madman
Super Moderator
* Testosterone plays an important role in the maintenance of male skeleton. Most studies of testosterone therapy have demonstrated some degree of improvement in BMD
* Based on elegant mechanistic studies (discussed below), the current thinking is that both testosterone and estradiol are essential to bone health with testosterone mainly having an anabolic effect on osteoblastic activity while estrogen is the main anti-resorptive hormone that triggers osteoclast apoptosis [15, 18, 21] (Fig. 1) [15].
* Men with profound androgen deficiency (organic hypogonadism) experience a much greater decline in BMD compared to men who have modestly low serum testosterone levels (e.g. age-related) and are also more responsive to treatment with testosterone.
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Fig. 1 An overview of the effects of testosterone and estrogen on bone remodeling. Both sex steroids inhibit osteoclastogenesis while testosterone also stimulates osteoblasts.
Fig. 2 Molecular mechanisms via which sex steroids mediate their effects on the male skeleton (Adapted from references 17–27)
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Male Skeleton and Bone Turnover
Based on elegant mechanistic studies (discussed below), the current thinking is that both testosterone and estradiol are essential to bone health with testosterone mainly having an anabolic effect on osteoblastic activity while estrogen is the main anti-resorptive hor- mone that triggers osteoclast apoptosis [15, 18, 21] (Fig. 1) [15].
==========
Mechanism of Action of Testosterone and Estrogen on the Male Skeleton
Mature osteoblasts are integral to bone health as they play a key role in the mineralization of bone matrix. Androgen receptors are present on osteoblasts and once bound, androgens stimulate further upregulation of androgen receptors on osteoblasts, inhibit apoptosis of osteoblasts, and promote their differentiation [15, 22, 23]. The antiresorptive effects of testosterone are mainly mediated via its aromatization to estradiol. Indeed, in healthy men whose endogenous testosterone is suppressed by administration of GnRH agonists, the effects of exogenous testosterone replacement on bone resorption are attenuated when these men are concurrently given aromatase inhibitors [22, 24]. Androgens do, however, have some independent effects on bone resorption. Indeed, it has been demonstrated that testosterone directly inhibits differentiation of monocytes into osteoclasts in the presence of macrophage stimulating factor and RANKL, an effect which is blocked by flutamide (androgen receptor antagonist) [25]. Other in vitro studies have shown that estradiol prevents osteocyte apoptosis and stimulates the production of transforming growth factor (TGF)-β [15, 26]. A mechanistic study of 70 men that assessed relative contributions of androgens and estrogens on bone remodeling found that both sex steroids inhibit bone resorption, however, estradiol was more potent while androgens played a key role in stimulating bone formation [24, 27].
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In addition to their direct action on osteocytes and osteoclasts, androgens also modulate bone metabolism indirectly via regulation of cytokines and growth factors within the bone microenvironment. For instance, androgens upregulate TGF-β and insulin-like growth factors (which promote osteoblastic differentiation and bone formation) while suppressing interleukin-6 expression (a cytokine that stimulates osteoclastogenesis) [18, 27, 28] (Fig. 2). One of the reasons why estradiol is more potent than testosterone in reducing bone resorption is because it increases serum concentrations of osteoprotegerin (OPG) (a soluble neutralizing receptor that binds to and inactivates RANKL—the final mediator of osteoclastogenesis) while testosterone reduces serum OPG levels [17–20, 27]. Another indirect mechanism by which testosterone positively impacts male skeleton is via its anabolic effects on skeletal muscles as mechanical loading and local release of myokines modulates bone turnover (12,17
============
Association of Age-Related Decline in Testosterone and Bone Health in Population Studies
In summary, these data suggest that both testosterone and estradiol have a positive impact on male skeletal health, and that higher SHBG levels (which results in reduced concentrations of bioavailable sex steroids) may have a detrimental impact on bone health.
=====
Decline in BMD and Fracture Risk in Men with Profound Androgen Deficiency
In summary, men with profound androgen deficiency experience accelerated bone loss, likely due to deficiency of both testosterone and estradiol, and are at a higher risk for fractures.
==========
Effects of Testosterone Replacement on BMD
In the following section, we briefly discuss studies of testosterone replacement in men with profound androgen deficiency due to pathologic conditions followed by large seminal trials (the T-Trials and the TRAVERSE trial) in middle-aged and older men with mild age-related decline in testosterone levels.
----------
Men with Pathologic (Organic) Hypogonadism
In summary, these data suggest that testosterone replacement is most efficacious in improving BMD in men who have unequivocal androgen deficiency and its aromatization to estradiol is important in imparting this benefit. Men with Age-Related Low Testosterone.
------
Bone Sub-study of the Testosterone Trials (T-Trials)
------
The TRAVERSE Trial
------
Conclusions
Testosterone plays an important role in the maintenance of bone health in men. Hypogonadism is associated with reduced bone mass with the degree of androgen deficiency directly related to the magnitude of bone loss. Men with profound androgen deficiency (organic hypogonadism) experience a much greater decline in BMD compared to men who have modestly low serum testosterone levels (e.g. age-related) and are also more responsive to treatment with testosterone. Although testosterone therapy improves BMD (to variable degrees) in different cohorts of men, this increase thus far has not translated into reduction in fracture rates. Therefore, we recommend that men who are at higher risk for fractures be treated with drugs that have proven anti-fracture efficacy.
