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1561 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 Terrence Diamond1 Joanne Campbell1 Carl Bryant1 William Lynch2 1 Metabolic Bone Unit, St. George Hospital, Kogarah, Sydney, Australia. 2 Urology Department, St George Hospital, Kogarah, Sydney, Australia. Address for reprints: Terrence Diamond, St. George Hospital, Department of Endocrinology, 32 Belgrave Street, Kogarah, Sydney 2217, Australia. Received December 19, 1997; revision received March 25, 1998; accepted March 25, 1998. © 1998 American Cancer Society BACKGROUND. Androgen receptor blocking agents have become an established form of therapy for men with disseminated prostate carcinoma. The purpose of this study was to evaluate markers of bone turnover and to measure bone mineral densities (BMD) in men with disseminated prostate carcinoma treated with combined androgen blockade prior to and after 6 months of intermittent cyclic etidronate therapy. METHODS. Twelve consecutive men with disseminated prostate carcinoma were evaluated at 0, 6, and 12 months after treatment with a long acting gonadotropinreleasing hormone agonist (goserelin acetate) and an androgen antagonist (flutamide). During the 6 –12 month period, patients were treated with adjuvant intermittent cyclic etidronate therapy and calcium supplementation. Lumbar spine BMD was measured by spinal quantitative computed tomography (QCT) and femoral neck BMD by dual energy X-ray absorptiometry (DXA). RESULTS. Combined androgen blockade resulted in all men achieving serum free testosterone concentrations of ,2.2 pmol/L (normal range, 38 –114 pmol/ L). The mean serum prostate specific antigen activities decreased from 130.8 6 46 to 6.9 6 4.4 ng/mL (P , 0.05). Although serum calcium, parathyroid hormone, and 25-hydroxyvitamin D measurements remained unchanged, serum bone Gla-protein concentrations and urinary deoxypyridinolene excretion rates increased significantly (P , 0.01, respectively). Mean lumbar spine QCT decreased by 6.6 6 1.5% from 76.5 mg/cm3 (95% confidence interval [95% CI], 57–96 mg/cm3) to 73.9 mg/cm3 (95% CI, 55–93 mg/cm3) (P , 0.001) and mean femoral neck DXA decreased by 6.5 6 1.3% from 0.94 g/cm2 (95% CI, 0.81–1.07 g/cm2) to 0.91 g/cm2 (95% CI, 0.79 –1.04 g/cm2) (P , 0.001). After treatment with adjuvant intermittent cyclic etidronate, mean lumbar spine QCT increased by 7.8 6 3.7% to a final value of 75 mg/cm3 (95% CI, 48.7–101 mg/cm3) (P 5 0.001 compared with the initial 6 months without intermittent cyclic etidronate therapy). Significant increases in BMD also were observed in the femoral neck and Ward’s triangle. CONCLUSIONS. Androgen receptor blocking agents have an established role in the treatment of disseminated prostate carcinoma. However, combined androgen blockade in elderly men with disseminated prostate carcinoma results in high bone turnover with significant cancellous bone loss. The results of this study show that adjuvant therapy with intermittent cyclic etidronate may prevent these changes and decrease the risk of spinal fractures. Cancer 1998;83:1561– 6. © 1998 American Cancer Society. KEYWORDS: prostate carcinoma, combined androgen blockade, osteoporosis, disseminated. 1562 CANCER October 15, 1998 / Volume 83 / Number 8 R ecent data have demonstrated increased survival in men with disseminated prostate carcinoma treated with androgen receptor blocking agents.1,2 These agents cause significant hypogonadism and bone loss in premenopausal women3 and elderly men.4 Although osteoporosis and spinal fractures have been reported in men with prostate carcinoma treated by orchiectomy,5–10 limited data are available regarding bone turnover studies and bone mineral densities (BMD) in men treated with androgen receptor blocking agents.11–14 To our knowledge, to date there are no data regarding the treatment or prevention of osteoporosis in men with prostate carcinoma. MATERIALS AND METHODS We studied 12 consecutive men with a mean age of 78.2 years (range, 60 – 89 years) referred with prostate carcinoma over a 12-month period. All men had histologic evidence of adenocarcinoma, an elevated prostate specific antigen level, and radioisotopic evidence of metastatic bone disease. Patients were studied at 0, 6, and 12 months after commencing treatment with a long-acting gonadotropin-releasing hormone (GnRH) agonist (goserelin acetate, 3.6 mg subcutaneously monthly) and an androgen antagonist (flutamide, 750 mg daily). During the second 6-month period they were treated with intermittent cyclic etidronate