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Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass

Se-Min Kim, Charit Taneja, Helena Perez-Pena, Vitaly Ryu, Anisa Gumerova, Wenliang Li, Naseer Ahmad, Ling-Ling Zhu, Peng Liu, Mehr Mathew, Funda Korkmaz, Sakshi Gera (+17 others)
2020 Proceedings of the National Academy of Sciences of the United States of America  

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We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe
more » ... pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine β-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a single methionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.
doi:10.1073/pnas.2000950117 pmid:32513693 fatcat:bz3c7ye7wndvhodqkehiv7rndi
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Se-Min Kim, Charit Taneja, Helena Perez-Pena, Vitaly Ryu, Anisa Gumerova, Wenliang Li, Naseer Ahmad, Ling-Ling Zhu, Peng Liu, Mehr Mathew, Funda Korkmaz, Sakshi Gera, Damini Sant, Elina Hadelia, Kseniia Ievleva, Tan-Chun Kuo, Hirotaka Miyashita, Li Liu, Irina Tourkova, Sarah Stanley, Daria Lizneva, Jameel Iqbal, Li Sun, Ronald Tamler, Harry C. Blair, Maria I. New, Shozeb Haider, Tony Yuen, Mone Zaidi. "Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass." Proceedings of the National Academy of Sciences of the United States of America 117.25 (2020) 202000950