madman
Super Moderator
Bone health in aging men (2022)
Karel David · Nick Narinx · Leen Antonio · Pieter Evenepoel · Frank Claessens · Brigitte Decallonne · Dirk Vanderschueren
Abstract
Osteoporosis does not only affect postmenopausal women but also aging men. The burden of disease is projected to increase with higher life expectancy both in females and males. Importantly, osteoporotic men remain more often undiagnosed and untreated compared to women. Sex steroid deficiency is associated with bone loss and increased fracture risk, and circulating sex steroid levels have been shown to be associated both with bone mineral density and fracture risk in elderly men. However, in contrast to postmenopausal osteoporosis, the contribution of a relatively small decrease of circulating sex steroid concentrations in the aging male to the development of osteoporosis and related fractures is probably only minor. In this review we provide several clinical and preclinical arguments in favor of a ‘bone threshold’ for the occurrence of hypogonadal osteoporosis, corresponding to a grade of sex steroid deficiency that in general will not occur in many elderly men. Testosterone replacement therapy has been shown to increase bone mineral density in men, however, data in osteoporotic aging males are scarce, and evidence on fracture risk reduction is lacking. We conclude that testosterone replacement therapy should not be used as a sole bone-specific treatment in osteoporotic elderly men.
1 Epidemiology of osteoporosis and fractures in aging men
2 Male versus female bone (accretion, maintenance, aging) – structural changes contribute to strength
3 Sex steroids and their impact on bone: is it androgen, estrogen, or both?
It is well recognized that sex steroids are essential for the development, as well as maintenance of both bone structure and density. Experimental data suggest a pivotal role for both estrogens and androgens, while in humans, estrogens seem to be the main sex steroids driving bone mass accrual, and similarly, for bone maintenance, estrogen deficiency is the most important determinant of sex steroid deficiency mediated bone loss.
The main circulating androgen in humans, testosterone (T) is being converted into estrogens, mainly into estradiol (E2), in peripheral tissues, such as fat, by the aromatase enzyme. In men, more than 85% of the circulating E2 levels originate from the peripheral aromatization of T. [64, 65] As such, T can exert its actions on bone both by stimulating the androgen receptor (AR) directly, or the estrogen receptor alpha (ERɑ) after aromatization. T is hence the ideal androgen since it integrates both ER and AR actions, which are both important for skeletal development on the one hand, and bone maintenance on the other.
The specific role of both androgens and estrogens and their respective receptors in experimental studies have been reviewed extensively. [43, 66] In summary, AR-related androgen action results in increased cortical apposition, and decreased resorption in the trabecular compartment in male mice. Estrogens, via ERɑ, also increase periosteal apposition and decrease cortical endosteal bone resorption, while next to decreased trabecular bone resorption, also increase trabecular bone formation. For the normal development of trabecular and periosteal bone growth, both presences of AR and ERɑ are essential in male mice during puberty. [67]
In humans, overt hypogonadism, and thereby loss of both AR and ER-mediated androgen actions, clearly results in low bone mass, both in regions that are mainly composed of cortical bone, such as the radius, as well as trabecular bone enriched regions, such as the spine. [68, 69] Likewise, men who are deprived of endogenous androgen production, such as prostate cancer patients treated with gonadotropin-releasing agonists, suffer from bone loss, as well as structural decay of bone both in the cortical and trabecular compartment, such as decreased cortical vBMD and loss of the number of trabeculae. [70–73] Consequently, prostate cancer patients treated with androgen deprivation therapy (ADT) had an increased fracture risk compared to both controls and prostate cancer patients not treated with ADT (Fig. 1). [74–77]
