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Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass.

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 ?-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.

SUBMITTER: Kim SM

PROVIDER: S-EPMC7321982 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass.

Kim Se-Min SM Taneja Charit C Perez-Pena Helena H Ryu Vitaly V Gumerova Anisa A Li Wenliang W Ahmad Naseer N Zhu Ling-Ling LL Liu Peng P Mathew Mehr M Korkmaz Funda F Gera Sakshi S Sant Damini D Hadelia Elina E Ievleva Kseniia K Kuo Tan-Chun TC Miyashita Hirotaka H Liu Li L Tourkova Irina I Stanley Sarah S Lizneva Daria D Iqbal Jameel J Sun Li L Tamler Ronald R Blair Harry C HC New Maria I MI Haider Shozeb S Yuen Tony T Zaidi Mone M

Proceedings of the National Academy of Sciences of the United States of America 20200608 25

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]

PMID: 32513693

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Project description:ImportanceTadalafil is used to treat erectile dysfunction after prostate cancer treatment, but its role as a preventive agent is undefined.ObjectivesTo determine primarily whether tadalafil preserved erectile function in men treated with radiotherapy for prostate cancer, and secondarily to determine whether participant- or partner-reported overall sexual function and sexual and marital satisfaction were affected.Design, setting, and participantsStratified, placebo-controlled, double-blind, parallel-group study with 1:1 randomization at 76 community-based and tertiary medical sites in the United States and Canada. Two hundred forty-two participants with intact erectile function scheduled to receive radiotherapy for prostate cancer were recruited between November 2009 and February 2012 with follow-up through March 2013.InterventionsOne hundred twenty-one participants were assigned 5 mg of tadalafil daily and 121 were assigned placebo for 24 weeks starting with external radiotherapy (63%) or brachytherapy (37%). Participant-reported International Index of Erectile Function response before radiotherapy and at weeks 2 and 4, between weeks 20 and 24, between weeks 28 and 30, and 1 year thereafter. Participants and partners could respond also to the Sexual Adjustment Questionnaire and to the Locke Marital Adjustment Test before radiotherapy, between weeks 20 and 24 and weeks 28 and 30, and at 1 year.Main outcomes and measuresPrimary outcome was off-drug spontaneous erectile function 28 to 30 weeks after radiotherapy started. Secondary end points were spontaneous erection at 1 year; overall sexual function and satisfaction; marital adjustment; and partner-reported satisfaction and marital adjustment at 28 to 30 weeks and 1 year, predictors of tadalafil response; and adverse events.ResultsAmong 221 evaluable participants, 80 (79%; 95% CI, 70%-88%) assigned to receive tadalafil retained erectile function between weeks 28 and 30 compared with 61 (74%; 95% CI, 63%-85%) assigned to receive placebo (P = .49); an absolute difference of 5% (95% CI, -9% to 19%). A significant difference was also not observed at 1 year (72%; 95% CI, 60%-84% vs 71%; 95% CI, 59%-84%; P = .93). Tadalafil was not associated with significantly improved overall sexual function or satisfaction; a significant difference was not observed in any domain subscale. Partners of men assigned tadalafil noted no significant effect on sexual satisfaction, and marital adjustment was not significantly improved in participants or partners.Conclusions and relevanceAmong men undergoing radiotherapy for prostate cancer, daily use of tadalafil compared with placebo did not result in improved erectile function. These findings do not support daily use of tadalafil to prevent erectile dysfunction in these patients.Trial registrationclinicaltrials.gov Identifier: NCT00931528.

Dataset Information

Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass.

Publications

Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass.

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