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Cross-sectional study of bone turnover during bicalutamide monotherapy for prostate cancer

      Abstract

      Objectives

      Monotherapy with bicalutamide increases serum concentrations of testosterone and estradiol. Because estrogens play an important role in male bone metabolism, bicalutamide monotherapy may have fewer adverse effects on bone than androgen-deprivation therapy with a gonadotropin-releasing hormone agonist.

      Methods

      In a cross-sectional study, we compared gonadal steroid levels and biochemical markers of bone turnover among three groups of men with prostate cancer: hormone-naive men, men treated with a gonadotropin-releasing hormone agonist, and men receiving bicalutamide monotherapy. Men with bone metastases or metabolic bone disease were excluded. Fifty-five eligible subjects were included in the analyses.

      Results

      Serum testosterone and estradiol concentrations were lower in men treated with a gonadotropin-releasing hormone agonist than in hormone-naive men or men receiving bicalutamide monotherapy (P <0.001 for each comparison). Serum testosterone and estradiol concentrations were higher in men receiving bicalutamide monotherapy than in the hormone-naive men (P <0.001). The mean serum urinary excretion of deoxypyridinoline, urinary excretion of N-telopeptide, and serum osteocalcin were significantly higher in men treated with a gonadotropin-releasing hormone agonist than in the other groups (P <0.05 for each comparison). In contrast, biochemical markers of bone turnover were similar for hormone-naive men and men receiving bicalutamide monotherapy (P >0.05 for each comparison).

