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Beyond the target: implications of Wnt pathway inhibitors on bone health
Clement Nachef1,2,3, Arnaud Vanjak4, Eric Haÿ5,6
1Rheumatology Department, Lariboisiere Hospital, Paris, France. clement.nachef@aphp.fr.
Abstract:
Wnt signaling inhibitors are under investigation as potential therapies for conditions characterized by upregulated Wnt signaling, such as cancers, hematological disorders, and organ fibrosis. However, because the Wnt pathway is essential for bone homeostasis, its inhibition can adversely affect skeletal health. This review focuses on the bone-related off-target effects of Wnt inhibitors currently in clinical development, specifically those evaluated in Phase I and II trials with available published data. We found that inhibitors targeting upstream components of the pathway-such as Wnt ligands or receptors (e.g., porcupine inhibitors, Ipafricept, or Vantictumab)-frequently lead to bone-related adverse effects, including fractures and early trial termination. Co-administration of bisphosphonates may help mitigate these effects. In contrast, downstream inhibitors (e.g., PRI-724, niclosamide) have not been linked to bone toxicity, although this may reflect either underreporting or a genuinely lower skeletal impact. Further preclinical studies are warranted to better understand these differential effects. A thorough understanding of bone-specific risks is critical as Wnt signaling inhibitors continue to advance in clinical development.
Insights
Wnt signaling inhibitors targeting upstream pathways can cause bone toxicity and fractures. Downstream inhibitors show fewer skeletal side effects, but more research is needed to confirm safety.
Area of Science:
- Oncology
- Pharmacology
- Skeletal Biology
Background:
- Wnt signaling pathway is crucial for normal cellular functions and implicated in various diseases like cancer.
- Wnt pathway inhibition is a therapeutic strategy for cancers and other disorders.
- However, Wnt pathway's role in bone homeostasis raises concerns about skeletal side effects of inhibitors.
Purpose of the Study:
- To review bone-related off-target effects of Wnt inhibitors in clinical development (Phase I/II).
- To analyze the impact of upstream versus downstream Wnt inhibitors on skeletal health.
- To inform clinical development strategies regarding bone toxicity.
Main Methods:
- Literature review of published data from Phase I and II clinical trials of Wnt inhibitors.
- Focus on inhibitors targeting different levels of the Wnt pathway (upstream vs. downstream).
- Analysis of reported bone-related adverse events and trial outcomes.
Main Results:
- Upstream Wnt inhibitors (targeting ligands/receptors) frequently caused bone toxicity, including fractures and early trial termination.
- Co-administration with bisphosphonates may reduce skeletal adverse effects.
- Downstream Wnt inhibitors showed no reported bone toxicity, possibly due to underreporting or lower skeletal impact.
Conclusions:
- Wnt inhibitors targeting upstream pathway components pose significant skeletal risks.
- Downstream inhibitors may offer a safer alternative regarding bone health, pending further investigation.
- Understanding and mitigating bone-specific risks is crucial for advancing Wnt inhibitor therapies.
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