madman
Super Moderator
Abstract: Bone fracture due to osteoporosis is an important issue in decreasing the quality of life for elderly men in the current aging society. Thus, osteoporosis and bone fracture prevention is a clinical concern for many clinicians. Moreover, testosterone has an important role in maintaining bone mineral density (BMD) among men. Some testosterone molecular mechanisms on bone metabolism have been currently established by many experimental data. Concurrent with a decrease in testosterone with age, various clinical symptoms and signs associated with testosterone decline, including decreased BMD, are known to occur in elderly men. However, the relationship between testosterone levels and osteoporosis development has been conflicting in human epidemiological studies. Thus, testosterone replacement therapy (TRT) is a useful tool for managing clinical symptoms caused by hypogonadism. Many recent studies support the benefit of TRT on BMD, especially in hypogonadal men with osteopenia and osteoporosis, although a few studies failed to demonstrate its effects. However, no evidence supporting the hypothesis that TRT can prevent the incidence of bone fracture exists. Currently, TRT should be considered as one of the treatment options to improve hypogonadal symptoms and BMD simultaneously in symptomatic hypogonadal men with osteopenia.
1. Introduction
Serum testosterone levels decrease by 1% annually with age in elderly men [1], which may induce various clinical symptoms of late-onset hypogonadism (LOH) syndrome [2]. LOH syndrome is involved in a cluster of clinical symptoms, including depression, irritability, sexual dysfunction, decreased muscle mass and strength, and decreased bone mineral density (BMD), visceral obesity, and metabolic syndrome, which have been thought to be associated with aging [3,4]. These symptoms and signs often impair the quality of life (QOL) in elderly men and are considered a serious public health concern in the current aging society. Thus, testosterone replacement therapy (TRT) is expected to be one of the tools for improving these clinical conditions and QOL in men with LOH syndrome. Consequently, its clinical use has substantially increased over the past years [5].
In particular, osteoporosis often causes compression spine fractures and femoral neck fractures in elderly men, resulting in a decrease in activities of daily living (ADL) and QOL. Estrogen, which is important for maintaining BMD, decreases immediately in women during menopause. However, testosterone, which decreases slowly with age, plays an important role in maintaining BMD in men. Therefore, osteoporosis occurs more commonly in elderly women than in men [6,7]. The prevalence of osteoporosis increases with age at <10%, 13%, 18%, and 21% for 40, 70–75, 75–80, and >80 years old men in Japan, respectively [8]. Moreover, about 12 million people are estimated to suffer from osteoporosis [6,7]. The incidence frequency of femoral neck fracture is fourfold more in men than in women with osteoporosis [9]. Thus, osteoporosis prevention is an important issue in maintaining ADL and QOL in elderly men.
BMD has a close correlation with serum testosterone levels in men. Moreover, testosterone levels immediately decrease because of androgen deprivation therapy (ADT) for prostate cancer, resulting in a decrease in BMD and osteoporosis. In addition, estradiol (E2) converted from testosterone by aromatase is deeply related to BMD maintenance. A relative decrease in estrogen level due to ADT also poses a risk for BMD loss [10,11]. In general, BMD decreases by about 2%–8% in 1 year after the commencement of ADT [12]. Furthermore, ADT increases the risk of decreased BMD at five- to tenfold compared to prostate cancer patients with normal testosterone levels. A meta-analysis demonstrated that 9%–53% of osteoporosis incidence was caused by ADT [13]. Consequently, patients with ADT have a definite higher risk of sustaining a fracture. Furthermore, ADT can increase the risk of proximal femur fractures by 1.5- to 1.8-fold [14,15]. The BMD decrease in these patients is caused by a decline in serum testosterone and estrogen levels by ADT.
As aforementioned, the association between testosterone deficiency and BMD loss has been currently clarified. It is believed that TRT can contribute to maintaining and increasing BMD among hypogonadal men. However, the efficacy of TRT for bone health in hypogonadal men has been currently less in consensus and more conflicting [16–21]. Therefore, this article reviewed the relationship between testosterone and BMD in men and mentioned the benefits of TRT on BMD among hypogonadal men
3. Molecular Roles of Sex Hormones on Bone Metabolism
Testosterone is converted to highly active dihydrotestosterone (DHT) by 5α-reductase in the cytoplasm of target cells [22,23]. Consequently, DHT can induce androgenic activity by binding to the androgen receptor (AR). Moreover, testosterone is converted to E2 by aromatase. E2 binds to the estrogen receptor (ER) and exerts estrogenic action. ERα and ERβ are the two ER subtypes. ERα is mainly associated with bone metabolism [10,24.].
AR is present in chondrocytes and osteoblasts, although its expression level widely varies by age and bone sites. Testosterone acts directly on osteoblasts by AR and can consequently promote bone formation [17]. In addition, testosterone has some indirect effects on bone metabolism through various cytokines and growth factors [17,25–28] (Figure 1). Furthermore, testosterone can increase AR expression level in osteoblasts, resulting in differentiation promotion and osteoblast and chondrocyte apoptosis proliferation [17,29]. Consequently, less evidence supporting the hypothesis that testosterone has any direct effects on osteoclasts have been shown [30].
