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Osteoporosis Prevention and Treatment Center (S.L.G., P.C.) and Division of Geriatric Medicine (S.L.G., N.M.R.), Department of Medicine; Departments of Health and Community Systems, Biostatistics, and Epidemiology (S.M.S.); and Department of Urology (J.B.N.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Roswell Cancer Center (D.L.T.), Buffalo, New York 14263
Address all correspondence and requests for reprints to: Susan L. Greenspan, M.D., Osteoporosis Prevention and Treatment Center, University of Pittsburgh, Kaufmann Medical Building, Suite 1110, 3471 Fifth Avenue, Pittsburgh, Pennsylvania 15213-3221. E-mail: griffithsd{at}msx.dept-med.pitt.edu.
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Abstract |
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Objective: We postulated that men on ADT would experience the greatest bone loss acutely after initiation of ADT.
Design and Setting: We conducted a 12-month prospective study at an academic medical center.
Patients or Other Participants: We studied 152 men with prostate cancer (30 with acute ADT, <6 months; 50 with chronic ADT, 
6 months; and 72 with no ADT) and 43 healthy age-matched controls.
Main Outcome Measures: We assessed bone mineral density (BMD) of the hip, wrist, total body, and spine; body composition; and markers of bone turnover.
Results: After 12 months, men receiving acute ADT had a significant reduction in BMD of 2.5 ± 0.6% at the total hip, 2.4 ± 1.0% at the trochanter, 2.6 ± 0.5% at the total radius, 3.3 ± 0.5% at the total body, and 4.0 ± 1.5% at the posteroanterior spine (all P < 0.05). Men with chronic ADT had a 2.0 ± 0.6% reduction in BMD at the total radius (P < 0.05). Healthy controls and men with prostate cancer not receiving ADT had no significant reduction in BMD. Both use and duration of ADT were associated with change in bone mass at the hip (P < 0.05). Men receiving acute ADT had a 10.4 ± 1.7% increase in total body fat and a 3.5 ± 0.5% reduction in total body lean mass at 12 months, whereas body composition did not change in men with prostate cancer on chronic ADT or in healthy controls (P < 0.05). Markers of bone formation and resorption were elevated in men receiving acute ADT after 6 and 12 months compared with the other men with prostate cancer and controls (P < 0.05). Men in the highest tertile of bone turnover markers at 6 months had the greatest loss of bone density at 12 months.
Conclusions: Men with prostate cancer who are initiating ADT have a 5- to 10-fold increased loss of bone density at multiple skeletal sites compared with either healthy controls or men with prostate cancer who are not on ADT, placing them at increased risk of fracture. Bone loss is maximal in the first year after initiation of ADT, suggesting initiation of early preventive therapy.
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Introduction |
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We have previously reported that men with prostate cancer receiving chronic ADT had significant decrease in bone mass at all skeletal sites vs. those who received no ADT. After 44 months of ADT, lateral spine bone mineral density (BMD) was 17% lower, with an equivalent decrease at the forearm compared with eugonadal men (2). Several retrospective studies (3, 4, 5, 6) have shown there is significant bone loss with ADT. More recently, several prospective studies and reviews (7, 8, 9, 10, 11, 12, 13, 14, 15) have confirmed these findings and shown that ADT and orchiectomy are associated with an increased risk of fracture in men with prostate cancer (15, 16, 17, 18, 19, 20).
One question that remains unanswered is whether or not ADT is associated with acute bone loss. We therefore designed a study to examine the rate of bone loss in men initiating ADT vs. those who are maintained on chronic ADT. A secondary aim was to compare the rate of bone loss in normal healthy men to patients with prostate cancer with or without ADT. We postulated that men with acute hypogonadism secondary to initiation of ADT would experience the most significant bone loss, similar to that of a newly postmenopausal woman. We further hypothesized that the bone loss resulting from acute ADT would be associated with increases in markers of bone turnover. To address these questions, we followed prostate cancer patients with and without ADT and healthy controls prospectively for 12 months.