therapy (Procter & Gamble Pharmaceuticals, Cincinnati, OH) (400 mg at bedtime for 2 weeks of every 3 months) and with daily calcium supplements (equivalent to 600 mg elemental calcium per day).15 No patient had thyroid, renal, or liver disease and none had received calcium, calcitriol, bisphosphonates, or calcitonin prior to entering the study. Two men had well controlled type II diabetes that was managed with oral hypoglycemic agents. Data on 113 healthy community dwelling men ages 70 –92 years residing in the same metropolitan area as the men presenting with prostate carcinoma were used as normal controls for baseline biochemistry and densitometry assessment. These men were recruited for a study on Muscle Mass Determinants in the Elderly (unpublished data). Longitudinal changes in bone densitometry performed in a subset of 12 of these men was used as comparative data for the longitudinal studies. After informed consent was obtained venous blood and an early morning fasting 2-hour urine sample were collected from all men for biochemical and hormonal measurements. Serum and urinary calcium and creatinine levels and serum alkaline phosphatase activities were determined by routine autoAnalyser methods. Serum parathyroid hormone, serum bone Gla- protein (a serologic marker of bone formation), and serum 25 hydroxyvitamin D were measured by immunoradiometric assay (Nichols Institute, San Clemente, CA). Serum free testosterone was measured by radioimmunoassay (Diagnostic Products Corporation, Santa Barbara, CA) and serum prostate specific antigen by microparticle enzyme immunoassay (Abbott Laboratories, Abbott Park, IL). Serum follicle-stimulating and luteinizing hormone and urinary deoxypyridinolene (a marker of bone resorption) were measured by chemiluminescence (Ciba Corning, Medfield, MA). A lateral thoracolumbar spine X-ray performed prior to commencing combined androgen blockade was used to assess for metastatic bone disease, vertebral crush fractures, and spondyloarthropathy. The BMD of the lumbar spine (anteroposterior; L2 to L4) and femoral neck was measured by dual energy X-ray absorptiometry (DXA) (Lunar DPX-L; Lunar Corporation, Madison, WI). The in vivo precision was 1.7% for measurements of the lumbar spine, 3.6% for measurements of the femoral neck, 3.3% for measurements of Ward’s triangle, and 2.2% for measurements of the femoral trochanter.16 BMD measurements were expressed in absolute terms as g/cm2 and as a percentage of the initial value. Osteoporosis was defined as a BMD measurement .2.5 standard deviations below the mean for a healthy population group ages 20 – 40 years. Longitudinal changes in BMD were expressed as percentage change and were calculated by subtracting the final BMD from the initial BMD and dividing this difference by the initial BMD. Percentage changes in BMD were calculated for each individual and the mean 6 standard error of the mean (SEM) derived for the groups. Lumbar spine BMD also was measured by quantitative computed tomography (QCT)17 using a General Electric Hi Speed scanner (General Electric Co., Milwaukee, WI). A lateral scout radiograph of the lumbar spine was obtained to permit precise positioning of the scanner. Baseline and follow-up measurements were performed by obtaining scans through lumbar vertebrae L2, L3, and L4. A mean lumbar spine QCT value was calculated for the three vertebral bodies and expressed as mg/cm3. The precision for this technique was 2.8%. All values were reported as the mean 6 SEM and, where appropriate, 95% confidence intervals (CI) were cited. Data were compared by the Student’s t test for paired data and analysis of variance. Statistical significance was assigned as P , 0.05. RESULTS Results of serum biochemistry, markers of bone turnover and bone densitometry performed at 0, 6, and 12 Bone Changes in Prostate Carcinoma/Diamond et al. 1563 TABLE 1 Serum Biochemistry, Markers of Bone Turnover, and Bone Mineral Density Measurements in Men with Prostate Carcinoma at 0, 6, and 12 Months after Therapy with Combined Androgen Blockade Patients (no) Calcium (2.40 6 0.02 mmol/L)a Phosphate (1.18 6 0.04 mmol/L) Creatinine (0.11 6 0.01 mmol/L) PTH (3.8 6 0.5 pmol/L) Free testosterone (38 6 1.2 pmol/L) PSA (,4 ng/mL) SAP (94 6 12 u/L) BGP (5.7 6 0.2 ng/mL) Urinary Ca/Cr (0.41 6 0.05 mmol/mmol) Urinary DPYD/Cr (0.54 6 0.05 nmol/mmol) Spinal QCT (99 6 6.2 mg/cm3) Femoral Neck DXA (0.94 6 0.03 g/cm2) Ward’s triangle DXA (0.73 6 0.03 g/cm2) Trochanter DXA (0.89 6 0.03 g/cm2) 0 mos (baseline) 6 mos (without etidronate) 12 mos (with