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Original Article |
Division of Endocrinology and Metabolism (P.T., L.G.R.) and Center on Aging (P.T.), Departments of Surgery (P.C.A.) and Radiation Oncology (R.D.D.), General Clinical Research Center (P.M.F., M.T., J.Z., C.O., L.G.R.), University of Connecticut Health Center, Farmington, Connecticut 06030-1317
Address all correspondence and requests for reprints to: Pamela Taxel, M.D., University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-1317. E-mail: taxel{at}nso.uchc.edu.
Abstract
To examine the effect of estradiol (E2) without the confounding effect of hypothalamic-pituitary feedback, we studied men with prostate cancer in whom gonadotropin secretion was suppressed by LH-releasing hormone agonists (LHRH-A). Fourteen men over 65 yr of age and receiving established LHRH-A treatment (EST group) without bony metastases and 12 men who received LHRH-A as neoadjuvant therapy for locally advanced prostate cancer (NEO group) were randomized (double blind) to receive either 1 mg/d micronized E2 (n = 12) or placebo (PL; n = 13) for 9 wk. E2, estrone, testosterone, SHBG, PTH, and 25-hydroxy- and 1,25-dihydroxyvitamin D levels as well as markers of bone resorption [N- and C-telopeptide cross-links (NTX and CTX) and deoxypyridinoline] and bone formation (bone-specific alkaline phosphatase, osteocalcin, and N-terminal type I collagen) were measured before LHRH-A in the NEO group, before [baseline (BL)] and after 9 wk of E2 or PL in all patients, and 6 wk after E2 treatment in the EST group. In the NEO group, hormone levels fell 3 wk after the initial LHRH-A injection, and deoxypyridinoline increased significantly (P = 0.006). At BL, the EST group had higher bone turnover due to the longer duration of LHRH-A treatment. With E2 treatment, E2 levels rose into the normal male range, and two resorption markers decreased significantly from BL by 33% for NTX (P < 0.001) and 28% for CTX (P = 0.009). Bone formation markers did not change. PTH increased by 43% from BL (P < 0.01) in the E2 group and decreased 16% from BL in the PL group (P < 0.01). Ionized calcium did not change in the E2 group, but increased in the PL group by 2.3% (P < 0.01). NTX and CTX increased 6 wk after E2 withdrawal in the EST group. We conclude that E2 inhibits bone resorption in hypogonadal men through a direct skeletal effect that is independent of PTH. Low dose estrogen may be an option for the prevention and/or treatment of bone loss in this population.
PROSTATE CANCER, a disease that primarily affects men over 60 yr of age, is the most common visceral malignancy in U.S. men and is the leading cause of cancer death in men (1). An important and widely used treatment modality for prostate cancer is LH-releasing hormone agonist (LHRH-A) therapy (e.g. leuprolide and goserelin) for the establishment of medical castration (2). Whereas this treatment was previously reserved for those with prostate cancer and bony metastases (3), it has more recently been used earlier in the course of the disease in men with locally advanced disease and no bone metastases or as neoadjuvant therapy before radiation or seed implantation. LHRH-A therapy, given in depot form, leads to castrate levels of testosterone (T) and estradiol (E2) in 3–4 wk (4). It has long been known that medical or surgical castration is effective in reducing prostate tumor growth (3). Sex hormones are well known to be essential in the maintenance of skeletal bone mass in men; thus, hypogonadism is an important risk factor for osteoporosis in men. As a result, large numbers of older men will be subject to one of the adverse effects of long-term hormonal ablation therapy, osteoporosis and consequent fractures. The potential increase in disease-free survival gained from this therapy coupled with the likelihood of age-related bone loss in older men could result in a significant increase in the incidence of fractures of the spine and hip, for which there is already evidence (5, 6, 7).
