Kinikuman
Well-known Member
Current Opinion in Urology
Issue: Volume 24(6), November 2014, p 608–613
Copyright: © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
INTRODUCTION
Both androgens and estrogens are important regulators of bone health, with estradiol being the dominant player. Male hypogonadism may lead to decreased bone mineral density (BMD) and increased fracture rates, as less testosterone is converted into estradiol. According to a systematic review and meta-analysis of risk factors associated with low bone mass-related fractures, hypogonadism had some of the higher odds ratios for fracture with 2.77 for natural hypogonadism and 1.53 for drug-induced hypogonadism [1]. Likewise, in the large European Male Aging Study of 2966 community-dwelling men aged 40–79, both moderate and severe clinical hypogonadism [three sexual symptoms and a total testosterone of 230–317 ng/dl (8–11 nmol/l) or less than 230 ng/dl (<8 nmol/l), respectively] were associated with lower estimated heel BMD after adjusting for age, BMI, smoking status and comorbidity [2].
This review examines the exciting new concept of the bone-testis axis, including relationships between sex steroids and osteocalcin and vitamin D. Hypogonadism is also explored in populations of men secondary to opioid use, HIV and transfusion-dependent thalassemia. Finally, the review summarizes trials of testosterone and bisphosphonate therapy on BMD, and less commonly, on fractures. For treatment decisions, the Endocrine Society came out with a clinical practice treatment guideline entitled ‘Osteoporosis in Men’ in 2012 [3].
Back to Top
OSTEOCALCIN AND TESTOSTERONE
Exciting research has found important cross-talk between the bone and testes, which has been described as the bone-testis axis. In particular, there has been a focus on osteocalcin, a peptide hormone produced by osteoblasts during bone formation and reflective of generalized bone turnover. Osteocalcin has been shown to play a major role in testosterone production and fertility in male mice. The positive association between osteocalcin and testosterone was also found in humans, using both a population-based sample of 1338 men in Germany (Study of Health in Pomerania) and a patient-based sample of 134 men with bone diseases, such as osteoporosis and osteomalacia [4[black small square]]. Using multivariable ordinary least square regression models, which adjusted for age, BMI and time of blood sampling, both of the sample populations had significant [beta] coefficients of 0.590 and 0.575. It turns out that osteocalcin is also produced in adipose tissue, another endocrine organ. In a prospective study of 76 obese men who underwent gastric bypass surgery, weight, reproductive hormones and total osteocalcin were measured before and 9 months after bariatric surgery [5[black small square]]. Multivariate analysis found impressive positive correlations between changes in testosterone levels and changes in osteocalcin levels, particularly in men with baseline total testosterone levels less than 346 ng/dl (<12 nmol/l) (correlation 0.784). This study concluded that the changes in Leydig cell activity were mostly correlated to total osteocalcin rather than to central luteinizing hormone stimulation.
Back to Top
VITAMIN D AND SEX STEROIDS
Vitamin D deficiency or insufficiency has been associated with numerous conditions from cancers to diabetes to obesity. Not including supplementation from vitamins or fortified foods, most of our vitamin D is synthesized in the skin from ultraviolet radiation. The relationship between vitamin D status, which is best measured by 25 (OH) vitamin D, and sex steroids in men has been explored in two large studies that showed inconsistent results. In cross-sectional data from 1362 men from the Health Professionals Follow-up Study, there was a correlation between 25 (OH) vitamin D and total testosterone, free testosterone and total estradiol using a multivariate adjusted model [6]. Comparing patients in the lowest quintile of vitamin D versus the highest, mean serum concentrations were 398 ng/dl (13.8 nmol/l) and 429 ng/dl (14.9 nmol/l) for total testosterone, 28 pg/ml (97.7 pmol/l) and 29 pg/ml (101.5 pmol/l) for free testosterone and 22 pg/ml (81.9 pmol/l) and 24 pg/ml (89.1 pmol/l) for total estradiol. A second study was the European Male Ageing Study that included cross-sectional data from 3369 community-dwelling men aged 40–79 from eight European countries [7]. Dividing the population into sufficient vitamin D [>=30 ng/ml (>=75 nmol/l)], sub-optimal vitamin D [20–30 ng/ml (50–74.9 nmol/l)] and deficient vitamin D [<20 ng/ml (<50 nmol/l)], there were no differences in serum levels of total testosterone and only modestly higher serum levels of free testosterone in the vitamin D sufficient group. However, no associations were found for 25 (OH) vitamin and sex hormones (total testosterone, free testosterone and total estradiol) after adjusting for age, BMI, smoking, alcohol use, physical activity and function, heart disease, hypertension, diabetes and depression. In both of these studies, there was an expected clear seasonal variation in vitamin D with higher levels in the summer that correspond to increased sun exposure [6,7]. A lack of seasonal variation in total and free testosterone signifies that higher levels of vitamin D are not a factor in increasing or maintaining testosterone levels.