In addition, testosterone deficiency promotes the activation of nuclear factor kappaB ligand (RANKL) production from osteoblasts, which contributes to the promotion of the differentiations and functions in osteoclasts. Increased RANKL level progresses bone resorption and decreases BMD [25,26]. Thus, testosterone positively regulates the expression of insulin-like growth factor-1 (IGF-1) and IGF-binding protein (IGF-BP) in osteoblasts. The differentiation and proliferation of chondrocytes and osteoblasts are induced by IGF and IGF-BP, and the suppression of apoptosis of chondrocytes promotes bone formation. Moreover, testosterone activates the expression of transforming growth factor-β (TGF-β) in osteoblasts and promotes the differentiation of osteoblasts [27]. Testosterone suppresses the activity of interleukins (IL)-6, which activates osteoclasts and promotes bone resorption. However, testosterone deficiency decreases in BMD through increased IL-6 activation [28].
E2 and ERα also play important roles in maintaining BMD in men and women. Estrogen has a greater effect than androgen in inhibiting bone resorption in men. Consequently, men with loss of ERα function exhibit extremely low BMD [31]. Male patients with aromatase deficiency have a marked decrease in BMD in trabecular and cortical bone. Thus, estrogen replacement therapy in these patients can improve BMD [32,33]. E2 generally regulates apoptosis and function of osteoclast, which contributes to BMD maintenance. Moreover, E2 deficiency may accelerate osteoclast apoptosis by increased tumor growth factor-β production [34,35]. IL-1, IL-6, IL-7, IGF-1, nuclear factor-κB (NFκB), RANKL, and tumor necrotic factor-α (TNFα) are the E2 target genes [36–39]. However, E2 deficiency increases IL-6, which reduces osteoblast proliferation and activity while increasing osteoclastic activity and increasing the expression of RANKL-mediated osteoclastogenesis [36,37]. Some experimental data showed that estrogen decrease also induces inflammatory cytokine, IL-1, and TNFα, resulting in BMD loss. However, this phenomenon does not occur in IL-1 receptor- or TNFα-deficient mice [38,39].
4. The Relationship between Hypogonadism and BMD in Humans
5. The Relationship between Testosterone and Bone Fracture
6. The Effects of TRT on Bone Health among Hypogonadal Men
7. Conclusions
Testosterone plays an important role in maintaining BMD and bone health among men. In addition, many molecular mechanisms of testosterone on bone metabolism have been currently established by many experimental data. Several recent studies demonstrated the benefit of TRT on BMD, especially in hypogonadal men with osteopenia and osteoporosis. However, a few studies failed to demonstrate its effects, and no evidence supporting the hypothesis that TRT can prevent bone fracture incidence exists. Further studies involving a large number of subjects and longer treatment duration are required to reach a more conclusive result regarding the effects of TRT on bone health.
Current evidence suggests that TRT is not recommended as a tool solely to enhance and maintain BMD for hypogonadal men. TRT should be considered as one of the treatment options to improve hypogonadal symptoms and BMD simultaneously in symptomatic hypogonadal men with osteopenia.
1. Introduction
Serum testosterone levels decrease by 1% annually with age in elderly men [1], which may induce various clinical symptoms of late-onset hypogonadism (LOH) syndrome [2]. LOH syndrome is involved in a cluster of clinical symptoms, including depression, irritability, sexual dysfunction, decreased muscle mass and strength, and decreased bone mineral density (BMD), visceral obesity, and metabolic syndrome, which have been thought to be associated with aging [3,4]. These symptoms and signs often impair the quality of life (QOL) in elderly men and are considered a serious public health concern in the current aging society. Thus, testosterone replacement therapy (TRT) is expected to be one of the tools for improving these clinical conditions and QOL in men with LOH syndrome. Consequently, its clinical use has substantially increased over the past years [5].
In particular, osteoporosis often causes compression spine fractures and femoral neck fractures in elderly men, resulting in a decrease in activities of daily living (ADL) and QOL. Estrogen, which is important for maintaining BMD, decreases immediately in women during menopause. However, testosterone, which decreases slowly with age, plays an important role in maintaining BMD in men. Therefore, osteoporosis occurs more commonly in elderly women than in men [6,7]. The prevalence of osteoporosis increases with age at <10%, 13%, 18%, and 21% for 40, 70–75, 75–80, and >80 years old men in Japan, respectively [8]. Moreover, about 12 million people are estimated to suffer from osteoporosis [6,7]. The incidence frequency of femoral neck fracture is fourfold more in men than in women with osteoporosis [9]. Thus, osteoporosis prevention is an important issue in maintaining ADL and QOL in elderly men.
