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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 3841-3846
Copyright © 2004 by The Endocrine Society

Raloxifene to Prevent Gonadotropin-Releasing Hormone Agonist-Induced Bone Loss in Men with Prostate Cancer: A Randomized Controlled Trial

Matthew R. Smith, Mary Anne Fallon, Hang Lee and Joel S. Finkelstein

Division of Hematology and Oncology (M.R.S., M.A.F.) and Endocrine Unit (J.S.F.), Department of Medicine, and the Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. Matthew R. Smith, Massachusetts General Hospital, Cox 640, 100 Blossom Street, Boston, Massachusetts 02114. E-mail: smith.matthew{at}mgh.harvard.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. Raloxifene increases bone mineral density in postmenopausal women, but its efficacy in hypogonadal men is not known. In a 12-month open-label study, men with nonmetastatic prostate cancer (n = 48) who were receiving a GnRH agonist were assigned randomly to raloxifene (60 mg/d) or no raloxifene. Bone mineral densities of the posteroanterior lumbar spine and proximal femur were measured by dual energy x-ray absorptiometry. Mean (±SE) bone mineral density of the posteroanterior lumbar spine increased by 1.0 ± 0.9% in men treated with raloxifene and decreased by 1.0 ± 0.6% in men who did not receive raloxifene (P = 0.07). Bone mineral density of the total hip increased by 1.1 ± 0.4% in men treated with raloxifene and decreased by 2.6 ± 0.7% in men who did not receive raloxifene (P < 0.001). Similar between-group differences were observed in the femoral neck (P = 0.06) and trochanter (P < 0.001). In men receiving a GnRH agonist, raloxifene significantly increases bone mineral density of the hip and tends to increase bone mineral density of the spine.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ANDROGEN DEPRIVATION THERAPY by either bilateral orchiectomies or chronic administration of a GnRH agonist is the cornerstone of treatment for metastatic prostate cancer. Additionally, GnRH agonists are often administered to men with recurrent or locally advanced nonmetastatic prostate cancer. In 1994, the total Medicare expenditure for treatment of prostate cancer was $1.4 billion, and greater than one third of that amount was spent for GnRH agonists (http://www.ahrq.gov/clinic/prossumm.htm).

Osteoporosis is an important complication of GnRH agonist treatment in men with prostate cancer. GnRH agonists decrease bone mineral density (1, 2, 3, 4) and increase fracture risk (5, 6, 7, 8).

Estrogens play an important role in skeletal homeostasis in normal men. Estrogen receptors are expressed in osteoblasts and osteoclasts (9, 10, 11). In older men, serum estradiol levels are positively associated with spinal bone mineral density and negatively associated with vertebral fracture risk (12, 13, 14). Estrogens contribute to the regulation of both bone formation and bone resorption in men (15, 16).

Raloxifene is a selective estrogen receptor modulator that mimics the effects of estrogens in bone without stimulatory effects in most other tissues (17). Raloxifene prevents early postmenopausal bone loss in women and reduces the rate of vertebral fractures in women with postmenopausal osteoporosis (18, 19). Less is known about the efficacy of raloxifene in men.

In this study, we evaluated the effects of raloxifene on bone mineral density in men receiving a GnRH agonist for nonmetastatic prostate cancer.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

Study participants were recruited at Massachusetts General Hospital (Boston, MA) between February 2000 and February 2002. All subjects were receiving treatment with a GnRH agonist for prostate cancer for 6 months or more at study entry. Subjects had a radionuclide bone scan within 6 months of initiating GnRH agonist treatment or 6 months before study entry. Men with bone metastases or evidence of progressive disease (serum prostate-specific antigen >150% nadir value) were excluded. Men with metabolic bone disease, history of treatment for osteoporosis, history of deep venous thrombosis or pulmonary embolus, serum calcium less than 8.4 or more than 10.6 mg/dl, or serum creatinine concentration more than 2.0 mg/dl (177 µmol/liter) were also excluded.

Study design

After a screening visit, eligible subjects were assigned randomly using computer-generated cards to receive raloxifene (Evista, Eli Lilly and Co., Indianapolis, IN; 60 mg by mouth daily) or no raloxifene for 12 months. Subjects were aware of their treatment assignment. Compliance was assessed with patient diaries. Subjects in both groups continued treatment with a GnRH agonist. All subjects received calcium carbonate (500 mg daily) and a daily multivitamin containing 400 IU vitamin D. There was no required run in period. Study personnel who performed or analyzed the main study outcomes were blinded to the treatment assignments.

