Is testosterone anti-resorptive?

Testosterone's Antiresorptive Effects on Bone

Testosterone has direct antiresorptive effects on bone through inhibition of osteoclastogenesis and bone resorption, functioning as an effective antiresorptive agent in bone metabolism. 1, 2

Mechanism of Action

Testosterone exerts its antiresorptive effects through multiple pathways:

1. Direct inhibition of osteoclastogenesis:

   • Testosterone directly inhibits osteoclast formation and bone resorption at physiological concentrations 1
   • Acts through androgen receptors (AR) in osteoblast-lineage cells 2, 3
   • Suppresses osteoclast surface and tartrate-resistant acid phosphatase expression 2

2. Indirect effects via osteoblasts:

   • Stimulates proliferation of preosteoblasts and differentiation of osteoblasts 4
   • Suppresses RANKL (receptor activator of nuclear factor k-B ligand) expression in osteoblasts 3
   • Reduces osteoclastogenesis supporting activity of osteoblasts 3

3. Dual pathways:

   • Acts directly through androgen receptors 1, 3
   • Acts indirectly through aromatization to estrogen, which then acts on estrogen receptors 4

Clinical Evidence

The antiresorptive effects of testosterone are supported by several clinical observations:

• In male AR knockout mice, bone loss occurs due to high bone turnover with increased bone resorption 3
• Testosterone replacement in orchidectomized mice partially prevents bone loss 3
• Testosterone has been shown to prevent botulinum toxin-induced bone loss independent of muscle effects 2
• Dihydrotestosterone (DHT), a non-aromatizable androgen, demonstrates antiresorptive effects on trabecular bone 2

Clinical Applications

Testosterone's antiresorptive properties have important clinical implications:

• Hypogonadal men: Age-related testosterone deficiency is a major factor in bone loss in elderly men 4

• Androgen deprivation therapy (ADT): Men with prostate cancer receiving ADT experience bone loss due to testosterone deficiency 5

  • Within 6 months of ADT initiation, men have a 5-year fracture risk of 19% versus 12% in matched controls 5

• Transgender healthcare: Testosterone therapy in transmasculine individuals needs monitoring for bone health 5

Comparison with Other Antiresorptives

While testosterone has antiresorptive properties, established antiresorptive medications are typically used for osteoporosis treatment:

• Bisphosphonates and denosumab are the most commonly used agents for managing bone loss during ADT 5
• Denosumab 60mg every 6 months reduces vertebral fracture risk by 62% in men on ADT 5
• For high fracture risk, oral bisphosphonates are first-line treatment, with IV bisphosphonates or denosumab for those with contraindications 6

Clinical Considerations

When considering testosterone for bone health:

• Maintain optimal levels of androgen to prevent osteoporosis in elderly men 4
• Consider that both androgen and estrogen are indispensable for bone formation, while estrogen is particularly important for suppressing bone resorption 4
• In men with osteoporosis, further research is required to determine the role of testosterone in treatment 5
• For men on ADT, antiresorptive therapy is recommended if BMD T-score is <-2.0 or with two or more risk factors for fracture 5

Conclusion

Testosterone functions as an antiresorptive agent through direct effects on osteoclastogenesis and indirect effects via osteoblasts. While it plays an important role in maintaining bone health in men, established antiresorptive medications remain the standard treatment for osteoporosis and treatment-induced bone loss.