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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2009 Oct 9;94(12):4785–4792. doi: 10.1210/jc.2009-0739

Effects of Aromatase Inhibition on Bone Mineral Density and Bone Turnover in Older Men with Low Testosterone Levels

Sherri-Ann M Burnett-Bowie 1, Elizabeth A McKay 1, Hang Lee 1, Benjamin Z Leder 1
PMCID: PMC2795655  PMID: 19820017

Abstract

Context: Aging is associated with declining gonadal steroid production, low bone mineral density (BMD), and fragility fractures. The efficacy and safety of testosterone replacement in older men remains uncertain.

Objective: The objective of the study was to assess the effects of aromatase inhibition on BMD in older men with low testosterone levels.

Design and Setting: This was a 1-yr, double-blind, randomized, placebo-controlled trial that was conducted at a tertiary care academic center in Boston, MA.

Participants: Participants included 69 men aged 60+ yr with borderline or low testosterone levels and hypogonadal symptoms.

Intervention: Intervention included 1 mg anastrozole daily or placebo.

Main Outcome Measures: Changes in gonadal steroid hormone levels, BMD, and bone turnover markers were measured.

Results: Mean serum testosterone increased from 319 ± 93 ng/dl at baseline to 524±139 ng/dl at month 3 (P < 0.0001) and declined slightly to 474 ± 145 ng/dl by 1 yr. Estradiol levels decreased from 15 ± 4 pg/ml at baseline to 12 ± 4 pg/ml at month 3 and then remained stable (P < 0.0001). Posterior-anterior (PA) spine BMD decreased in the anastrozole group as compared with placebo (P = 0.0014). In the anastrozole group, PA spine BMD decreased from 1.121 ± 0.141 g/cm2 to 1.102 ± 0.138 g/cm2, whereas in the placebo group, PA spine BMD increased from 1.180 ± 0.145 g/cm2 to 1.189 ± 0.146 g/cm2. Qualitatively similar, but not statistically significant, changes occurred at the other sites. Bone turnover markers were not affected by anastrozole therapy.

Conclusions: In older men, aromatase inhibition increases testosterone levels, decreases estradiol levels, and appears to decrease BMD. Aromatase inhibition does not improve skeletal health in aging men with low or low normal testosterone levels.

Aromatase inhibitor therapy increases testosterone in older men with low testosterone levels.

Testosterone and estradiol are critical for normal bone development and maintenance in men (1,2,3). Male aging is associated with declines in both androgen and estrogen levels (4). These age-related decreases in gonadal steroids are associated with a number of health problems, including low bone mineral density (BMD) and an increased incidence of fragility fractures (5). Testosterone administration is a potentially beneficial therapy in aging hypogonadal men, although questions remain as to its safety and efficacy. Furthermore, some of the risks and adverse effects of testosterone administration may be mediated by its conversion to estradiol (6,7,8,9,10). Aromatase inhibitor therapy lowers circulating estradiol by blocking its conversion from testosterone. In so doing, negative feedback signals at the hypothalamus and pituitary are reduced, the production of GnRH and LH increase and testosterone production increases (11). Thus, an aromatase inhibitor may be a safer (given the lowering of estrogen levels) and more convenient (given the oral formulation) way to replace testosterone in hypogonadal men. We have previously shown that anastrozole (Arimidex; AstraZeneca Pharmaceuticals, Wilmington, DE), a potent orally administered aromatase inhibitor used in breast cancer treatment, increases testosterone production and normalizes serum testosterone in older men with low testosterone levels (12,13). Given the importance of both testosterone and estradiol in male skeletal health, it is possible that anastrozole therapy could improve bone health (by increasing testosterone) or worsen bone health (by lowering estradiol), as has been demonstrated in women with breast cancer (14). To investigate the effects of aromatase inhibition on bone metabolism, we assessed the effects of daily anastrozole administration on BMD and bone turnover markers (BTMs) in men aged 60 yr or older with low or low normal testosterone levels, who participated in a 1-yr, double-blind, randomized, placebo-controlled trial (13).