Evidence for the role of E2 in bone metabolism in men has recently been demonstrated in observational studies (8, 9, 10, 11) and in reports of low bone density and tall stature in men with mutations in the estrogen receptor or in aromatase (12, 13, 14), the enzyme that converts androgens to estrogens (15). As T may exert its effect through aromatization to E2, the relative contributions of these individual hormones are difficult to determine. Although there is epidemiological evidence to suggest the importance of E2 in male bone metabolism, there are only a few short-term studies in men that have evaluated the effect of T or E2 alone (16, 17). A unique disease model in which to better understand the role of E2 in male bone metabolism is that of men undergoing hormonal suppression with LHRH-A for locally advanced prostate cancer. This therapy leads to hypogonadism, with both low T and E2 levels. Treating these men with E2 is medically acceptable and allows testing the effect of E2 alone on bone metabolism. In this study we tested the hypothesis that older men undergoing LHRH-A treatment for prostate cancer (without evidence of bony metastases) would demonstrate decreased bone turnover, as measured by biochemical markers, in response to 1 mg/d micronized 17ß-estradiol for 9 wk.
Subjects and Methods
Study population
Community-living men over 60 yr of age and receiving treatment with LHRH-A therapy either for failure of primary treatment for localized prostate cancer or as neoadjuvant treatment before radiation or seed implantation were eligible for this study. Men from the greater Hartford area were recruited by newspaper advertisements, contacts at senior citizen centers, and physician referrals. Subjects with bone metastases secondary to prostate carcinoma, as diagnosed by bone scan or prostate-specific antigen (PSA) level greater than 20 ng/ml; chronic medical conditions such as kidney, gastrointestinal, or liver disease; significant coronary disease or thromboembolic disorders; diseases of bone metabolism; or taking medications known to cause or treat osteoporosis (other than calcium or vitamin D supplementation) were excluded.
Protocol
This was a 9-wk, randomized, double-blind, placebo (PL)-controlled trial of 1 mg/d micronized 17ß-estradiol vs. PL. Micronized 17ß-estradiol was purchased from the manufacturer, and both E2 and PL pills were compounded by the University of Connecticut Health Center pharmacy in a capsule with lactose to appear identical. All subjects were receiving depot LHRH-A therapy. Fourteen men were receiving established LHRH-A therapy (EST group) with clinical stage T4 disease, and 13 men were receiving neoadjuvant treatment (NEO group) before external beam radiation or seed implantation, clinical stage T2-3 disease. The EST and NEO groups were randomized independently, so that approximately equal numbers of men were in the E2 and placebo arms. The NEO group had measurements before initiation of therapy of LHRH-A treatment (screening visit) and 3 wk after this initial injection, which is designated as the baseline (BL) visit. All subjects gave informed consent according to the guidelines of the institutional review board of University of Connecticut Health Center. Men who agreed to participate in the study underwent complete medical history and physical examination. Twenty-seven men were enrolled, and 25 men completed the study [1 subject in the NEO group was included in the NEO 3-wk analysis (Table 2
), but was excluded from the intervention analysis (E2 vs. PL) due to noncompliance; a second subject in the NEO group was excluded from the invention analysis because of a missing 3-wk data point].
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). All subjects underwent a graded exercise treadmill test (Bruce protocol) to rule out occult coronary artery disease before the BL visit. All subjects in the EST and NEO groups were randomized to E2 (1 mg/d micronized E2) or PL for 9 wk at the BL visit. In the EST group, blood and urine were collected for measurements of biochemical markers of bone turnover and hormone levels at BL, after 9 wk of treatment (E2 vs. PL), and 6 wk posttreatment. In the NEO group, blood and urine for markers and hormones were collected at screening (before the first LHRH-A injection), after 3 wk (BL), and then after 9 wk of treatment (E2 vs. PL). Men in the NEO group did not have a posttreatment observation time point, as this corresponded to their radiation treatment. Sex and calciotropic hormones and lipid parameters were measured at the same time points as biochemical markers in the EST and NEO groups.
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BMD measurement
Areal bone mineral content (grams per square centimeter) of the proximal femur, lumbar spine, and total body were measured by dual energy x-ray absorptiometry using a DPX-IQ or L (Lunar Corp., Madison, WI). Same-day reproducibility (with repositioning) of the left proximal femur in men and women aged 65–77 yr is: lumbar spine, 2.2%; femoral neck, 1.4%; total hip, 1.1%; and trochanter, 1.7%. Spine and femur scans were performed at medium speed unless body size dictated slow speed. Total body scans were performed at fast speed.
