Pubertal exposure to rising blood concentrations of sex steroids, partly in concert with transiently increased activity of the somatotropic axis, is instrumental in a pubertal acceleration of bone growth and acquisition of bone mass, followed by growth inhibition and closure of the epiphyseal cartilages in late puberty. As is illustrated by experiments of nature, i.e. subjects with aromatase deficiency or lack of functional oestrogen receptor α, and with androgen insensitivity syndrome, oestrogens are essential for skeletal maturation, acquisition of bone mass and epiphyseal closure, but androgen receptor-mediated action is required for achievement of optimal peak bone mass and size. In prepubertal causes of hypogonadism failure of timely and full pubertal development, and thus suboptimal sex steroid exposure, osteoporosis results from deficient accretion of bone mass and size. Potential for reversibility by testosterone administration depends on the advancement of skeletal maturation.
Acquired profound hypogonadism in adulthood, e.g. following androgen deprivation therapy for prostate cancer, induces a state of high bone turnover with accelerated bone loss and increased fracture risk, which results from combined deficiency of testosterone and oestradiol, its main aromatisation product.
Ageing is accompanied by a limited progressive decrease of serum total testosterone levels, a marked increase of serum SHBG, which results in a more marked decline of the non SHBG-bound serum testosterone fractions readily available for biological action. Whereas serum oestradiol is well maintained, there is a decline of the non SHBG-bound serum fractions. There is considerable between subject variability of these age-related changes. As to their implication for bone homeostasis, literature data concur to indicate that it is primarily oestrogen deficiency that contributes to the determination of senile bone loss.
In general, beneficial effects of testosterone treatment on bone mineral density have been limited to men with initially frank hypogonadism. On the other hand, osteoporotic hypogonadal men have been shown to be equally responsive to specific osteoporosis medication, e.g. bisphosphonates, denosumab or teriparatide, than eugonadal osteoporotic men.