      Conclusions

      Biochemical markers of bone turnover are elevated in men receiving gonadotropin-releasing hormone agonist treatment but not in men receiving bicalutamide monotherapy. These observations suggest that bicalutamide monotherapy may maintain bone mineral density and prevent fractures.
      Osteoporosis is an important complication of androgen-deprivation therapy. Androgen-deprivation therapy by either bilateral orchiectomies or administration of a gonadotropin-releasing hormone agonist increases biochemical markers of osteoblast and osteoclast activity,
      • Maillefert J.F.
      • Sibilia J.
      • Michel F.
      • et al.
      Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma.
      ,
      • Smith M.R.
      • McGovern F.J.
      • Zietman A.L.
      • et al.
      Pamidronate to prevent bone loss in men receiving gonadotropin releasing hormone agonist therapy for prostate cancer.
      decreases bone mineral density,
      • Maillefert J.F.
      • Sibilia J.
      • Michel F.
      • et al.
      Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma.
      ,
      • Smith M.R.
      • McGovern F.J.
      • Zietman A.L.
      • et al.
      Pamidronate to prevent bone loss in men receiving gonadotropin releasing hormone agonist therapy for prostate cancer.
      ,
      • Eriksson S.
      • Eriksson A.
      • Stege R.
      • et al.
      Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens.
      ,
      • Diamond T.
      • Campbell J.
      • Bryant C.
      • et al.
      The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma longitudinal evaluation and response to intermittent cyclic etidronate therapy.
      and increases fracture risk.
      • Daniell H.W.
      Osteoporosis after orchiectomy for prostate cancer.
      ,
      • Townsend M.F.
      • Sanders W.H.
      • Northway R.O.
      • et al.
      Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma.
      ,
      • Hatano T.
      • Oishi Y.
      • Furuta A.
      • et al.
      Incidence of bone fracture in patients receiving luteinizing hormone-releasing hormone agonists for prostate cancer.
      ,
      • Oefelein M.G.
      • Ricchuiti V.
      • Conrad W.
      • et al.
      Skeletal fracture associated with androgen suppression induced osteoporosis the clinical incidence and risk factors for patients with prostate cancer.
      The duration of androgen-deprivation therapy, white race, and low body mass index are associated with higher fracture rates.
      • Oefelein M.G.
      • Ricchuiti V.
      • Conrad W.
      • et al.
      Skeletal fracture associated with androgen suppression induced osteoporosis the clinical incidence and risk factors for patients with prostate cancer.
      Several lines of evidence have indicated that estrogens play an important role in male bone development and metabolism. First, men with rare genetic syndromes resulting in estrogen deficiency or estrogen resistance have delayed skeletal development and low bone mineral density.
      • Smith E.P.
      • Boyd J.
      • Frank G.R.
      • et al.
      Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man.
      ,
      • Morishima A.
      • Grumbach M.M.
      • Simpson E.R.
      • et al.
      Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens.
      ,
      • Bilezikian J.P.
      • Morishima A.
      • Bell J.
      • et al.
      Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency.
      Second, serum estrogen levels are positively associated with bone mineral density
      • Slemenda C.W.
      • Longcope C.
      • Zhou L.
      • et al.
      Sex steroids and bone mass in older men positive associations with serum estrogens and negative associations with androgens.
      ,
      • Khosla S.
      • Melton III, L.J.
      • Atkinson E.J.
      • et al.
      Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women a key role for bioavailable estrogen.
      ,
      • Greendale G.A.
      • Edelstein S.
      • Barrett-Connor E.
      Endogenous sex steroids and bone mineral density in older women and men the Rancho Bernardo Study.
      and negatively associated with vertebral fracture risk.
      • Barrett-Connor E.
      • Mueller J.E.
      • von Muhlen D.G.
      • et al.
      Low levels of estradiol are associated with vertebral fractures in older men, but not women the Rancho Bernardo Study.
      Third, serum concentrations of estrogen, but not testosterone, predict changes in bone mineral density and biochemical markers of bone turnover in older men.
      • Khosla S.
      • Melton III, L.J.
      • Atkinson E.J.
      • et al.
      Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men.
      Finally, androgen-deprivation therapy with estrogens does not decrease bone mineral density or increase biochemical markers of osteoclast activity in men with prostate cancer.
      • Eriksson S.
      • Eriksson A.
      • Stege R.
      • et al.
      Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens.
      ,
      • Scherr D.
      • Pitts Jr, W.R.
      • Vaughn Jr, E.D.
      Diethylstilbesterol revisited androgen deprivation, osteoporosis and prostate cancer.
      Bicalutamide (Casodex) is a nonsteroidal antiandrogen that competitively inhibits the action of androgens by binding to androgen receptors in the target tissue.
      • Furr B.J.
      ICI 176,334—a new, pure, peripherally-selective anti-androgen preclinical studies.
      Monotherapy with bicalutamide (150 mg orally daily) results in similar survival to androgen-deprivation therapy for men with nonmetastatic prostate cancer.
      • Iversen P.
      • Tyrrell C.J.
      • Kaisary A.V.
      • et al.
      Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer results from two multicenter randomized trials at a median follow-up of 4 years.
      ,
      • Tyrrell C.J.
      • Kaisary A.V.
      • Iversen P.
      • et al.
      A randomised comparison of “Casodex” (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer.
      ,
      • Boccardo F.
      • Rubagotti A.
      • Barichello M.
      • et al.
      Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients results of an Italian Prostate Cancer Project study.
      ,
      • Iversen P.
      • Tyrrell C.J.
      • Kaisary A.V.
      • et al.
      Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer 6.3 years of followup.
      In men with bone metastases, however, bicalutamide monotherapy is less effective than androgen-deprivation therapy.
      • Tyrrell C.J.
      • Kaisary A.V.
      • Iversen P.
      • et al.
      A randomised comparison of “Casodex” (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer.
      Adjuvant bicalutamide decreases the risk of disease progression for men undergoing standard therapy for clinically localized or locally advanced nonmetastatic prostate cancer.
      • Wirth M.
      • Tyrrell C.
      • Wallace M.
      • et al.
      Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression.
      ,

      Wirth M, See W, McLeod D, et al: Bicalutamide (Casodex) 150 mg as immediate or adjuvant therapy in 8113 men with localized or locally advanced prostate cancer (abstract). Proc Am Soc Clin Oncol 20: 177a, 2001

      Bicalutamide monotherapy is approved to treat early-stage prostate cancer in more than 30 countries, including the United Kingdom.
      Bicalutamide monotherapy increases serum concentrations of testosterone and estradiol.
      • Verhelst J.
      • Denis L.
      • Van Vliet P.
      • et al.
      Endocrine profiles during administration of the new non-steroidal anti-androgen Casodex in prostate cancer.
      Because estrogen is an important determinant of bone metabolism in men, bicalutamide monotherapy may lack the adverse skeletal effects associated with gonadotropin-releasing hormone agonist treatment. To evaluate this hypothesis, we compared biochemical markers of bone turnover in a cross-sectional study of three groups of men with nonmetastatic prostate cancer: hormone-naive men, men treated with a gonadotropin-releasing hormone agonist, and men receiving bicalutamide monotherapy.

