Testosterone and Male Bone Health: A Puzzle of Interactions

Abstract Sex steroids are pivotal in skeletal development and maintenance throughout life. Testosterone primarily drives male cortical bone growth and periosteal expansion, particularly during puberty, while estradiol (E2) is essential for trabecular bone formation and inhibiting resorption. The conversion of testosterone to dihydrotestosterone and E2, the transport proteins, the somatotropic axis, and the nonandrogenic functions of the testis underscore the intricate interplay protecting male bone health. Clinical models, including estrogen resistance, aromatase deficiency, and complete androgen insensitivity syndromes, highlight E2’s critical role in maintaining male bone integrity. The use of aromatase inhibitors and androgen deprivation therapy reveals the adverse effects of estrogen and androgen blockade, often resulting in substantial bone loss. Gender-affirming hormone therapies provide further insights into testosterone's influence on cortical bone during development and the maintenance role of sex steroids in adulthood. This review digs into the link between male hypogonadism and osteoporosis, emphasizing testosterone replacement therapy (TRT) and findings from major trials, including T-Trial Bone, T4Bone, and TRAVERSE Fracture. While TRT has been shown to improve bone mineral density, its effect on fracture risk remains inconclusive. Unexpected findings from the TRAVERSE Fracture trial highlight the importance of caution and confirm that antiresorptive therapies remain the first-line treatment for male osteoporosis. Investigating the synergistic effects of combining TRT with antiresorptive therapies, the effect of therapeutic timing on peak bone mass accrual, and the role of confounders in fracture risk are promising areas for future research to optimize male skeletal health.