Subjects and Methods

Study subjects

The details of subject recruitment and enrollment have been previously described (13). Men 60 yr or older were recruited through advertisements and mass mailings. Eligible subjects had serum testosterone between 150 and 300 ng/dl on a single measure or between 300 and 350 ng/dl on two consecutive measures that were obtained on different days; normal serum LH and prolactin; and a positive response to the St. Louis University Androgen Deficiency in Aging Males questionnaire. The Androgen Deficiency in Aging Males questionnaire defines a positive response as either: 1) yes to question 1 (“do you have a decrease in libido?”) or question 7 (“are your erections less strong?”) or 2) yes to three of the remaining eight questions (15). Subjects with a history of acute urinary retention, prostate nodules on digital rectal examination, or prostate-specific antigen (PSA) greater than 2.5 μg/liter were excluded. Additionally, subjects with known testicular or pituitary disease, obstructive sleep apnea, malignancy, hypercoagulable syndrome, thromboembolic disease, or use of drugs known to affect steroid hormone or SHBG levels were excluded from participation. The Human Research Committee of Partners HealthCare System approved the study and subjects provided written informed consent.

Of the 2470 men screened by telephone, 632 presented for screening and 114 were found to be eligible by the above criteria. Of these, 88 enrolled in the study and 69 subjects completed the first 12 months on study medication and form the basis of this report (Fig. 1).

Figure 1.

Figure 1

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Flow of patients through the trial. ADAM, Androgen Deficiency in Aging Males.

Study protocol

Using a randomly varying blocking scheme, subjects were randomized by computer-generated assignment in a blinded 1:1 ratio to receive either anastrozole 1 mg daily or matching placebo for 12 months. Subjects were seen at baseline, 3, 6, and 12 months. At each visit, which occurred in the morning, a fasting blood sample was collected for measurement of hormones and BTM. Dual x-ray absorptiometry (DXA) and quantitative computerized tomography (QCT) were performed at baseline and month 12. Medication compliance was assessed through the use of diaries and returned pill counts.

Laboratory methods

Total testosterone was measured by double-antibody RIA (Diagnostic Products, Los Angeles CA) with sensitivity of 4 ng/dl and intra- and interassay coefficients of variation (CVs) of 6.9 and 7.5%, respectively. Bioavailable testosterone was measured by differential precipitation of testosterone bound to globulins with 50% ammonium sulfate after equilibration of the serum sample with [3H]T. Sensitivity of the BT assay was 5 ng/dl with intra- and interassay CVs of 7.9 and 8.6%. Total serum estradiol was measured using an ultrasensitive competitive RIA after extraction and chromatographic purification (Diagnostic System Laboratory Inc., Webster, TX) with sensitivity of 2.2 pg/ml and intra- and interassay CVs of 6.5 and 9.7%. Serum dihydrotestosterone (DHT) was measured by double-antibody nonextraction RIA (I-125) using a commercial kit (Diagnostic System Laboratory) with sensitivity 4 ng/dl and intra- and interassay CVs of 7.9 and 8.4%.

Bone-specific alkaline phosphatase (bone ALP) was measured by ELISA (Quidel Inc., San Diego, CA) with sensitivity 0.7 U/liter and intra- and interassay CVs of 4–6 and 5–8%, respectively. N-terminal propeptide of type I procollagen (PINP) was measured by quantitative RIA (Immunodiagnostic Systems, Inc., Fountain Hills, AZ) with sensitivity of 2 μg/liter and intra- and interassay CVs of 6.5–10.2 and 6.0–9.8%, respectively. Osteocalcin (OC) was measured by solid-phase enzyme-amplified sensitivity immunoassay (American Laboratory Products Company, Ltd., Salem, NH) with sensitivity of 0.4 ng/ml and intra- and interassay CVs of 0.8–1.1 and 4.0–6.6%, respectively. C-terminal telopeptide of type 1 collagen (CTX) was measured by ELISA (Immunodiagnostic System, Inc., Fountain Hills, AZ) with sensitivity of 0.02 ng/ml and intra- and interassay CVs of 1.7–3.0 and 2.5–10.9%, respectively. Serum N-telopeptide of type 1 collagen (NTX) was measured by ELISA (Wampole Laboratories, Inc., Princeton, NJ) with sensitivity of 3.2 nm bone collagen equivalent and intra- and interassay CVs of 4.6 and 6.9%, respectively. Osteoprotegerin (OPG) was measured by enzyme immunoassay (American Laboratory Products Company, Ltd., Salem, NH) with a sensitivity of 0.14 pm and intra- and interassay CVs of 4–10 and 7–8%, respectively.