etidronate) 12 2.45 6 0.03 1.17 6 0.04 0.11 6 0.01 4.2 6 0.4 43.7 6 3.5 130.8 6 46c 98.6 6 13 4.4 6 0.5 0.32 6 0.03 5.6 6 0.4 76.5 6 8.8f 0.94 6 0.06 0.67 6 0.05f 0.88 6 0.07 11 2.42 6 0.07 1.25 6 0.04 0.10 6 0.01 3.5 6 0.4 2.3 6 0.6b,c 8 6 5.6d 92 6 9.6 5.9 6 0.3e 0.69 6 0.2e 7.9 6 0.5b,f 73.9 6 8.5b,f 0.91 6 0.03b,f 0.63 6 0.05e,f 0.84 6 0.04f 8 2.39 6 0.03 1.27 6 0.07 0.11 6 0.01 3.0 6 0.4 3.0 6 0.7b,c 6.8 6 4.4d 127 6 4.9 6.1 6 0.5e 0.60 6 0.1e 6.9 6 0.2b,f 75 6 11.1e,f 0.92 6 0.03e 0.65 6 0.06f,g 0.90 6 0.07 PTH: parathyroid hormone; PSA: prostate specific antigen; SAP: serum alkaline phosphatase; BGP: bone Gla-protein; Ca/Cr: calcium/creatinine ratio; DPYD/Cr: deoxypyridinolene/creatinine ratio; QCT: bone density measured by quantitative computed tomography; DXA: bone density measured by dual energy X-ray absorptiometry. Values are presented as the mean 6 the standard error of the mean. a Data in parentheses are the normal reference range for 113 age-matched healthy controls. b P , 0.001 compared with value at 0 months. c P , 0.001 versus controls. d P , 0.05 compared with value at 0 months. e P , 0.01 compared with value at 0 months. f P , 0.01 versus controls. g P , 0.05 compared with value at 6 months. months are recorded in Table 1. One man died during the initial 6 months of the study and an additional 3 men died during the final 6 months of the study. Combined androgen blockade resulted in all men achieving serum free testosterone concentrations of ,2.2 pmol/L (normal range, 38 –114 pmol/L) and serum gonadotrophin measurements of ,5 mu/L (normal range, 5–21 mu/L). The mean serum prostate specific antigen activities decreased from 130.8 6 46 ng/mL to 6.8 6 4.4 ng/mL (P , 0.05) after 12 months of therapy. Individual serum prostate specific antigen activities normalized in 9 of the 11 men after 6 months of therapy and remained within the normal reference range in 6 of the 8 men after 12 months of therapy. Serum calcium, phosphate, and parathyroid hormone measurements remained unchanged during the study. No man had evidence of subclinical vitamin D deficiency. Serum bone Gla-protein, a marker of bone formation, increased after combined androgen blockade by approximately 34% from 4.4 6 0.5 to 5.9 6 0.3 ng/mL (P , 0.01) and remained persistently elevated in 5 men despite intermittent cyclic etidronate therapy. Conversely, urinary deoxypyridinoline excretion, a marker of bone resorption, increased after combined androgen blockade by approximately 41% from 5.6 6 0.4 to 7.9 6 0.5 nmol/mmol of creatinine (P , 0.001). However, after intermittent cyclical etidronate therapy, urinary deoxypyridinoline excretion rates decreased to a mean value of 6.9 6 0.2 nmol/mmol of creatinine, but still remained above the normal reference range in 6 men. Spinal radiography performed prior to commencing combined androgen blockade demonstrated vertebral fractures (T12 and L1) in two men with prostate carcinoma. There was no evidence of lumbar spine metastases or osteosclerosis secondary to prostate carcinoma in any patient. Lumbar spine BMD measured by DXA was pseudoelevated and uninterpretable in 9 of the 12 men (75%). This was due to significant lumbar spine disk degeneration and facet joint hypertrophy.18 Figure 1 shows the individual lumbar spine QCT and femoral neck DXA measurements performed at 0, 6, and 12 months after therapy. Osteoporosis of the lumbar spine (QCT) and femoral neck (DXA) was present in 9 (75%) and 4 (33%), respectively, of the 12 men prior to commencing therapy. After 6 months of combined androgen blockade, mean lumbar spine QCT decreased by 6.6% from 76.5 mg/cm3 (95% CI, 57–96) to 73.9 mg/cm3 (95% CI, 1564 CANCER October 15, 1998 / Volume 83 / Number 8 FIGURE 1. Individual lumbar spine (squares) and femoral neck (circles) bone mineral density (BMD) values in men with disseminated prostate carcinoma. Lumbar spine BMD was measured by quantitative computed tomography (QCT) and expressed as mg/cm3. Femoral neck BMD was measured using dual energy X-ray absorptiometry (DXA) and expressed as g/cm2. Closed symbols: densities recorded at 0 months after combined androgen blockade; open symbols: densities recorded at 6 months after combined androgen blockade; shaded symbols: densities recorded at 12 months after combined androgen blockade and intermittent cyclic etidronate therapy. The shaded area in the figure represents the normal bone mineral density reference range. The horizontal bars represent mean bone mineral density values. The P value represents a comparison between bone mineral density values at 0 – 6 months and 6 –12 months (Student’s t test for paired data). 