On the flip side, interesting new data suggest that testiculopathy is directly related to lower levels of vitamin D and lower BMD. Researchers at the University of Padova studied a group of 125 testicular cancer survivors with normal testosterone levels who underwent unilateral orchiectomy followed by either surveillance, radiotherapy or chemotherapy [8[black small square]]. As compared with 41 controls, the testicular cancer patients had lower mean levels of 25 (OH) vitamin D3 [17 ± 8 ng/ml (42 ± 21 nmol/l) versus 30 ± 15 ng/ml (75 ± 38 nmol/l)], higher levels of parathyroid hormone (73 ± 29 versus 50 ± 14 ng/l) and lower BMD at the spine (1.003 ± 0.146 versus 1.179 ± 0.119 g/cm2). In fact, 24% of the cases had Z-scores less than -2 SD as compared with none of the controls. The second part of the study looked at 10 men with hypogonadotropic hypogonadism (mean age 26) before and after 3 months of treatment with human chorionic gonadotropin and follicle-stimulating hormone. This treatment caused not only an expected rise in total testosterone and estradiol, but also an increase in 25 (OH) vitamin D3 from 15 ± 7 ng/ml (38 ± 18 nmol/l) to 24 ± 9 ng/ml (59 ± 23 nmol/l). The authors hypothesize that decreased Leydig cells could explain these findings, as they express most of the enzymes involved in vitamin D metabolism.
Back to Top
OPIOIDS, HYPOGONADISM AND BONE
Hypogonadism secondary to opiate use has been well established. Two studies have shown a very high prevalence of hypogonadism in men receiving intrathecal opioids [9,10]. Nonetheless, the BMD data in this population show inconsistent findings. One study looked at BMD in 20 men aged 47–69 years with chronic noncancer pain who were all receiving intrathecal morphine for a median duration of 100 months [9]. In this study, 75% of patients had biochemical hypogonadism with a calculated free testosterone less than 52 pg/ml (<180 pmol/l). Despite the high rates of hypogonadism, Z-scores were not that abnormal: -0.1 at the femoral neck, -0.4 at the total hip and +0.3 at the radius. The corresponding T-scores were -1.1, -1.1 and -0.4. In another small study of chronic pain patients on intrathecal opioids (morphine or hydromorphone), 87% of men not already on testosterone supplementation were found to be hypogonadal with total testosterone concentrations less than 288 ng/dl (<10 nmol/l) [10]. This study compared BMD between a group of 16 men who were not on testosterone supplementation with 11 men who had been on testosterone supplementation for a mean of 9 years. The lowest mean T-scores at any site were -0.73 for the testosterone group versus -1.61 for the untreated group. Similarly, the lowest mean Z-scores were -0.15 for the testosterone group versus -0.94 for the untreated group. This study implies that TRT is associated with improved BMD, but fracture data are not available.
Given that BMD is a surrogate marker for fracture, an important question is whether the cumulative use of opioids is related to risk of fracture and if so, via what mechanism. This was elegantly explored in a case-control study using the large General Practice Research Database in the UK [11[black small square][black small square]]. Within this study (mean age of 62), there were 5087 men with a first-time fracture of the hip, humerus or wrist and 20 230 matched male controls. Results from both genders showed that current opioid users were 1.14–1.38 times as likely to have fracture as compared with nonusers. This increased risk was not seen among past users of opioids. Increased risk of fracture was seen with morphine, dihydrocodeine, codeine, tramadol and propoxyphene, but not with buprenorphine. Dividing the cases by cumulative number of opioid prescriptions, men who received 1–3 prescriptions had odds ratios for fracture of around 1.5–4.5, whereas men who received 6–100 prescriptions had no increased risk. The message of this study is that the mechanism of fractures appears to be related to the acute CNS side-effects of opioids (i.e., sedation and dizziness), as opposed to hypogonadism from chronic opioid use.
