Bisphosphonates in multiple myeloma: a network meta-analysis.Cochrane Database Syst Rev. 2012 May 16CD
Bisphosphonates are specific inhibitors of osteoclastic activity and used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010.
To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus nonamino bisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw and hypocalcemia.
We searched MEDLINE, LILACS, EMBASE (December 2009 to October 2011) and the Cochrane Controlled Trials Register (all years, latest Issue September 2011) to identify all randomized trials in MM up to October 2011 using a combination of text and MeSH terms. We also handsearched relevant meeting proceedings (December 2009 to October 2011).
Any randomized controlled trial (RCT) assessing the role of bisphosphonates and observational studies or case reports examining bisphosphonate-related osteonecrosis of the jaw in patients with MM were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) under a random-effects model. Statistical heterogeneity was explored using metaregression.
In this update, we included 2 studies (2464 patients) that were not part of our last Cochrane review published in 2010. In this review we included 16 RCTs comparing bisphosphonates with either placebo or no treatment and 4 RCTs with a different bisphosphonate as a comparator. The 20 included RCTs enrolled 6692 patients. Overall methodological quality of reporting was moderate. Thirty per cent (6/20) of trials reported the method of generating the randomization sequence. Forty per cent (8/20) of trials had adequate allocation concealment. Withdrawals and dropouts were described in 60% (12/20) of trials. Pooled results showed no direct effect of bisphosphonates on OS compared with placebo or no treatment (HR 0.96, 95% CI 0.82 to 1.13; P = 0.64). However, there was a statistically significant heterogeneity among the included RCTs (I(2) = 55%, P = 0.01) for OS. To explain this heterogeneity we performed a metaregression assessing the relationship between bisphosphonate potency and improvement in OS, which found indicating an OS benefit with zoledronate (P = 0.058). This provided a further rationale for performing network meta-analyses of the various types of bisphosphonates that were not compared head to head in RCTs. Results from network meta-analyses showed superior OS with zoledronate compared with etidronate (HR 0.43, 95% CI 0.16 to 0.86) and placebo (HR 0.61, 95% CI 0.28 to 0.98). However, there was no difference between zoledronate and other bisphosphonates. Pooled analysis did not demonstrate a beneficial effect of bisphosphonates compared with placebo or no treatment in improving PFS (HR 0.70, 95% CI 0.41 to 1.19; P = 0.18) There was no heterogeneity among trials reporting PFS estimates (I(2) = 35%, P = 0.20).Pooled analysis demonstrated a beneficial effect of bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; I(2) = 7%), skeletal-related events (SRE) (RR 0.80, 95% CI 0.72 to 0.89; I(2) = 2%) and amelioration of pain (RR 0.75, 95% CI 0.60 to 0.95; I(2) = 63%). The network meta-analysis did not show any difference in the incidence of osteonecrosis of the jaw (5 RCTs, 3198 patients) between bisphosphonates. Rates of osteonecrosis of the jaw in observational studies (9 studies, 1400 patients) ranged from 0% to 51%. The pooled results (6 RCTs, 1689 patients) showed no statistically significant increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.60; P = 0.11).The pooled results (3 RCTs, 1002 patients) showed no statistically significant increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74). The network meta-analysis did not show any differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used.