3.1 Aromatization of androgens and impact on bone structure and density
3.2 AR versus ERɑ-mediated androgen actions and impact on bone structure and density
3.3 Experimental evidence for low estrogens as driver of bone resorption in men
4 Impact of decreasing circulating sex steroid concentration on bone structure and density in ageing men
5 Association of bone mineral density and/ or fracture risk in elderly men with their circulating sex steroid levels
6 Importance of calcium and vitamin D
7 Physical activity and muscle strength
8 Risk of falls and prevention
9 Bone-specific treatment of osteoporosis
10 Testosterone replacement therapy and bone
11 Evaluation of male osteoporosis
11.1 Case history and physical examination
11.2 Laboratory assessment and screening for secondary causes: is this needed in the elderly population?
11.3 Dual X-ray absorptiometry: is it as useful in men as in women?
11.4 Fracture risk Assessment Tool: in men as well?
11.5 Vertebral fracture screening: also relevant in men
12 Management and treatment: are they different in men compared to women?
Treatment of male osteoporosis is similar to postmenopausal osteoporosis. [277] It should include lifestyle changes, calcium and vitamin D substitution, as well as the use of bonespecifc treatments (Fig. 2). First, certain lifestyle factors such as smoking and alcohol intake should be addressed. Patients should be advised to regularly exercise to improve strength and balance, thereby reducing the risk of falls. [287] Secondly, the advised intake of calcium is 1000–1200 mg daily, preferably via diet, if not with supplementation. [312] 25(OH)D levels of >20 ng/mL should be targeted, mostly vitamin D intake of 800 IU daily is sufficient to attain this goal. [161, 287, 313–315] Finally, the use of TRT alone as anti-osteoporotic drug is not recommended, similar to the advice against the use of hormonal replacement therapy as sole agent for osteoporosis in postmenopausal women. Specific bone-targeted therapies are recommended if fracture risk is high. Bisphosphonates are still the most commonly used therapy, due to their wide availability and low cost; however, first-line treatment might also differ due to country-specific reimbursement criteria. Guidelines support the use of bone-specific treatment in men with a history of low-impact fracture of the vertebrae and hip, men with a T-score ≤-2.5, and older men with a combination of osteopenia on BMD and FRAX derived 10-year hip fracture probability of ≥3% or 10-year MOF probability of ≥20%. [264, 287] Finally, in addition to TRT, hypogonadal osteoporosis should be treated with anti-osteoporotic drugs similar to primary age-related osteoporosis without severe underlying hypogonadism and not left untreated since it is a well-recognized additional risk factor for fractures.
13 Conclusion
Osteoporosis imposes a major health burden which is expected only to increase with higher life expectancies. It is a condition not limited to postmenopausal women but also affects aging men, and the diagnostic and therapeutic gap in male osteoporosis is large and remains larger compared to women. In humans, estrogens are the main drivers of hypogonadism-associated bone loss as seen in postmenopausal osteoporosis and severely androgen-deprived men; therefore, aromatization of T seems to be important for the maintenance of male bone. Although positive correlations between declining sex steroid levels, mainly free and bioavailable fractions, and decline in bone density and increase in fracture risk in older men have been demonstrated, the contribution of sex steroid deficiency to age-related bone loss seems to be small in community-dwelling men (Fig. 1). Determination of circulating sex steroid levels in older men does not improve fracture risk prediction. TRT is able to increase BMD in hypogonadal men, especially when T levels are <200 ng/dL. In this review, we have discussed several clinical as well as preclinical arguments in favor of a ‘bone threshold’ for hypogonadal osteoporosis, corresponding to a grade of sex steroid deficiency that in general will not occur in many elderly men. Data on BMD evolution in osteoporotic older men treated with TRT are scarce, and TRT is still without evidence for fracture risk reduction. Hence, TRT is not recommended as a bone-specific treatment for male osteoporosis. The diagnosis and treatment of male osteoporosis are therefore largely similar to postmenopausal osteoporosis (Fig. 2). Bone-specific treatments have been shown to increase bone mineral density, and for some also fracture risk reduction in both primary male osteoporosis and hypogonadism-related osteoporosis in men.
Karel David · Nick Narinx · Leen Antonio · Pieter Evenepoel · Frank Claessens · Brigitte Decallonne · Dirk Vanderschueren
Abstract
Osteoporosis does not only affect postmenopausal women but also aging men. The burden of disease is projected to increase with higher life expectancy both in females and males. Importantly, osteoporotic men remain more often undiagnosed and untreated compared to women. Sex steroid deficiency is associated with bone loss and increased fracture risk, and circulating sex steroid levels have been shown to be associated both with bone mineral density and fracture risk in elderly men. However, in contrast to postmenopausal osteoporosis, the contribution of a relatively small decrease of circulating sex steroid concentrations in the aging male to the development of osteoporosis and related fractures is probably only minor. In this review we provide several clinical and preclinical arguments in favor of a ‘bone threshold’ for the occurrence of hypogonadal osteoporosis, corresponding to a grade of sex steroid deficiency that in general will not occur in many elderly men. Testosterone replacement therapy has been shown to increase bone mineral density in men, however, data in osteoporotic aging males are scarce, and evidence on fracture risk reduction is lacking. We conclude that testosterone replacement therapy should not be used as a sole bone-specific treatment in osteoporotic elderly men.
1 Epidemiology of osteoporosis and fractures in aging men
2 Male versus female bone (accretion, maintenance, aging) – structural changes contribute to strength
3 Sex steroids and their impact on bone: is it androgen, estrogen, or both?
It is well recognized that sex steroids are essential for the development, as well as maintenance of both bone structure and density. Experimental data suggest a pivotal role for both estrogens and androgens, while in humans, estrogens seem to be the main sex steroids driving bone mass accrual, and similarly, for bone maintenance, estrogen deficiency is the most important determinant of sex steroid deficiency mediated bone loss.
The main circulating androgen in humans, testosterone (T) is being converted into estrogens, mainly into estradiol (E2), in peripheral tissues, such as fat, by the aromatase enzyme. In men, more than 85% of the circulating E2 levels originate from the peripheral aromatization of T. [64, 65] As such, T can exert its actions on bone both by stimulating the androgen receptor (AR) directly, or the estrogen receptor alpha (ERɑ) after aromatization. T is hence the ideal androgen since it integrates both ER and AR actions, which are both important for skeletal development on the one hand, and bone maintenance on the other.
