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Original Studies |
Neuroendocrine Unit (W.F., A.K., S.G.) and Endocrine Unit (J.F.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Neuroendocrine Unit, Bulfinch 457B, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: sgrinspoon{at}partners.org
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Abstract |
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Compared with controls, lumbar spine BMD (1.021 ± 0.018 vs. 1.084 ± 0.025 g/cm2; P = 0.04) and total hip BMD (0.951 ± 0.017 vs. 1.070 ± 0.019 g/cm2; 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.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The anabolic effects of testosterone and progressive resistance training therapy on lean body mass and muscle function in men with AIDS wasting have recently been reported (7, 8). In addition, testosterone increases BMD in non-HIV-infected men with both congenital and acquired hypogonadism (9, 10). In this study we examined the independent effects of testosterone and progressive resistance training on BMD in eugonadal men with AIDS wasting.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fifty-four eugonadal (serum free testosterone, >42 pmol/L) HIV-infected men with the AIDS wasting syndrome (weight <90% IBW or weight loss >10% of baseline weight) between the ages of 27 and 51 yr were recruited from the multidisciplinary HIV practice at Massachusetts General Hospital and from newspaper advertisements. Weight, medication history, and serum testosterone levels were assessed at a screening visit (11). Exclusionary criteria for participation in the study included diagnosis of new opportunistic infection within 6 weeks of the study, unstable angina, aortic stenosis, uncontrolled hypertension, severe neuropathy, arthritis, or other contraindication to exercise. Additional exclusionary criteria included intractable diarrhea (six or more stools per day), current substance abuse, initiation of protease inhibitor use within 6 weeks of study entry, abnormal prostate-specific antigen, symptomatic prostatism, history of prostate malignancy, bipolar disorder, hemoglobin less than 9 g/dL, platelet count less than 50,000 cells/mm3, and serum creatinine greater than 177 µmol/L. Men receiving parenteral nutrition, megestrol acetate, glucocorticoids, androgens, estrogens, GH, or other anabolic agents within 3 months of the study were excluded. All men provided written informed consent, and the study was approved by the human research committee of Massachusetts General Hospital. The effect of testosterone on body composition, muscle cross-sectional area, muscle function, and hormonal parameters has been previously reported in these men (8). Thirty-five healthy control subjects between the ages of 22 and 50 yr were also recruited using signs posted at Massachusetts General Hospital. None of the control subjects was receiving medication or had any illness known to affect bone metabolism.
Informed consent was obtained from subjects, and the guidelines for human experimentation of the U.S. Department of Health and Human Services and the Massachusetts General Hospital subcommittee on human studies were followed in conducting this research.
Protocol
HIV-infected men. Participating subjects with AIDS wasting were stratified for weight above or below 90% ideal body weight and randomized to receive testosterone enanthate (200 mg/week, im; Bio-Technology General Corp., Iselin, NJ) or placebo and simultaneously to receive progressive resistance training three times per week or no training over 12 weeks in a 2 x 2 factorial study design (12). Randomization to testosterone was blinded to patient and investigator.
Subjects were admitted to the General Clinical Research Center at Massachusetts General Hospital for an in-patient baseline evaluation including body composition and bone turnover markers. Lumbar spine, proximal femur, and total body BMD were assessed by dual energy x-ray absorptiometry (DXA). Blood and morning 2-h urine samples were obtained at the baseline and 12 week visits. Subjects were instructed how to self-administer im injections. Subjects unable or unwilling to self-administer study medication received weekly injections by the nursing staff of the General Clinical Research Center. Subjects were seen at 6 and 12 weeks to assess compliance using testosterone levels, review of injection records, and empty vial counts. At the final 3 month visit, subjects underwent repeat assessment of regional total body BMD and body composition by DXA.
Subjects randomized to resistance training underwent progressive strength training three times per week for 12 weeks. A standardized dynamic progressive resistance training regimen was supervised by a licensed physical therapist at Massachusetts General Hospital using Life Circuit machines (Life Fitness, Franklin Park, IL). Subjects performed leg extension, leg curl, leg press, lattisimus dorsi pulldown, arm curl, and triceps extension using a predetermined weight. Baseline 1-repetition maximum (1-RM; defined as the maximal load that could be lifted throughout the joint range of motion once) was assessed taking the best of three efforts. Each set consisted of six to eight repetitions. During weeks 1 and 2 subjects performed two sets at 60% 1-RM. During weeks 3–6, subjects performed two sets at 70% 1-RM. During weeks 7–9, subjects performed two sets at 70% 1-RM and one set at 80% 1-RM. During weeks 10–12, subjects performed three sets at 80% 1-RM. Subjects also performed 30 min of aerobic exercise on a stationary bicycle three times per week, including a 5-min warm-up period and a 5-min cool-down period. Target heart rate was 60–70% of the maximal predicted rate (220 - age in years). Attendance was monitored, and subjects were asked to limit other exercise to normal daily activity during the study.