* Based on elegant mechanistic studies (discussed below), the current thinking is that both testosterone and estradiol are essential to bone health with testosterone mainly having an anabolic effect on osteoblastic activity while estrogen is the main anti-resorptive hormone that triggers osteoclast apoptosis [15, 18, 21] (Fig. 1) [15].
* Men with profound androgen deficiency (organic hypogonadism) experience a much greater decline in BMD compared to men who have modestly low serum testosterone levels (e.g. age-related) and are also more responsive to treatment with testosterone.
======
Fig. 1 An overview of the effects of testosterone and estrogen on bone remodeling. Both sex steroids inhibit osteoclastogenesis while testosterone also stimulates osteoblasts.
Fig. 2 Molecular mechanisms via which sex steroids mediate their effects on the male skeleton (Adapted from references 17–27)
==============
===========
Male Skeleton and Bone Turnover
Based on elegant mechanistic studies (discussed below), the current thinking is that both testosterone and estradiol are essential to bone health with testosterone mainly having an anabolic effect on osteoblastic activity while estrogen is the main anti-resorptive hor- mone that triggers osteoclast apoptosis [15, 18, 21] (Fig. 1) [15].
==========
Mechanism of Action of Testosterone and Estrogen on the Male Skeleton
Mature osteoblasts are integral to bone health as they play a key role in the mineralization of bone matrix. Androgen receptors are present on osteoblasts and once bound, androgens stimulate further upregulation of androgen receptors on osteoblasts, inhibit apoptosis of osteoblasts, and promote their differentiation [15, 22, 23]. The antiresorptive effects of testosterone are mainly mediated via its aromatization to estradiol. Indeed, in healthy men whose endogenous testosterone is suppressed by administration of GnRH agonists, the effects of exogenous testosterone replacement on bone resorption are attenuated when these men are concurrently given aromatase inhibitors [22, 24]. Androgens do, however, have some independent effects on bone resorption. Indeed, it has been demonstrated that testosterone directly inhibits differentiation of monocytes into osteoclasts in the presence of macrophage stimulating factor and RANKL, an effect which is blocked by flutamide (androgen receptor antagonist) [25]. Other in vitro studies have shown that estradiol prevents osteocyte apoptosis and stimulates the production of transforming growth factor (TGF)-β [15, 26]. A mechanistic study of 70 men that assessed relative contributions of androgens and estrogens on bone remodeling found that both sex steroids inhibit bone resorption, however, estradiol was more potent while androgens played a key role in stimulating bone formation [24, 27].
--
In addition to their direct action on osteocytes and osteoclasts, androgens also modulate bone metabolism indirectly via regulation of cytokines and growth factors within the bone microenvironment. For instance, androgens upregulate TGF-β and insulin-like growth factors (which promote osteoblastic differentiation and bone formation) while suppressing interleukin-6 expression (a cytokine that stimulates osteoclastogenesis) [18, 27, 28] (Fig. 2). One of the reasons why estradiol is more potent than testosterone in reducing bone resorption is because it increases serum concentrations of osteoprotegerin (OPG) (a soluble neutralizing receptor that binds to and inactivates RANKL—the final mediator of osteoclastogenesis) while testosterone reduces serum OPG levels [17–20, 27]. Another indirect mechanism by which testosterone positively impacts male skeleton is via its anabolic effects on skeletal muscles as mechanical loading and local release of myokines modulates bone turnover (12,17
============
Association of Age-Related Decline in Testosterone and Bone Health in Population Studies
In summary, these data suggest that both testosterone and estradiol have a positive impact on male skeletal health, and that higher SHBG levels (which results in reduced concentrations of bioavailable sex steroids) may have a detrimental impact on bone health.
=====
Decline in BMD and Fracture Risk in Men with Profound Androgen Deficiency
In summary, men with profound androgen deficiency experience accelerated bone loss, likely due to deficiency of both testosterone and estradiol, and are at a higher risk for fractures.
==========
Effects of Testosterone Replacement on BMD
In the following section, we briefly discuss studies of testosterone replacement in men with profound androgen deficiency due to pathologic conditions followed by large seminal trials (the T-Trials and the TRAVERSE trial) in middle-aged and older men with mild age-related decline in testosterone levels.
----------
Men with Pathologic (Organic) Hypogonadism
In summary, these data suggest that testosterone replacement is most efficacious in improving BMD in men who have unequivocal androgen deficiency and its aromatization to estradiol is important in imparting this benefit. Men with Age-Related Low Testosterone.
------
Bone Sub-study of the Testosterone Trials (T-Trials)
------
The TRAVERSE Trial
------
Conclusions
Testosterone plays an important role in the maintenance of bone health in men. Hypogonadism is associated with reduced bone mass with the degree of androgen deficiency directly related to the magnitude of bone loss. Men with profound androgen deficiency (organic hypogonadism) experience a much greater decline in BMD compared to men who have modestly low serum testosterone levels (e.g. age-related) and are also more responsive to treatment with testosterone. Although testosterone therapy improves BMD (to variable degrees) in different cohorts of men, this increase thus far has not translated into reduction in fracture rates. Therefore, we recommend that men who are at higher risk for fractures be treated with drugs that have proven anti-fracture efficacy.