After randomization, subjects were evaluated at the Mallinckrodt General Clinical Research Center at Massachusetts General Hospital at baseline, 6, and 12 months. Serum and urine samples were obtained at each visit and stored at –80 C. Bone mineral density and body composition were measured by DXA at baseline, 6, and 12 months. The institutional review board of Dana Farber Partners Cancer Care approved the study. All subjects gave written informed consent.

Study endpoints

The bone mineral density of the posteroanterior lumbar spine and proximal femur was determined by DXA using a Hologic QDR 4500A densitometer (Hologic, Inc., Waltham, MA). Lean and fat mass were also determined by DXA (software version 11.2, Hologic, Inc.).

Serum concentrations of testosterone (Diagnostic Products, Los Angeles, CA), estradiol (Nichols Institute, San Juan Capistrano, CA), 25-hydroxyvitamin D (DiaSorin, Stillwater, MN), PTH (Nichols Institute), and amino-terminal propeptide of type I collagen (DiaSorin) were measured by RIAs or immunoradiometric assays. The lower limits of detection for serum testosterone and estradiol were 6 ng/dl (0.2 nmol/liter) and 3 pg/ml (11 pmol/liter), respectively. Urinary deoxypyridinoline (Metra Biosystems, Mountain View, CA) was measured by enzyme immunoassay. Serum cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride concentrations were measured by colorimetric enzymatic assays on an automated clinical chemistry analyzer (Roche Diagnostics/Roche Molecular Biochemicals, Indianapolis, IN).

Statistical analyses

The primary study endpoint was the percent change in the bone mineral density of the posteroanterior lumbar spine from baseline to 12 months. The power calculations for this study assume a 3.0% SD of the change from baseline (2) and dropout rate of 20%. The sample size of 48 subjects (24 subjects/group) provides 80% power to detect a difference of at least 2.8% using a two-sided t test ({alpha} = 0.05). Percent changes in bone mineral density, body composition, gonadal steroids, and biochemical markers of bone turnover from baseline to 12 months were compared between groups using t tests (20). All data were included in the efficacy analyses, including data from subjects who discontinued treatment early.

Statistical analyses were performed using SAS version 8.1 (SAS Institute, Inc., Cary, NC). Values are reported as means ± SE unless specified otherwise. All P values are two sided, and values less than 0.05 are considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Characteristics of the subjects

Forty-eight eligible subjects were recruited between February 2000 and February 2002. Forty-four subjects completed the baseline evaluation (Fig. 1Go). Baseline characteristics of men assigned to raloxifene and men assigned to no raloxifene were similar (Table 1Go).



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  		FIG. 1. Flow diagram.

 

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  		TABLE 1. Baseline characteristics

 
Forty-one subjects completed study testing (Fig. 1Go). One man assigned to raloxifene died from causes unrelated to prostate cancer or study treatment at month 2. Two men in the group that did not receive raloxifene treatment withdrew before completing the study; one man withdrew after he was diagnosed with lung cancer at month 6, and another man withdrew after he developed progressive disease at month 7. No other subject experienced disease progression during the study. All available data were included in the efficacy analyses, including data from a subject who discontinued treatment after 6 months due to an adverse event.

Gonadal steroids

Mean serum testosterone levels at baseline were in the castrate range in both groups (Table 1Go). Changes in serum total testosterone, estradiol, and SHBG levels did not differ significantly between the groups (Fig. 2Go).



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  		FIG. 2. Changes in mean (±SE) serum concentrations of total testosterone, estradiol, and SHBG. P values are for between-group comparisons of the percentage change from baseline to 12 months.

 
Bone mineral density

The mean (±SE) bone mineral density of the posteroanterior lumbar spine increased by 1.0 ± 0.9% in the men treated with raloxifene and decreased by 1.0 ± 0.6% in the men who did not receive raloxifene (P = 0.07) (Fig. 3AGo). The between-group differences in percent change from baseline to 12 months was 2.0% (95% confidence interval, –0.2–4.0%).



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  		FIG. 3. Mean (±SE) changes from baseline in bone mineral density. P values are for between-group comparisons of the percentage change from baseline to 12 months.

 
Mean changes in bone mineral density of the total hip and trochanter differed significantly between groups. Bone mineral density of the total hip increased by 1.1 ± 0.4% in the men treated with raloxifene and decreased by 2.6 ± 0.7% in men who did not receive raloxifene (P < 0.001) (Fig. 3BGo). Bone mineral density of the trochanter increased by 1.6 ± 0.5% in the men treated with raloxifene and decreased by 2.4 ± 0.8% in men who did not receive raloxifene (P < 0.001) (Fig. 3CGo). Bone mineral density of the femoral neck increased by 0.3 ± 0.8% in the men treated with raloxifene and decreased by 1.7 ± 0.6% in men who did not receive raloxifene (P = 0.06) (Fig. 3DGo). The between-group differences in percent change from baseline to 12 months were 3.7% (95% confidence interval, 2.0–5.4%) for the total hip, 3.9% (95% confidence interval, 1.9–5.9%) for the trochanter, and 2.0% (95% confidence interval, –0.1–4.0%) for the femoral neck.

