Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass
Abstract
Significance Tadalafil and vardenafil are among the most widely used drugs for erectile dysfunction, which affects nearly 19% of men over 20 y of age. Older men also suffer from age-related bone loss resulting in crippling fractures. We show that in mice, both agents act on bone cells, resulting in the formation of new bone and reduced removal of old bone. Because of this net gain in bone mass, we posit that tadalafil and vardenafil could be used for cotreating erectile dysfunction and osteoporosis in men of advancing age, as well as for treating osteoporosis in postmenopausal women. We recommend future clinical studies to establish the capability of these drugs to increase bone density and reduce fracture risk in humans. 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,…
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