BMD of the posterior-anterior spine, total hip, femoral neck, and total body were determined from DXA total-body scan (QDR 4500A; Hologic, Bedford, MA) using software version 11.1. The sd for in vivo measurements of the posterior-anterior spine, total hip, femoral neck, and total body were 0.005, 0.006, 0.007, and 0.012 g/cm2, respectively. Trabecular BMD of the midbody of the first four lumbar vertebrae was assessed by QCT with a GE model 9800 scanner (General Electric Medical Systems, Milwaukee, WI) (16). The precision error for this technique is 3–5 mg/cm3.

Study end points

The primary study end point was the change in posterior-anterior spine BMD by DXA with anastrozole, compared with placebo. Secondary end points included the change in total body, femoral neck, and total hip BMD by DXA, the change in trabecular BMD by QCT and the change in markers of bone formation (bone ALP, OC, and PINP), markers of bone resorption (CTX and NTX), and OPG.

Statistical analysis

All subjects who received a BMD measurement at months 0 and 12 were included in this analysis. Data are summarized as mean ± sd. Differences in the baseline characteristics between the anastrozole and placebo groups were examined using t test. Data from our laboratory were used to calculate the power to detect a clinically significant change in posterior-anterior spine BMD based on a study in which elderly men were treated with alendronate (17). In that study, the sd of the change in posterior-anterior spine BMD was 2.5%. Given the present study’s sample size of 69, there was 90% probability of detecting a treatment effect of anastrozole on posterior-anterior spine BMD of 1.7% or more (α = 0.05). Between-group differences in primary and secondary end points were assessed by repeated-measure ANOVA. The ANOVA model included group, time, and (group) (time) interaction; the model was adjusted for the baseline level of each variable. A secondary analysis was performed to compare the between-group differences at each time point using t test as well as the within-group changes in these outcomes between time points using repeated-measures ANOVA. An additional secondary analysis was performed to assess the relationship between baseline testosterone and estradiol levels (measured in tertiles) and the change in BMD at each site and relationship between the change in testosterone and estradiol (measured in tertiles) and the change in BMD at each site. P < 0.05 was considered statistically significant.

Results

Baseline characteristics and gonadal steroid levels

We previously reported the baseline characteristics and the effects of aromatase inhibition on gonadal steroid levels (13). In summary, there were no significant differences at baseline in the two groups, except for small differences in estradiol levels (Table 1). Additionally, there were no significant differences between the 69 subjects who completed the study and the 19 who did not complete all study visits (data not shown). Anastrozole therapy increased mean serum testosterone at all time points (P < 0.0001 vs. placebo for repeated measures ANOVA) (Fig. 2A). Specifically, mean serum testosterone increased from 319 ± 93 ng/dl at baseline to 524 ± 139 ng/dl at month 3 (P < 0.0001 vs. baseline). From months 3 to 12, however, whereas testosterone levels remained significantly higher than baseline and placebo, there was a notable decline. Specifically, mean serum testosterone decreased to 505 ± 143 ng/dl at month 6 and to 474 ± 145 ng/dl at month 12 (P = 0.03 compared with month 3). Anastrozole therapy also increased mean bioavailable testosterone (Fig. 2B) and DHT levels (Fig. 2C) (P < 0.0001 vs. placebo for repeated measures ANOVA). Similar to testosterone, bioavailable testosterone and DHT levels declined between months 3 and 12 but remained significantly higher than baseline and placebo (P < 0.0001). The effects of anastrozole on estradiol were more modest than its effects on androgens (Fig. 2D). Estradiol levels decreased from 15 ± 4 pg/ml at baseline to 12 ± 4 pg/ml at month 3 and remained stable thereafter (P = 0.0004 vs. placebo for repeated measures ANOVA). Anastrozole therapy lowered SHBG levels (P = 0.0013 vs. placebo for repeated measures ANOVA) (Fig. 2E). Mean testosterone, bioavailable testosterone, DHT, estradiol, and SHBG were unchanged in the placebo group.