Back to Top
SPECIAL POPULATIONS
Men with HIV have multiple comorbid conditions that may increase their risk for lower BMD. In a cross-sectional study of 285 HIV-infected patients (75% of whom were men and with a mean age of 46), 38% were classified with osteopenia and 6% with osteoporosis [12]. Overall, 8% of men had total testosterone levels less than 300 ng/dl (<10.4 nmol/l) with a prevalence of over 16% in men over age 50. In a multivariate linear regression analysis, hypogonadism was not a major contributor to lower BMD. Instead, the main predictors were high rates of vitamin D levels less than 20 ng/ml (<50 nmol/l) (61%), secondary hyperparathyroidism (27%) and hepatitis C coinfection (45%).
Another special population is patients with transfusion-dependent thalassemia. Chronic iron overload from transfusions may lead to multiple endocrine complications, including hypogonadism. In a study of 81 men with transfusion-dependent thalassemia with a median age of 37, 44% had two measurements of total testosterone less than 230 ng/dl (< 8 nmol/l) or were already on TRT [13]. Virtually, all of the cases of hypogonadism were secondary (hypogonadotropic). As compared with the eugonadal men, hypogonadal men had Z-scores that were similar or even slightly better (-2.05 and -1.95 at the lumbar spine; -1.44 and -1.27 at the femoral neck). In this population, hypogonadism appears to have a weak relationship with BMD.
Back to Top
TESTOSTERONE REPLACEMENT THERAPY
Table 1[14–22]. Similar to previous research with TRT, these studies generally found greater improvements in BMD with the intramuscular testosterone (undecanoate or esters) formulations as compared with the topical (gel) or oral (undecanoate) formulations.
Several interesting findings have emerged among these recent studies. In a trial of 45 men with a mean age of 53 and a high prevalence of Klinefelter's syndrome (n = 22), intramuscular therapy with testosterone undecanoate significantly improved T-scores in all patients [18]. Although the biggest gains in BMD occurred within the first year, there was no plateau effect for the gains for the 6-year duration of the registry. To illustrate, the mean T-scores were -3.1 at baseline, -2.6 at 1 year and -1.4 at 6 years. In a large 1 year randomized controlled trial (RCT) of 322 symptomatic aging men (mean age 59) with calculated free testosterone levels less than 0.26 nmol/l, treatment with oral testosterone undecanoate showed statistically significant increases in BMD at the lumbar spine and total hip but only in the 240 mg/day group [14]. Both the 160 mg/day and 240 mg/day doses showed reductions in osteocalcin and type 1 collagen C-telopeptide at 1 year. In a retrospective chart review of younger men aged 20–50 with total testosterone levels less than 350 mg/dl (<12 nmol/l) and/or free testosterone levels less than 1.5 ng/dl, treatment with clomiphene citrate (25 mg daily or 50 mg three times weekly) was associated with a loss of BMD at the lumbar spine [19]. This study highlights the need for further research to look at the short and long-term risks of antiestrogens and aromatase inhibitors, which has been understudied in male populations.
Three small studies have looked at the effects of TRT on BMD in men with hypopituitarism. All three studies found that TRT over a mean follow-up of 19–56 months was associated with a 4.5–6.3% increase in BMD at the lumbar spine [20–22]. Two of these studies also reported a 2.3–5.4% increase in BMD at the total hip [20,21]. Two of the studies reported a 2.1–4.5% increase in BMD at the femoral neck [20,22]. In a retrospective study of 12 men (mean age 56) with hypogonadism secondary to hypopituitarism after surgery for a pituitary adenoma, replacement therapy with intramuscular testosterone undecanoate for 19–21 months had a modest effect on BMD [22]. Important details about this cohort were that all men had a short duration of hypogonadism (8 months), normal baseline BMD and growth hormone deficiency for which replacement was provided. This study found that increases in BMD were correlated to increases in testosterone concentrations but not to changes in estradiol, insulin-like growth factor 1 or free T4. Another finding was that shorter androgen receptor CAG repeat polymorphisms were independently associated with greater improvement in BMD with testosterone replacement. Previous studies have shown inconsistent results when looking at CAG repeat length regarding BMD and effects of testosterone on BMD.