In men treated with raloxifene, changes in bone mineral density of posteroanterior lumbar spine and total hip did not correlate with either baseline estradiol levels or baseline free estrogen index (data not shown).

Biochemical markers of bone turnover

Serum concentrations of amino-terminal propeptide of type I collagen and urinary excretion of deoxypyridinoline were elevated at baseline (Table 1Go). Mean serum concentrations of amino-terminal propeptide of type I collagen decreased by 20.3 ± 9.3% in the men treated with raloxifene and increased by 13.9 ± 11.1% in men who did not receive raloxifene (P = 0.03) (Fig. 4AGo). Urinary excretion of deoxypyridinoline decreased by 6.4 ± 7.8% in the men treated with raloxifene and increased by 10.3 ± 5.4% in men who did not receive raloxifene (P = 0.10) (Fig. 4BGo). The between-group differences in percent change from baseline to 12 months was 34.2% (95% confidence interval, 4.2–64.2%) for amino-terminal propeptide of type I collagen and 16.6% (95% confidence interval, –3.7–37.0%) for urinary excretion of deoxypyridinoline.



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  		FIG. 4. Mean (±SE) changes from baseline in biochemical markers of bone turnover. P values are for between-group comparisons of the percentage change from baseline to 12 months.

 
In men treated with raloxifene, changes serum concentration of amino-terminal propeptide of type I collagen and urinary excretion of deoxypyridinoline did not correlate with either baseline estradiol levels or baseline free estrogen index (data not shown).

Body composition and serum lipoproteins

Mean changes in body mass index, lean mass, fat mass, and serum lipoproteins did not differ significantly between groups (Table 2Go).


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  		TABLE 2. Percentage changes in body composition and serum lipoproteins from baseline to 12 months

 
Adverse events

One man had a pulmonary embolus after 6 months of treatment with raloxifene. Subsequent testing revealed no factors associated with increased thromboembolic risk except for an elevated plasma homocysteine level. There were no other serious treatment-related adverse events.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study demonstrates that raloxifene increases bone mineral density of the hip and tends to increase bone mineral density of the spine in men receiving a GnRH agonist for prostate cancer. To our knowledge, this is the first randomized controlled trial to evaluate the effects of raloxifene on bone mineral density in men. The changes in bone mineral density observed in our subjects are comparable with the increases in bone mineral density in postmenopausal women treated with raloxifene (18). Bone density changes of similar magnitude reduce vertebral fracture risk in postmenopausal women with osteoporosis (19).

In postmenopausal women, raloxifene decreases markers of both bone formation and bone resorption (18, 21, 22). In our study, raloxifene significantly decreased serum concentration of amino-terminal propeptide of type I collagen, a marker of bone formation. Raloxifene also tended to decrease urinary excretion of deoxypyridinoline, a marker of bone resorption. These preliminary observations suggest that raloxifene increases bone mineral density by similar mechanisms in postmenopausal women and severely hypogonadal men.

Tamoxifen increases bone mineral density in postmenopausal women but decreases bone mineral density in premenopausal women (23, 24). Similarly, the effects of raloxifene on bone mineral density in men may depend on baseline estradiol levels. In our study of severely hypogonadal men (mean serum estradiol, 6 ± 1 pg/ml), raloxifene significantly increased bone mineral density of the hip. In a study of mildly hypogonadal elderly men (mean serum estradiol, 28 ± 2 pg/ml), raloxifene had no significant effect of biochemical markers of bone turnover (25). Changes in bone turnover correlated with baseline estradiol levels, however, suggesting that the efficacy of raloxifene may depend on estradiol levels (25). Baseline estradiol levels did not predict changes in bone mineral density or biochemical markers of bone turnover in our subjects, probably because estradiol levels were uniformly low.

Most other studies of men receiving treatment with a GnRH agonist have evaluated the effects of initial therapy. In contrast, the median duration of prior treatment in our subjects was more than 2 yr. Bone mineral density decreased in our control subjects at similar rate to that reported in men receiving initial GnRH agonist treatment (2). In addition, baseline levels of urinary deoxypyridinoline in our subjects were similar to those reported in men during short-term GnRH agonist treatment (2, 26). These observations suggest that long-term treatment with a GnRH agonist is associated with a persistent high bone turnover state and steady decline in bone mineral density.