Control subjects. Male control subjects without HIV infection were concurrently evaluated in a single out-patient visit with assessment of fasting (before 1000 h) bone turnover markers (serum osteocalcin level and urinary N-telopeptide and deoxypyridinoline to creatinine ratios) and BMD (lumbar spine, proximal femur, and total body) by DXA.
Experimental methods
Body composition analysis. Fasting weight and percent ideal body weight were measured on the first day of each visit (13). The BMD of the posterior-anterior lumbar spine and proximal femur were determined by DXA (QDR-4500 densitometer, Hologic, Inc., Waltham, MA) in control subjects and at the baseline visit in the HIV-infected subjects (SD of 0.01 g/cm2 for posterior-anterior spine, total hip, and femoral neck are reported for the QDR 4500). The reproducibility of regional lumbar spine BMD was 0.006 g/cm2 based upon data obtained at Massachusetts General Hospital. BMD expressed as a standardized T-score refers to comparison of the individual BMD with BMD determinations of normal populations of young, gender-matched individuals compiled by the manufacturer for the lumbar spine and compared with the NHANES III database for the total hip. Regional lumbar spine BMD was determined at baseline and 3 months in the HIV-infected men from total body DXA scans.
Biochemical and immunological assays. Serum total and free testosterone levels were measured by RIA (Diagnostics Products, Los Angeles, CA). The intraassay coefficients of variation (CVs) were 5–12% and 3.2–4.3%, respectively. Serum estradiol was measured by double antibody RIA (Diagnostics Systems Laboratories, Inc., Webster, TX) with an intraassay CV of 6.5–8.9%. Serum estrone levels were measured by double antibody RIA (ICN Pharmaceuticals, Inc., Costa Mesa, CA) with an intraassay CV of 4.4–9.4%. CD4+ lymphocyte counts were measured by flow cytometry (Becton Dickinson and Co., San Jose, CA). Viral load was determined using the Amplicor HIV-1 Monitor Test (Roche, Branchburg, NJ). Serum osteocalcin levels were measured using a double antibody immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a sensitivity of 0.08 nmol/L, an interassay CV of 3.0–5.5%, and an intraassay CV of 2.5–4.3%. Urinary N-telopeptide excretion was measured by competitive inhibition enzyme-linked immunosorbent assay (Ostex International, Inc., Seattle WA) with an interassay CV of 10.2–12.5% and an intraassay CV of 5.0–8.6%. Urinary deoxypyridinoline excretion was measured using a competitive enzyme immunoassay (Metra Biosystems, Mountain View, CA) with a sensitivity of 1.1 nmol/L, an interassay CV of 4.2–7.6%, and an intraassay CV of 4.9–8.5%.
Statistical analysis
At baseline, BMD and biochemical markers of bone turnover were compared between the men with the AIDS wasting syndrome and control subjects using Student’s two-sided t test. We used standard least squares multivariate models to compare BMD in men with AIDS wasting with control men while controlling for BMI differences between groups. BMD and turnover markers were compared among the HIV-infected men by protease inhibitor status and duration of protease inhibitor use using Student’s two-sided t test. The independent effects of testosterone and resistance training were analyzed simultaneously in a 2 x 2 factorial model. Testing for an interaction term revealed no interaction between testosterone and exercise on regional lumbar spine BMD, allowing both variables to be analyzed independently. Changes in regional BMD at the lumbar spine from the total body scan were compared between the treatment groups by analysis of covariance controlling for baseline values. P < 0.05 was considered statistically significant. Values are presented as the mean ± SEM unless otherwise indicated.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Baseline clinical characteristics
Baseline characteristics of men with AIDS wasting and control
subjects are shown in Table 1
. Body mass
index (22.1 ± 0.4 vs. 25.9 ± 0.7
kg/m2; P < 0.0001) and percent
fat mass (18.1 ± 0.8% vs. 23.0 ± 1.2%;
P = 0.0006) were significantly lower in men with AIDS
wasting than in controls. Serum-free testosterone levels were normal in
all subjects, although they were slightly higher in men with AIDS
wasting.
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Table 2 shows BMD and markers of
bone turnover of the men with AIDS wasting and control subjects. BMD
and T-scores for the posterior-anterior lumbar spine and the total hip
regions were significantly lower in the men with AIDS wasting than in
the control group (Fig. 1). Femoral neck
BMD was not different between groups. T-scores were lower in men with
AIDS wasting at the lumbar spine and total hip. Among men with AIDS
wasting, BMD of the total hip was associated with body mass index (BMI;
r = 0.39; P = 0.006). In a multivariate model
controlling for BMI, BMD at the total hip remained significantly lower
in men with AIDS wasting (P = 0.0003). In a similar
model comparing men with AIDS wasting to control men, BMD at the lumbar
spine lost significance, but still trended lower when controlling for
BMI (P = 0.08). The mean serum osteocalcin level was
lower in HIV men than in control subjects (Table 2 and Fig. 2). In contrast, urinary N-telopeptide
excretion was higher in the men with AIDS wasting than in controls
(Table 2 and Fig. 2). Urinary deoxypyridinoline excretion trended
higher in men with AIDS wasting, although the difference was not
statistically significant (Table 2).
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Age and BMI were not different among subjects using protease
inhibitors and those not using protease inhibitors. Protease inhibitor
use was not associated with significant differences in BMD or T-scores
(Table 3). Both serum osteocalcin levels
and urinary deoxypyridinoline excretion were higher in HIV-infected men
receiving protease inhibitor therapy compared with those not using
protease inhibitors (Table 3). Among men taking protease inhibitors,
the duration of protease inhibitor use was not significantly associated
with any specific measurement of BMD (data not shown).
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The baseline characteristics of the men with AIDS wasting syndrome
in the different treatment groups were previously reported
(8). The groups did not differ with respect to age,
weight, BMI, total body fat content, total body lean content, CD4
count, viral load, total testosterone, free testosterone, estrone,
estradiol, or lumbar spine BMD. The lumbar spine regional BMD (measured
on the total body DXA scan) was strongly associated with measurement of
posterior-anterior lumbar spine BMD by DXA (r = 0.93;
P < 0.0001; Fig. 3).
Regional lumbar spine BMD increased significantly in subjects treated
with testosterone compared with the placebo group controlling for
baseline values (+2.4 ± 1.3 vs. -1.3 ± 1.0%,
testosterone vs. placebo, respectively; P =
0.02; Fig. 4). In contrast, resistance
training did not affect lumbar spine regional BMD (+0.8 ± 1.0
vs. +0.4 ± 1.3%, training vs. no training;
P = 0.70; Fig. 5). The
serum osteocalcin level did not change in either the testosterone or
exercise treatment group over the 3-month treatment period (change in
serum osteocalcin, 0.10 ± 0.37 vs. 0.54 ± 0.46
nmol/L, testosterone vs. placebo, P = 0.48;
0.54 ± 0.36 vs. 0.14 ± 0.49 nmol/L, resistance
training vs. no resistance training, P =
0.51). At the end of the 3-month treatment period, 10 of the 21 men
with AIDS wasting randomized to testosterone demonstrated trough total
and free testosterone values above the upper limit of normal. At
baseline, men with AIDS wasting had mean estrone and estradiol levels
of 131.7 ± 7.8 and 83.1 ± 4.1 pmol/L, respectively. Both
estrone (+77.7 ± 17.8, +4.8 ± 7.0 pmol/L; P = 0.0003) and
estradiol (+63.5 ± 29.7, +1.8 ± 4.4 pmol/L; P = 0.04)
significantly increased in the testosterone treatment group compared
with the placebo group. Among subjects randomized to testosterone
therapy, changes in estrone and estradiol levels over the 3-month
treatment period did not significantly correlate with the change in
lumbar spine BMD (estrone: r = 0.42; P = 0.064;
estradiol: r = 0.02; P = 0.93) on whole body DXA,
although there was a trend toward a correlation to the change in
estrone levels.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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HIV disease is associated with many factors that might reduce BMD. Hypogonadism is a frequent complication of advanced HIV disease and may be a major factor in the development of osteopenia (1, 15). AIDS wasting is a manifestation of advanced HIV disease and is characterized by reduced body weight and lean body mass that may contribute to reduced BMD, possibly due to decreased mechanical loading. Wasting is also associated with reduced physical activity, which may, in turn, contribute to osteopenia (16). Inflammatory cytokine activation and malabsorption may also contribute to bone loss in HIV-infected men (17, 18, 19).
In this study we investigated BMD and bone turnover in eugonadal men with AIDS wasting. Lumbar spine and total hip BMD were significantly lower in HIV-infected men than in age-matched control men, with mean T-scores of -0.62 and -0.65 SD, respectively. It is unknown whether this degree of osteopenia reflects an increase in fracture risk in this population. Weakness and poor functional status may further increase the risk of clinical fractures. The finding of reduced BMD is consistent with an earlier study that reported a more modest reduction in spinal BMD in HIV-infected men, although it is not clear whether these men had AIDS or wasting (5). Hip BMD was not measured, and gonadal status was not clearly defined in this prior report. Our subjects all had normal free testosterone levels, indicating that reduced BMD in HIV-infected men with wasting cannot be attributed to hypogonadism.
