madman
Super Moderator
Late Onset Hypogonadism (LOH): bone health
Abstract
Background. Bone health is underdiagnosed and undermanaged in men. Bone loss occurs in men with hypogonadism and in aging men. Thus, patients with a diagnosis of late-onset hypogonadism (LOH) are at risk of osteoporosis and osteoporotic fractures.
Objectives. To provide an update on research data and clinical implications regarding bone health in men with LOH by reviewing literature articles on this issue.
Materials and Methods. A thorough search of listed publications in PubMed on bone health in older men with hypogonadism and was performed and other articles derived from these publications were further identified.
Results. LOH may be associated with reduced bone mineral density (BMD). From a pathophysiological perspective, the detrimental effects of testosterone (T) deficiency on BMD are partly ascribed to relative estrogen deficiency and both serum T and serum estradiol (E2) needs to be above 200 ng/dL and 20 pg/mL to prevent bone loss. The effects of exogenous T on BMD are controversial but most of the studies confirm that testosterone replacement therapy (TRT) increases BMD and prevents further bone loss in men with hypogonadism. No data are available on TRT and the prevention of fractures.
Discussion and Conclusion. In men with documented LOH, a specific clinical workup should be addressed to the diagnosis of osteoporosis in order to program subsequent follow-up and consider specific bone active therapy. TRT should be started according to guidelines of male hypogonadism while keeping in mind that it may also have positive effects also on bone health in men with LOH.
Introduction
Bone health in men is a partially neglected health issue since it is less investigated than in the female counterpart 1-3. Even the clinical trials investigating the efficacy of bone active drugs involve a smaller number of men than females and not all of these drugs, which are available on the market for the treatment of female osteoporosis, have been approved also for men by regulatory agencies 3,4. At present, evidence from several studies have unequivocally proved that male osteoporosis i) is often secondary to other clinical conditions 3,5, ii) occurs later in life compared to women in the majority of cases3, and iii) osteoporotic fractures are associated with higher morbidity and mortality in elderly men compared to women 1,6,7. Among secondary osteoporosis, male hypogonadism is one of the most important risk factors and accounts for the progressive bone loss in aging men, especially in case of a diagnosis of late-onset hypogonadism (LOH) 1,8. Serum testosterone (T), in fact, decreases with advancing age in elderly men and the amount of serum estradiol (E2) tends to decrease accordingly 9; the same occurs for bone loss during aging 1-3. Traditionally, T was considered the main sex steroid acting on male bone, but starting from the Nineties, the pivotal role exerted by estrogens started to rise 10-13 thanks to the description of the first cases of men with congenital estrogen deficiency due to estrogen resistance 14 and aromatase deficiency 15,16. The observation that a condition of severe estrogen deficiency was constantly associated with the arrest of skeletal maturation, and to severe bone loss resulting in osteopenia or osteoporosis in adult men with these rare diseases 17,18 opened the way to fully understand the role of estrogens on bone as well as on other male physiological processes 12, 19-2.
Pathophysiology of T deficiency and its metabolites in bone
Sex steroids, both androgens, and estrogens exert direct and indirect effects on bone tissue and regulate bone homeostasis 23-25. Estrogens derive from androgens after the aromatization of the A ring of androgens through the activity of the CYP19A1 enzyme, named aromatase, is expressed in many male tissues 11,12,26.
*Effects of T on bone
T exerts direct and indirect effects on bone 27-30. Direct effects of T involves several cells within the bone; among them, human mesenchymal stem cells, osteoblasts, and osteocytes express the androgen receptor and are target cells for T31; vice versa osteoclasts are not targeted cells for direct action of T and androgens regulate osteoclast proliferation and activity indirectly through the modulation of the receptor activator of nuclear factor (RANK ligand) 27. T and its metabolite dihydrotestosterone (DHT) exert anabolic action on osteocytes and osteoblasts by promoting cell proliferation and probably also their differentiation 32, but the latter effect is less clear 27,28. Furthermore, T inhibits apoptosis of osteoblasts 33. Locally produced androgens (i.e. DHT) within the bone contribute together with the circulating quote to support the direct effect of androgens on bone and account for different percentages of sex steroids within the tissue compared to blood concentration 29.
The indirect effect of androgens on bone cells may be mediated by several cytokines and by the local production of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) that are known to be under the control of T 27. Other indirect effects on bone are mediated by the mechanical load exerted by the muscle masses surrounding the bone. As muscle mass depends on serum T and hypogonadism leads to sarcopenia, this indirect effect is of great relevance for bone homeostasis 1,34,35. Both hypogonadism 19,36 and aging 37 lead to the physiological reduction of body muscle masses and sarcopenia in older men thus promoting bone loss due to mechanical strain 38 and postural instability, thus increasing the risk of fracture due to osteoporosis or increased incidence of falls 38,39 due to altered muscle-bone cross-talk 40.