The specific role of both androgens and estrogens and their respective receptors in experimental studies have been reviewed extensively. [43, 66] In summary, AR-related androgen action results in increased cortical apposition, and decreased resorption in the trabecular compartment in male mice. Estrogens, via ERɑ, also increase periosteal apposition and decrease cortical endosteal bone resorption, while next to decreased trabecular bone resorption, also increase trabecular bone formation. For the normal development of trabecular and periosteal bone growth, both presences of AR and ERɑ are essential in male mice during puberty. [67]
In humans, overt hypogonadism, and thereby loss of both AR and ER-mediated androgen actions, clearly results in low bone mass, both in regions that are mainly composed of cortical bone, such as the radius, as well as trabecular bone enriched regions, such as the spine. [68, 69] Likewise, men who are deprived of endogenous androgen production, such as prostate cancer patients treated with gonadotropin-releasing agonists, suffer from bone loss, as well as structural decay of bone both in the cortical and trabecular compartment, such as decreased cortical vBMD and loss of the number of trabeculae. [70–73] Consequently, prostate cancer patients treated with androgen deprivation therapy (ADT) had an increased fracture risk compared to both controls and prostate cancer patients not treated with ADT (Fig. 1). [74–77]
3.1 Aromatization of androgens and impact on bone structure and density
3.2 AR versus ERɑ-mediated androgen actions and impact on bone structure and density
3.3 Experimental evidence for low estrogens as driver of bone resorption in men
4 Impact of decreasing circulating sex steroid concentration on bone structure and density in ageing men
5 Association of bone mineral density and/ or fracture risk in elderly men with their circulating sex steroid levels
6 Importance of calcium and vitamin D
7 Physical activity and muscle strength
8 Risk of falls and prevention
9 Bone-specific treatment of osteoporosis
10 Testosterone replacement therapy and bone
11 Evaluation of male osteoporosis
11.1 Case history and physical examination
11.2 Laboratory assessment and screening for secondary causes: is this needed in the elderly population?
11.3 Dual X-ray absorptiometry: is it as useful in men as in women?
11.4 Fracture risk Assessment Tool: in men as well?
11.5 Vertebral fracture screening: also relevant in men
12 Management and treatment: are they different in men compared to women?
Treatment of male osteoporosis is similar to postmenopausal osteoporosis. [277] It should include lifestyle changes, calcium and vitamin D substitution, as well as the use of bonespecifc treatments (Fig. 2). First, certain lifestyle factors such as smoking and alcohol intake should be addressed. Patients should be advised to regularly exercise to improve strength and balance, thereby reducing the risk of falls. [287] Secondly, the advised intake of calcium is 1000–1200 mg daily, preferably via diet, if not with supplementation. [312] 25(OH)D levels of >20 ng/mL should be targeted, mostly vitamin D intake of 800 IU daily is sufficient to attain this goal. [161, 287, 313–315] Finally, the use of TRT alone as anti-osteoporotic drug is not recommended, similar to the advice against the use of hormonal replacement therapy as sole agent for osteoporosis in postmenopausal women. Specific bone-targeted therapies are recommended if fracture risk is high. Bisphosphonates are still the most commonly used therapy, due to their wide availability and low cost; however, first-line treatment might also differ due to country-specific reimbursement criteria. Guidelines support the use of bone-specific treatment in men with a history of low-impact fracture of the vertebrae and hip, men with a T-score ≤-2.5, and older men with a combination of osteopenia on BMD and FRAX derived 10-year hip fracture probability of ≥3% or 10-year MOF probability of ≥20%. [264, 287] Finally, in addition to TRT, hypogonadal osteoporosis should be treated with anti-osteoporotic drugs similar to primary age-related osteoporosis without severe underlying hypogonadism and not left untreated since it is a well-recognized additional risk factor for fractures.
13 Conclusion
Osteoporosis imposes a major health burden which is expected only to increase with higher life expectancies. It is a condition not limited to postmenopausal women but also affects aging men, and the diagnostic and therapeutic gap in male osteoporosis is large and remains larger compared to women. In humans, estrogens are the main drivers of hypogonadism-associated bone loss as seen in postmenopausal osteoporosis and severely androgen-deprived men; therefore, aromatization of T seems to be important for the maintenance of male bone. Although positive correlations between declining sex steroid levels, mainly free and bioavailable fractions, and decline in bone density and increase in fracture risk in older men have been demonstrated, the contribution of sex steroid deficiency to age-related bone loss seems to be small in community-dwelling men (Fig. 1). Determination of circulating sex steroid levels in older men does not improve fracture risk prediction. TRT is able to increase BMD in hypogonadal men, especially when T levels are <200 ng/dL. In this review, we have discussed several clinical as well as preclinical arguments in favor of a ‘bone threshold’ for hypogonadal osteoporosis, corresponding to a grade of sex steroid deficiency that in general will not occur in many elderly men. Data on BMD evolution in osteoporotic older men treated with TRT are scarce, and TRT is still without evidence for fracture risk reduction. Hence, TRT is not recommended as a bone-specific treatment for male osteoporosis. The diagnosis and treatment of male osteoporosis are therefore largely similar to postmenopausal osteoporosis (Fig. 2). Bone-specific treatments have been shown to increase bone mineral density, and for some also fracture risk reduction in both primary male osteoporosis and hypogonadism-related osteoporosis in men.