55–93) (P , 0.001); the mean femoral neck DXA decreased by 6.5% from 0.94 g/cm2 (95% CI, 0.81–1.07) to 0.91 g/cm2 (95% CI, 0.79 –1.04) (P , 0.001) and the mean Ward’s triangle DXA decreased by 7.5% from 0.67 g/cm2 (95% CI, 0.55– 0.78) to 0.63 g/cm2 (95% CI, 0.53– 0.74) (P , 0.001). These changes in BMD were significantly greater than that recorded in the 12 healthy age-matched men without prostate carcinoma who were assessed over the same period. Their mean spinal QCT decreased by 2.5% per year, mean femoral neck DXA by 0.9% per year, and mean Ward’s triangle DXA by 0.7% per year (P , 0.001, respectively, compared with BMD changes in men with prostate carcinoma receiving combined androgen blockade). Table 2 shows the percent change in BMD measurements (95% CI) in men treated with combined androgen blockade, prior to and after 6 months of intermittent cyclic etidronate therapy. The mean lumbar spine QCT increased by 7.8% (95% CI, 20.8 –16.6) and the mean Ward’s triangle DXA increased by 1.9% (95% CI, 24 –7.9) after intermittent cyclic etidronate therapy (P 5 0.01 and P 5 0.04, respectively, compared with the initial 6 months without intermittent cyclic etidronate therapy). DISCUSSION Recent case studies and short reports have demonstrated that elderly men with disseminated prostate carcinoma treated by either orchiectomy or with androgen blockade will experience hypogonadal symptoms and may be at risk for developing high turnover osteoporosis and skeletal fractures.5–14 In this longitudinal study we recorded a 6.6% reduction in lumbar spine and a 6.5% reduction in femoral neck BMD after 6 months of therapy with a long-acting GnRH agonist (goserelin acetate) and an androgen antagonist (flutamide). The decrease in BMD was similar to that previously reported in premenopausal women3 and elderly men4 treated with GnRH agonists and was much greater than expected in an age-matched control group.19 This significant bone loss is of major clinical relevance because many of the men presenting with prostate carcinoma are elderly with preexisting osteoporosis. In our study 75% of men had spinal QCT evidence of osteoporosis and two already had preexisting spinal fractures prior to commencing treatment with combined androgen blockade. Hypogonadism remains an important cause of male osteoporosis and skeletal fractures.20 –24 Both cortical and cancellous bone loss have been reported to occur within 6 months of developing hypogonadism after either GnRH agonist therapy or orchiectomy. Rates of bone loss vary from 2–7% depending on the methods of BMD assessment.4,6 In this study, lumbar spine DXA measurements were confounded by coexisting spondyloarthropathy and hence spinal QCT, a more sensitive method of BMD analysis,18,25 was used to determine cancellous bone loss. On average, a 6 –7% loss in BMD was recorded from the lumbar spine and the majority of regions of the femoral neck within 6 months of combined androgen blockade. This data is similar to the bone loss reported by Eriksson et al.6 who performed dual photon absorptiometry of the distal forearm and the femoral neck on 11 men, prior to and 12 months after orchiectomy for prostate carcinoma. The histomorphometric changes of hypogonadism include high bone turnover,22 trabecular plate perforation, and osteoclast activation.23 These findings often are reflected by increases in the noninvasive markers of bone turnover.24 As demonstrated in this study, combined androgen blockade resulted in all men achieving castrate levels of serum free testosterone concentrations accompanied by significant increases in serum bone Gla-protein concentrations and urinary deoxypyridinolene excretion rates. Similar findings have been noted by Percival et al.,9 who investigated 28 men with disseminated prostate carcinoma treated by orchiectomy. They found significant increases in serum alkaline phosphatase activities and urinary hydroxyproline excretion rates, associated with histologic evidence of active erosion surfaces. Bone Changes in Prostate Carcinoma/Diamond et al. 1565 TABLE 2 Percentage Change in Bone Mineral Density in Men with Prostate Carcinoma Treated with Combined Androgen Blockade, prior to and after 6 Months of Intermittent Cyclic Etidronate Therapy Combined androgen blockade a BMD Without ICT Spinal QCT Femoral neck Ward’s triangle Trochanter 26.6% (210 to 23.2) 26.5% (29.5 to 23.5) 27.5% (212.4 to 22.7) 26.2% (210.5 to 22) With ICTb P value 7.8% (20.8 to 16.6) 22.4% (26.6 to 1.7) 