BMD has a close correlation with serum testosterone levels in men. Moreover, testosterone levels immediately decrease because of androgen deprivation therapy (ADT) for prostate cancer, resulting in a decrease in BMD and osteoporosis. In addition, estradiol (E2) converted from testosterone by aromatase is deeply related to BMD maintenance. A relative decrease in estrogen level due to ADT also poses a risk for BMD loss [10,11]. In general, BMD decreases by about 2%–8% in 1 year after the commencement of ADT [12]. Furthermore, ADT increases the risk of decreased BMD at five- to tenfold compared to prostate cancer patients with normal testosterone levels. A meta-analysis demonstrated that 9%–53% of osteoporosis incidence was caused by ADT [13]. Consequently, patients with ADT have a definite higher risk of sustaining a fracture. Furthermore, ADT can increase the risk of proximal femur fractures by 1.5- to 1.8-fold [14,15]. The BMD decrease in these patients is caused by a decline in serum testosterone and estrogen levels by ADT.
As aforementioned, the association between testosterone deficiency and BMD loss has been currently clarified. It is believed that TRT can contribute to maintaining and increasing BMD among hypogonadal men. However, the efficacy of TRT for bone health in hypogonadal men has been currently less in consensus and more conflicting [16–21]. Therefore, this article reviewed the relationship between testosterone and BMD in men and mentioned the benefits of TRT on BMD among hypogonadal men
3. Molecular Roles of Sex Hormones on Bone Metabolism
Testosterone is converted to highly active dihydrotestosterone (DHT) by 5α-reductase in the cytoplasm of target cells [22,23]. Consequently, DHT can induce androgenic activity by binding to the androgen receptor (AR). Moreover, testosterone is converted to E2 by aromatase. E2 binds to the estrogen receptor (ER) and exerts estrogenic action. ERα and ERβ are the two ER subtypes. ERα is mainly associated with bone metabolism [10,24.].
AR is present in chondrocytes and osteoblasts, although its expression level widely varies by age and bone sites. Testosterone acts directly on osteoblasts by AR and can consequently promote bone formation [17]. In addition, testosterone has some indirect effects on bone metabolism through various cytokines and growth factors [17,25–28] (Figure 1). Furthermore, testosterone can increase AR expression level in osteoblasts, resulting in differentiation promotion and osteoblast and chondrocyte apoptosis proliferation [17,29]. Consequently, less evidence supporting the hypothesis that testosterone has any direct effects on osteoclasts have been shown [30].
In addition, testosterone deficiency promotes the activation of nuclear factor kappaB ligand (RANKL) production from osteoblasts, which contributes to the promotion of the differentiations and functions in osteoclasts. Increased RANKL level progresses bone resorption and decreases BMD [25,26]. Thus, testosterone positively regulates the expression of insulin-like growth factor-1 (IGF-1) and IGF-binding protein (IGF-BP) in osteoblasts. The differentiation and proliferation of chondrocytes and osteoblasts are induced by IGF and IGF-BP, and the suppression of apoptosis of chondrocytes promotes bone formation. Moreover, testosterone activates the expression of transforming growth factor-β (TGF-β) in osteoblasts and promotes the differentiation of osteoblasts [27]. Testosterone suppresses the activity of interleukins (IL)-6, which activates osteoclasts and promotes bone resorption. However, testosterone deficiency decreases in BMD through increased IL-6 activation [28].
E2 and ERα also play important roles in maintaining BMD in men and women. Estrogen has a greater effect than androgen in inhibiting bone resorption in men. Consequently, men with loss of ERα function exhibit extremely low BMD [31]. Male patients with aromatase deficiency have a marked decrease in BMD in trabecular and cortical bone. Thus, estrogen replacement therapy in these patients can improve BMD [32,33]. E2 generally regulates apoptosis and function of osteoclast, which contributes to BMD maintenance. Moreover, E2 deficiency may accelerate osteoclast apoptosis by increased tumor growth factor-β production [34,35]. IL-1, IL-6, IL-7, IGF-1, nuclear factor-κB (NFκB), RANKL, and tumor necrotic factor-α (TNFα) are the E2 target genes [36–39]. However, E2 deficiency increases IL-6, which reduces osteoblast proliferation and activity while increasing osteoclastic activity and increasing the expression of RANKL-mediated osteoclastogenesis [36,37]. Some experimental data showed that estrogen decrease also induces inflammatory cytokine, IL-1, and TNFα, resulting in BMD loss. However, this phenomenon does not occur in IL-1 receptor- or TNFα-deficient mice [38,39].
4. The Relationship between Hypogonadism and BMD in Humans
5. The Relationship between Testosterone and Bone Fracture
6. The Effects of TRT on Bone Health among Hypogonadal Men
7. Conclusions
Testosterone plays an important role in maintaining BMD and bone health among men. In addition, many molecular mechanisms of testosterone on bone metabolism have been currently established by many experimental data. Several recent studies demonstrated the benefit of TRT on BMD, especially in hypogonadal men with osteopenia and osteoporosis. However, a few studies failed to demonstrate its effects, and no evidence supporting the hypothesis that TRT can prevent bone fracture incidence exists. Further studies involving a large number of subjects and longer treatment duration are required to reach a more conclusive result regarding the effects of TRT on bone health.
Current evidence suggests that TRT is not recommended as a tool solely to enhance and maintain BMD for hypogonadal men. TRT should be considered as one of the treatment options to improve hypogonadal symptoms and BMD simultaneously in symptomatic hypogonadal men with osteopenia.
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