One of the studies prospectively randomized 32 men with hypogonadism and growth hormone deficiency to testosterone alone or to testosterone plus growth hormone for 2 years [20]. The combination therapy did not provide any additional benefit over testosterone therapy alone for structural and mechanical parameters of the distal tibia as assessed by magnetic resonance microimaging and finite element analysis. Testosterone treatment increased trabecular bone volume fraction by 9.6%, axial stiffness by 9.8% and thickness by 2.6%. Testosterone treatment had mixed effects on cortical bone by increasing thickness but decreasing bone volume fraction and axial stiffness.
Back to Top
BISPHOSPHONATE THERAPY AND FRACTURES
One large RCT was able to assess fracture risk in 1127 men with osteoporosis treated with two zolendronic acid infusions administered a year apart [23]. For new morphometric vertebral fractures over a 2-year follow-up, this study found an absolute risk reduction of 3.25% with a number needed to treat of 31. There was no statistically significant reduction in clinical vertebral or nonvertebral fractures. In this trial, 23% of men had total testosterone levels less than 350 ng/dl (<12 nmol/l), but the testosterone level did not affect antifracture efficacy.
Back to Top
CONCLUSION
The bone-testis axis represents an area ripe for continued investigation. Osteocalcin may turn out to be an important player in maintaining normal testosterone levels. From a management perspective, the potential benefit of TRT on fracture prevention in different populations of male hypogonadism is unknown. The major limitation of the trials described is the use of a surrogate endpoint – change in BMD – which may or may not translate into altered fracture incidence. As was shown in one large epidemiological study, chronic hypogonadism actually did not increase fracture risk in opioid users, whereas CNS effects did. What is needed in the field are large adequately powered RCTs of TRT and other therapies to assess potential changes in the rate of fracture.
Issue: Volume 24(6), November 2014, p 608–613
Copyright: © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
INTRODUCTION
Both androgens and estrogens are important regulators of bone health, with estradiol being the dominant player. Male hypogonadism may lead to decreased bone mineral density (BMD) and increased fracture rates, as less testosterone is converted into estradiol. According to a systematic review and meta-analysis of risk factors associated with low bone mass-related fractures, hypogonadism had some of the higher odds ratios for fracture with 2.77 for natural hypogonadism and 1.53 for drug-induced hypogonadism [1]. Likewise, in the large European Male Aging Study of 2966 community-dwelling men aged 40–79, both moderate and severe clinical hypogonadism [three sexual symptoms and a total testosterone of 230–317 ng/dl (8–11 nmol/l) or less than 230 ng/dl (<8 nmol/l), respectively] were associated with lower estimated heel BMD after adjusting for age, BMI, smoking status and comorbidity [2].
This review examines the exciting new concept of the bone-testis axis, including relationships between sex steroids and osteocalcin and vitamin D. Hypogonadism is also explored in populations of men secondary to opioid use, HIV and transfusion-dependent thalassemia. Finally, the review summarizes trials of testosterone and bisphosphonate therapy on BMD, and less commonly, on fractures. For treatment decisions, the Endocrine Society came out with a clinical practice treatment guideline entitled ‘Osteoporosis in Men’ in 2012 [3].