Biochemical markers of bone turnover
Serum and urine samples were collected between 0700 and 0930 h after a 10- to 12-h fast, divided into 0.5-ml aliquots, and stored at –70 C. Bone marker assays were run in duplicate after one thaw; all samples for an individual were assayed using the same kit. All bone marker assays were performed in the Core Laboratory of the General Clinical Research Center at University of Connecticut Health Center unless otherwise specified.
Markers of bone resorption were urinary cross-linked N- and C-telopeptides of type 1 collagen (NTX and CTX) and total deoxypyridinoline cross-links (DPyr). NTX and CTX were measured by ELISA (Ostex International, Inc., Seattle, WA; Osteometer A/S, Copenhagen, Denmark; and Metra Biosystems, Mountain View, CA, respectively). Intraassay variability was 7.6% for NTX and 4.4% for CTX. DPyr was measured by competitive enzyme immunoassy with an intraassay variability of 5.4%. Interassay variability for all resorption markers was less than 10%.
Markers of bone formation were bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and N-terminal type I procollagen peptides (PINP). BSAP was measured by ELISA (Metra Biosystems), OC by immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA), and PINP by RIA (Orion Diagnostica, Inc., Espoo, Finland). The percentage within-run coefficient of variation in the core laboratory is 5% for BSAP, 4.6% for OC, and 6% for PINP.
Hormone measurements
Sex hormone measurements included E2, estrone (E1), total T, and SHBG. Assays for total T, E2, E1 SHBG, FSH, and LH were measured by Endocrine Sciences, Inc. (Calabasas Hills, CA.). T, E2, and E1 were measured by RIA, and SHBG was determined by a competitive binding assay. The free estrogen index was calculated as follows: E2 + E1/SHBG. The free androgen index was calculated as: total T/SHBG.
Calciotropic hormones included intact PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D. PTH was measured in the General Clinical Research Center core laboratory at University of Connecticut Health Center by sandwich immunoassay (ELISA, Diagnostic Systems Laboratories, Inc., Webster, TX), 25-hydroxyvitamin D was determined by competitive protein binding assay, and 1,25-dihydroxyvitamin D was measured by RIA (Endocrine Sciences, Inc.).
Statistical methods
A series of repeated measures ANOVA models was conducted to examine changes in bone markers and hormone levels over time. The between-subjects design factors in these models were treatment group (E2 or PL) and entry group (NEO or EST group), and the within-subject factor was time. All of the subjects in both groups were assessed at BL (time 1) and again 9 wk later (time 2). The dependent variables were the bone markers and hormone levels. Both the absolute change and the percentage change from BL for each marker and hormone were examined. Separate models were calculated for each dependent variable. Pearson product-moment correlations also were calculated to examine the associations between hormones and bone markers at BL and at 9 wk.
Results
Subject characteristics
BL characteristics of the 25 men in the E2 and PL groups are shown in Table 1. There were no differences in age, body mass index, BMD, PSA, urinary calcium levels, and calcium intake between the E2 and PL groups. The mean duration of LHRH-A therapy in the EST group was 31 months, with a range of 1–99 months. There was no difference in mean duration of therapy in the E2 or PL group at BL. Although WHO criteria have not been established for fracture risk in men, using femoral neck t-scores of below -2.5 to define osteoporosis and between –1.0 and –2.5 to define osteopenia, 3 of 25 men had osteoporosis at BL, 13 of 25 had osteopenia, and 9 of 25 had a normal BMD.
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Table 2
shows the pre-LHRH-A (screen) and BL (3 week postinjection) hormone and bone turnover marker data for 12 men on neoadjuvant treatment. Screening (pre-LHRH-A) hormones and bone turnover markers were all within the normal male range. Body mass index correlated with femoral neck and total hip BMD (r = 0.68 and 0.67; P < 0.05, respectively). After 3 wk, there were significant declines in E2, E1, T, and PINP. DPyr increased significantly (P = 0.006), and a similar trend was noted for NTX and CTX (P = 0.06, respectively). Three of the 12 men in the NEO group reported mild hot flashes after 3 wk of LHRH-A treatment; none of the men reported breast tenderness in that time period.
Effects of estrogen therapy
Sex hormones.