The reduced serum osteocalcin level and the increase in urinary N-telopeptide excretion suggest that bone formation and resorption may be uncoupled in men with AIDS wasting. This pattern of bone turnover is analogous to that found in anorexia nervosa (20, 21) and other severe chronic illnesses (22). A similar pattern of uncoupled bone turnover was previously reported in a group of men and women with HIV infection (3), although gonadal status was not reported in these subjects. Therefore, the impact of hypogonadism on bone turnover could not be determined.
Tebas et al. recently reported a higher prevalence of osteopenia and osteoporosis in men with HIV infection receiving protease inhibitors than in both HIV-infected men not taking protease inhibitors and non-HIV-infected controls (6). In contrast, the use of protease inhibitors was not associated with any specific measure of BMD in our subjects. However, both serum osteocalcin levels and urinary deoxypyridinoline excretion were higher in subjects receiving protease inhibitors, suggesting an increased rate of bone turnover in this group. The different findings between our study and that of Tebas et al. may be explained by the populations studied. None of the subjects in our study had HIV lipodystrophy syndrome, and all met strict criteria for the AIDS wasting syndrome. In contrast, men with fat redistribution and the lipodystrophy syndrome were included in the study by Tebas et al. The mechanism by which protease inhibitor use may reduce BMD in HIV disease is unknown, but may relate to fat deposition resulting in an abnormal marrow microenvironment. This may in part explain why in our study of men with AIDS wasting, an effect of protease inhibitors on BMD was not seen.
Lumbar spine BMD increased with short-term, high dose testosterone therapy in these men, even though they were eugonadal at baseline. In contrast, exercise therapy did not increase BMD, although lean body mass increased significantly. Lean body mass increased by a 2-fold greater extent (+4.3 vs. +2.3 kg) in response to testosterone than in response to resistance training (8), which may account for the relatively greater effect of testosterone on BMD. In addition, both serum estrone and estradiol levels increased in the testosterone therapy group, possibly contributing to the increase in BMD. Pharmacological testosterone therapy increases BMD in eugonadal men with AIDS wasting, similar to prior findings in eugonadal men with vertebral fractures (23). Most prior studies have examined the effect of testosterone replacement on BMD in hypogonadal men. Whereas increases in BMD are probably beneficial, serum HDL cholesterol levels decreased in response to high dose testosterone administration in these men (8). Therefore, any recommendation to administer testosterone to improve BMD in eugonadal men with AIDS wasting must be made with caution, as the long-term effects of testosterone therapy on other metabolic and cardiovascular parameters remain unknown.
Serum osteocalcin levels did not change in response to
testosterone treatment in this study. The effects of androgens on bone
markers are complex. Androgen receptors are present on osteoblasts
(24). In vitro studies suggest that androgens
decrease bone resorption (25). 5
-Dihydrotestosterone, a
nonaromatizable androgen, decreased serum osteocalcin levels in
oophorectomized rats (26). Serum osteocalcin levels
increased in postmenopausal females treated with estrogen and
methyltestosterone (27). Testosterone
administration reduced bone specific alkaline phosphatase levels in
hypogonadal men (10). In eugonadal non-HIV-infected men,
testosterone administration had no effect on serum osteocalcin levels
after 3 months, but it reduced serum osteocalcin levels and bone
resorption indexes after 6 months of therapy (23). One
potential explanation for the absence of change in osteocalcin level in
response to testosterone is a mixed effect of testosterone in this
population. Direct anabolic effects on bone may be offset by estrogenic
effects from peripheral conversion. Furthermore, this study population
is unique, in that osteocalcin levels are low at baseline. Further
studies on the mechanisms of testosterone effects on bone density in
men with AIDS wasting are needed.
Our study has several limitations. The change in lumbar spine BMD was determined using the lumbar spine regional measurement obtained from the total body DXA scan. This measurement correlates strongly with standard lumbar spine BMD. Although our subjects were eugonadal and were without symptoms of hypogonadism at the time of enrollment, we cannot exclude the possibility that subjects may have had a prior history of hypogonadism contributing to the observed bone loss.
Our findings have several important implications. As the prognosis of men with HIV infection continues to improve with the advances in highly active antiretroviral therapy, reduced BMD may increase the risk for symptomatic fractures in this population. By increasing BMD, androgen therapy may reduce this risk. Further studies to investigate the natural history of bone loss in HIV disease and the long-term effects of androgen therapy on BMD in men with AIDS wasting are needed. Additional studies are also needed to investigate the mechanisms of uncoupled bone turnover and the effects of protease inhibitor therapy in this population.
In conclusion, we have demonstrated that eugonadal men with AWS have reduced BMD at the lumbar spine and total hip and that bone turnover may be uncoupled in these men. Testosterone therapy increases BMD in this population.
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Acknowledgments |
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Footnotes |
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Received September 11, 2000.
Revised February 1, 2001.
Accepted February 6, 2001.
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References |
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