Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

Area of Science:

• Oncology
• Pharmacology
• Bone Biology

Background:

• Dysregulated Wnt signaling drives cancers, fibrosis, and vascular diseases.
• Wnt pathway inhibitors show therapeutic promise but face challenges balancing efficacy and toxicity.
• Wnt signaling is critical for bone homeostasis, influencing osteoblast and osteoclast differentiation.

Purpose of the Study:

• To investigate the skeletal effects of porcupine (PORCN) inhibitors, which block Wnt secretion.
• To assess if bone loss induced by PORCN inhibition can be mitigated by co-administered bone-protective agents.

Main Methods:

• Mice were treated with two distinct PORCN inhibitors (LGK974 and ETC-159).
• Skeletal changes were evaluated using micro-computed tomography and histomorphometry.
• The effect of alendronate, a bisphosphonate, on PORCN inhibitor-induced bone toxicity was assessed.

Main Results:

• PORCN inhibitor treatment led to significant bone loss (decreased volume and density) within 4 weeks.
• Bone marrow exhibited a notable increase in adipocytes following PORCN inhibitor exposure.
• Alendronate co-administration mitigated bone loss and prevented bone marrow adipocyte accumulation induced by ETC-159.

Conclusions:

• Acute inhibition of Wnt signaling via PORCN blockade negatively impacts bone homeostasis.
• Co-administration of bone-protective agents like alendronate can counteract PORCN inhibitor-induced skeletal toxicity.
• Mitigating bone toxicity may enhance the therapeutic application of Wnt pathway inhibitors in various diseases.