ArticleProceedings of the National Academy of Sciences of the United States of America2020
Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Assessing the therapeutic potential of PDE-5 inhibitors in adults: Insights from a multi-omics study.Physiological reports · 2026Article
- Phosphodiesterase inhibitors as emerging therapeutics for skeletal disorders: A comprehensive review of mechanisms and repurposing potential.Bone reports · 2026Review
- Advances in the regulation of bone metabolism by central nuclei: a new perspective on the brain-bone axis.Frontiers in neuroscience · 2026Review
- Targeting the central and peripheral nervous system to regulate bone homeostasis: mechanisms and potential therapies.Military Medical Research · 2025Review
- Article
- A plasma membrane-associated form of the androgen receptor enhances nuclear androgen signaling in osteoblasts and prostate cancer cells.Science signaling · 2024Article
- Tadalafil Rescues the p.M325T Mutant of Best1 Chloride Channel.Molecules (Basel, Switzerland) · 2023Article
- Article
- Protein Kinase G2 Is Essential for Skeletal Homeostasis and Adaptation to Mechanical Loading in Male but Not Female Mice.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2023Article
- Crosstalk between bone and other organs.Medical review (2021) · 2022Review
- Tadalafil and Steroid Hormones Interactions in Adipose, Bone and Prostate Tissues: Focus on Translational Perspectives.International journal of molecular sciences · 2022Review
- Repurposing existing products to accelerate injury recovery (REPAIR) of military relevant musculoskeletal conditions.Frontiers in bioengineering and biotechnology · 2022Article
- Combinations of Freeze-Dried Amorphous Vardenafil Hydrochloride with Saccharides as a Way to Enhance Dissolution Rate and Permeability.Pharmaceuticals (Basel, Switzerland) · 2021Article
- The NO-cGMP-PKG pathway in skeletal remodeling.Annals of the New York Academy of Sciences · 2021Review
- Recent Advances in Osteoclast Biological Behavior.Frontiers in cell and developmental biology · 2021Review
- Inhibition of Phosphodiesterase 5 Promotes the Aromatase-Mediated Estrogen Biosynthesis in Osteoblastic Cells by Activation of cGMP/PKG/SHP2 Pathway.Frontiers in endocrinology · 2021Article
Corrections and comments
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Authors and funding
29 authors at 4 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.