Table 1.

Baseline characteristics

Clinical or biochemical end points Anastrozole group (n = 34) Placebo group (n = 35) P
Age (yr) 66 ± 4 65 ± 4 ns
BMI (kg/m2) 30 ± 5 32 ± 5 ns
Testosterone (ng/dl) 319 ± 93 337 ± 96 ns
Bioavailable testosterone (ng/dl) 77 ± 23 89 ± 34 ns
Estradiol (pg/ml) 15 ± 4 19 ± 5 0.001
DHT (ng/dl) 53 ± 21 55 ± 20 ns
SHBG (nmol/liter) 32 ± 10 31 ± 12 ns
Posterior-anterior spine BMD (g/cm2) 1.121 ± 0.141 1.180 ± 0.145 ns
Femoral neck BMD (g/cm2) 0.850 ± 0.119 0.882 ± 0.127 ns
Total hip BMD (g/cm2) 1.052 ± 0.145 1.104 ± 0.135 ns
Total body BMD (g/cm2) 1.249 ± 0.088 1.295 ± 0.110 ns
Posterior-anterior spine by QCT (mg/cm3) 101 ± 22 107 ± 28 ns
Bone ALP (U/liter) 23 ± 7 25 ± 8 ns
PINP (ng/ml) 32 ± 14 33 ± 10 ns
OC (ng/ml) 11 ± 4 10 ± 4 ns
NTX (nm BCE) 13 ± 5 11 ± 4 ns
CTX (ng/ml) 0.50 ± 0.25 0.44 ± 0.22 ns
OPG (p/M) 4.8 ± 1.5 4.3 ± 1.3 ns
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All values are presented as mean ± sd. Systeme international conversion factors: testosterone and bioavailable testosterone (nanomoles per liter), 0.0347; estradiol (picomoles per liter), 3.671; DHT (nanomoles per liter), 0.0344. BMI, Body mass index; BCE, bone collagen equivalent; ns, not significant (P ≥ 0.05). 

Figure 2.

Figure 2

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Mean (± se) percent change in testosterone (A), bioavailable testosterone (B), DHT(C), estradiol (D), and SHBG (E) with anastrozole (solid line) vs. placebo (dashed line) for 12 months. *, P < 0.05 compared with placebo for each time point.

BMD and BTMs

The changes in BMD with anastrozole therapy are shown in Fig. 3. After 12 months, posterior-anterior spine BMD by DXA decreased in the treatment group (from 1.121 ± 0.141 to 1.102 ± 0.138 g/cm2), whereas it increased in the placebo group (from 1.180 ± 0.145 to 1.189 ± 0.146 g/cm2) (P = 0.0014 for the between group difference) (Fig. 3A). Similarly trabecular BMD by QCT decreased slightly in the treatment group (from 101 ± 22 to 99 ± 23 mg/cm3) and increased slightly in the placebo group (from 107 ± 28 to 109 ± 27 mg/cm3), but this was not statistically significant (P = 0.187 for the between group comparison) (Fig. 3B). Qualitatively similar between-group changes in BMD were observed at the femoral neck, total hip, and total body (Fig. 3, C–E); however, none of these changes were statistically significant.

Figure 3.

Figure 3

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Mean (± se) change in posterior-anterior spine BMD by DXA (A), trabecular (lumbar spine) BMD by QCT (B), femoral neck BMD by DXA (C), total hip BMD by DXA (D), and total body BMD by DXA (E) with anastrozole or placebo for 12 months. *, P < 0.05 compared with placebo.

