madman
Super Moderator
Historically, osteoporosis has been viewed as a disease of women, with research, trials of interventions and guidelines predominantly focused as such. It is apparent, however, that this condition causes a substantial health burden in men also, and that its assessment and management must ultimately be addressed across both sexes. In this article, an international multidisciplinary working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases presents GRADE-assessed recommendations for the diagnosis, monitoring and treatment of osteoporosis in men. The recommendations are based on a comprehensive review of the latest research related to diagnostic and screening approaches for osteoporosis and its associated high fracture risk in men, covering disease burden, appropriate interpretation of bone densitometry (including the use of a female reference database for densitometric diagnosis in men) and absolute fracture risk, thresholds for treatment, and interventions that can be used therapeutically and their health economic evaluation. Future work should specifically address the efficacy of anti-osteoporosis medications, including denosumab and bone-forming therapies.
*Approaches to fracture risk assessment in men
-BMD and absolute fracture risk
-Stratified targeting of anti-osteoporosis medications
-Biochemical assessment
*Therapeutic interventions for men with osteoporosis
-Antiresorptive agents (bisphosphonates and denosumab)
-Anabolic agents
-Hormone replacement therapy
Reductions in sex steroid production and increases in levels of sex hormone binding globulin (SHBG) reduce the availability of free testosterone in men as they age 63,88.Testosterone is released from the testes in response to luteinizing hormone stimulation and is converted to oestradiol via aromatase (CYP19A1). Oestradiol is thought to mediate the major downstream effects on bone homeostasis as it acts on osteoclasts, osteoblasts and osteocytes via binding to α and β oestrogen receptors. Indeed, oestradiol was shown to mediate the main effects of testosterone on bone homeostasis in healthy men 20–50 years of age treated with a gonadotropin hormone-releasing hormone (GnRH)analogue to suppress endogenous testosterone and receiving testosterone replacement with or without an aromatase inhibitor 89–91. Profound hypogonadism, such as in androgen deprivation therapy for prostate cancer, is a well known cause of osteoporosis and increased fracture risk. As for endogenous sex steroid levels in community-dwelling older men, most data suggest a role of low oestradiol levels in increased bone loss and fracture risk and, with some exceptions 90, no clear association of testosterone levels with bone loss and fracture incidence 91.
One of the important initiatives in understanding the role of testosterone replacement in men was the series of ‘T-trials’ emanating from the National Institute on Aging. The T-trial specifically for bone demonstrated a significant increase (7%) in lumbar spine trabecular volumetric BMD after 1 year of testosterone replacement 92. Bone microarchitectural benefits were also observed after 2 years of testosterone replacement (compared with placebo), with significant increases in cortical volumetric BMD (3%) and significant increases in areal BMD at the lumbar spine and hip 93
However, consistently robust benefits of testosterone replacement therapy have not been demonstrated. In a systematic review and meta-analysis of testosterone therapy, benefit was only observed in lumbar spine BMD and only in a hypogonadal population 62.
Answers might come from the TRAVERSE (Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men) trial of testosterone supplementation versus placebo (in men with hypogonadal symptoms, low serum testosterone levels and high cardiovascular risk), which demonstrated cardiovascular safety of supplementation as the primary end point ;the supplementary material in this paper states that clinical fracture outcomes will be discussed in a future publication 94.
The potential for hormone replacement therapy to benefit BMD in hypogonadal men supports the assessment of serum total or free testosterone levels in men undergoing investigation for osteoporosis,and in those with established osteoporosis. However, there is a lack of controlled data on fracture incidence in response to testosteronet herapy, and owing to the specificity of this treatment for men, it is not possible to ‘bridge’ from the effects on fracture in studies in women.
