The safety profile of denosumab in oncology beyond the safety of denosumab as an anti-osteoporotic agent: still more to learn

ABSTRACT

Introduction

Initially endorsed as an antiosteoporotic agent, denosumab ‒ human monoclonal antibody inhibiting the receptor activator of nuclear factor kappa-B ligand (RANKL)‒ has currently shown an anticancer potential, rationalizing its exploitation in oncology. A prerequisite for leveraging denosumab in oncology is a favorable safety profile.

Areas covered

The present review provides an overview of the adverse events of denosumab in oncology, with a focus on hypocalcemia, medication-related osteonecrosis of the jaw, atypical femoral fracture(s), post-denosumab vertebral fractures, increased risk of infections, and excess of second primary cancer. Representative studies addressing the safety and efficacy of denosumab compared to bisphosphonates in oncology are summarized. Critical gaps in the literature concerning the safety of denosumab in oncology are highlighted as opposed to plenty of available safety data on denosumab as an antiosteoporotic agent.

Expert opinion

Despite the generally acceptable safety profile of denosumab in oncology, many issues remain unresolved. Further research is mandatory to counteract current challenges, namely: (i) validation of risk factors for adverse events; (ii) elucidation of the pathophysiology of the adverse events in search of actionable molecular pathways; (iii) illumination of the association of denosumab with increased risk of infections and/or second primary cancer; (iv) establishment of optimal diagnostic, and therapeutic protocols.

KEYWORDS:

• Atypical femoral fractures
• denosumab-related infections
• denosumab- related second primary cancer
• hypocalcemia
• osteonecrosis of the jaw
• post-denosumab vertebral fractures
• safety

Article highlights

• The multifaceted role of RANKL in cancer rationalizes exploiting denosumab ‒a human monoclonal antibody inhibiting RANKL‒ in oncology.

• Contrary to the plethora of available data concerning the safety of denosumab as an antiosteoporotic agent, our understanding of the safety of denosumab in oncology is still incomplete.

• Leveraging denosumab in oncology is interrelated with manageable, though challenging, adverse events, including hypocalcemia, medication-related osteonecrosis of the jaw, atypical femoral fractures, post-denosumab fractures, increased risk of infections, and/or second primary cancer.

• The alarming, yet inconsistent, correlation of denosumab with increased risk of infections and/or second primary cancer insinuates a complex immunomodulatory role of denosumab, which merits further evaluation.

• Whether the safety profile of denosumab in oncology extends beyond safety issues regarding denosumab as an antiosteoporotic agent remains an open question.

• Future research on the safety profile of denosumab should focus on the empowerment of a personalized, evidence-based, diagnostic, and therapeutic approach.

• The path forward for harnessing denosumab in oncology is to ensure that the therapeutic efficacy outweighs the risk of adverse events.

This box summarizes the key points contained in the article.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.