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Subjects and Methods |
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Men with prostate cancer without metastatic disease, who had previous surgery and/or radiation, were recruited from the private practices of the University of Pittsburgh Physicians; normal healthy controls were recruited through local newspaper advertisements. The men with prostate cancer were grouped as having 1) no ADT, 2) acute ADT (initiating ADT within the last 6 months), or 3) chronic ADT (treated with ADT for 6 months or longer). ADT constituted either orchiectomy or treatment with GnRH agonists, antiandrogen therapy, or combinations of these. A group of healthy, normal, age-matched men without prostate cancer also participated in this study. Men were excluded if they had any disease or were taking any medication known to affect bone and mineral metabolism. The protocol was approved by the Institutional Review Board at the University of Pittsburgh. Written informed consent was obtained from all subjects before their enrollment. Outcome measures were assessed at baseline and at 6 and 12 months.
Outcome measures
BMD and ultrasound. BMD of the nondominant hip (total hip, femoral neck, trochanter, and intertrochanter), posteroanterior (PA) spine (L1–L4), lateral spine (L2–L4), nondominant forearm (total and one-third distal radius), and total body were measured by dual-energy x-ray absorptiometry using a QDR-4500A bone densitometer (Hologic, Inc., Bedford, MA). The coefficient of variation of BMD of older patients at our institution is 1.3% at the PA spine, 1.4% at the total hip, and 2.1% at the lateral spine. We have previously reported a coefficient of variation (CV) of 2.0% at the one-third distal radius (21). If a subject had a previous fracture at the nondominant hip or forearm, the opposite (dominant) side was measured throughout the study.
Measures of body habitus and dietary calcium intake. Measures of body habitus included height (cm), weight (kg), and body mass index [weight (kg)/height (m2)]. Height was measured to the nearest 1 cm using a Harpenden stadiometer (Holtain Ltd., Crymych, Dyfed, UK), and weight was measured with a Health-O-Meter balance beam scale (Sunbeam, Boca Raton, FL). We also examined percent body fat and lean body mass with body composition software on the QDR-4500A bone densitometer. Dietary calcium intake was assessed with a standard food frequency questionnaire (22).
Markers of bone turnover and gonadal status. Markers of bone formation included serum intact N-terminal propeptide of type I procollagen (P1NP) (µg/liter; Diasorin, Inc., Stillwater, MN) with intraassay CV of 4.14%, bone-specific alkaline phosphatase (BSAP) (Alkphase-B, U/liter; Quidel Corp., Mountain View, CA) with intraassay CV of 3.9–5.8%, and intact osteocalcin (Novocalcin, ng/ml; Quidel) with intraassay CV of 4.8–10.0%. For bone resorption, a second morning urine specimen was collected for creatinine and N-telopeptide cross-linked collagen type 1 (NTx) (nmol bone collagen equivalents/mmol creatinine), measured with an ELISA (Osteomark; Ostex International, Seattle, WA) with intraassay CV of 5–19%. Gonadal status was assessed with serum testosterone, free testosterone, and serum LH. We measured serum 25-hydroxyvitamin D by RIA (Nichols Advantage; Nichols Institute Diagnostics, San Juan Capistrano, CA) with intraassay CV of 5.3–6.1% and intact PTH (pg/ml; Bayer Centaur PTH immunoassay; Bayer, Tarrytown, NY) with intraassay CV of 4.6–7.8%. Total testosterone was measured by competitive immunoassay (ng/dl; Diagnostic Products Corp., Los Angeles, CA) with intraassay CV of 2.4–8.3%. Free testosterone was measured by tracer equilibrium dialysis (pg/ml; Nichols Institute) with intraassay CV of 4.2–11.6%. Estradiol was measured by a chemiluminescence assay (Bayer Centaur) with intraassay CV of 6.97%.
Clinical protocol
Participants visited the University of Pittsburgh General Clinical Research Center (Montefiore University Hospital, Pittsburgh, PA) at baseline and at 6 and 12 months.