      Material and methods

      Subjects had locally advanced, lymph node-positive, or recurrent prostate cancer and no bone metastases by bone scan. We included subjects with no prior hormonal therapy (group 1, hormone naive), subjects undergoing current treatment with a gonadotropin-releasing hormone agonist (group 2, gonadotropin-releasing hormone agonist); and those undergoing current monotherapy with bicalutamide (Casodex, AstraZeneca, London, UK) 150 mg daily (group 3, bicalutamide monotherapy). All subjects in groups 2 and 3 had been treated for 6 months. All subjects in groups 2 and 3 received supplemental calcium carbonate (500 mg daily) and a daily multivitamin containing 400 IU vitamin D during their hormonal therapy. Men with Paget’s disease, hyperthyroidism, Cushing’s disease, hyperprolactinemia, chronic liver disease, or chronic renal insufficiency (serum creatinine concentration greater than 2.0 mg/dL [177 μmol/L]) were excluded. Men were also excluded if they had received glucocorticoids, bisphosphonates, calcitonin, or suppressive doses of thyroxine within 1 year. The institutional review board reviewed and approved the study, and all subjects gave written informed consent.
      Serum and second-voided urine samples were obtained between 8 and 10 am and stored at −80°F. Serum concentrations of testosterone (Diagnostic Products, Los Angeles, Calif), estradiol (Nichols Institute, San Juan Capistrano, Calif), and osteocalcin (Nichols Institute) were measured by radioimmunoassays. Serum bone-specific alkaline phosphatase (Metra Biosystems, Mountain View, Calif), urinary N-telopeptide (Osteomark, Ostex International, Seattle, Wash), and urinary deoxypyridinoline (Metra Biosystems, Mountain View, Calif) were measured by enzyme immunoassays.
      Values are reported as the mean ± standard error. Results were compared between the groups using t tests. All P values are two-sided, and values less than 0.05 were considered statistically significant.