*Effects of E2 on bone
Estrogens in men exert their action through the binding to the ERs. Nuclear ER-alpha and ER-beta and the transmembrane G protein-coupled receptor GPR30 (GPER30) are expressed in human male tissue. The nuclear receptors account for genomic effects of estrogens, while the GPR30 transmembrane receptor accounts for non-genomic, rapid effects of estrogens 11,12,26.
In men locally produced estrogens in bone come from androgens thanks to aromatase that is expressed in fibroblasts and other bone cells (i.e. osteoblasts and osteoclasts) 12,41; the same occurs in tissues surrounding the bone such as the adipose tissue and the bone marrow 26. Circulating estrogens, as well as locally produced estrogens, exert their effect on bone through the binding to both ER-alpha and ER-beta that is expressed in the following bone cells: osteoblasts, osteoclasts, and osteocytes 42, all these cell types express also GPER 30,43,44. Furthermore, estrogens increase osteocytes vitality and inhibit their apoptosis 45, induce apoptosis of osteoclasts 46, and inhibit their differentiation through the modulation of RANKL 42. The final result is the decrease of bone resorption operated by osteoclasts 47. On the contrary, estrogens promote/maintain bone formation by osteoblasts through an antiapoptotic effect 48 and by stimulating their differentiation 49. Apart from direct effects, estrogens modulate other hormones and cytokines involved in bone physiology (indirect effects), among them the GH/IGF-1 network being one of the most important 50. Finally, estrogens positively modulate the bone response to mechanical strain 51,52 similar to what androgens do 38,40.
*LOH, relative estrogen deficiency and osteoporosis in men
LOH and Bone Mineral Density (BMD)
Bone health: clinical approach in men with LOH
*Clinical examinations
*Sex Steroids Measurements
*Biochemical evaluation of bone metabolism
*Imaging
*Fracture risk in men with LOH
Effects of T treatment on bone in LOH patients
Follow-up
Physical activity and the prevention of further bone loss
Treatment of osteopenia/osteoporosis in men with LOH
Unresolved Issues
Conclusions
The assessment of bone health should be included in the clinical work-up of men with LOH bearing in mind that osteoporosis is undermanaged and underdiagnosed in older men and remains less investigated by researchers than in the female counterpart. Bone health, in fact, may be considered a rare case of gender health inequality favoring women rather than men 2,3. Normative data obtained by studies on the male population are urgently needed for both DXA reference values and FRAX risk calculation in order to better tailor the diagnosis and the follow-up of men with osteoporosis. Andrological consultation performed in men with LOH represents an opportunity for male health 173 including bone 4.
Abstract
Background. Bone health is underdiagnosed and undermanaged in men. Bone loss occurs in men with hypogonadism and in aging men. Thus, patients with a diagnosis of late-onset hypogonadism (LOH) are at risk of osteoporosis and osteoporotic fractures.
Objectives. To provide an update on research data and clinical implications regarding bone health in men with LOH by reviewing literature articles on this issue.
Materials and Methods. A thorough search of listed publications in PubMed on bone health in older men with hypogonadism and was performed and other articles derived from these publications were further identified.
Results. LOH may be associated with reduced bone mineral density (BMD). From a pathophysiological perspective, the detrimental effects of testosterone (T) deficiency on BMD are partly ascribed to relative estrogen deficiency and both serum T and serum estradiol (E2) needs to be above 200 ng/dL and 20 pg/mL to prevent bone loss. The effects of exogenous T on BMD are controversial but most of the studies confirm that testosterone replacement therapy (TRT) increases BMD and prevents further bone loss in men with hypogonadism. No data are available on TRT and the prevention of fractures.
Discussion and Conclusion. In men with documented LOH, a specific clinical workup should be addressed to the diagnosis of osteoporosis in order to program subsequent follow-up and consider specific bone active therapy. TRT should be started according to guidelines of male hypogonadism while keeping in mind that it may also have positive effects also on bone health in men with LOH.
Introduction
Bone health in men is a partially neglected health issue since it is less investigated than in the female counterpart 1-3. Even the clinical trials investigating the efficacy of bone active drugs involve a smaller number of men than females and not all of these drugs, which are available on the market for the treatment of female osteoporosis, have been approved also for men by regulatory agencies 3,4. At present, evidence from several studies have unequivocally proved that male osteoporosis i) is often secondary to other clinical conditions 3,5, ii) occurs later in life compared to women in the majority of cases3, and iii) osteoporotic fractures are associated with higher morbidity and mortality in elderly men compared to women 1,6,7. Among secondary osteoporosis, male hypogonadism is one of the most important risk factors and accounts for the progressive bone loss in aging men, especially in case of a diagnosis of late-onset hypogonadism (LOH) 1,8. Serum testosterone (T), in fact, decreases with advancing age in elderly men and the amount of serum estradiol (E2) tends to decrease accordingly 9; the same occurs for bone loss during aging 1-3. Traditionally, T was considered the main sex steroid acting on male bone, but starting from the Nineties, the pivotal role exerted by estrogens started to rise 10-13 thanks to the description of the first cases of men with congenital estrogen deficiency due to estrogen resistance 14 and aromatase deficiency 15,16. The observation that a condition of severe estrogen deficiency was constantly associated with the arrest of skeletal maturation, and to severe bone loss resulting in osteopenia or osteoporosis in adult men with these rare diseases 17,18 opened the way to fully understand the role of estrogens on bone as well as on other male physiological processes 12, 19-2.
