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.


OBJECTIVE
This update of the first review published in 2002. We have also analyzed observational studies targeting osteonecrosis of jaw (ONJ).


METHODS
We searched the literature using the methods outlined in the previous review. We also searched observational studies or case reports examining ONJ.


METHODS
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.


METHODS
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.


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%).


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.
Center for Evidence-based medicine and Health Outcomes Research, University of South Florida, Tampa, Florida, USA.
Rahul
R
Mhaskar
Jasmina
J
Redzepovic
Keith
K
Wheatley
Otavio Augusto Camara
OA
Clark
Branko
B
Miladinovic
Axel
A
Glasmacher
Ambuj
A
Kumar
Benjamin
B
Djulbegovic
D000970:Antineoplastic Agents / Q000627:therapeutic use; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001847:Bone Diseases / Q000188:drug therapy* / Q000401:mortality; D004164:Diphosphonates / Q000009:adverse effects / Q000627:therapeutic use*; D050723:Fractures, Bone / Q000517:prevention & control; D006801:Humans; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D016103:Spinal Fractures / Q000517:prevention & control
D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates