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From the Clinical Research Centers |
Departments of Medicine (P.J.S., H.P., P.H., L.L., A.D., S.K., M.F.A., J.G.H., B.L.S.) and Biostatistics and Epidemiology (J.A.B., J.H.H., J.St., J.Sa., B.L.S.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Dr. Peter J. Snyder, 3450 Hamilton Walk, Philadelphia, Pennsylvania 19104-6087.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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We randomized 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.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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One possible consequence of this decrease in testosterone is a decrease in bone density. As men age, their bone density decreases (5, 6), as does that of men whose serum testosterone is low because of pituitary or testicular disease (7, 8, 9). When hypogonadal men are treated with testosterone, their bone densities increase (10).
We hypothesized that increasing the serum testosterone concentrations of elderly men to those levels found in young men would increase their bone densities. We tested this hypothesis by selecting healthy men over 65 yr of age, assigning them randomly to receive either testosterone or placebo, and measuring bone mineral density repeatedly during 3 yr of treatment.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We recruited healthy men over 65 yr of age by direct mailings to alumni of the University of Pennsylvania and Temple University and by newspaper and television announcements. We included men who had a serum testosterone concentration at least 1 SD below the mean for healthy young men (<475 ng/dL; 16.5 nmol/L) and a bone mineral density of the lumbar spine (L2–L4) below the mean for healthy young men (<1.26 g/cm2).
We excluded men who had a history of pituitary or testicular disease or were taking androgen preparations. We also excluded men who had diseases that affect bone, such as chronic renal disease or malabsorption, or were taking medications or drugs that affect bone, such as bisphosphonates, diphenylhydantoin, or more than three alcoholic drinks a day. Additionally, we excluded men who had a history of prostate cancer, a palpable prostate nodule, a serum prostate-specific antigen concentration above 4.0 ng/mL, a Boyarsky symptom score greater than 16 (11), a corrected urine flow rate less than 16 mL/min (12), or a postvoiding residual urine volume in the bladder by ultrasound greater than 100 mL.
Over 1000 men volunteered and were interviewed by telephone, and 598 were screened in person and by blood sampling. One hundred and eight men met the above criteria and enrolled. The committee on studies involving humans of the University of Pennsylvania approved the protocol, and each subject gave informed consent in writing.
Study design
Subjects were stratified by pretreatment serum testosterone
[
350 ng/dL (12.1 nmol/L) vs. 351–475 ng/dL (12.2–16.5
nmol/L)] and bone mineral density (<85% and 85–100% of the values
for 20- to 40-yr-old men). Within each stratum subjects were assigned
randomly to receive either testosterone or placebo. The randomization
code was known only to the data manager (J.H.H.), research pharmacist,
and safety monitoring board until the last subject completed his
participation.
Testosterone was administered by scrotal patch (Testoderm, provided by Alza Corp., Palo Alto, CA); placebo patches were identical in appearance to testosterone patches. Each subject was asked to wear a patch at all times except when bathing, change the patch once a day, and shave the scrotum twice a week. Each subject began by wearing a 60-cm2 testosterone patch, which delivers approximately 6 mg testosterone/24 h, or a 60-cm2 placebo patch. The data manager reviewed serum testosterone concentrations every 3 months and directed a decrease in patch size to 40 cm2 if a man’s serum testosterone was above 1000 mg/dL (34.7 nmol/L) or a reeducation in patch technique if a man in the testosterone-treated group had a value less than 250 ng/dL above baseline. To maintain the blinding in both of the above manipulations, the data manager directed that a man in the placebo-treated group be treated similarly.
We asked men who were consuming less than four dairy servings a day or equivalent before initiation of treatment to take one tablet a day of OsCal 500 + D (500 mg elemental calcium with 125 U vitamin D; SmithKline Beecham, Philadelphia, PA), which we provided. On this basis, we provided OsCal to all but six men in the placebo group and all but four men in the testosterone group.
Assessment of bone mineral density
We measured bone mineral density in the lumbar spine (L2–L4) and three sites in the hip before treatment and after 6, 12, 24, and 36 months of treatment by dual energy x-ray absorptiometry using a Lunar Corp. (Madison, WI) DPX scanner with acquisition software versions 3.1–3.61. Coefficients of variation for this technique at our site were 0.9% for L2–L4, 1.2% for the femoral neck, 2.9% for Ward’s triangle, and 1.5% for the trochanter. Scanning a phantom every 2 weeks during the course of the study gave stable results. All scans from the same subject were analyzed by a single operator (P.H.) at a single sitting without knowledge of the subject’s treatment status. Lateral radiographs of the lumbar spine were taken before treatment and again after 36 months of treatment.
Assays related to testosterone and bone metabolism
Serum for testosterone, sex hormone-binding globulin, and bone-specific alkaline phosphatase determinations was drawn in the morning three times before beginning treatment and 3–5 h after patch application once at 3 and 6 months and then every 6 months during treatment. Urine was collected for 24 h once before treatment and after 6, 12, 24, and 36 months of treatment for creatinine and N-telopeptide determinations. All samples were frozen at -70 C until the end of the study. Serum testosterone was measured by RIA, and sex hormone-binding globulin was measured by immunoradiometric assay using kits from Diagnostic Systems Laboratories, Inc. (Webster, TX). The serum concentration of free testosterone was calculated from the total testosterone and sex hormone-binding globulin concentrations using a computer program provided by Dr. Stephen Plymate based on equations developed by Sodergard (13). Serum bone-specific alkaline phosphatase was measured by immunoradiometric assay using a kit (Tandem R Ostase) from Beckman Coulter, Inc. (Columbia, MD). Urinary N-telopeptide was measured by enzyme-linked immunoabsorbant assay using a kit (Osteomark) from Ostex International, Inc. (Seattle, WA). Intraassay coefficients of variation for all of the assays were less than 5%, and interassay coefficients of variation were less than 10%. For each assay, all samples from each subject were measured in the same assay run.
Assessment of potential deleterious effects of testosterone
We tested each man for the possible development of prostate
diseases and erythrocytosis at 3 months, 6 months, and then every 6
months. We tested for sleep apnea at 6 and 12 months and then every 12
months. We tested for prostate cancer by manual examination and
prostate-specific antigen. If a nodule was detected or if the
prostate-specific antigen increased by 1.5 ng/mL in 2 yr (14) or by 2.0
ng/mL or more (trigger values) at any time, confirmed by repeat
determination, the subject was referred for prostate biopsy. We tested
for urinary obstruction by the Boyarsky symptom score (11), for urine
flow rate (12) using a Urodyn 1000 urine flow meter (Medtronic-Dantec
Corp., Allendale, NJ), and for residual urine in the bladder after
voiding by a hand-held ultrasound instrument (BladderScan BVI 2000,
Diagnostic Ultrasound Corp., Redmond, WA). Erythrocytosis was
determined by hematocrit and hemoglobin. Sleep apnea was assessed by a
portable instrument, EdenTrace 680 (EdenTec Corp, Eden Prairie, MN).
For each study, a respiratory distress index was calculated by adding
the number of apneic (>10 s of cessation of airflow) and hypopneic
(cessation of airflow <10 s but accompanied by a fall of 
4% in
oxyhemoglobin saturation) episodes during that night’s sleep and
dividing by the number of hours of sleep.
Statistical analyses
All analyses were performed using an intent to treat approach. For the 12 subjects who did not complete the protocol, the last observation of each parameter was carried forward to all subsequent time points. Within each group, the significance of the change over time was tested using the paired t test. Between groups, the principal test was the independent sample t test, comparing the mean change over time between the two treatment groups. We confirmed the results of this analysis using an analysis of covariance, comparing the final values adjusted for the pretreatment values. Because these two tests gave similar results, only the results of the comparisons of the differences are presented. For bone mineral density, we also performed repeated measures ANOVA, incorporating all of the bone mineral density data over time.