BL and 9-wk changes in sex steroids are shown in Table 3. The data are shown for the four groups: EST-E2, EST-PL, NEO-E2, and NEO-PL. BL values of sex hormone levels were below the normal range in both the EST and NEO groups as would be anticipated. There were no significant differences between the groups at BL, with the exception of E2, which was slightly higher in both NEO groups. After 9 wk of intervention, E2 levels increased from BL by 11-fold in the EST-E2 group (P = 0.002) and by over 12-fold in the NEO-E2 group (P = 0.06) and were above the normal male range in the latter group. No significant changes occurred in either PL group (EST-PL or NEO-PL). E1 levels increased from BL in both EST-E2 and NEO-E2 groups (P = 0.002 and P = 0.04, respectively), and T decreased by 25% of BL in the NEO-E2 group (P = 0.026).
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. Some markers of bone turnover (both resorption and formation) were significantly higher in the EST groups at BL as would be anticipated due to the longer duration of LHRH-A treatment. With E2 treatment, NTX decreased by 38% and 25% from BL in the EST-E2 and NEO-E2 groups, respectively (P = 0.004 and 0.023, respectively), and CTX decreased by 41% and 9% in the EST-E2 (P = 0.004) and NEO-E2 groups (P = NS), respectively. In the NEO-PL group, NTX continued to increase significantly (P = 0.04), whereas the other markers of bone resorption and formation (with the exception of BSAP, which remained stable) showed a similar trend.
Data for other turnover markers did not differ in the EST and NEO groups. Figure 2 shows individual data and mean percentage changes from BL ± SE in the E2 vs. PL treatment groups (pooled data) for the three markers of bone resorption. NTX, CTX, and DPyr decreased by 33% (P 
0.001), 28% (P = 0.009), and 14% (P = 0.07) from BL, respectively. In the PL group, PINP increased by 23% of BL (P = 0.02; data not shown).
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Table 4 shows calciotropic hormone and lipid data for the E2 and PL groups at BL and 9 wk. Ionized calcium was within normal range for both groups at BL and decreased by 1.3% from BL in the E2 group (P = NS) and increased by 2.3% from BL in the PL group (P = 0.003), and after 9 wk there was a significant difference in mean percent change between the two groups (P = 0.01). The urinary Ca/creatinine ratio decreased by 11% of BL after 9 wk in the E2-treated group (P = NS) and increased by 75% of BL in the PL group (P = 0.006), and there was a significant difference between the groups at 9 wk (P = 0.003). The 25-hydroxyvitamin D levels were within the normal range at BL for both groups and did not change significantly in either group after 9 wk (Fig. 3). PTH levels were within the normal range at BL for both groups, increased by 43% compared with BL in the E2 group (P = 0.001), and decreased by 16% of BL in the PL group (P 0.001). Although the mean percentage change in ionized Ca with E2 treatment did not decrease significantly (-1.3%), the percentage changes in ionized calcium still correlated inversely with the mean percentage change in PTH in the E2-treated group (r = -0.66; P = 0.02). In the four-group analysis there were similar responses in the EST and NEO groups; however, PTH increased by 57% of BL (P = 0.005) in the EST-E2 group, and by 23% of BL in the NEO-E2 group (P = NS) after 9 wk of E2 treatment. The 1,25-dihydroxyvitamin D levels were normal at BL for both groups, and the pooled E2-treated groups increased by 15% of BL after 9 wk of treatment, but did not reach significance. In the E2-treated groups, the level of 1,25-dihydroxyvitamin D correlated with the percentage change in PTH at 9 wk (r = 0.57; P = 0.05).
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Pooled data for lipid changes are shown in Table 4. BL lipid levels did not differ and were within the normal range for both the E2 and PL groups. After 9 wk, there was an 8% decrease from BL in low density lipoprotein levels in the E2 group (P = 0.05), but no significant difference between the groups in any other lipid parameters after 9 wk. PSA decreased significantly from BL in the E2 group by 45% (P = 0.008) and by 46% of BL in the PL group (P 0.001; Table 4). When the data were analyzed for the four groups (data not shown), there were no significant differences between EST-E2 and the EST-PL and the NEO-E2 and the NEO-PL groups at the end of the treatment period; however, the NEO-E2 had a decrease in PSA of 81% from BL compared a 14% decrease in EST-E2 group, and these changes between groups were significant (P = 0.004). The NEO-PL and the EST-PL showed decreases in PSA of 65% and 30%, respectively, but these changes did not reach statistical significance (P = 0.06).