For the above reasons, serum free or total testosterone levels should be measured as a facet of the investigatory ‘work-up’ for osteoporosis in men. Testosterone therapy might be indicated in the case of symptomatic deficiency, with the decision to recommend testosterone therapy made on the basis of a holistic assessment of the patient across bone, cardiometabolic and sexual function, ideally in conjunction with endocrinology expertise. Furthermore, hypogonadal men with osteoporosis should usually be treated with an established anti-osteoporosis medication, regardless of whether testosterone therapy is instituted, in order to most effectively reduce fracture risk.
*Efficacy summary
From the studies reported above, it is clear that anti-osteoporosis medications can substantially benefit the male skeleton in the case of osteoporosis via the accrual of BMD, but also via demonstrated improvements in fracture outcomes 70. First-line treatment with oral bisphosphonates followed by second-line deployment of intravenous bisphosphonates and denosumab is supported as an approach to anti-resorptive therapy (driven by the relative ease and cost of administration of these oral agents, compared with health care professional-delivered intravenous and subcutaneous preparations). For those men who would benefit from initial bone-forming therapy,the available data on BMD supports the utility of abaloparatide (Fig. 1), although further studies and collection of data on teriparatide should be a research priority.
*Health economic aspects
*Physical exercise and a balanced diet
The skeletal benefits of physical activity, a balanced diet and calcium and vitamin D supplementation have been well-documented.
-Exercise
-Falls
-Balanced diet and supplementation
In general, 800–1200 mg of calcium should be consumed via the diet on a daily basis; calcium supplementation can be considered if the daily intake is below 800 mg and vitamin D supplementation (800 IU) should be considered for those at an increased risk of fracture and those in whom vitamin D levels are insufficient 41.
*Patient perspectives of osteoporosis in men
Conclusions
In conclusion, osteoporosis in men continues to be a substantial clinical and health economic concern for health care workers, policy-makers and, most importantly, patients. Medications for reducing fracture risk exist and evidence of their efficacy is presented above, as are robust recommendations to enable clinicians to navigate this potentially difficult area of clinical practice. In terms of treatment, these guidelines advocate the use of oral anti-resorptive agents as first-line agents in men at a high risk of fracture and the use of bone-forming agents followed sequentially by anti-resorptive agents in men at a very high risk of fracture (with abaloparatide supported by the strongest data with respect to BMD changes), following an approach similar to that advocated for women with osteoporosis 41
We finish by emphasizing that osteoporosis in men is an area of relative neglect, and that further research, investment and focus is required to address some fundamental areas of the disease in this patient group.
*Approaches to fracture risk assessment in men
-BMD and absolute fracture risk
-Stratified targeting of anti-osteoporosis medications
-Biochemical assessment
*Therapeutic interventions for men with osteoporosis
-Antiresorptive agents (bisphosphonates and denosumab)
-Anabolic agents
-Hormone replacement therapy
Reductions in sex steroid production and increases in levels of sex hormone binding globulin (SHBG) reduce the availability of free testosterone in men as they age 63,88.Testosterone is released from the testes in response to luteinizing hormone stimulation and is converted to oestradiol via aromatase (CYP19A1). Oestradiol is thought to mediate the major downstream effects on bone homeostasis as it acts on osteoclasts, osteoblasts and osteocytes via binding to α and β oestrogen receptors. Indeed, oestradiol was shown to mediate the main effects of testosterone on bone homeostasis in healthy men 20–50 years of age treated with a gonadotropin hormone-releasing hormone (GnRH)analogue to suppress endogenous testosterone and receiving testosterone replacement with or without an aromatase inhibitor 89–91. Profound hypogonadism, such as in androgen deprivation therapy for prostate cancer, is a well known cause of osteoporosis and increased fracture risk. As for endogenous sex steroid levels in community-dwelling older men, most data suggest a role of low oestradiol levels in increased bone loss and fracture risk and, with some exceptions 90, no clear association of testosterone levels with bone loss and fracture incidence 91.
