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. 2017 Dec 18;12(12):CD003188.
doi: 10.1002/14651858.CD003188.pub4.

Bisphosphonates in multiple myeloma: an updated network meta-analysis

Rahul Mhaskar  1 , Ambuj Kumar, Branko Miladinovic, Benjamin Djulbegovic
Affiliations

Bisphosphonates in multiple myeloma: an updated network meta-analysis

Rahul Mhaskar et al. Cochrane Database Syst Rev. .

Abstract

Background: Bisphosphonates are specific inhibitors of osteoclastic activity and are 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 and 2012.

Objectives: To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus non-aminobisphosphonates) 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 (ONJ) and hypocalcemia.

Search methods: We searched MEDLINE, Embase (September 2011 to July 2017) and the CENTRAL (2017, Issue 7) to identify all randomized controlled trial (RCT) in MM up to July 2017 using a combination of text and MeSH terms.

Selection criteria: Any randomized controlled trial (RCT) comparing bisphosphonates versus placebo/no treatment/bisphosphonates and observational studies or case reports examining bisphosphonate-related ONJ 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) using a random-effects model. We used meta-regression to explore statistical heterogeneity. Network meta-analysis using Bayesian approach was conducted.

Main results: In this update, we included four new studies (601 participants), resulting in a total of 24 included studies.Twenty RCTs compared bisphosphonates with either placebo or no treatment and four RCTs involved another bisphosphonate as a comparator. The 24 included RCTs enrolled 7293 participants. Pooled results showed that there was moderate-quality evidence of a reduction in mortality with on OS from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I2 = 65%) for OS. To explain this heterogeneity we performed a meta-regression assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta-analyses of the various types of bisphosphonates that were not compared head-to-head in RCTs. Results from network meta-analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates (low-quality evidence). There is probably a similar risk of non-vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants; moderate-quality evidence). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants; moderate-quality evidence) and skeletal-related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants; moderate-quality evidence). The evidence for less pain with bisphosphonates was of very low quality (RR 0.75, 95% CI 0.60 to 0.95; eight studies; 1281 participants).Bisphosphonates may increase ONJ compared with placebo but the confidence interval is very wide (RR 4.61, 95% CI 0.99 to 21.35; P = 0.05; six studies; 1284 participants; low-quality evidence). The results from the network meta-analysis did not show any evidence for a difference in the incidence of ONJ (eight RCTs, 3746 participants) between bisphosphonates. Data from nine observational studies (1400 participants) reported an incidence of 5% to 51% with combination of pamidronate and zoledronate, 3% to 11% with zoledronate alone, and 0% to 18% with pamidronate alone.The pooled results showed no evidence for a difference in 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 1.59; seven studies; 1829 participants; low-quality evidence).The pooled results showed no evidence for a difference in 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; three studies; 1090 participants; low-quality evidence). The results from network meta-analysis did not show any evidence for differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used.

Authors' conclusions: Use of bisphosphonates in participants with MM reduces pathological vertebral fractures, SREs and pain. Bisphosphonates were associated with an increased risk of developing ONJ. For every 1000 participants treated with bisphosphonates, about one patient will suffer from the ONJ. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or non-aminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate was found to be better than placebo and first-generation bisposphonate (etidronate) in pooled direct and indirect analyses for improving OS and other outcomes such as vertebral fractures. Direct head-to-head trials of the second-generation bisphosphonates are needed to settle the issue if zoledronate is truly the most efficacious bisphosphonate currently used in practice.

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Conflict of interest statement

RM: None known.

AK: None known.

BM: None known.

BD: None known.

Figures

1
1
Bisphosphonate chemical structures
2
2
Study flowchart
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
4
4
Bisphosphonate potency metaregression for overall survival. HR: Hazard ratio.
5
5
Randomized controlled trial (RCT) network for overall survival (OS), progression free survival (PFS) and skeletal related events (SREs).
6
6
A: Ranking probabilities of competing bisphosphonates. The size of each bar corresponds to the probability of each treatment to be at a specific rank. OS: Overall survival; PFS: Progression‐free survival; SRE: Skeletal‐related events; Osteonecrosis; GI: Gastrointestinal toxicity; Hyper: Hypercalcemia. B: Surface under the cumulative ranking curve (SUCRA) plots for each treatment. The outcomes are listed on the horizontal axis. SUCRA for each outcome are on the vertical axis.
7
7
Funnel plot of comparison: 1 Bisphosphonates vs. control (efficacy), outcome: 1.6 Pain.
1.1
1.1. Analysis
Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 2 Progression‐free survival.
1.3
1.3. Analysis
Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 3 Vertebral fractures.
1.4
1.4. Analysis
Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 4 Non‐vertebral fractures.
1.5
1.5. Analysis
Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 5 Total skeletal‐related events.
1.6
1.6. Analysis
Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 6 Pain.
1.7
1.7. Analysis
Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 7 Incidence of hypercalcemia.
2.1
2.1. Analysis
Comparison 2 Bisphosphonates vs. control (adverse effects), Outcome 1 Osteonecosis of jaw.
2.2
2.2. Analysis
Comparison 2 Bisphosphonates vs. control (adverse effects), Outcome 2 Gastrointestinal toxicity (grade III/IV).
2.3
2.3. Analysis
Comparison 2 Bisphosphonates vs. control (adverse effects), Outcome 3 Hypocalcaemia.
2.4
2.4. Analysis
Comparison 2 Bisphosphonates vs. control (adverse effects), Outcome 4 Renal dysfunction.
3.1
3.1. Analysis
Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 1 Allocation concealment (vertebral fractures).
3.2
3.2. Analysis
Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 2 Blinding (vertebral fractures).
3.3
3.3. Analysis
Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 3 Randomization method (vertebral fractures).
3.4
3.4. Analysis
Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 4 Type of data analysis (vertebral fractures).
3.5
3.5. Analysis
Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 5 Description of withdrawals and drop outs (vertebral fractures).
3.6
3.6. Analysis
Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 6 Alpha error (vertebral fractures).
3.7
3.7. Analysis
Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 7 Beta error (vertebral fractures).
3.8
3.8. Analysis
Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 8 Gastrointestinal toxicity (grade III/IV: oral vs IV bisphosphonates)).
See this image and copyright information in PMC

Update of

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Ali 2001 {published data only}
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