We then used linear regression to determine whether the effect of testosterone treatment, as measured by the difference between the treatment groups in mean changes in bone mineral density during the 36 months of treatment, depended on the pretreatment serum testosterone concentration in a linear fashion. The regression model (15) used pretreatment serum testosterone, treatment group, and their interaction as predictor variables and the change in bone mineral density as the outcome variable. Fisher’s exact test was used to compare the frequency of dichotomous events between groups. All analyses were performed using either SAS version 6.12 or STATA version 5 (STATA Corp., College Station, TX). All P values reported are two-sided; a significance level of less than 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Before treatment, the two treatment groups did not differ significantly
from each other in age, height, weight, or serum testosterone, sex
hormone-binding globulin, or calculated free testosterone
concentrations (Table 1
).
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The mean serum testosterone concentration in the placebo-treated
group did not change during the 36 months of the study (Fig. 1). The mean serum testosterone
concentration in the testosterone-treated group 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) by the sixth month of treatment and
remained relatively stable for the remainder of the study (Fig. 1).
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).
The mean serum free testosterone concentration in the placebo-treated
group did not change during the course of the study (Fig. 1). The mean
serum free testosterone concentration in the testosterone-treated group
increased from 5.0 ± 1.6 ng/dL (0.17 ± 0.06 nmol/L) before
treatment to 9.5 ± 4.2 ng/dL (0.35 ± 0.15 nmol/L) by the
sixth month of treatment and remained relatively stable for the
remainder of the study (Fig. 1).
Bone mineral density and markers of bone metabolism
The bone mineral densities of the lumbar spine (L2–L4) were
similar in the two treatment groups before treatment and increased
significantly (P < 0.001) during 3 yr of treatment in
each group (Table 2). The increase was
0.030 ± 0.050 g/cm2 (2.5 ± 0.6%) in the
placebo group and 0.048 ± 0.060 g/cm2 (4.2 ±
0.8%) in the testosterone group (Fig. 2). The increase was not significantly
different in the men treated with testosterone from that in the men
treated with placebo. Adjusting for baseline bone mineral density or
baseline serum testosterone did not affect the analysis of the bone
mineral density results, nor did excluding those vertebrae with obvious
sclerotic areas.
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). Repeating this analysis after
excluding those vertebrae with obvious sclerotic changes gave similar
results.
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There was no significant change in the bone mineral densities of the
three sites in the hip in either group during the 36 months of
treatment (Table 2), nor was there a change in bone-specific alkaline
phosphatase or urinary N-telopeptides in either group during treatment
(Table 2).
Lumbar spine radiographs showed a compression fracture of only one L2–L4 vertebra of one subject before treatment and of only the same vertebra in the same subject at 36 months. In the 96 men who completed the study, the radiographs showed osteophytes in L2–L4 vertebrae of 56 men (29 in the testosterone group and 27 in the placebo group) before treatment and in 57 men (29 in the testosterone group and 28 in the placebo group) at 36 months.
Potential adverse effects of testosterone treatment
Several parameters were monitored because they reflect potential
adverse effects of testosterone. Twenty-seven subjects had 29
clinically significant prostate events during the 3 yr of the study
(Table 3), 16 in the testosterone-treated
group and 11 in the placebo-treated group (by 2-sided Fisher’s exact
test, P = 0.337). The most common event was an increase
in prostate-specific antigen above the trigger values (see
Subjects and Methods); in 16 men the increase did not
persist when the test was repeated 1–2 months later, and in 4 it did.
Prostate biopsy in those 4 detected prostate cancer in 1.
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), but increased by a relatively small,
but statistically significant (P < 0.001), amount by 6
months of treatment in the testosterone-treated group and remained
relatively stable for the remainder of the study (Fig. 4). The urine
flow rate, volume of urine in the bladder after voiding, and Boyarski
symptom score were similar in the two groups before treatment and did
not change significantly in either group during treatment (Table 4).