Statistical analysis
Descriptive statistics were computed to characterize the four groups of subjects (no ADT, acute ADT, chronic ADT, and control) using appropriate measures of central tendency and dispersion. Continuous baseline descriptions were reported as mean ± SD by group. To assess for group differences on baseline subject characteristics and outcomes at baseline and 6 and 12 months follow-up, ANOVA (or the Brown-Forsythe group comparison if group variances were unequal or the nonparametric Kruskal-Wallis procedure if dependent variables were nonnormally distributed and not transformable) and 
2 tests of independence were used. Pairwise multiple comparisons were conducted if omnibus tests were significant. The effect of groups on the longitudinal outcomes of bone mass, body composition, and markers of resorption and formation were analyzed using repeated-measures analysis with a mixed modeling approach (23). The PROC MIXED procedure in SAS (version 8.2; SAS Institute, Cary, NC) was employed for fitting these models. Based on these analyses, the actual values or changes predicted over time for endpoints by group were reported as mean ± SE Backward stepwise linear regression analysis using a P value of 0.05 for the removal of predictor variables was employed to identify predictors of the percent change in PA spine, total hip, trochanter, femoral neck, and total radius BMD at 12 months relative to baseline values, considering ADT (yes or no), duration of ADT (in months), age, and total testosterone as potential predictors. Correlational analyses using either the parametric Pearson product-moment correlation coefficient or nonparametric Spearman rank-order correlation coefficient were also performed to investigate the relationship between changes in bone mass and changes in biomarkers. Additionally, P1NP, BSAP, osteocalcin, and NTx at 6 months were divided into tertiles to examine the relationship between grouped versions of these biomarkers and percent changes in BMD from baseline to 12 months. The level of statistical significance was set at 0.05 (two-tailed).
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Results |
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At baseline, 186 men with prostate cancer were evaluated; 34 were excluded (i.e. 22 men with metastatic cancer, seven men on bisphosphonates, three men on an experimental medication, one man with hyperparathyroidism, and one man with Paget’s disease). The baseline clinical characteristics for the remaining 152 men with prostate cancer and 43 healthy controls are shown in Table 1
. Of the men with prostate cancer, 80 received ADT and 72 did not. The mean duration of ADT therapy was 2.9 ± 1.5 months for men with acute androgen deprivation (acute ADT; n = 30) and 33.2 ± 33.4 months for men with chronic androgen deprivation (chronic ADT; n = 50). For the men who received acute ADT, 12 were on GnRH agonists, one was on antiandrogens, and 17 were on combined therapy (GnRH agonists plus antiandrogens). For the men on chronic ADT, 24 were on GnRH agonists, six had an orchiectomy, and 20 were on combined therapy. Of the men with prostate cancer, six were of African-American descent, two were of Asian descent, and the remainder were of Caucasian descent (n = 138). In the group of controls, six men were of African-American descent, and the rest were of Caucasian descent (n = 37). There was no significant difference in the white-nonwhite racial distribution between participants with prostate cancer and healthy control participants (P = 0.10). Participants were, on average, 68.0 ± 8.1 yr of age (age range, 43–88 yr). There was a significant difference (P < 0.01) in age across the four groups; men on chronic ADT were the oldest. The groups were similar with respect to weight, height, and body mass index at baseline.
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; P < 0.001 for both).
At baseline, mean prostate-specific antigen was significantly higher in men receiving chronic ADT compared with those in other groups (P < 0.05; Table 2). As expected, baseline levels of total testosterone, free testosterone, and estradiol were significantly lower in men with ADT compared with prostate cancer participants with no ADT and with healthy controls (Table 2; P < 0.001 for all).
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BMD of the total radius was significantly lower in men on chronic ADT than in controls, men on acute ADT, and men with prostate cancer on no ADT (P < 0.05; Table 3). There was also a trend for lower BMD at the one-third distal radius and total body in men on chronic ADT vs. men in the other three groups. At baseline, 7% of men on no ADT, 13% of men on acute ADT, 24% of men on chronic ADT, and 14% of healthy controls were classified with osteoporosis according to the World Health Organization criteria (24, 25).
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). Six participants had vitamin D deficiency (two associated with secondary hyperparathyroidism) and were encouraged to increase their vitamin D supplementation. Serum P1NP, a marker of bone formation, was significantly higher at baseline in men with acute or chronic ADT compared with men on no ADT or controls (P < 0.001; Table 2). Osteocalcin, another marker of bone formation, was also significantly higher at baseline in men with chronic ADT compared with all other groups (P < 0.001; Table 2). Urinary NTx, a marker of bone resorption, was significantly higher at baseline in men receiving acute or chronic ADT compared with men with prostate cancer with no ADT and controls (P < 0.001; Table 2). Longitudinal changes
During the 12-month study, 42 participants (22%) discontinued the study, including 12 (17%) participants on no ADT, four (13%) participants on acute ADT, 18 (36%) participants on chronic ADT, and eight (19%) healthy controls. For the men with prostate cancer who discontinued the study, three (2%) had progression of disease, 10 (7%) were placed on bisphosphonates by their physician, seven (5%) were lost to follow-up, and 14 (9%) discontinued for other reasons.
