Denosumab vs. Zoledronic Acid for Metastatic Bone Disease: A Comprehensive Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Metastatic bone disease (MBD) presents significant challenges in patient management, leading to skeletal-related events (SREs), compromised health-related quality of life, and heightened pain experiences. Denosumab (Dmab) and zoledronic acid (ZA) are bone-modifying agents (BMAs) commonly employed to mitigate the sequelae of MBD. Previous meta-analyses have assessed primary outcomes such as overall survival, pathological fractures, radiation to bone, and the time to SREs within studies. However, a single comprehensive analysis comparing their efficacy across multiple primary and secondary outcomes, as well as cost-effectiveness in specific cancer types, has not yet been conducted. Methods: A literature search identified relevant randomized controlled trials (RCTs), and the primary outcomes included overall survival, pathologic fractures, radiation to bone, and the time to SREs within studies. Secondary outcomes included adverse events, pain, analgesia usage, quality of life, and cost. Results: Meta-analysis revealed that Dmab effectively reduced the need for bone-targeted radiation therapy and was superior to ZA in delaying the time to SREs, except in multiple myeloma. Dmab also reduced pathological fracture incidences in breast cancer patients by 39%. Conclusions: Our analysis suggests that while both agents similarly impact overall survival and disease progression, Dmab offers advantages in SRE reduction and improved HRQoL and pain outcomes with lower rates of opioid usage, albeit with higher risks of hypocalcemia and osteonecrosis in some subgroups. The consensus on cost-effectiveness is mixed and varies based on the cancer type and healthcare system, with some studies favoring Dmab's superior efficacy and safety, while others find ZA more cost-effective due to its lower cost. This study underscores the potential of Dmab as a preferred BMA for MBD management, especially for high-risk skeletal complications, while highlighting cancer-specific safety considerations. Further research is warranted to refine cancer-specific BMA use and optimize MBD management strategies.

Keywords: bone metastasis; denosumab; metastatic bone disease; multiple myeloma; zoledronic acid; “bone cancer”.

Figure 1

The PRISMA flow diagram illustrating the study selection process for meta-analysis and systematic review of Dmab versus ZA.

Figure 2

Quality assessment of included studies for risk of bias [13,14,15,16,24,25,26]. “+” = low risk of bias; “?” = minimal information and cannot judge risk of bias.

Figure 3

Skeletal-related events in MBD patients treated with Dmab vs. ZA. (a) Overall survival, (b) overall disease progression, (c) pathological fracture, (d) radiation to the bone, (e) time to first on-SRE within study, (f) time to first and subsequent SRE within study.

Figure 4

Summary of AEs by primary cancer type.

Figure 5

(a) Time (months) to worsening pain in patients with no or mild pain at baseline. (b) Time (months) to increased pain interference in patients with no pain at baseline—aggregate score.