In postmenopausal women, raloxifene increases the risk for venous thromboembolic events by approximately 3-fold (19). One subject in our study had a pulmonary embolus. In considering raloxifene for the treatment or prevention of osteoporosis in men with prostate cancer, the potential reduction in fracture risk must be weighed against the increased risk for thromboembolic events.

Bisphosphonates also prevent bone loss in men receiving GnRH agonist therapy for prostate cancer. In two randomized controlled trials, intravenous pamidronate prevented bone loss in men treated with a GnRH agonist (2, 27). In another randomized controlled trial, intravenous zoledronic acid increased bone mineral density in men treated with a GnRH agonist or bilateral orchiectomies (28). Additional studies are needed to compare the efficacy and safety of raloxifene with bisphosphonates in hypogonadal men.

In postmenopausal women, raloxifene significantly decreases serum concentrations of total cholesterol and low-density lipoprotein cholesterol (18). In contrast, raloxifene did not significantly change serum total cholesterol and low-density lipoprotein cholesterol concentrations in our severely hypogonadal male subjects. Raloxifene also had no effect on serum concentrations of total lipid profiles in mildly hypogonadal men (25). Additional studies are needed to determine whether selective estrogen receptor modulators have gender-specific effects on lipoprotein metabolism.

Our study has limitations. Although personnel who performed or analyzed the main outcomes were blinded to treatment assignments to minimize any potential bias, the open-label design may have influenced study outcomes through unintended effects on subject behavior. In addition, the open-label design may have influenced adverse event reporting. The study was designed to compare changes in bone mineral density. Larger studies are required to assess differences in fracture incidence.

In summary, raloxifene significantly increased bone mineral density of the hip and tended to increase bone mineral density of the spine in men receiving a GnRH agonist for prostate cancer. Raloxifene may represent a novel therapy to prevent bone loss in hypogonadal men.


   Acknowledgments
 
We thank the dedicated staffs of Mallinckrodt General Clinical Research Center and Massachusetts General Hospital Bone Density Center.


   Footnotes
 
This work was supported by the Prostate Cancer Foundation, by a National Institutes of Health Clinical Associate Physician Award (to M.R.S.), and by grants from the National Institutes of Health (to J.S.F.) (K24 DK02759) and the Mallinckrodt General Clinical Research Center (M01-RR-01066). The study sponsors played no role in the study design, in collection, analysis, and interpretation of data, or in writing of this report.

Received December 4, 2003.

Accepted May 7, 2004.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Meeting Report from Skeletal Complications of Malignancy IV: A symposium jointly sponsored by The Paget Foundation for Paget's Disease of Bone and Related Disorders, the National Cancer Institute, and the University of Virginia School of Medicine * April 28-30, 2005 in Bethesda, Maryland, USA
IBMS BoneKEy, March 1, 2006; 3(3): 15 - 42.
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 Eur J EndocrinolHome page
V Rochira, A Balestrieri, B Madeo, L Zirilli, A R M Granata, and C Carani
Osteoporosis and male age-related hypogonadism: role of sex steroids on bone (patho)physiology
Eur. J. Endocrinol., February 1, 2006; 154(2): 175 - 185.
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 J. Clin. Endocrinol. Metab.Home page
S. L. Greenspan, P. Coates, S. M. Sereika, J. B. Nelson, D. L. Trump, and N. M. Resnick
Bone Loss after Initiation of Androgen Deprivation Therapy in Patients with Prostate Cancer
J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6410 - 6417.
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 JCOHome page
M. R. Smith, W. C. Lee, J. Brandman, Q. Wang, M. Botteman, and C. L. Pashos
Gonadotropin-Releasing Hormone Agonists and Fracture Risk: A Claims-Based Cohort Study of Men With Nonmetastatic Prostate Cancer
J. Clin. Oncol., November 1, 2005; 23(31): 7897 - 7903.
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 Eur J EndocrinolHome page
A. Mueller, R. Dittrich, H. Binder, W. Kuehnel, T. Maltaris, I. Hoffmann, and M. W Beckmann
High dose estrogen treatment increases bone mineral density in male-to-female transsexuals receiving gonadotropin-releasing hormone agonist in the absence of testosterone
Eur. J. Endocrinol., July 1, 2005; 153(1): 107 - 113.
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 IBMS BoneKEyHome page
E. Seeman and G. J. Strewler
Clinical and Basic Research Papers - July 2004 Selections
IBMS BoneKEy, September 1, 2004; 1(9): 1 - 5.
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