After 12 months, men receiving acute ADT had, on average, a significant reduction in BMD of 2.5 ± 0.6% at the total hip, 2.4 ± 1.0% at the trochanter, 2.6 ± 0.5% at the total radius, 3.3 ± 0.5% at the total body, and 4.0 ± 1.5% at the PA spine (Fig. 1; all P < 0.05). The reductions at the total hip, trochanter, and total body were significantly different (P < 0.05) compared with the other three groups, with some differences becoming statistically significant as early as 6 months (Fig. 1). Healthy controls and men with prostate cancer not receiving ADT had no significant loss of bone at any skeletal site during the 12 months of the study (Fig. 1), with the exception of the control men who had a statistically significant loss in total radius BMD at 12 months (–0.72 ± 2.0%; P < 0.05). Men on chronic ADT had a continuing reduction in BMD only at the total radius (P < 0.05; Fig. 1).
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6 months) and healthy controls demonstrated no significant change in bone mass at the hip after 1 yr of follow-up (P = 0.853 and P = 0.949, respectively). ADT use and duration of ADT were significant predictors of percent change in trochanter BMD (R2 = 0.07; P < 0.01) and total body BMD (R2 = 0.15; P < 0.001) at 12 months. ADT use (P < 0.01) was negatively related to percent change in BMD of the trochanter and total body at 12 months, whereas duration of ADT (P < 0.05) was positive, similar to the pattern of findings observed for the total hip. The men with prostate cancer on acute ADT had a significant increase in percent total fat mass and reduction in percent total lean mass after 6 and 12 months compared with their baseline values (7.7 ± 1.2% and –2.6 ± 0.4% at 6 months and 10.4 ± 1.7% and –3.5 ± 0.5% at 12 months, respectively; all P < 0.001) and with other groups of men with prostate cancer. Body composition did not change in healthy controls or in men with prostate cancer on chronic ADT. Men with prostate cancer on no ADT had a small increase in fat mass at 12 months (2.1 ± 1.0%; P < 0.05).
Measures of bone and mineral metabolism (serum PTH, 25-hydroxyvitamin D, and calcium) remained stable in all groups during the longitudinal follow-up. At 12 months, serum estradiol was lower in men on acute ADT (10.3 ± 1.6 pg/ml) vs. men with prostate cancer who were not on ADT (14.8 ± 1.4 pg/ml; P < 0.05) or healthy controls (19.5 ± 1.2 pg/ml; P < 0.05). After 12 months, serum P1NP, BSAP, and osteocalcin were elevated in men with acute ADT compared with all other groups (all P < 0.05; Fig. 2). Urinary NTx remained elevated after 6 and 12 months in the men with acute ADT compared with men not on ADT (all P < 0.05; Fig. 2).
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Men in the highest tertile of bone turnover at 6 months had the greatest loss of bone density at 12 months (Fig. 3). The highest tertile of P1NP at 6 months (P1NP > 57.4 µg/liter) was associated with a 2.0% decrease in BMD at the PA spine, a 1.2% decrease at the femoral neck, a 1.6% decrease at the trochanter, a 1.5% decrease at the total hip, and a 2.4% decrease at the total radius after 12 months (all P < 0.05 between tertiles; Fig. 3). When limited to only men on ADT, a somewhat similar pattern of findings was observed for percent changes in BMD at 12 months, where the highest tertile of P1NP at 6 months was defined as P1NP greater than 78.52 µg/liter. Even with this smaller sample size, significant differences in percent change in BMD at 12 months were observed for P1NP tertile groups for PA spine (P < 0.05), total hip (P < 0.05), total radius (P < 0.01), and total body (P < 0.001). Similar associations were observed with other markers of bone formation and resorption. For example, the highest tertile of BSAP at 6 months (BSAP > 13.1 ng/ml) was associated with a 1.7% decrease in PA spine BMD, a 0.5% decrease in femoral neck BMD, and a 2.2% decrease in total radius BMD (all P < 0.05 between tertiles), with a similar trend for a 1.1% decrease at the total hip (P = 0.06 between tertiles). There were similar associations in the 6-month levels of serum osteocalcin and urinary NTx. In a similar analysis, there were fewer significant associations when we used the baseline values of these markers or the percent change in markers over 6 months.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Men receiving acute ADT had elevated biochemical markers of bone resorption and bone formation compared with eugonadal men with prostate cancer and healthy controls, consistent with previous observations (27, 31). Together, the increased bone turnover and reduced BMD may be responsible for the increased fracture rate described in these patients (3, 4, 16, 17, 19). Furthermore, in our participants, elevation of biochemical markers of bone turnover after 6 months was associated with reduction in BMD at multiple skeletal sites after 12 months, suggesting that increased bone turnover is a mediator of bone loss. This association may help to identify a subgroup of men at high risk of bone loss and fracture after androgen suppression.
Men with prostate cancer on acute ADT had levels of estradiol that were 47% lower than healthy controls; these levels were 31% lower than those of men with prostate cancer who were not on ADT. Both testosterone and its aromatase metabolite, estradiol, fall rapidly and significantly after orchiectomy or GnRH agonist therapy. Testosterone and estradiol are both important determinants of peak bone mass in men (32). Two men with aromatase deficiency had a marked increase in BMD and reduced markers of bone turnover after estradiol treatment (33, 34). However, there is also increasing evidence that estradiol has a major role in the regulation of bone metabolism in men (35, 36, 37). In elderly men treated with both a GnRH agonist and an aromatase inhibitor, estrogen but not testosterone prevented an increase in bone resorption (38). Furthermore, in prostate cancer patients receiving hormonal suppression, estradiol therapy reduced bone turnover (39).
The rate of bone loss in men with prostate cancer starting ADT was 5- to 10-fold higher than in either healthy age-matched controls or men with prostate cancer with normal hormone levels. Our findings at the hip were similar to the rate of bone loss found in a multicenter study that enrolled only men with prostate cancer who were initiating ADT with or without an iv bisphosphonate (40). However, we observed double the rate of bone loss at the spine. In comparison, men on chronic ADT and healthy controls had a stable spine BMD over 12 months, and men with prostate cancer on no ADT had a slight increase. This maintenance or improvement in spine BMD may have been a result of a slower rate of bone turnover in these groups, coupled with atypical calcifications from osteoarthritis that falsely elevate the spine in older patients (31, 41, 42). After 3 yr of hormonal suppression, radius bone loss continued at a higher rate in men receiving ADT compared with men in the other groups. This is clinically relevant because BMD is closely associated with fracture risk in men, and wrist BMD is a strong predictor of osteoporotic fracture in men (43). Moreover, fractures are associated with reduced survival in men with prostate cancer independent of metastasis (44).
The strengths of the study include the large number of participants, prospective design, and inclusion of both healthy age-matched controls and prostate cancer patients with normal testosterone. In addition, we used a single dual-energy x-ray absorptiometry instrument for all BMD comparisons. A limitation of the study is that participants were not randomized to receive androgen suppression therapy. Thus, those patients with ADT may have had more aggressive prostate cancer. However, prostate-specific antigen remained stable during the study in all subject groups, suggesting that ADT rather than prostate cancer was the principal cause of bone loss and increased markers of bone turnover. Moreover, we had minimal impact on the compliance of androgen suppression. Some physicians may have permitted drug holidays or may have been less strict about androgen suppression. This would allow testosterone levels to rise above the castrate range. Another limitation of our study is that men were encouraged to initiate osteoporosis preventive measures (i.e. calcium, vitamin D, and exercise), which would have slowed bone loss in all groups. Finally, men on chronic ADT who had low bone mass and had been placed on bisphosphonates were excluded from the study at baseline, effectively removing a high-risk population.
This study demonstrates both acute and longer-term effects of androgen suppression for prostate cancer on bone health. We found that the rate of bone loss is maximal in the first year after androgen suppression is initiated, which suggests that antiresorptive therapy may be most effective if prescribed during this period. Recently, investigators have demonstrated that raloxifene may prevent bone loss in men on chronic ADT (45), and iv zoledronic acid may prevent bone loss in men receiving acute ADT (40). Additional studies are required to determine the effects of oral bisphosphonates in this at-risk population.
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Acknowledgments |
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Footnotes |
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First Published Online September 27, 2005
Abbreviations: ADT, Androgen deprivation therapy; BMD, bone mineral density; BSAP, bone-specific alkaline phosphatase; CV, coefficient of variation; NTx, N-telopeptide cross-linked collagen type 1; PA, posteroanterior; P1NP, N-terminal propeptide of type I procollagen.
Received January 27, 2005.
Accepted September 19, 2005.
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