The changes in bone formation (bone ALP, PINP, and OC), bone resorption (CTX and NTX), and OPG are shown in Fig. 4. Anastrozole therapy did not affect bone turnover.

Figure 4.

Figure 4

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Mean (± se) change in bone ALP (A), PINP (B), OC (C), CTX (D), (E) NTX, and OPG (F) with anastrozole (solid line) vs. placebo (dashed line) for 12 months. There were no statistically significant differences between the treatment and placebo groups.

As a secondary analysis, we investigated whether the BMD response to anastrozole therapy was influenced by either the baseline testosterone or estradiol level. Furthermore, we wanted to investigate whether the magnitude of the change in testosterone or estradiol levels with anastrozole therapy affected the BMD response. Specifically, we tested whether those subjects in the lowest or highest tertile of each variable (baseline testosterone, baseline estradiol, change in testosterone, or change in estradiol) had differential BMD response. We did not detect any significant differences in response based on the baseline or change in gonadal steroid levels (data not shown).

Subject withdrawal and compliance

Subjects were withdrawn for the following safety criteria: hematocrit greater than 50%; PSA increase of greater than 0.4 μg/liter at month 3; PSA increase of greater than 0.8 μg/liter at month 6; or other laboratory or physical examination abnormalities at the discretion of the study physician. No subject was withdrawn for an increase in hematocrit. Prostate-related withdrawals are shown in Table 2. As previously described (13), study subject withdrawal was balanced between the anastrozole (n = 11) and placebo (n = 8) groups. Additionally, compliance was excellent as assessed by medication diaries and pill counts (13). With one exception, subjects took more than 95% of the study medication.

Table 2.

Prostate-related study withdrawal

Reason for withdrawal Subjects (n) Group assignment (n)
Prostate cancer 1 Placebo
Benign prostate nodule (calcium deposit) 1 Anastrozole
Increase in PSA 5 Anastrozole (3), placebo (2)
Increase in BPH symptoms 1 Placebo
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BPH, Benign prostatic hypertrophy. 

Discussion

In this study, we examined the effects of 12 months of daily anastrozole therapy on BMD and markers of bone formation and resorption in older men with low normal serum testosterone. As previously described, aromatase inhibition increased testosterone levels by about 50%, resulting in levels that were generally in the mideugonadal range for young men (13). Aromatase inhibition also modestly decreased estradiol (∼20%), although mean levels remained in the normal range. Additionally, anastrozole therapy increased bioavailable testosterone and DHT compared with placebo. These increases in androgen levels and the associated mild decrease in estradiol were associated with a statistically significant decrease in posterior-anterior spine BMD vs. placebo as measured by DXA and qualitatively similar, although nonsignificant, changes at the other bone sites. In contrast, bone turnover was not affected by aromatase inhibition. The observed changes in BMD were not affected by baseline testosterone or estradiol levels or the magnitude of change in testosterone or estradiol with anastrozole administration.

Testosterone and estrogen are important for the maintenance of skeletal health in adult men. In some prior cross-sectional or longitudinal analyses of the relationship between gonadal steroids and BMD, both testosterone and estradiol have been independently associated with BMD in aging men (18,19,20). However, in some studies there was greater association between estradiol and BMD in older men (21,22,23), whereas in others, there was greater association between testosterone and BMD (24,25,26). Interventional studies in which gonadal steroid levels are manipulated have been insightful. Specifically, studies rendering men either selectively estrogen deficient, selectively androgen deficient or deficient in both hormones have demonstrated that both testosterone and estrogen have independent roles in maintaining normal bone turnover (27,28,29). The apparent loss of BMD at the posterior-anterior spine in this study suggests that the observed increase in testosterone with aromatase inhibition was insufficient to overcome the effects of selective estrogen deficiency on the skeleton. Alternately, it is possible that if aromatase inhibition had produced higher serum testosterone levels then BMD would have been maintained.

