• Rahul Mhaskar, Jasmina Redzepovic, Keith Wheatley, Otavio Augusto Camara Clark, Branko Miladinovic, Axel Glasmacher, Ambuj Kumar, and Benjamin Djulbegovic.
• Center for Evidence-based medicine and Health Outcomes Research, University of South Florida, Tampa, Florida, USA.
• Cochrane Db Syst Rev. 2010 Mar 17 (3): CD003188.

BackgroundBisphosphonates 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.ObjectivesThis update of the first review published in 2002. We have also analyzed observational studies targeting osteonecrosis of jaw (ONJ).Search StrategyWe searched the literature using the methods outlined in the previous review. We also searched observational studies or case reports examining ONJ.Selection CriteriaWe 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 AnalysisWe 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 ResultsThis 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' ConclusionsAdding 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.

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