      Results

      Fifty-five eligible subjects were included in the analyses. Subject characteristics, including age, race, body mass index, and serum concentrations of 25-hydroxyvitamin D, were similar in the three groups (Table I). The mean serum prostate-specific antigen concentration was higher in the hormone-naive men than in the other groups.
      TABLE IPatient characteristics
      Group 1, Hormone NaiveGroup 2, GnRH AgonistGroup 3, Bicalutamide Monotherapy
      Subjects (n)152218
      Age (yr)66 ± 266 ± 263 ± 2
      Duration of hormonal treatment (mo)0 ± 06 ± 0
      P < 0.05, group 1 vs. group 2.
      6 ± 0
      P < 0.05, group 1 vs. group 3.
      ,
      P < 0.05, group 2 vs. group 3.
      White race (%)939594
      Body mass index (kg/m2)27 ± 127 ± 128 ± 1
      25-Hydroxyvitamin D (ng/mL)23 ± 226 ± 227 ± 2
      Prostate-specific antigen (ng/mL)17.2 ± 8.00.7 ± 0.23.4 ± 2.6
      Key: GnRH = gonadotropin-releasing hormone.
      Data presented as the mean ± standard error, unless noted otherwise.
      * P < 0.05, group 1 vs. group 2.
      P < 0.05, group 1 vs. group 3.
      P < 0.05, group 2 vs. group 3.
      The serum concentrations of gonadal steroids differed significantly among the groups (Table II) . The serum testosterone and estradiol concentrations were lower in men receiving a gonadotropin-releasing hormone agonist than in hormone-naive men or men receiving bicalutamide monotherapy (P <0.001 for each comparison). The serum testosterone and estradiol concentrations were significantly higher in men receiving bicalutamide monotherapy than in hormone-naive men (P <0.001).
      TABLE IIGonadal steroids and biochemical markers of bone turnover in men with nonmetastatic prostate cancer
      Group 1, Hormone NaiveGroup 2, GnRH AgonistGroup 3, Bicalutamide MonotherapyP Values
      1 vs. 21 vs. 32 vs. 3
      Testosterone (ng/dL)397 ± 3614 ± 2
      P < 0.05, group 1 vs. group 2.
      678 ± 38
      P < 0.05, group 1 vs. group 3.
      ,
      P < 0.05, group 2 vs. group 3.
      <0.0001<0.001<0.001
      Estradiol (pg/mL)27 ± 27 ± 1
      P < 0.05, group 1 vs. group 2.
      50 ± 5
      P < 0.05, group 1 vs. group 3.
      ,
      P < 0.05, group 2 vs. group 3.
      <0.0001<0.001<0.001
      Urinary excretion of deoxypyridinoline (nmol BCE/mmol creatinine)4.8 ± 0.37.3 ± 0.5
      P < 0.05, group 1 vs. group 2.
      5.4 ± 0.4
      P < 0.05, group 2 vs. group 3.
      <0.001>0.25>0.005
      Urinary excretion of N-telopeptides (nmol BCE/mmol creatine)24 ± 350 ± 4
      P < 0.05, group 1 vs. group 2.
      22 ± 3
      P < 0.05, group 2 vs. group 3.
      <0.001>0.69<0.001
      Bone-specific alkaline phosphatase (nmol/L)19 ± 120 ± 119 ± 2>0.60>0.99>0.66
      Osteocalcin (ng/mL)22 ± 231 ± 2
      P < 0.05, group 1 vs. group 2.
      18 ± 2
      P < 0.05, group 2 vs. group 3.
      >0.01>0.18<0.001
      Key: GnRH = gonadotropin-releasing hormone; BCE = bone collagen equivalents.
      Data presented as the mean ± standard error, unless noted otherwise.
      * P < 0.05, group 1 vs. group 2.
      P < 0.05, group 1 vs. group 3.
      P < 0.05, group 2 vs. group 3.
      Biochemical markers of bone turnover were significantly higher in men receiving a gonadotropin-releasing hormone agonist than in either hormone-naive men or men receiving bicalutamide monotherapy (Table II). The mean urinary excretion of deoxypyridinoline and N-telopeptide, markers of osteoclast activity, were markedly higher in men receiving a gonadotropin-releasing hormone agonist than in men in the other groups (P <0.05 for each comparison). The mean serum concentrations of osteocalcin, a marker of osteoblast activity, were higher in men receiving a gonadotropin-releasing hormone agonist than in men in the other groups (P <0.05 for each comparison). In contrast, urinary and serum markers of bone turnover were similar in hormone-naive men and men receiving bicalutamide monotherapy (P >0.05 for each comparison). The serum concentration of bone-specific alkaline phosphatase did not differ significantly among the groups.

      Comment

      These results demonstrate that biochemical markers of bone turnover are elevated in men with nonmetastatic prostate cancer receiving gonadotropin-releasing hormone agonist treatment. In contrast, the levels of bone turnover markers in men receiving bicalutamide monotherapy were similar to those in hormone-naive men. Biochemical markers of bone turnover correlate with rates of bone loss and predict fractures independent of bone mineral density.
      • van Daele P.L.
      • Seibel M.J.
      • Burger H.
      • et al.
      Case-control analysis of bone resorption markers, disability, and hip fracture risk the Rotterdam study.
      ,
      • Garnero P.
      • Hausherr E.
      • Chapuy M.C.
      • et al.
      Markers of bone resorption predict hip fracture in elderly women the EPIDOS Prospective Study.
      ,
      • Garnero P.
      • Sornay-Rendu E.
      • Claustrat B.
      • et al.
      Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women the OFELY study.
      ,
      • Ross P.D.
      • Kress B.C.
      • Parson R.E.
      • et al.
      Serum bone alkaline phosphatase and calcaneus bone density predict fractures a prospective study.
      Our results suggest that bicalutamide monotherapy may preserve bone mineral density and prevent fractures. Additional studies are needed to evaluate prospectively the effects of bicalutamide monotherapy on bone mineral density and fracture risk.
      Our results are consistent with a report that bone mineral density was normal in a cohort of men receiving bicalutamide monotherapy.
      • Iversen P.
      • Tyrrell C.J.
      • Kaisary A.V.
      • et al.
      Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer 6.3 years of followup.
      Our results are also consistent with the preliminary report of a randomized controlled trial.

