Bisphosphonates in multiple myeloma: an updated network meta-analysis.

Area of Science:

• Oncology
• Pharmacology
• Evidence-Based Medicine

Background:

• Bisphosphonates are osteoclast inhibitors used in multiple myeloma (MM) treatment.
• Their efficacy in reducing fractures and pain is established, but impact on overall survival (OS) requires clarification.
• This review updates previous Cochrane analyses from 2002, 2010, and 2012.

Purpose of the Study:

• To assess benefits and harms of bisphosphonates (amino- vs. non-aminobisphosphonates) in MM management.
• To determine if bisphosphonates improve OS, progression-free survival (PFS), and reduce skeletal-related morbidity.
• To evaluate effects on pain, quality of life, hypercalcemia, gastrointestinal toxicity, osteonecrosis of the jaw (ONJ), and hypocalcemia.

Main Methods:

• Searched MEDLINE, Embase, and CENTRAL databases up to July 2017 for randomized controlled trials (RCTs) in MM.
• Included RCTs comparing bisphosphonates to placebo/no treatment, or other bisphosphonates; observational studies for ONJ.
• Extracted data, performed meta-analysis using random-effects models, and conducted network meta-analysis (Bayesian approach).

Main Results:

• Twenty-four RCTs (7293 participants) were included. Moderate-quality evidence suggests bisphosphonates reduce pathological vertebral fractures (RR 0.74) and skeletal-related events (SREs) (RR 0.74).
• Overall survival (OS) benefit is uncertain (HR 0.90), with heterogeneity noted. Zoledronate showed potential OS benefit versus etidronate (HR 0.56) and placebo (HR 0.67).
• Bisphosphonates may increase ONJ risk (RR 4.61, low-quality evidence). No significant differences found for PFS, non-vertebral fractures, pain (very low quality), gastrointestinal symptoms, or hypocalcemia between bisphosphonates.

Conclusions:

• Bisphosphonates effectively reduce vertebral fractures, SREs, and pain in MM patients, but carry an increased risk of ONJ.
• No specific aminobisphosphonate or non-aminobisphosphonate showed superiority across all outcomes.
• Zoledronate demonstrated potential benefits for OS and vertebral fractures compared to placebo and etidronate; further head-to-head trials are warranted.