Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass

Area of Science:

• Bone biology and pharmacology
• Neuroendocrinology
• Drug discovery

Background:

• Erectile dysfunction drugs tadalafil and vardenafil target phosphodiesterase type 5A (PDE5A).
• PDE5A is present in bone cells and specific brain regions, suggesting potential roles beyond erectile function.
• The skeletal effects of PDE5A inhibitors are not fully understood.

Purpose of the Study:

• To investigate the effects of tadalafil and vardenafil on bone metabolism in mice.
• To identify the mechanisms underlying the skeletal actions of PDE5A inhibitors.
• To explore the expression and localization of PDE5A in bone and brain.

Main Methods:

• In vivo administration of tadalafil and vardenafil to mice.
• Analysis of bone formation and resorption markers.
• Gene expression profiling in osteoblasts.
• Immunohistochemistry and retrograde tracing to determine PDE5A localization.
• Structural modeling of drug-target interactions.

Main Results:

• Both tadalafil and vardenafil significantly increased bone gain in mice.
• Drugs enhanced osteoblastic bone formation and inhibited osteoclast formation.
• PDE5A was expressed in mouse and human bone, and in key brain regions controlling sympathetic output.
• PDE5A inhibitors induced an antianabolic sympathetic signal in osteoblasts, yet resulted in net bone gain.
• Tadalafil showed greater osteoprotective potency than vardenafil in mice, contrary to human data.

Conclusions:

• PDE5A inhibitors exert anabolic and antiresorptive effects on the skeleton, leading to bone gain.
• The bone-protective effects involve a balance between central and peripheral actions of PDE5A inhibitors.
• Differential drug-target interactions explain the reversed potencies observed in mice versus humans.