Testosterone and Male Bone Health: A Puzzle of Interactions.

Testosterone primarily drives cortical bone growth and periosteal expansion in males, particularly during puberty, while estradiol is essential for trabecular bone formation and inhibiting resorption.

• The distinct roles of testosterone and estradiol in male skeletal development are established through the review of physiological mechanisms.
• Testosterone's effects are predominantly on cortical bone and periosteal expansion.
• Estradiol's role is critical for trabecular bone formation and suppression of bone resorption in males.

Clinical models of estrogen resistance, aromatase deficiency, and complete androgen insensitivity syndrome highlight estradiol's critical role in maintaining male bone integrity.

• These clinical models serve as natural experiments demonstrating the relative contributions of estrogen versus androgen signaling to male bone health.
• Estrogen resistance and aromatase deficiency result in impaired bone integrity despite normal or elevated testosterone levels.
• Complete androgen insensitivity syndrome provides evidence distinguishing androgenic from estrogenic effects on bone.

Aromatase inhibitors and androgen deprivation therapy result in substantial bone loss in men.

• The adverse skeletal effects of both estrogen and androgen blockade are documented through clinical use of these therapies.
• Aromatase inhibitors reduce conversion of testosterone to estradiol, implicating estrogen deprivation in bone loss.
• Androgen deprivation therapy reveals the adverse effects of androgen blockade on male bone health.

Gender-affirming hormone therapies provide insights into testosterone's influence on cortical bone during development and the maintenance role of sex steroids in adulthood.

• Gender-affirming hormone therapy data are used as a clinical model to understand sex steroid effects on bone.
• These therapies illustrate testosterone's specific influence on cortical bone parameters during developmental periods.
• The data also inform understanding of how sex steroids maintain skeletal integrity in adulthood.

Testosterone replacement therapy has been shown to improve bone mineral density in hypogonadal men.

• Evidence from major clinical trials including T-Trial Bone, T4Bone, and TRAVERSE Fracture is reviewed.
• TRT demonstrates measurable improvements in bone mineral density as an outcome.
• The effect on fracture risk, however, remains inconclusive based on available trial data.

The TRAVERSE Fracture trial produced unexpected findings regarding testosterone replacement therapy and fracture outcomes.

• The TRAVERSE Fracture trial is described as yielding 'unexpected findings' in the context of TRT and skeletal outcomes.
• These findings 'highlight the importance of caution' when interpreting TRT's role in fracture prevention.
• The trial results confirm that antiresorptive therapies remain the first-line treatment for male osteoporosis.

The conversion of testosterone to dihydrotestosterone and estradiol, transport proteins, the somatotropic axis, and nonandrogenic testicular functions all contribute to the intricate interplay protecting male bone health.

• Multiple biochemical pathways and hormonal axes are identified as contributing to male skeletal protection.
• Testosterone metabolism via 5-alpha reductase to dihydrotestosterone and via aromatase to estradiol are both implicated.
• Nonandrogenic functions of the testis are noted as part of the complex system maintaining male bone health.

Antiresorptive therapies remain the first-line treatment for male osteoporosis.

• This conclusion is reinforced by the unexpected findings from the TRAVERSE Fracture trial.
• TRT's inconclusive effect on fracture risk supports maintaining antiresorptive agents as the primary therapeutic approach.
• The review emphasizes 'the importance of caution' regarding TRT as a primary osteoporosis treatment.

Investigating synergistic effects of combining TRT with antiresorptive therapies, therapeutic timing for peak bone mass accrual, and the role of confounders in fracture risk are identified as promising areas for future research.

• Three specific research areas are highlighted as priorities for optimizing male skeletal health.
• The effect of therapeutic timing on peak bone mass accrual is identified as an understudied area.
• The role of confounders in fracture risk assessment is noted as requiring further investigation.