title: Effects of testosterone supplementation in the aging male. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. Alendronate for the treatment of osteoporosis in men. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. Testosterone Deficiency As a Risk Factor for Hip Fractures in Men: A Case‐Control Study Effect of testosterone treatment on bone mineral density in men over 65 years of age. A randomized trial of testosterone therapy in males with rheumatoid arthritis. Osteopenia in eugonadal men with acquired immune deficiency syndrome wasting syndrome. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. Randomized placebo‐controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy
abstract: Serum and rogen levels decline with aging in normal males , such that a significant number of men over 60 yr of age will have a mean serum total testosterone ( T ) level near the low end of the normal adult range . It is not known whether lower T levels in older men have an effect on and rogen-responsive organ systems , such as muscle , bone , bone marrow , and prostate , nor are there data to evaluate the relative benefits and risks of T supplementation in older men . We assessed the physiological and biochemical effects of T therapy in 13 healthy men , 57 - 76 yr old , who had low or borderline low serum T levels ( < or = 13.9 nmol/L ) .  Intramuscular testosterone enanthate ( TE ; 100 mg weekly ) and placebo injections were given for 3 months each . Before treatment and at the end of both 3-month treatment regimens , lean body mass , body fat , biochemical parameters of bone turnover , hematological parameters , lipoprotein profiles , and prostate parameters [ such as prostate-specific antigen ( PSA ) ] were evaluated . Serum T levels rose in all subjects with TE treatment , such that the lowest level of T during a week 's period was 19.7 + /- 0.7 nmol/L ( mean + /- SE ) . After 3 months of TE treatment , lean body mass was significantly increased , and urinary hydroxyproline excretion was significantly depressed . With TE treatment , there was a significant increase in hematocrit , a decline in total cholesterol and low density lipoprotein cholesterol , and a sustained increase in serum PSA levels . Placebo treatment led to no significant changes in any of these parameters . We conclude that short term ( 3 months ) TE supplementation to healthy older men who have  serum T levels near or below the lower limit of normal for young adult men results in an increase in lean body mass and possibly a decline in bone resorption , as assessed by urinary hydroxyproline excretion , with some effect on serum lipoproteins , hematological parameters , and PSA . The sustained stimulation of PSA and the increase in hematocrit that occur with physiological TE supplementation suggest that older men should be screened carefully and followed periodically throughout T therapy Older men , particularly those with low serum testosterone ( T ) levels , might benefit from T therapy to improve bone mineral density ( BMD ) and reduce fracture risk . Concerns exist , however , about the impact of T therapy on the prostate in older men . We hypothesized that the combination of T and finasteride ( F ) , a 5 alpha-reductase inhibitor , might increase BMD in older men without adverse effects on the prostate . Seventy men aged 65 yr or older , with a serum T less than 12.1 nmol/liter on two occasions , were r and omly assigned to receive one of three regimens for 36 months : T enanthate , 200 mg i m every 2 wk with placebo pills daily ( T-only ) ; T enanthate , 200 mg every 2 wk with 5 mg F daily ( T+F ) ; or placebo injections and pills ( placebo ) . Low BMD was not an inclusion criterion . We obtained serial measurements of BMD of the lumbar spine and hip by dual x-ray absorptiometry . Prostate-specific antigen ( PSA ) and prostate size were measured at baseline and during treatment to assess the impact of therapy on the prostate . Fifty men completed the 36-month protocol . By an intent-to-treat analysis including all men for as long as they contributed data , T therapy for 36 months increased BMD in these men at the lumbar spine [ 10.2 + /- 1.4 % ( mean percentage increase from baseline + /- SEM ; T-only ) and 9.3 + /- 1.4 % ( T+F ) vs. 1.3 + /- 1.4 % for placebo ( P < 0.001 ) ] and