MM). However, the exact clinical role of bisphosphonates in MM remains unclear. Objectives: This update of the first review published in 2002. We have also analyzed observational studies targeting osteonecrosis of jaw (ONJ). Search strategy: We searched the literature using the methods outlined in the previous review. We also searched observational studies or case reports examining ONJ. Selection criteria: We selected RCTs with a parallel design related to the use of bisphosphonate in myeloma. We also selected observational studies or case reports examining bisphosphonates related to ONJ. Data collection and analysis: We have reported pooled data using either hazard ratio or risk ratio and, when appropriate, as absolute risk reduction and the number needed to treat to prevent or to cause a pathological event. We have assessed statistical heterogeneity and reported I-2 statistic. Main results: This review includes 17 trials with 1520 patients analyzed in bisphosphonates groups, and 1490 analyzed in control groups. In comparison with placebo/no treatment, the pooled analysis demonstrated the beneficial effect of bisphosphonates on prevention of pathological vertebral fractures (RR = 0.74 (95% CI: 0.62 to 0.89), P = 0.001), total skeletal related events (SREs) (RR = 0.80 (95% CI: 0.72 to 0.89), P <0.0001) and on amelioration of pain (RR = 0.75 (95% CI: 0.60 to 0.95), P = 0.01). We found no significant effect of bisphosphonates on overall survival (OS), progression-free survival (PFS), hypercalcemia or on the reduction of non-vertebral fractures. The indirect meta-analyses did not find the superiority of any particular type of bisphosphonate over others. Only two RCTs reported ONJ. The identified observational studies suggested that ONJ may be a common event (range: 0% to 51%). Authors' conclusions: Adding bisphosphonates to the treatment of MM reduces pathological vertebral fractures, SREs and pain but not mortality. Assuming the baseline risk of 20% to 50% for vertebral fracture without treatment, we estimate that between eight and 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Assuming the baseline risk of 31% to 76% for pain amelioration without treatment, we estimate that between five to 13 MM patients should be treated to reduce pain in one patient. Also, with the baseline risk of 35% to 86% for SREs without treatment, we estimate that between six and 15 MM patients should be treated to prevent SRE(s) in one patient. No bisphoshphonate appears to be superior to others.