Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

Abstract

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably, simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

Bone loss: Drug combination reduces toxicity of cancer treatment

Potential bone loss caused by cancer drugs could be mitigated by administering an existing osteoporosis drug. Over-activation of the Wnt signaling pathway, which helps maintain healthy tissues and bone development, is often found in cancer. Scientists are trialing cancer drugs that block a key enzyme PORCN and therefore inhibit Wnt signaling, but these drugs may also adversely affect patients’ bone structure. David Virshup at Duke-NUS Medical School in Singapore and Bart Williams at the Van Andel Research Institute in Michigan, US, and co-workers found that mice treated with PORCN -inhibiting cancer drugs lost bone volume and density within four weeks of exposure. The team then combined the cancer drug with another drug, alendronate, which is already used to treat osteoporosis. This combination targeted aberrant Wnt signaling and limited bone toxicity in the mice.

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