Preventing Bone Loss During Androgen Deprivation Therapy for Prostate Cancer: Early Experience with Neridronate

European Urology European Urology 47 (2005) 575 581 Preventing Bone Loss During Androgen Deprivation Therapy for Prostate Cancer: Early Experience with Neridronate Carlo Magno a, *, Giuseppina Anastasi a, Nunziata Morabito b, Agostino Gaudio b, Domenica Maisano b, Fabio Franchina b, Alessandro Galì a, Nicola Frisina b, Darwin Melloni a a Department of Urology, University of Messina, Via Garibaldi 118, 98122, Messina, Italy b Department of Internal Medicine, University of Messina, Messina, Italy Accepted 18 January 2005 Available online 30 January 2005 Abstract Objective: Androgen-deprivation therapy (ADT) is the usual treatment for locally advanced or metastatic prostate cancer. Osteoporosis is a common complication of ADT. The aim of our study was to evaluate the efficacy of neridronate, a relatively new bisphosphonate to prevent bone loss during androgen ablation. Methods: Sixty patients with prostate cancer and osteoporosis were enrolled and randomly assigned to 2 different treatment regimes: group A (30 patients) treated with maximum androgenic blockage (MAB), and group B (30 patients) treated with bicalutamide 150 mg. Each group was divided in 2 subgroups A1 A2 and B1 B2. All patients received calcium and cholecalciferol supplements (500 mg of elemental calcium and 400 IU cholecalciferol) daily. The A2 and B2 subgroups were also treated with neridronate (25 mg intramuscular monthly). Lumbar and femoral bone mineral density (BMD) was evaluated by dualenergy X-ray absorptiometry (DXA), both at baseline and after one year of treatment. Deoxypyridinoline (DPD) and bone-alkaline phosphatase (B-ALP) were determined at the beginning, midstudy and at the end. Results: Patients treated only with calcium and cholecalciferol (A1, B1 subgroups) showed a marked bone loss after 6, and 12 months, with increased levels of DPD and BALP, compared to baseline values. Patients treated with neridronate (A2 et B2 subgroups) showed unchanged levels of these markers. After one year of treatment, lumbar and total hip BMD decreased significantly in patients treated only with calcium and cholecalciferol (A1 subgroup: 4.9% and 1.9% respectively). BMD did not change significantly at any site in patients treated also with neridronate (A2 subgroup: +1% and +0.8% respectively). Lumbar and total hip BMD did not change significantly ( 1.5% and 1% respectively) in B1 subgroup. In B2 subgroup an important increase in lumbar spine and the total hip BMD was shown (+2.5% and 1.6% respectively). No relevant side effects were recorded during our study. Conclusion: In conclusion, neridronate is an effective and safe treatment in preventing bone loss in men receiving ADT for prostate cancer. # 2005 Elsevier B.V. All rights reserved. Keywords: Androgen deprivation therapy; Neridronate; Bisphosphonates; Osteoporosis; Prostate cancer 1.Introduction * Corresponding author. E-mail address: carlo.magno@tin.it (C. Magno). Androgen deprivation therapy is standard treatment for locally advanced or metastatic prostate cancer. This is readily achieved through the use of GnRH agonists 0302-2838/$ see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2005.01.012

576 C. Magno et al. / European Urology 47 (2005) 575 581 depot, which provides a reliable means of medical castration [1]. Early primary androgen deprivation therapy (ADT) improves survival in men with locally advanced, non metastatic prostate cancer [2] who assume therapy for years. Large population studies show at long follow-up some of the complications of ADT treatment. As a matter of fact such therapy decreases BMD [3,4] and increases the risk of fracture [5,6]. This risk increases with the duration of treatment, so osteoporosis is an important complication of androgen-deprivation therapy [7]. Recent reports [8 10] have shown a high prevalence of pre-existing osteopenia and osteoporosis in men with prostate cancer, with a consistent risk of further bone loss during ADT. ADT has other adverse effects, including decrease in lean body mass and muscle size [8,11,12] that may result in frailty and increase risk of falling in older men. It seems reasonable to perform a bone densitometry before ADT because it could detect patients at high risk of developing osteoporosis [13]. Bicalutamide, a non steroidal