Back to Top
OSTEOCALCIN AND TESTOSTERONE
Exciting research has found important cross-talk between the bone and testes, which has been described as the bone-testis axis. In particular, there has been a focus on osteocalcin, a peptide hormone produced by osteoblasts during bone formation and reflective of generalized bone turnover. Osteocalcin has been shown to play a major role in testosterone production and fertility in male mice. The positive association between osteocalcin and testosterone was also found in humans, using both a population-based sample of 1338 men in Germany (Study of Health in Pomerania) and a patient-based sample of 134 men with bone diseases, such as osteoporosis and osteomalacia [4[black small square]]. Using multivariable ordinary least square regression models, which adjusted for age, BMI and time of blood sampling, both of the sample populations had significant [beta] coefficients of 0.590 and 0.575. It turns out that osteocalcin is also produced in adipose tissue, another endocrine organ. In a prospective study of 76 obese men who underwent gastric bypass surgery, weight, reproductive hormones and total osteocalcin were measured before and 9 months after bariatric surgery [5[black small square]]. Multivariate analysis found impressive positive correlations between changes in testosterone levels and changes in osteocalcin levels, particularly in men with baseline total testosterone levels less than 346 ng/dl (<12 nmol/l) (correlation 0.784). This study concluded that the changes in Leydig cell activity were mostly correlated to total osteocalcin rather than to central luteinizing hormone stimulation.
Back to Top
VITAMIN D AND SEX STEROIDS
Vitamin D deficiency or insufficiency has been associated with numerous conditions from cancers to diabetes to obesity. Not including supplementation from vitamins or fortified foods, most of our vitamin D is synthesized in the skin from ultraviolet radiation. The relationship between vitamin D status, which is best measured by 25 (OH) vitamin D, and sex steroids in men has been explored in two large studies that showed inconsistent results. In cross-sectional data from 1362 men from the Health Professionals Follow-up Study, there was a correlation between 25 (OH) vitamin D and total testosterone, free testosterone and total estradiol using a multivariate adjusted model [6]. Comparing patients in the lowest quintile of vitamin D versus the highest, mean serum concentrations were 398 ng/dl (13.8 nmol/l) and 429 ng/dl (14.9 nmol/l) for total testosterone, 28 pg/ml (97.7 pmol/l) and 29 pg/ml (101.5 pmol/l) for free testosterone and 22 pg/ml (81.9 pmol/l) and 24 pg/ml (89.1 pmol/l) for total estradiol. A second study was the European Male Ageing Study that included cross-sectional data from 3369 community-dwelling men aged 40–79 from eight European countries [7]. Dividing the population into sufficient vitamin D [>=30 ng/ml (>=75 nmol/l)], sub-optimal vitamin D [20–30 ng/ml (50–74.9 nmol/l)] and deficient vitamin D [<20 ng/ml (<50 nmol/l)], there were no differences in serum levels of total testosterone and only modestly higher serum levels of free testosterone in the vitamin D sufficient group. However, no associations were found for 25 (OH) vitamin and sex hormones (total testosterone, free testosterone and total estradiol) after adjusting for age, BMI, smoking, alcohol use, physical activity and function, heart disease, hypertension, diabetes and depression. In both of these studies, there was an expected clear seasonal variation in vitamin D with higher levels in the summer that correspond to increased sun exposure [6,7]. A lack of seasonal variation in total and free testosterone signifies that higher levels of vitamin D are not a factor in increasing or maintaining testosterone levels.
On the flip side, interesting new data suggest that testiculopathy is directly related to lower levels of vitamin D and lower BMD. Researchers at the University of Padova studied a group of 125 testicular cancer survivors with normal testosterone levels who underwent unilateral orchiectomy followed by either surveillance, radiotherapy or chemotherapy [8[black small square]]. As compared with 41 controls, the testicular cancer patients had lower mean levels of 25 (OH) vitamin D3 [17 ± 8 ng/ml (42 ± 21 nmol/l) versus 30 ± 15 ng/ml (75 ± 38 nmol/l)], higher levels of parathyroid hormone (73 ± 29 versus 50 ± 14 ng/l) and lower BMD at the spine (1.003 ± 0.146 versus 1.179 ± 0.119 g/cm2). In fact, 24% of the cases had Z-scores less than -2 SD as compared with none of the controls. The second part of the study looked at 10 men with hypogonadotropic hypogonadism (mean age 26) before and after 3 months of treatment with human chorionic gonadotropin and follicle-stimulating hormone. This treatment caused not only an expected rise in total testosterone and estradiol, but also an increase in 25 (OH) vitamin D3 from 15 ± 7 ng/ml (38 ± 18 nmol/l) to 24 ± 9 ng/ml (59 ± 23 nmol/l). The authors hypothesize that decreased Leydig cells could explain these findings, as they express most of the enzymes involved in vitamin D metabolism.