in the hip [ 2.7 + /- 0.7 % ( T-only ) and 2.2 + /- 0.7 % ( T+F ) vs. -0.2 + /- 0.7 % for placebo , ( P < or = 0.02 ) ] . Significant increases in BMD were seen also in the intertrochanteric and trochanteric regions of the hip . After 6 months of therapy , urinary deoxypyridinoline ( a bone-resorption marker ) decreased significantly compared with baseline in both the T-only and T+F groups ( P < 0.001 ) but was not significantly reduced compared with the placebo group . Over 36 months , PSA increased significantly from baseline in the T-only group ( P < 0.001 ) . Prostate volume increased in all groups during the 36-month treatment period , but this increase was significantly less in the T+F group compared with both the T-only and placebo groups ( P = 0.02 ) . These results demonstrate that T therapy in older men with low serum T  increases vertebral and hip BMD over 36 months , both when administered alone and when combined with F. This finding suggests that dihydrotestosterone is not essential for the beneficial effects of T on BMD in men . In addition , the concomitant administration of F with T appears to attenuate the impact of T therapy on prostate size and PSA and might reduce the chance of benign prostatic hypertrophy or other prostate-related complications in older men on T therapy . These findings have important implication s for the prevention and treatment of osteoporosis in older men with low T levels BACKGROUND Despite its association with disability , death , and increased medical costs , osteoporosis in men has been relatively neglected as a subject of study . There have been no large , controlled trials of treatment in men . METHODS In a two-year double-blind trial , we studied the effect of 10 mg of alendronate or placebo , given daily , on bone mineral density in 241 men ( age , 31 to 87 years ; mean , 63 ) with osteoporosis . Approximately one third had low serum free testosterone concentrations at base line ; the rest had normal concentrations . Men with other secondary causes of osteoporosis were excluded . All the men received calcium and vitamin D supplements . The main outcome measures were the percent changes in lumbar-spine , hip , and total-body bone mineral density . RESULTS The men who received alendronate had a mean ( + /-SE ) increase in bone mineral density of 7.1+/-0.3 percent at the lumbar spine , 2.5+/-0.4 percent at the femoral neck , and 2.0+/-0.2 percent for the total body ( P<0.001 for all comparisons with base line ) . In contrast , men who received placebo had an increase in lumbar-spine bone mineral density of 1.8+/-0.5 percent ( P<0.001 for the comparison with base line ) and no significant changes in femoral-neck or total-body bone mineral density . The increase in bone mineral density in the alendronate group was greater than that in the placebo group at all measurement sites ( P<0.001 ) . The incidence of vertebral fractures was lower in the alendronate group than in the placebo group ( 0.8 percent vs. 7.1 percent , P=0.02 ) . Men in the placebo group had a 2.4-mm decrease in height , as compared with a decrease of 0.6 mm in the alendronate group ( P=0.02 ) . Alendronate was generally well tolerated . CONCLUSIONS In men with osteoporosis , alendronate significantly increases spine , hip , and total-body bone mineral density and helps prevent vertebral fractures and decreases in height BACKGROUND A large proportion of men over 65 years of age have bioavailable testosterone levels below the reference range of young adult men . The impact of this on musculoskeletal health and the potential for improvement in function in this group with testosterone supplementation require investigation . METHODS Sixty-seven men ( mean age 76 + /- 4 years , range 65 - -87 ) with bioavailable testosterone levels below 4.44 nmol/l ( lower limit for adult normal range ) were r and omized to receive transdermal testosterone  ( two 2.5-mg patches per day ) or placebo patches for 1 year . All men received 500 mg supplemental calcium and 400 IU vitamin D. Outcome measures included sex hormones ( testosterone , bioavailable testosterone , sex-hormone binding globulin [ SHBG ] , estradiol , and estrone ) , bone mineral density ( BMD ; femoral neck , Ward 's triangle , trochanter , lumbar spine , and total body ) , bone turnover markers , lower extremity muscle strength , percent body fat , lean body mass , hemoglobin , hematocrit , prostate symptoms , and prostate specific antigen ( PSA ) levels . RESULTS Twenty-three men ( 34 % ) withdrew from the study ; 44 men completed the trial . In these men , bioavailable testosterone levels increased from 3.2 + /- 1.2 nmol/l ( SD ) to 5.6 + /- 3.5 nmol/l ( p < .002 ) at 12 months in the testosterone group , whereas no change occurred in the control group . Although there was no change in estradiol levels in either group , estrone levels increased in the testosterone group ( 103 + /- 26 pmol/l to 117 + /- 33 pmol/l ; p < .017 ) . The testosterone group had a 0.3 % gain in femoral neck BMD , whereas the control group lost 1.6 % over 12 months ( p = .015 ) . No significant changes were seen in markers of bone turnover in either group . Improvements in muscle strength were seen in both groups at 12 months compared with baseline scores . Strength increased 38 % ( p = .017 ) in the testosterone group and 27 % in the control group ( p = .06 ) , with no statistical difference between the groups . In the testosterone group , body fat decreased from 26.3 + /- 5.8 % to 24.6 + /- 6.5 % ( p = .001 ) , and lean body mass increased from 56.2 + /- 5.3 kg to 57.2 + /- 5.1 kg ( p = .001 ) , whereas body mass did not change . Men receiving testosterone had an increase in PSA from 2.0 + /- 1.4 microg/l to 2.6 + /- 1.8 microg/l ( p = .04 ) , whereas men receiving placebo had an increase in PSA from 1.9 + /- 1.0 microg/l to 2.2 + /- 1.5 microg/l ( p = .09 ) . No significant differences between groups were seen in hemoglobin , hematocrit , symptoms or signs of benign prostate hyperplasia , or PSA levels . CONCLUSIONS Transdermal testosterone ( 5 mg/d ) prevented bone loss at the femoral neck , decreased body fat , and increased lean body mass in a group of healthy men over age 65 with low bioavailable testosterone levels . In addition , both testosterone and placebo groups demonstrated gains in lower extremity muscle strength , possibly due to the beneficial effects of vitamin D. Testosterone did result in a modest increase in PSA levels but result ed in no change in signs or symptoms of prostate hyperplasia Long-term glucocorticoid therapy  in men is associated with loss of bone and muscle mass as well as a decrease in serum testosterone . We tested the effect of two and rogens , testosterone and its minimally aromatizable analog n and rolone , on muscle mass ( dual x-ray absorptiometry ) , muscle strength ( knee flexion and extension by isokinetic dynamometry ) , bone mineral density ( BMD ) , and quality of life ( Qualeffo-41 question naire ) in 51 men on a mean daily prednisone dose of 12.6 + /- 2.2 mg . Men were r and omized , double blind , to testosterone ( 200 mg mixed esters ) , n and rolone decanoate ( 200 mg ) , or placebo given every fortnight by i m injection for 12 months . At 12 months , both and rogens increased muscle mass ( mean change from baseline + 3.5 % , + 5.8 % , and -0.9 % in testosterone , n and rolone , and placebo groups , respectively , P < 0.0001 ) and muscle strength ( P < 0.05 ) . Lumbar spine BMD increased significantly only in men treated with testosterone ( 4.7 + /- 1.1 % , P < 0.01 ) . There was no significant change in hip or total body BMD . Testosterone , but not n and rolone or placebo , improved overall quality of life ( P < 0.001 ) . These results suggest that and rogen therapy may have a role in ameliorating adverse effects of glucocorticoid therapy such as muscle and bone loss and aromatization is necessary for and rogen action on bone but not on muscle The pharmacokinetics , efficacy , and safety of the And roderm testosterone ( T ) transdermal system ( TTD ) and intramuscular T enanthate injections ( i.m . ) for the treatment of male hypogonadism were compared in a 24-week multicenter , r and omized , parallel-group study . Sixty-six adult hypogonadal men ( 22 - 65 years of age ) were withdrawn from prior i.m . treatment for 4 - 6 weeks and then r and omly assigned to treatment with TTD ( two 2.5-mg systems applied nightly ) or i.m . ( 200 mg injected every 2 weeks ) ; there were 33 patients per group . Twenty-six patients in the TTD group and 32 in the i.m . group completed the study .  