Administering aromatizable testosterone to hypogonadal older men increases testosterone, estradiol, and BMD. In most studies, this increase in BMD is associated with decreased bone resorption, although increased bone formation has also been reported (30,31,32,33,34,35), the latter possibly related to the pharmacological dose or parenteral route of administration. Notably, in a prior study in which aromatizable testosterone was administered to hypogonadal older men, similar to our cohort, BMD changed without concomitant changes in BTM (36). It is unclear why we observed significant decreases in posterior-anterior spine BMD but no accompanying change in BTM with anastrozole therapy. Given the discordance between BMD and BTM changes, it remains possible that the decrease in posterior-anterior spine BMD was a chance finding. However, the qualitatively similar BMD changes at the other sites make this somewhat less likely. Furthermore, it is important to note that BMD is only one parameter contributing to bone strength. Bone strength is impacted by bone quality, bone mass, and bone geometry. Specifically, periosteal apposition may offset endosteal or endocortical bone resorption, thus creating bone that is of wider diameter (37). Interestingly, gonadal steroids may have differential effects on periosteal apposition, wherein testosterone stimulates periosteal apposition and estradiol inhibits it (38). Thus, it is possible that aromatase inhibition therapy could induce beneficial changes in bone geometry and hence skeletal health (39). Conversely, however, recent observational data suggest that estradiol has a more dominant effect on bone geometry than testosterone; thus, aromatase inhibition, by lowering estradiol, may negatively impact bone geometry (40).

In a prior 3-month, double-blind, placebo-controlled study of 37 elderly men with low testosterone levels treated with anastrozole, we demonstrated similar increases in mean testosterone levels to those observed in this study (41). Similar increases in testosterone were also reported in a short-term study in which eugonadal older men were given anastrozole 2 mg daily (42). In that study, Taxel et al. (42) observed changes in BTM with anastrozole therapy; however, the men were eugonadal, received a higher dose of anastrozole, and were not compared with a placebo group. Importantly, in our earlier short-term study (41), we also did not observe any change in BTM, but this study was not long enough to provide meaningful insight regarding the effect of aromatase inhibition on BMD.

Limitations of this study deserve mention. Given the small sample size, whereas we had sufficient power to detect small changes in posterior-anterior spine BMD, we did not have adequate power to detect small changes at other sites. Additionally, the observed 20% dropout rate had the potential to introduce bias. Reassuringly, the dropout rate was balanced between the treatment and placebo groups and thus should not have affected our results. Furthermore, at baseline there were no differences in the subjects who completed the study vs. those who did not complete all study visits.

In summary, anastrozole therapy given over 12 months increased serum testosterone and modestly reduced estradiol levels in men aged 60 yr and older with low or low normal testosterone levels. Whereas we restored testosterone levels into the midnormal range for healthy young men, BMD at the spine decreased compared with the placebo group. Coupled with its lack of benefit in improving body composition (13), aromatase inhibition does not appear to be an optimal therapy for hypogonadism in aging.

Acknowledgments

We are grateful to the staff of the Massachusetts General Hospital Mallinckrodt General Clinical Research Center for the implementation of the study protocol.

Footnotes

This work was supported by National Institute of Health Grants K23-RR-161310 (to B.Z.L.), R01-AG-025099-03 (to B.Z.L.), and M01-RR-01066 (to the Mallinckrodt General Clinical Research Center) and AstraZeneca Pharmaceuticals.

Disclosure Summary: The authors have nothing to disclose.

First Published Online October 9, 2009

For editorial see page 4665

Abbreviations: BMD, Bone mineral density; bone ALP, bone-specific alkaline phosphatase; BTM, bone turnover marker; CTX, C-terminal telopeptide of type 1 collagen; CV, coefficient of variation; DHT, dihydrotestosterone; DXA, dual x-ray absorptiometry; NTX, N-telopeptide of type 1 collagen; OC, osteocalcin; OPG, osteoprotegerin; PINP, N-terminal propeptide of type I procollagen; PSA, prostate-specific antigen; QCT, quantitative computerized tomography.