Back to Top
OPIOIDS, HYPOGONADISM AND BONE
Hypogonadism secondary to opiate use has been well established. Two studies have shown a very high prevalence of hypogonadism in men receiving intrathecal opioids [9,10]. Nonetheless, the BMD data in this population show inconsistent findings. One study looked at BMD in 20 men aged 47–69 years with chronic noncancer pain who were all receiving intrathecal morphine for a median duration of 100 months [9]. In this study, 75% of patients had biochemical hypogonadism with a calculated free testosterone less than 52 pg/ml (<180 pmol/l). Despite the high rates of hypogonadism, Z-scores were not that abnormal: -0.1 at the femoral neck, -0.4 at the total hip and +0.3 at the radius. The corresponding T-scores were -1.1, -1.1 and -0.4. In another small study of chronic pain patients on intrathecal opioids (morphine or hydromorphone), 87% of men not already on testosterone supplementation were found to be hypogonadal with total testosterone concentrations less than 288 ng/dl (<10 nmol/l) [10]. This study compared BMD between a group of 16 men who were not on testosterone supplementation with 11 men who had been on testosterone supplementation for a mean of 9 years. The lowest mean T-scores at any site were -0.73 for the testosterone group versus -1.61 for the untreated group. Similarly, the lowest mean Z-scores were -0.15 for the testosterone group versus -0.94 for the untreated group. This study implies that TRT is associated with improved BMD, but fracture data are not available.
Given that BMD is a surrogate marker for fracture, an important question is whether the cumulative use of opioids is related to risk of fracture and if so, via what mechanism. This was elegantly explored in a case-control study using the large General Practice Research Database in the UK [11[black small square][black small square]]. Within this study (mean age of 62), there were 5087 men with a first-time fracture of the hip, humerus or wrist and 20 230 matched male controls. Results from both genders showed that current opioid users were 1.14–1.38 times as likely to have fracture as compared with nonusers. This increased risk was not seen among past users of opioids. Increased risk of fracture was seen with morphine, dihydrocodeine, codeine, tramadol and propoxyphene, but not with buprenorphine. Dividing the cases by cumulative number of opioid prescriptions, men who received 1–3 prescriptions had odds ratios for fracture of around 1.5–4.5, whereas men who received 6–100 prescriptions had no increased risk. The message of this study is that the mechanism of fractures appears to be related to the acute CNS side-effects of opioids (i.e., sedation and dizziness), as opposed to hypogonadism from chronic opioid use.
Back to Top
SPECIAL POPULATIONS
Men with HIV have multiple comorbid conditions that may increase their risk for lower BMD. In a cross-sectional study of 285 HIV-infected patients (75% of whom were men and with a mean age of 46), 38% were classified with osteopenia and 6% with osteoporosis [12]. Overall, 8% of men had total testosterone levels less than 300 ng/dl (<10.4 nmol/l) with a prevalence of over 16% in men over age 50. In a multivariate linear regression analysis, hypogonadism was not a major contributor to lower BMD. Instead, the main predictors were high rates of vitamin D levels less than 20 ng/ml (<50 nmol/l) (61%), secondary hyperparathyroidism (27%) and hepatitis C coinfection (45%).
Another special population is patients with transfusion-dependent thalassemia. Chronic iron overload from transfusions may lead to multiple endocrine complications, including hypogonadism. In a study of 81 men with transfusion-dependent thalassemia with a median age of 37, 44% had two measurements of total testosterone less than 230 ng/dl (< 8 nmol/l) or were already on TRT [13]. Virtually, all of the cases of hypogonadism were secondary (hypogonadotropic). As compared with the eugonadal men, hypogonadal men had Z-scores that were similar or even slightly better (-2.05 and -1.95 at the lumbar spine; -1.44 and -1.27 at the femoral neck). In this population, hypogonadism appears to have a weak relationship with BMD.
Back to Top
TESTOSTERONE REPLACEMENT THERAPY
Table 1[14–22]. Similar to previous research with TRT, these studies generally found greater improvements in BMD with the intramuscular testosterone (undecanoate or esters) formulations as compared with the topical (gel) or oral (undecanoate) formulations.