Pathophysiology of T deficiency and its metabolites in bone
Sex steroids, both androgens, and estrogens exert direct and indirect effects on bone tissue and regulate bone homeostasis 23-25. Estrogens derive from androgens after the aromatization of the A ring of androgens through the activity of the CYP19A1 enzyme, named aromatase, is expressed in many male tissues 11,12,26.
*Effects of T on bone
T exerts direct and indirect effects on bone 27-30. Direct effects of T involves several cells within the bone; among them, human mesenchymal stem cells, osteoblasts, and osteocytes express the androgen receptor and are target cells for T31; vice versa osteoclasts are not targeted cells for direct action of T and androgens regulate osteoclast proliferation and activity indirectly through the modulation of the receptor activator of nuclear factor (RANK ligand) 27. T and its metabolite dihydrotestosterone (DHT) exert anabolic action on osteocytes and osteoblasts by promoting cell proliferation and probably also their differentiation 32, but the latter effect is less clear 27,28. Furthermore, T inhibits apoptosis of osteoblasts 33. Locally produced androgens (i.e. DHT) within the bone contribute together with the circulating quote to support the direct effect of androgens on bone and account for different percentages of sex steroids within the tissue compared to blood concentration 29.
The indirect effect of androgens on bone cells may be mediated by several cytokines and by the local production of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) that are known to be under the control of T 27. Other indirect effects on bone are mediated by the mechanical load exerted by the muscle masses surrounding the bone. As muscle mass depends on serum T and hypogonadism leads to sarcopenia, this indirect effect is of great relevance for bone homeostasis 1,34,35. Both hypogonadism 19,36 and aging 37 lead to the physiological reduction of body muscle masses and sarcopenia in older men thus promoting bone loss due to mechanical strain 38 and postural instability, thus increasing the risk of fracture due to osteoporosis or increased incidence of falls 38,39 due to altered muscle-bone cross-talk 40.
*Effects of E2 on bone
Estrogens in men exert their action through the binding to the ERs. Nuclear ER-alpha and ER-beta and the transmembrane G protein-coupled receptor GPR30 (GPER30) are expressed in human male tissue. The nuclear receptors account for genomic effects of estrogens, while the GPR30 transmembrane receptor accounts for non-genomic, rapid effects of estrogens 11,12,26.
In men locally produced estrogens in bone come from androgens thanks to aromatase that is expressed in fibroblasts and other bone cells (i.e. osteoblasts and osteoclasts) 12,41; the same occurs in tissues surrounding the bone such as the adipose tissue and the bone marrow 26. Circulating estrogens, as well as locally produced estrogens, exert their effect on bone through the binding to both ER-alpha and ER-beta that is expressed in the following bone cells: osteoblasts, osteoclasts, and osteocytes 42, all these cell types express also GPER 30,43,44. Furthermore, estrogens increase osteocytes vitality and inhibit their apoptosis 45, induce apoptosis of osteoclasts 46, and inhibit their differentiation through the modulation of RANKL 42. The final result is the decrease of bone resorption operated by osteoclasts 47. On the contrary, estrogens promote/maintain bone formation by osteoblasts through an antiapoptotic effect 48 and by stimulating their differentiation 49. Apart from direct effects, estrogens modulate other hormones and cytokines involved in bone physiology (indirect effects), among them the GH/IGF-1 network being one of the most important 50. Finally, estrogens positively modulate the bone response to mechanical strain 51,52 similar to what androgens do 38,40.
*LOH, relative estrogen deficiency and osteoporosis in men
LOH and Bone Mineral Density (BMD)
Bone health: clinical approach in men with LOH
*Clinical examinations
*Sex Steroids Measurements
*Biochemical evaluation of bone metabolism
*Imaging
*Fracture risk in men with LOH
Effects of T treatment on bone in LOH patients
Follow-up
Physical activity and the prevention of further bone loss
Treatment of osteopenia/osteoporosis in men with LOH
Unresolved Issues
Conclusions
The assessment of bone health should be included in the clinical work-up of men with LOH bearing in mind that osteoporosis is undermanaged and underdiagnosed in older men and remains less investigated by researchers than in the female counterpart. Bone health, in fact, may be considered a rare case of gender health inequality favoring women rather than men 2,3. Normative data obtained by studies on the male population are urgently needed for both DXA reference values and FRAX risk calculation in order to better tailor the diagnosis and the follow-up of men with osteoporosis. Andrological consultation performed in men with LOH represents an opportunity for male health 173 including bone 4.
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