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). Of the 12 men who were anemic
(hemoglobin, <12.5 g/dL; hematocrit, <40%) before treatment, 4 of
the 7 in the testosterone-treated group experienced increases to normal
during treatment, but so did 2 of the 5 men who were initially anemic
in the placebo-treated group. Three men treated with testosterone
developed persistent erythrocytosis (hemoglobin, >17.5 g/dL;
hematocrit, >52%) during treatment.
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). Two men, 1
in each treatment group, experienced persistent increases in
respiratory distress index from fewer than 5 apneic and hypopneic
episodes/h to more than 15 episodes/h during the course of the
study. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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An increase in bone mineral density of the lumbar spine after testosterone treatment only in those men whose pretreatment serum testosterone concentration was relatively low is consistent with other information concerning the effect of testosterone on bone. In a study of 12 men who were castrated in adulthood and did not receive testosterone replacement, the bone mineral density of the spine was lower the longer the time after castration (9), suggesting that a decrease in the serum testosterone concentration decreases bone density. In a study of 29 hypogonadal men treated with 100 mg testosterone enanthate once a week for 18 months, bone mineral density of the spine increased by 5% (10), suggesting that an increase in the serum testosterone concentration of hypogonadal men to normal restores bone density at least in part. To what degree the effect of testosterone on bone occurs directly and to what degree it is mediated via conversion to estradiol is unclear, but some direct effect seems possible, because human osteoblast-like cells in culture express androgen receptors (16), and mouse bone cells in culture proliferate in response to androgens that cannot be converted to estrogens (17).
The failure of bone mineral density at three sites in the hip to increase during testosterone treatment even in men with relatively low pretreatment serum testosterone concentrations could be at least partly related to the slower response of this bone to changes in gonadal steroids. In postmenopausal women, the bone mineral density of the hip does not increase as much in response to estrogen treatment as does that of the spine (18, 19, 20).
The failure to observe an effect of testosterone on markers of bone turnover could reflect the relatively mild overall degree of hypogonadism in these men. In a study of men who were frankly hypogonadal and previously untreated, testosterone treatment decreased urinary deoxypyridinoline and bone-specific alkaline phosphatase (10), and in a study of elderly men whose pretreatment serum testosterone concentrations were below 350 ng/dL, testosterone treatment decreased urinary hydroxyproline excretion (21).
The increase in bone mineral density of the spine in both treatment groups could have resulted at least in part from an increase in calcium and vitamin D intake in both groups. On the basis of a dietary history before treatment, we instructed all but 6 men in the placebo group and all but 4 in the testosterone group to take 1 pill daily containing 500 mg elemental calcium and 125 U vitamin D. In a recent study of 176 men over 65 yr of age who took 500 mg elemental calcium and 700 U vitamin D daily for 3 yr (22), the mean increase in spinal bone mineral density was slightly, but significantly, greater than that in a placebo group and was of a magnitude (2.1%) similar to that in the men who took calcium but not testosterone in the present study (2.5%).
We also measured several parameters that reflect conditions that testosterone might exacerbate. Testosterone treatment was associated with a small increase in the mean serum prostate-specific antigen concentration, but no increases in other parameters that reflect prostate disease. Testosterone treatment was also associated with small increases in mean hemoglobin and hematocrit values and the development of erythrocytosis in three men. Testosterone treatment was not associated with an increase in the respiratory distress index. Testosterone treatment, in short, was not associated with obvious deleterious effects. However, because this study was not designed to have sufficient statistical power to evaluate potential deleterious effects, we cannot draw definite conclusions about the risk of administering testosterone to men over 65 yr of age.
We conclude that increasing the serum testosterone concentration of men over 65 yr of age to that found in young men for 3 yr did not increase lumbar spine bone density overall, but did increase it in men with low pretreatment serum testosterone concentrations.
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Acknowledgments |
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Footnotes |
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Received October 23, 1998.
Revised December 16, 1998.
Revised February 17, 1999.
Accepted February 24, 1999.
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References |
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