Several interesting findings have emerged among these recent studies. In a trial of 45 men with a mean age of 53 and a high prevalence of Klinefelter's syndrome (n = 22), intramuscular therapy with testosterone undecanoate significantly improved T-scores in all patients [18]. Although the biggest gains in BMD occurred within the first year, there was no plateau effect for the gains for the 6-year duration of the registry. To illustrate, the mean T-scores were -3.1 at baseline, -2.6 at 1 year and -1.4 at 6 years. In a large 1 year randomized controlled trial (RCT) of 322 symptomatic aging men (mean age 59) with calculated free testosterone levels less than 0.26 nmol/l, treatment with oral testosterone undecanoate showed statistically significant increases in BMD at the lumbar spine and total hip but only in the 240 mg/day group [14]. Both the 160 mg/day and 240 mg/day doses showed reductions in osteocalcin and type 1 collagen C-telopeptide at 1 year. In a retrospective chart review of younger men aged 20–50 with total testosterone levels less than 350 mg/dl (<12 nmol/l) and/or free testosterone levels less than 1.5 ng/dl, treatment with clomiphene citrate (25 mg daily or 50 mg three times weekly) was associated with a loss of BMD at the lumbar spine [19]. This study highlights the need for further research to look at the short and long-term risks of antiestrogens and aromatase inhibitors, which has been understudied in male populations.
Three small studies have looked at the effects of TRT on BMD in men with hypopituitarism. All three studies found that TRT over a mean follow-up of 19–56 months was associated with a 4.5–6.3% increase in BMD at the lumbar spine [20–22]. Two of these studies also reported a 2.3–5.4% increase in BMD at the total hip [20,21]. Two of the studies reported a 2.1–4.5% increase in BMD at the femoral neck [20,22]. In a retrospective study of 12 men (mean age 56) with hypogonadism secondary to hypopituitarism after surgery for a pituitary adenoma, replacement therapy with intramuscular testosterone undecanoate for 19–21 months had a modest effect on BMD [22]. Important details about this cohort were that all men had a short duration of hypogonadism (8 months), normal baseline BMD and growth hormone deficiency for which replacement was provided. This study found that increases in BMD were correlated to increases in testosterone concentrations but not to changes in estradiol, insulin-like growth factor 1 or free T4. Another finding was that shorter androgen receptor CAG repeat polymorphisms were independently associated with greater improvement in BMD with testosterone replacement. Previous studies have shown inconsistent results when looking at CAG repeat length regarding BMD and effects of testosterone on BMD.
One of the studies prospectively randomized 32 men with hypogonadism and growth hormone deficiency to testosterone alone or to testosterone plus growth hormone for 2 years [20]. The combination therapy did not provide any additional benefit over testosterone therapy alone for structural and mechanical parameters of the distal tibia as assessed by magnetic resonance microimaging and finite element analysis. Testosterone treatment increased trabecular bone volume fraction by 9.6%, axial stiffness by 9.8% and thickness by 2.6%. Testosterone treatment had mixed effects on cortical bone by increasing thickness but decreasing bone volume fraction and axial stiffness.
Back to Top
BISPHOSPHONATE THERAPY AND FRACTURES
One large RCT was able to assess fracture risk in 1127 men with osteoporosis treated with two zolendronic acid infusions administered a year apart [23]. For new morphometric vertebral fractures over a 2-year follow-up, this study found an absolute risk reduction of 3.25% with a number needed to treat of 31. There was no statistically significant reduction in clinical vertebral or nonvertebral fractures. In this trial, 23% of men had total testosterone levels less than 350 ng/dl (<12 nmol/l), but the testosterone level did not affect antifracture efficacy.
Back to Top
CONCLUSION
The bone-testis axis represents an area ripe for continued investigation. Osteocalcin may turn out to be an important player in maintaining normal testosterone levels. From a management perspective, the potential benefit of TRT on fracture prevention in different populations of male hypogonadism is unknown. The major limitation of the trials described is the use of a surrogate endpoint – change in BMD – which may or may not translate into altered fracture incidence. As was shown in one large epidemiological study, chronic hypogonadism actually did not increase fracture risk in opioid users, whereas CNS effects did. What is needed in the field are large adequately powered RCTs of TRT and other therapies to assess potential changes in the rate of fracture.