      Sieber PR, Keliier DL, Kahnoski RJ, et al: Bone mineral density is maintained during bicalutamide (‘Casodex’) treatment (abstract). Proc Am Soc Clin Oncol 21: 196a, 2002

      In a multicenter study, 103 men with nonmetastatic prostate cancer were randomly assigned to bicalutamide (150 mg daily) monotherapy or androgen-deprivation therapy. The primary study endpoint was a change in bone mineral density after 2 years. Changes in bone mineral density differed significantly between the groups. In men receiving androgen-deprivation therapy, bone mineral density decreased by 5.4% in the lumbar spine and 4.4% in the hip. In contrast, bone mineral density increased by 2.4% in the lumbar spine and 1.1% in the hip in men receiving bicalutamide monotherapy.
      Men treated with bicalutamide had higher serum testosterone and estradiol levels than did the hormone-naive men in our study. These results are consistent with a prior report that bicalutamide monotherapy increases serum testosterone and estradiol concentrations.
      • Verhelst J.
      • Denis L.
      • Van Vliet P.
      • et al.
      Endocrine profiles during administration of the new non-steroidal anti-androgen Casodex in prostate cancer.
      Bicalutamide monotherapy also increases serum luteinizing hormone concentrations,
      • Verhelst J.
      • Denis L.
      • Van Vliet P.
      • et al.
      Endocrine profiles during administration of the new non-steroidal anti-androgen Casodex in prostate cancer.
      suggesting that bicalutamide crosses the blood-brain barrier and binds to hypothalamic androgen receptors. Accordingly, treatment-related increases in serum gonadal steroid levels appear to result from central feedback.
      Estrogens play an important role in male bone metabolism, although the relative contributions of estrogen and testosterone remain controversial.
      • Khosla S.
      • Melton III, L.J.
      • Riggs B.L.
      Clinical review 144 estrogen and the male skeleton.
      Osteoblasts express androgen receptors, and androgens stimulate osteoblast proliferation and differentiation. Osteoclasts do not express androgen receptors, although androgens may inhibit osteoclast activation by indirect mechanisms. Our results do not exclude the possibility that treatment-related increases in serum testosterone levels or the bone-specific effects of bicalutamide contribute to the normal marker profile in the bicalutamide-treated subjects.
      Hormonal therapy for prostate cancer has a variety of adverse effects. Common side effects of gonadotropin-releasing hormone agonists include loss of libido, vasomotor flushing, fatigue, anemia, weight gain, decreased muscle mass, and increased fat mass. Nipple tenderness and breast enlargement are characteristic side effects of bicalutamide monotherapy. Critical evaluation of the overall impact of hormonal therapy on patients’ quality of life requires consideration of both skeletal and nonskeletal adverse effects.
      Our study has limitations. The study design was cross-sectional, and prospective studies are needed to confirm the results. Age, race, body mass index, and serum concentrations of 25-hydroxyvitamin D were similar in all groups, but unintended imbalances in other characteristics may have contributed to the observed differences in bone turnover markers. The subjects were evaluated after 6 months of treatment. Although biochemical markers of bone turnover appear to reach a steady state within 6 months,
      • Smith M.R.
      • McGovern F.J.
      • Zietman A.L.
      • et al.
      Pamidronate to prevent bone loss in men receiving gonadotropin releasing hormone agonist therapy for prostate cancer.
      somewhat different results may be observed after a longer treatment period. Finally, most subjects were white, and treatment-related changes in biochemical markers of bone turnover may vary in other racial groups.

      Conclusions

      Biochemical markers of bone turnover are elevated in men receiving gonadotropin-releasing hormone agonist treatment but not in men receiving bicalutamide monotherapy. These observations suggest that bicalutamide monotherapy may maintain bone mineral density and prevent fractures.

      Acknowledgements

      We thank the dedicated staff of the Mallinckrodt General Clinical Research Center.

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