One of the important initiatives in understanding the role of testosterone replacement in men was the series of ‘T-trials’ emanating from the National Institute on Aging. The T-trial specifically for bone demonstrated a significant increase (7%) in lumbar spine trabecular volumetric BMD after 1 year of testosterone replacement 92. Bone microarchitectural benefits were also observed after 2 years of testosterone replacement (compared with placebo), with significant increases in cortical volumetric BMD (3%) and significant increases in areal BMD at the lumbar spine and hip 93
However, consistently robust benefits of testosterone replacement therapy have not been demonstrated. In a systematic review and meta-analysis of testosterone therapy, benefit was only observed in lumbar spine BMD and only in a hypogonadal population 62.
Answers might come from the TRAVERSE (Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men) trial of testosterone supplementation versus placebo (in men with hypogonadal symptoms, low serum testosterone levels and high cardiovascular risk), which demonstrated cardiovascular safety of supplementation as the primary end point ;the supplementary material in this paper states that clinical fracture outcomes will be discussed in a future publication 94.
The potential for hormone replacement therapy to benefit BMD in hypogonadal men supports the assessment of serum total or free testosterone levels in men undergoing investigation for osteoporosis,and in those with established osteoporosis. However, there is a lack of controlled data on fracture incidence in response to testosteronet herapy, and owing to the specificity of this treatment for men, it is not possible to ‘bridge’ from the effects on fracture in studies in women.
For the above reasons, serum free or total testosterone levels should be measured as a facet of the investigatory ‘work-up’ for osteoporosis in men. Testosterone therapy might be indicated in the case of symptomatic deficiency, with the decision to recommend testosterone therapy made on the basis of a holistic assessment of the patient across bone, cardiometabolic and sexual function, ideally in conjunction with endocrinology expertise. Furthermore, hypogonadal men with osteoporosis should usually be treated with an established anti-osteoporosis medication, regardless of whether testosterone therapy is instituted, in order to most effectively reduce fracture risk.
*Efficacy summary
From the studies reported above, it is clear that anti-osteoporosis medications can substantially benefit the male skeleton in the case of osteoporosis via the accrual of BMD, but also via demonstrated improvements in fracture outcomes 70. First-line treatment with oral bisphosphonates followed by second-line deployment of intravenous bisphosphonates and denosumab is supported as an approach to anti-resorptive therapy (driven by the relative ease and cost of administration of these oral agents, compared with health care professional-delivered intravenous and subcutaneous preparations). For those men who would benefit from initial bone-forming therapy,the available data on BMD supports the utility of abaloparatide (Fig. 1), although further studies and collection of data on teriparatide should be a research priority.
*Health economic aspects
*Physical exercise and a balanced diet
The skeletal benefits of physical activity, a balanced diet and calcium and vitamin D supplementation have been well-documented.
-Exercise
-Falls
-Balanced diet and supplementation
In general, 800–1200 mg of calcium should be consumed via the diet on a daily basis; calcium supplementation can be considered if the daily intake is below 800 mg and vitamin D supplementation (800 IU) should be considered for those at an increased risk of fracture and those in whom vitamin D levels are insufficient 41.
*Patient perspectives of osteoporosis in men
Conclusions
In conclusion, osteoporosis in men continues to be a substantial clinical and health economic concern for health care workers, policy-makers and, most importantly, patients. Medications for reducing fracture risk exist and evidence of their efficacy is presented above, as are robust recommendations to enable clinicians to navigate this potentially difficult area of clinical practice. In terms of treatment, these guidelines advocate the use of oral anti-resorptive agents as first-line agents in men at a high risk of fracture and the use of bone-forming agents followed sequentially by anti-resorptive agents in men at a very high risk of fracture (with abaloparatide supported by the strongest data with respect to BMD changes), following an approach similar to that advocated for women with osteoporosis 41
We finish by emphasizing that osteoporosis in men is an area of relative neglect, and that further research, investment and focus is required to address some fundamental areas of the disease in this patient group.