TTD treatment produced circadian variations in the levels of total T , bioavailable T , dihydrotestosterone , and estradiol within the normal physiological ranges . i.m . treatment produced supraphysiological levels of T , bioavailable T , and estradiol ( but not dihydrotestosterone ) for several days after each injection . Mean morning sex hormone levels were within the normal range in greater proportions of TTD patients ( range , 77 - 100 % ) than i.m . patients ( range , 19 - 84 % ) . Both treatments normalized LH levels in approximately 50 % of patients with primary hypogonadism ; however , LH levels were suppressed to the subnormal range in 31 % of i.m . patients vs. 0 % of TTD patients . Both treatments maintained sexual function ( assessed by question naire and Rigiscan ) and mood ( Beck Depression Inventory ) at the prior treatment levels . Prostate-specific antigen levels , prostate volumes , and lipid and serum chemistry parameters were comparable in both treatment groups . Transient skin irritation from the patches was reported by 60 % of the TTD patients , but caused only three patients ( 9 % ) to discontinue treatment . i.m . treatment produced local reactions in 33 % of patients and was associated with significantly more abnormal hematocrit elevations ( 43.8 % of patients ) compared with TTD treatment ( 15.4 % of patients ) . Gynecomastia resolved more frequently during TTD treatment ( 4 of 10 patients ) than with i.m . treatment ( 1 of 9 patients ) . Although both treatments seem to be efficacious for replacing T in hypogonadal men , the more physiological sex hormone levels and profiles associated with TTD may offer possible advantages over i.m . in minimizing excessive stimulation of erythropoiesis , preventing/ameliorating gynecomastia , and not over-suppressing gonadotropins The objective of this study was to determine whether decreased gonadal function is a risk factor for hip fracture in elderly men . The study was a matched case-control study performed at an in-hospital orthopedic service at a semi-rural and academic tertiary care center . The patients were seventeen men who presented with hip fractures after simple falls over a 10-month period , 11 men with a history of hip fractures in the preceding 25 months , and 28 r and omly selected age- , race- , and living status-matched control subjects ( mean age 73 years ) . Serum pooled total testosterone ( 9.2 ± 5.5 nmol/ L vs. 12.8 ± 5.4 nmol/L ; p < 0.02 ) and free testosterone ( 37.9 ± 18.8 pmol/L vs. 48.4 ± 20.6 pmol/L ; p < 0.03 ) were significantly lower in hip fracture vs. control patients . Testosterone deficiency was found in 20 ( 71 % ) hip fracture men vs. 9 ( 32 % ) of the controls ( p = 0.003 ; odds ratio 5.3 ) . Analysis of testosterone values within the stratum of absence of any chronic disorder revealed similar results . Serum 25-hydroxyvitamin D levels were significantly lower in the hip fracture group than in control men ( p < 0.001 ) . The conclusion is that gonadal deficiency appears to be an important and heretofore understudied risk factor for hip fractures in men . Prevention of hip fractures in men may involve early recognition and treatment of testosterone As men age , their serum testosterone concentrations decrease , as do their bone densities . Because bone density is also low in hypogonadal men , we hypothesized that increasing the serum testosterone concentrations of men over 65 yr to those found in young men would increase their bone densities . We r and omized 108 men over 65 yr of age to wear either a testosterone patch or a placebo patch double blindly for 36 months . We measured bone mineral density by dual energy x-ray absorptiometry before and during treatment . Ninety-six men completed the entire 36-month protocol . The mean serum testosterone concentration in the men treated with testosterone increased from 367 + /- 79 ng/dL ( + /-SD ; 12.7 + /- 2.7 nmol/L ) before treatment to 625 + /- 249 ng/dL ( 21.7 + /- 8.6 nmol/L ; P < 0.001 ) at 6 months of treatment and remained at that level for the duration of the study . The mean bone mineral density of the lumbar spine increased ( P < 0.001 ) in both the placebo-treated ( 2.5 + /- 0.6 % ) and testosterone-treated ( 4.2 + /- 0.8 % ) groups , but the mean changes did not differ between the groups . Linear regression analysis , however , demonstrated that the lower the pretreatment serum testosterone concentration , the greater the effect of testosterone treatment on lumbar spine bone density from 0 - 36 months ( P = 0.02 ) . This analysis showed a minimal effect ( 0.9 + /- 1.0 % ) of testosterone treatment on bone mineral density for a pretreatment serum testosterone concentration of 400 ng/dL ( 13.9 nmol/L ) , but an increase of 5.9 + /- 2.2 % for a pretreatment testosterone concentration of 200 ng/dL ( 6.9 nmol/L ) . Increasing the serum testosterone concentrations of normal men over 65 yr of age to the midnormal range for young men did not increase lumbar spine bone density overall , but did increase it in those men with low pretreatment serum testosterone concentrations Thirty-five male patients , aged 34 - 79 yr , with definite rheumatoid arthritis ( RA ) were recruited from out-patient clinics and r and omized to receive monthly injections of testosterone enanthate 250 mg or placebo as an adjunct therapy for 9 months . Endpoints included disease activity parameters and bone mineral density ( BMD ) . At baseline , there were negative correlations between the ESR and serum testosterone ( r = -0.42 , P < 0.01 ) and BMD ( hip , r = -0.65 , P < 0.01 ) . A total of 29.6 % of all patients had at least one vertebral fracture , most having multiple fractures . Back pain , however , was not more prevalent in fracture patients ( 55 % vs 50 % ) . Disease activity was significantly higher in the fracture group ( joint score P < 0.05 , rheumatoid factor P < 0.01 ) . Thirty patients completed the trial , 15 receiving testosterone and 15 receiving placebo . There were significant rises in serum testosterone , dihydrotestosterone and oestradiol in the treatment group . There was no significant effect of treatment on disease activity overall , five patients receiving testosterone underwent a " flare ' . Differences in mean BMD following testosterone or placebo were non-significant ( spine : + 1.2 % vs -1.1 % ; femur : -0.3 % vs + 0.3 % ) . There was no suggestion of a positive effect of testosterone on disease activity in men with RA Multiple endocrine and metabolic consequences of human immunodeficiency virus ( HIV ) infection exist that may contribute to  bone loss in men with the acquired immune deficiency syndrome ( AIDS ) wasting syndrome . Recent studies suggest that anabolic strategies can increase lean body mass in men with AIDS wasting . Prior studies have not examined the effects of anabolic agents on bone mineral density ( BMD ) or bone turnover in these men . To determine the effects of testosterone and progressive resistance training on BMD and bone turnover in eugonadal men with AIDS wasting , we r and omly assigned 54 eugonadal men with AIDS wasting ( weight < 90 % IBW or weight loss > 10 % from preillness baseline ) to receive either testosterone enanthate ( 200 mg/week , i m ) or placebo and to progressive resistance training ( 3 times/week ) or no training in a 2 x 2 factorial study design for 3 months . The BMD of the lumbar spine , proximal femur , and total body ; lean body mass ; and fat mass were measured by dual energy x-ray absorptiometry . Total body scans were repeated after 12 weeks of therapy . Baseline bone turnover and BMD were compared with those in 35 age-matched healthy non-HIV-infected control subjects . Compared with controls , lumbar spine BMD ( 1.021 + /- 0.018 vs. 1.084 + /- 0.025 g/cm(2 ) ; P = 0.04 ) and total hip BMD ( 0.951 + /- 0.017 vs. 1.070 + /- 0.019 g/cm(2 ) ; P < 0.0001 ) were reduced in men with AIDS wasting . T-scores were lower in men with AIDS wasting at the lumbar spine ( -0.62 + /- 0.17 vs. -0.07 + /- 0.23 , P = 0.05 ) and total hip ( -0.65 + /- 0.11 vs. + 0.20 + /- 0.014 , P < 0.0001 ) . Total hip T scores were less than -1.0 in 33 % of men with AIDS wasting . Neither the use of protease inhibitors nor the duration of protease inhibitors use correlated with BMD . Serum osteocalcin levels were lower ( 3.63 + /- 0.29 vs. 4.54 + /- 0.31 nmol/L ; P < 0.04 ) and urinary N-telopeptide excretion was higher ( 45.4 + /- 4.5 vs. 26.8 + /- 3.0 nmol BCE/mmol creatinine ; P = 0.004 ) in men with AIDS wasting than in controls . Lumbar spine BMD , as assessed on regional total body dual energy x-ray absorptiometry scan , increased over the 12-week treatment period in response to testosterone ( + 2.4 + /- 1.3 vs. -1.3 + /- 1.0 % , testosterone vs. placebo , respectively ; P = 0.02 ) , but not in response to training ( + 0.8 + /- 1.0 vs. + 0.4 + /- 1.3 % , training vs. no training ; P = 0.70 ) . Lumbar spine and total hip BMD are reduced in eugonadal men with AIDS wasting .  