Effects of estrogen withdrawal
In the EST group, hormone and bone turnover markers were measured 6 wk after discontinuation of E2 therapy. E2 and E1 levels returned to BL levels, whereas T and SHBG remained unchanged. NTX and CTX increased by 48% and 49% from the 9-wk treatment values, but remained below BL values [19 ± 6% (P = 0.015) and 25 ± 9% (P = 0.028), respectively], reflecting the residual effect of E2. Two markers of bone formation, PINP and BSAP, decreased from their 9 wk values by 18 ± 7% (P = 0.03) and 9 ± 3% (P = 0.02), respectively, at the 6 wk posttreatment point. This delayed decrease in formation markers is often seen when postmenopausal women are treated with E2 replacement.
Side effects
In general, E2 was well tolerated in both the NEO and EST groups. In E2 group, 3 of 13 men had mild to moderate breast tenderness after 9 wk of treatment; no breast tenderness was reported in PL group. Four of 12 men in the E2 group reported a reduction of hot flashes compared with BL; however, 4 subjects reported increases in this symptom. Three of those 4 were within 4 months of initiation of LHRH-A therapy. In the PL group, 8 of 13 subjects reported increased hot flashes from none to mild/moderate at BL to severe after 9 wk; 6 of these 8 men were in the NEO group; 3 of 13 reported no hot flashes at all, and 1 man reported severe hot flashes throughout the entire study. Mood changes were reported as absent at BL to mild at the end of the study in 1 man in the NEO-E2 group and 1 man in the NEO-PL group; 1 man in the NEO-PL group was started on antidepressants.
Discussion
Our results show that older men who receive LHRH-A for neoadjuvant therapy or who are receiving established therapy for locally advanced prostate cancer demonstrate an increase in markers of bone turnover and respond to short-term E2 treatment with a significant decrease in bone resorption. This response to E2 therapy is associated with increased PTH levels. Moreover, 9 wk of E2 treatment prevented the further rise in bone resorption in men who receive neoadjuvant therapy. There were few changes in bone formation markers.
The initial response to LHRH-A therapy at 3 wk was a decline to castrate T levels, which is consistent with other studies in which 95% or more of patients show a similar decline within 30 d of initial injection (4). Early changes in markers of bone turnover have been evaluated by Smith et al. (18). They showed a similar early rise in NTX and DPyr; our study showed similar increases (P = 0.006 for DPyr) as well as an increase in CTX. However, in their study OC and BSAP are increased by 10–20% of BL within the first 2–4 wk, whereas in the present study OC and PINP decreased, and BSAP was unchanged. Our previous work with aromatase inhibition showed a decrease in bone formation markers with decreased E2 levels despite an increase in T (19). Falahati et al. (16) found that two markers of bone formation, OC and PINP, decreased after androgen and estrogen withdrawal and increased with either E2 or T replacement. A study of E2 replacement in postmenopausal women also showed an increase in bone formation in the first 3 wk of treatment, with a later decrease as bone turnover was suppressed (20). These data suggest that E2 is anabolic as well as antiresorptive.
Several researchers have measured the effect of established or long-term LHRH-A therapy on markers of bone turnover in men with prostate cancer. In agreement with our study, Stoch et al. (21) found that mean urinary NTX was elevated at 78 nmol/liter BCE/mmol/liter creatinine in 41 men after a minimum of 6 months of LHRH-A therapy compared with 65 nmol/liter BCE/mmol/liter creatinine in the present study. Fairney et al. (22) and Scherr et al. (23) also reported similar results in men with prostate cancer receiving LHRH-A treatment in their studies. Mean BSAP (units per liter) and OC (nanograms per milliliter) values were 36 and 11, respectively, in their studies compared with 28 and 12, respectively, in the present study (EST group).