References

  1. Finkelstein JS, Klibanski A, Neer RM, Greenspan SL, Rosenthal DI, Crowley Jr WF 1987 Osteoporosis in men with idiopathic hypogonadotropic hypogonadism. Ann Intern Med 106:354–361 [DOI] [PubMed] [Google Scholar]
  2. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS 1994 Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331:1056–1061 [DOI] [PubMed] [Google Scholar]
  3. Bertelloni S, Baroncelli GI, Federico G, Cappa M, Lala R, Saggese G 1998 Altered bone mineral density in patients with complete androgen insensitivity syndrome. Horm Res 50:309–314 [DOI] [PubMed] [Google Scholar]
  4. Kaufman JM, Vermeulen A 2005 The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 26:833–876 [DOI] [PubMed] [Google Scholar]
  5. Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy 2004 Testosterone and health outcomes. In: Liverman CT, Blazer DG, eds. Testosterone and aging. Washington, DC: National Academies Press; 32–111 [Google Scholar]
  6. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J 2002 Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333 [DOI] [PubMed] [Google Scholar]
  7. Risbridger GP, Bianco JJ, Ellem SJ, McPherson SJ 2003 Oestrogens and prostate cancer. Endocr Relat Cancer 10:187–191 [DOI] [PubMed] [Google Scholar]
  8. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones 3rd BN, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J 2003 Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289:2651–2662 [DOI] [PubMed] [Google Scholar]
  9. Arnold JT, Le H, McFann KK, Blackman MR 2005 Comparative effects of DHEA vs. testosterone, dihydrotestosterone, and estradiol on proliferation and gene expression in human LNCaP prostate cancer cells. Am J Physiol Endocrinol Metab 288:E573–E584 [DOI] [PubMed] [Google Scholar]
  10. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM 2006 Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 91:1995–2010 [DOI] [PubMed] [Google Scholar]
  11. Veldhuis JD, Dufau ML 1987 Estradiol modulates the pulsatile secretion of biologically active luteinizing hormone in man. J Clin Invest 80:631–638 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C 2004 Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels. J Clin Endocrinol Metab 89:1174–1180 [DOI] [PubMed] [Google Scholar]
  13. Burnett-Bowie SM, Roupenian KC, Dere ME, Lee H, Leder BZ 2009 Effects of aromatase inhibition in hypogonadal older men: a randomized, double-blind, placebo-controlled trial. Clin Endocrinol (Oxf) 70:116–123 [DOI] [PubMed] [Google Scholar]
  14. Eastell R, Hannon RA, Cuzick J, Dowsett M, Clack G, Adams JE 2006 Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res 21:1215–1223 [DOI] [PubMed] [Google Scholar]
  15. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, Perry 3rd HM 2000 Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 49:1239–1242 [DOI] [PubMed] [Google Scholar]
  16. Rosenthal DI, Ganott MA, Wyshak G, Slovik DM, Doppelt SH, Neer RM 1985 Quantitative computed tomography for spinal density measurement. Factors affecting precision. Invest Radiol 20:306–310 [DOI] [PubMed] [Google Scholar]
  17. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM 2003 The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 349:1216–1226 [DOI] [PubMed] [Google Scholar]
  18. Center JR, Nguyen TV, Sambrook PN, Eisman JA 1999 Hormonal and biochemical parameters in the determination of osteoporosis in elderly men. J Clin Endocrinol Metab 84:3626–3635 [DOI] [PubMed] [Google Scholar]
  19. van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW 2000 Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 85:3276–3282 [DOI] [PubMed] [Google Scholar]
  20. Mellström D, Johnell O, Ljunggren O, Eriksson AL, Lorentzon M, Mallmin H, Holmberg A, Redlund-Johnell I, Orwoll E, Ohlsson C 2006 Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. J Bone Miner Res 21:529–535 [DOI] [PubMed] [Google Scholar]
  21. Greendale GA, Edelstein S, Barrett-Connor E 1997 Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study. J Bone Miner Res 12:1833–1843 [DOI] [PubMed] [Google Scholar]
