Targeting Wnt signaling pathway with small-molecule therapeutics for treating osteoporosis.

Small molecules are emerging as potential candidates for treating osteoporosis by activating canonical Wnt signaling. These candidates work either by inhibiting DKK-1, sclerostin, SFRP-1, NOTUM, and S1P lyase or by preventing β-catenin degradation through inhibition of GSK-3β, or by targeting Dvl-CXXC5 and axin/β-catenin interactions. While many of these anti-osteoporotic small molecules are in preclinical development, the paucity of FDA-approved small molecules, or promising candidates, that have progressed to clinical trials for treating bone disorders through this mechanism poses a challenge. Despite advancements in computer-aided drug design, it is rarely employed for designing Wnt signaling activators to treat osteoporosis, and high-throughput screen (HTS) remains the primary method for discovering initial hits. Acknowledging the promising therapeutic potential of these compounds in addressing bone diseases, this review underscores the need for further mechanistic elucidation to enhance our understanding of their applications. Additionally, caution must be exercised in the design of small molecule-based Wnt activators due to their association with oncological risks.