Several researchers have examined the results of androgen deprivation and estrogen treatment on markers of bone turnover, with results similar to ours. Carlstrom et al. (24) showed that serum markers of bone resorption and formation increased significantly in 13 patients treated with orchidectomy over an 18-month period, whereas markers of bone formation decreased significantly in 15 patients receiving im polyestradiol phosphate. More recently, Scherr et al. (23) demonstrated that urinary NTX was within the normal male range in 20 men treated with 1 mg diethylstilbestrol (with either orchidectomy or therapy with LHRH-A) compared with androgen deprivation therapy alone. In the present study urinary NTX and CTX were significantly decreased in the EST-E2 group, and the rise in resorption was prevented by E2 treatment in the NEO-E2 group.
In the present study PTH increased in response to E2, presumably as a consequence of direct inhibition of bone resorption and a decrease in serum calcium. Although the differences in serum calcium were small, PTH secretion is quite sensitive to such changes. This indicates that E2 has a local effect on bone turnover that is independent of PTH action. Contrary to our results, Khosla et al. (25) studied older postmenopausal women (>20 yr since menopause) receiving E2 treatment (mean, 5.6 yr) and demonstrated lower PTH levels as well as decreased bone turnover compared with women who were not taking E2. He concluded that E2 appears to reverse the age-related increases in PTH. It is conceivable that our results were opposite these findings due to the short duration of the present study.
A role for estrogen in the regulation of bone turnover in men was based initially on findings in men with genetic defects in the estrogen receptor or aromatase (12, 13, 14), the enzyme that converts androgens to estrogens (15), as well as observational studies (8, 9, 10, 11). More recently, in a short-term study of 60 older men in whom both gonadotropin secretion and aromatase conversion were suppressed, Falahati et al. (16) demonstrated that E2 is the principal sex steroid regulating bone resorption. In another study of younger men, age 20–44 yr, Leder et al. concluded that both E2 and T play fundamental and separate roles in the maintenance of normal bone turnover in men (17).
The studies by Falahati et al. (16) and our own data using inhibitors of aromatase (19) suggest that estrogen may stimulate bone formation as well as inhibit bone resorption in men. In the present study there was no evidence of such stimulation; however, this may have been because the decrease in bone resorption after 9 wk of treatment resulted in a sufficient decrease in bone remodeling to mask any direct anabolic effect. In women, markers of bone formation were significantly decreased by estrogen therapy at 9 wk (26).
In conclusion, we have found that in two populations of men treated with LHRH-A therapy for prostate cancer, either neoadjuvant LHRH-A before radiation or brachytherapy, or in those with a rising PSA but without bone metastases, there is an increase in markers of bone resorption that can be reversed by estrogen. This model, which eliminates the confounding effect of feedback from the hypothalamus and pituitary, may be ideal for further evaluation of the dose response and mechanism of action of estrogen in men. The present study is limited by the small number of subjects and the short duration of treatment to definitively establish efficacy and tolerability of E2 in this population. However, men with prostate cancer receiving LHRH-A therapy are at increased risk for bone loss and osteoporotic fracture, and the number of such patients is likely to increase. If low doses of E2 can prevent bone loss in this population with minimal adverse effects, this may represent an appropriate therapy for the prevention of severe bone loss and osteoporotic fractures in this population.
Acknowledgments
We are grateful to all the personnel at the General Clinical Research Center involved with this study, and to all the wonderful male volunteers without whom this study would not be possible.
Footnotes
This work was supported by a Clinical Associate Physician award under the auspices of General Clinical Research Center NIH Grant MO1-RR-06192 and Claude Pepper Older Americans Independence Center Grant Award 5P60-AG-13631 and Donahue Foundation Grant DF99-072.
Abbreviations: BL, Baseline; BMD, bone mineral density; BSAP, bone-specific alkaline phosphatase; CTX, C-telopeptide cross-links; DPyr, deoxypyridinoline; E1, estrone; E2, estradiol; EST, established LH-releasing hormone agonist therapy; LHRH-A, LH-releasing hormone agonist; NEO, neoadjuvant therapy; NTX, N-telopeptide cross-links; OC, osteocalcin; PINP, N-terminal type I procollagen peptide; PL, placebo; PSA, prostate-specific antigen; T, testosterone.
Received April 4, 2002.
Accepted July 31, 2002.
References
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|
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|
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|
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|
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|
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|
 |
|
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, men in the NEO group. *, P 