Biochemical markers of bone turnover suggest that bone formation and bone resorption are uncoupled in these men . Testosterone administration , but not resistance training , over 3 months increases lumbar spine BMD in eugonadal men with AIDS wasting A decline in testicular function is recognized as a common occurrence in older men . However data are sparse regarding the effects of hypogonadism on age-associated physical and cognitive declines . This study was undertaken to examine the year-long effects of testosterone administration in this patient population . Fifteen hypogonadal men ( mean age 68 + /- 6 yr ) were r and omly assigned to receive a placebo  , and 17 hypogonadal men ( mean age 65 + /- 7 yr ) were r and omly assigned to receive testosterone .  Hypogonadism was defined as a bioavailable testosterone < 60 ng/dL. The men received injections of placebo or 200 mg testosterone cypionate biweekly for 12 months . The main outcomes measured included grip strength , hemoglobin , prostate-specific antigen , leptin , and memory .  Testosterone improved bilateral grip strength ( P < 0.05 by ANOVA ) and increased hemoglobin ( P < 0.001 by ANOVA ) . The men assigned to testosterone had greater decreases in leptin than those assigned to the control group ( mean + /- SEM : -2.0 + /- 0.9 ng/dL vs. 0.8 + /- 0.7 ng/dL ; P < 0.02 ) . There were no significant changes in prostate-specific antigen or memory .  Three subjects receiving placebo and seven subjects receiving  testosterone  withdrew from the study . Three of those seven withdrew because of an abnormal elevation in hematocrit .  Testosterone supplementation improved strength , increased hemoglobin , and lowered leptin levels in older hypogonadal men .  Testosterone may have a role in the treatment of frailty in males with hypogonadism ; however , older men receiving testosterone must be carefully monitored because of its potential risks Young adult males who can not produce or respond to estrogen ( E ) are osteopenic , suggesting that E may regulate bone turnover in men , as well as in women . Both bioavailable E and testosterone ( T ) decrease substantially in aging men , but it is unclear which deficiency is the more important factor contributing to the increased bone resorption and impaired bone formation that leads to their bone loss . Thus , we addressed this issue directly by eliminating endogenous T and E production in 59 elderly men ( mean age 68 years ) , study ing them first under conditions of physiologic T and E replacement and then assessing the impact on bone turnover of withdrawing both T and E , withdrawing only T , or only E , or continuing both . Bone resorption markers increased significantly in the absence of both hormones and were unchanged in men receiving both hormones . By two-factor ANOVA , E played the major role in preventing the increase in the bone resorption markers , whereas T had no significant effect . By contrast , serum osteocalcin , a bone formation marker , decreased in the absence of both hormones , and both E and T maintained osteocalcin levels . We conclude that in aging men , E is the dominant sex steroid regulating bone resorption , whereas both E and T are important in maintaining bone formation OBJECTIVE Testosterone deficiency is associated with significant morbidity , and and rogen replacement in overt hypogonadism is clearly beneficial . However , there are few data concerning the response to therapy in young men with mild testosterone deficiency
target: Intramuscular testosterone moderately increased lumbar bone density in men ; the results on femoral neck bone density are inconclusive .
  Without bone fracture data , the available trials offer weak and indirect inferences about the clinical efficacy of testosterone on osteoporosis prevention and treatment in men
background: CONTEXT And rogen-deficient men are at increased risk of osteoporosis .
  The extent to which testosterone can prevent and treat osteoporosis in men remains unclear .