1.9% (24 to 7.9) 0.6% (26.4 to 7.7) P 5 0.01 P 5 0.02 P 5 0.04 P 5 0.08 BMD: bone mineral density; ICT: intermittent cyclic etidronate therapy; QCT: bone density measured by quantitative computed tomography. Values are the mean percentage change in bone mineral density after 6 months of therapy (95% confidence interval). P values were established using the Student’s t test for paired data. a Mean values calculated for 11 of the 12 mean at 0–6 months on combined androgen blockade (1 man died). b Mean values calculated for 8 of the 12 men at 6–12 months on combination of combined androgen blockade and intermittent cyclic etidronate therapy (4 men died). Although combined androgen blockade has been demonstrated to improve long term survival in elderly men with disseminated prostate carcinoma,1,2 the prolonged effects of hypogonadism and osteoporosis may result in an increase risk for skeletal fractures. A recent report by Daniell10 recorded a significant increase in osteoporotic fractures in men with prostate carcinoma treated with orchiectomy. By 9 years, men treated with orchiectomy had a 50% greater risk of having a first osteoporotic fracture than men treated without orchiectomy (P , 0.001). A similar finding has been reported in men with disseminated prostate carcinoma treated with GnRH agonists alone. In a retrospective chart and telephone interview, Townsend et al.14 recorded a history of bone fractures in 20 of 224 men (9%) with prostate carcinoma treated for up to 96 months with GnRH agonists, with 5% being attributable to osteoporosis. These data emphasize the importance of differentiating between hypogonadal osteoporosis and metastatic bone disease as a cause for fractures in men treated for disseminated prostate carcinoma. Recent studies have emphasized the role of bisphosphonates in the treatment of cancer and related metabolic bone disorders.26 These antiresorptive agents include drugs such as clodronate, etidronate, and pamidronate, which have been shown to inhibit osteoclastogenesis and to cause apoptosis of active osteoclasts.27 Clodronate has been used effectively for the management of bone pain associated with metastatic prostate carcinoma,28 and intermittent cyclic etidronate has been demonstrated to prevent bone loss in women treated with GnRH agonists,29 whereas pamidronate routinely is used for lytic bone diseases and hypercalcemia of malignancy.30 In this study we evaluated the role of adjuvant intermittent cyclic etidronate therapy for the prevention of high turnover osteoporosis in men with disseminated prostate carcinoma treated for 6 months with combined androgen blockade. During the 6 months of therapy with intermittent cyclic etidronate, the spinal bone loss observed with combined androgen blockade nearly completely reversed, whereas the femoral neck bone loss was retarded. These findings were associated with a tendency for normalization in bone turnover as reflected by decreases in serum bone Gla-protein concentrations and urinary deoxypyridinolene excretion rates. In a previous study by Clarke et al.5 intravenous pamidronate administered weekly for 4 weeks then alternate weekly for 6 months, prevented the high bone turnover changes accompanying orchiectomy without significantly affecting tumor burden. Recent data suggest that the role of bisphosphonates also may reside in their ability to delay the progression of prostatic skeletal metastases.31 The limitation of this study includes its small sample size with power limitations, lack of appropriate controls, and the study design. Nevertheless, our data demonstrate that combined androgen blockade in elderly men with disseminated prostate carcinoma may result in high bone turnover associated with significant cancellous bone loss. Adjuvant therapy with intermittent cyclic etidronate partially prevented these changes and hence decreased the risk of spinal fractures. We eagerly await randomized clinical trials assessing the role of the more potent bisphosphonates for the prevention of osteoporosis and metastatic bone disease in men with disseminated prostate carcinoma treated with either orchiectomy or GnRH agonist therapy. REFERENCES 1. McLeod DG. Hormonal therapy in the treatment of carcinoma of the prostate. Cancer 1995;75:1914. 1566 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. CANCER October 15, 1998 / Volume 83 / Number 8 Garnick MB. Hormonal therapy in the management of prostate cancer: from Huggins to the present. Urology 1997; 49(Suppl 3a):5–15. 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