  22. Slemenda CW, Longcope C, Zhou L, Hui SL, Peacock M, Johnston CC 1997 Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens. J Clin Invest 100:1755–1759 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Khosla S, Melton 3rd LJ, Atkinson EJ, O'Fallon WM, Klee GG, Riggs BL 1998 Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab 83:2266–2274 [DOI] [PubMed] [Google Scholar]
  24. Murphy S, Khaw KT, Cassidy A, Compston JE 1993 Sex hormones and bone mineral density in elderly men. Bone Miner 20:133–140 [DOI] [PubMed] [Google Scholar]
  25. Rudman D, Drinka PJ, Wilson CR, Mattson DE, Scherman F, Cuisinier MC, Schultz S 1994 Relations of endogenous anabolic hormones and physical activity to bone mineral density and lean body mass in elderly men. Clin Endocrinol (Oxf) 40:653–661 [DOI] [PubMed] [Google Scholar]
  26. Boonen S, Vanderschueren D, Cheng XG, Verbeke G, Dequeker J, Geusens P, Broos P, Bouillon R 1997 Age-related (type II) femoral neck osteoporosis in men: biochemical evidence for both hypovitaminosis D- and androgen deficiency-induced bone resorption. J Bone Miner Res 12:2119–2126 [DOI] [PubMed] [Google Scholar]
  27. Falahati-Nini A, Riggs BL, Atkinson EJ, O'Fallon WM, Eastell R, Khosla S 2000 Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 106:1553–1560 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Leder BZ, LeBlanc KM, Schoenfeld DA, Eastell R, Finkelstein JS 2003 Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab 88:204–210 [DOI] [PubMed] [Google Scholar]
  29. Lee H, Finkelstein JS, Miller M, Comeaux SJ, Cohen RI, Leder BZ 2006 Effects of selective testosterone and estradiol withdrawal on skeletal sensitivity to parathyroid hormone in men. J Clin Endocrinol Metab 91:1069–1075 [DOI] [PubMed] [Google Scholar]
  30. Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E 1997 Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab 82:2386–2390 [DOI] [PubMed] [Google Scholar]
  31. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, Dlewati A, Staley J, Santanna J, Kapoor SC, Attie MF, Haddad Jr JG, Strom BL 1999 Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 84:1966–1972 [DOI] [PubMed] [Google Scholar]
  32. Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL 2004 Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 89:503–510 [DOI] [PubMed] [Google Scholar]
  33. Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla Man C, Tindall DJ, Melton 3rd LJ, Smith GE, Khosla S, Jensen MD 2006 DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 355:1647–1659 [DOI] [PubMed] [Google Scholar]
  34. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS 2004 Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 89:2085–2098 [DOI] [PubMed] [Google Scholar]
  35. Tenover JS 1992 Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 75:1092–1098 [DOI] [PubMed] [Google Scholar]
  36. Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG 2001 Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 56:M266–M272 [DOI] [PubMed] [Google Scholar]
  37. Seeman E, Delmas PD 2006 Bone quality—the material and structural basis of bone strength and fragility. N Engl J Med 354:2250–2261 [DOI] [PubMed] [Google Scholar]
  38. Duan Y, Beck TJ, Wang XF, Seeman E 2003 Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging. J Bone Miner Res 18:1766–1774 [DOI] [PubMed] [Google Scholar]
  39. Ahlborg HG, Johnell O, Turner CH, Rannevik G, Karlsson MK 2003 Bone loss and bone size after menopause. N Engl J Med 349:327–334 [DOI] [PubMed] [Google Scholar]
  40. Travison TG, Araujo AB, Beck TJ, Williams RE, Clark RV, Leder BZ, McKinlay JB 2009 Relation between serum testosterone, serum estradiol, sex hormone-binding globulin, and geometrical measures of adult male proximal femur strength. J Clin Endocrinol Metab 94:853–860 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Leder BZ, Finkelstein JS 2005 Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men. Osteoporos Int 16:1487–1494 [DOI] [PubMed] [Google Scholar]
  42. Taxel P, Kennedy DG, Fall PM, Willard AK, Clive JM, Raisz LG 2001 The effect of aromatase inhibition on sex steroids, gonadotropins, and markers of bone turnover in older men. J Clin Endocrinol Metab 86:2869–2874 [DOI] [PubMed] [Google Scholar]

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