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Overcoming natural Wnt inhibition to optimize therapy

The Wnt signalling pathway is the target of current anabolic therapies for osteoporosis. Studies in 2018 have revealed more about endogenous control of Wnt-related signalling, including mechanisms of natural Wnt inhibition and new anabolic signalling pathways that could be harnessed to overcome the challenges posed by current therapies.

Key advances

  • Upregulation of endogenous Wnt inhibitors in bone might be responsible for the plateau in the anabolic effect of anti-sclerostin therapy and the limited efficacy of anti-Dickkopf-related protein 1 therapy2,3.

  • Wnt1 signalling might be a new anabolic pathway that is low-density lipoprotein receptor-related protein 5 (LRP5)-independent4.

  • Sphingosine-1-phosphate, previously thought to be a coupling factor, might be an anti-resorptive therapeutic target5.

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Fig. 1: Challenges posed by therapies that target canonical Wnt signalling.


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The work of the author is supported by the St Vincent’s Institute Brenda Shanahan Fellowship and by the State Government of Victoria’s Operational Infrastructure Scheme. The author thanks T. J. Martin for helpful discussions during the preparation of this work.

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Correspondence to Natalie A. Sims.

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The author declares no competing interests.

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Sims, N.A. Overcoming natural Wnt inhibition to optimize therapy. Nat Rev Rheumatol 15, 67–68 (2019).

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