Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 25; pp. 14386 - 14394
• Main Authors: Kim, Se-Min, Taneja, Charit, Perez-Pena, Helena, Ryu, Vitaly, Gumerova, Anisa, Li, Wenliang, Ahmad, Naseer, Zhu, Ling-Ling, Liu, Peng, Mathew, Mehr, Korkmaz, Funda, Gera, Sakshi, Sant, Damini, Hadelia, Elina, Ievleva, Kseniia, Kuo, Tan-Chun, Miyashita, Hirotaka, Liu, Li, Tourkova, Irina, Stanley, Sarah, Lizneva, Daria, Iqbal, Jameel, Sun, Li, Tamler, Ronald, Blair, Harry C., New, Maria I., Haider, Shozeb, Yuen, Tony, Zaidi, Mone
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.06.2020
• Subjects: Aging - physiology; Animals; Biological Sciences; Biomedical materials; Bone and Bones - cytology; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone Density - drug effects; Bone Density - physiology; Bone growth; Bone mass; Brain; Brain - cytology; Brain - drug effects; Brain - metabolism; Cell Differentiation - drug effects; Cyclic Nucleotide Phosphodiesterases, Type 5 - chemistry; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Dopamine; Dopamine β-monooxygenase; Drug Repositioning; Drugs; Erectile dysfunction; Erectile Dysfunction - complications; Erectile Dysfunction - drug therapy; Humans; Hydroxylase; Hypothalamus; Localization; Locus coeruleus; Male; Methionine; Mice; Middle Aged; Models, Animal; Models, Molecular; Neurons - drug effects; Neurons - metabolism; Osteoblasts; Osteoblasts - drug effects; Osteoblasts - physiology; Osteoclasts - drug effects; Osteoclasts - physiology; Osteogenesis; Osteogenesis - drug effects; Osteoporosis - complications; Osteoporosis - drug therapy; Osteoporotic Fractures - etiology; Osteoporotic Fractures - prevention & control; Paraventricular nucleus; Phosphodiesterase; Phosphodiesterase 5 Inhibitors - chemistry; Phosphodiesterase 5 Inhibitors - pharmacology; Phosphodiesterase 5 Inhibitors - therapeutic use; Primary Cell Culture; Skeleton; Sympathetic nerves; Tadalafil - chemistry; Tadalafil - pharmacology; Tadalafil - therapeutic use; Vardenafil Dihydrochloride - chemistry; Vardenafil Dihydrochloride - pharmacology; Vardenafil Dihydrochloride - therapeutic use; Viruses; resorption; computational modeling; osteoporosis; PDE5 inhibitor; cyclic GMP
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2000950117

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 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.