antiandrogen, preserves BMD compared with castration, because it has no influence on levels of testosterone [14] There is not enough data concerning the treatment or prevention of osteoporosis in men with prostate cancer and many recommendations are based on studies of postmenopausal osteoporosis. Lifestyle modification including smoking cessation, moderation in alcohol consumption, regular exercise, supplemental calcium and vitamin D should be encouraged. Recent studies have evaluated the efficacy of bisphosphonates, such as pamidronate [15] and zoledronate [16,17], to prevent bone loss during androgen deprivation therapy. Men with osteoporosis before androgen deprivation or who develop it during treatment and/or experiencing adverse skeletal events may require bisphosphonates. Although alendronate, is the only bisphosphonate approved for treatment of osteoporosis [18], it has not been evaluated in men receiving ADT. Neridronate (6-amino-1-hydroxyexilidene-1,1-bisphosphonate) is a nitrogen containing bisphosphonate, structurally similar to alendronate and pamidronate, that potently inhibits osteoclast-mediated bone resorption, which has been employed, for treatment of Paget s disease [19 21] and hypercalcemia associated with cancer [22]. In addition, intravenous neridronate increases BMD in women with postmenopausal osteoporosis [23] and in patients with osteogenesis imperfecta [24]. At present, there are no controlled studies with neridronate on prevention or treatment of osteoporosis in men receiving ADT. In this study we evaluated whether intramuscular neridronate prevents bone loss in men undergoing androgen deprivation for prostate cancer. 2.Methods 2.1. Patients We studied 60 osteoporotic patients with locally advanced prostate cancer (T2 4 NX M0). Mean age was 73, 4 years (range 68 80). None of them had undergone surgery, chemotherapy or radiotherapy. Patients with Paget s disease, hyperthyroidism, Cushing s disease, hyperparathyroidism, hyperprolactinemia, chronic liver disease, or chronic renal insufficiency, previous treatment with drugs interfering with bone metabolism (androgens, glucocorticoids, bisphosphonates, calcitonin, or suppressive doses of thyroxine) were excluded. Patients were randomly assigned to two different treatment regimes: group A (30 patients) was treated with maximum androgenic blockage (triptoreline depot and bicatulamide, 50 mg daily) and group B (30 patients) with bicalutamide (150 mg daily). Each group was divided in two subgroups: A1 A2 and B1 B2. The A1 and B1 subgroups (30 patients, mean age 75.2 4.5 yr, BMI 25.2 2.9 kg/m 2 ) were both treated with a daily calcium and cholecalciferol supplement (500 mg of elemental calcium and 400 IU cholecalciferol). The A2 and B2 subgroups (30 patients, mean age 74.5 3.7 yr, BMI 25.8 3.7 kg/m 2 ) all received in addition to the calcium and cholecalciferol supplement, 25 mg of neridronate (Nerixia; Abiogen Pharma SpA, Pisa, Italy) given intramuscularly every month. Treatment lasted 1 year. Patients and investigators knew the treatment. The study was performed according to the principles of the Declaration of Helsinki, and an informed consent was obtained in every case. 2.2. Measurements of bone mineral density BMD was measured in all patients by a DXA densitometer (HOLOGIC QDR 4500 W), at base line and after 12 months, at the lumbar spine (L2 to L4) in A-P projection, at total hip and femoral neck. The instrument was calibrated on a daily basis according to the manufacturer s instructions. Reproducibility was calculated as a coefficient of variation (CV) obtained by weekly measurements of a standard phantom on the instrument and by repeated measurements obtained on three patients of different ages. The CV of the instrument that we used was 0.5% with standard phantom; in vivo we calculated a CV of 1.1% for the lumbar spine, 1.2% for total hip and 1.5% for neck. BMD data were expressed as grams per square centimetre. 2.3. Measurements of biochemical values At base-line after 6 and 12 months, fasting blood samples were taken for measurement of serum calcium (Ca, normal range 8.2 10.4 mg/dl), phosphorus (P, normal range 2.5 4.6 mg/dl), parathyroid hormone (PTH, normal range 12 72 pg/ml), bone-alkaline phosphatase (B-ALP, normal range 15.0 41.3 IU/L), 25-hydroxyvitamin D (25-OHD, normal range 20 120 ng/ml), 17-beta estradiol (E2, normal range 10 56 pg/ml), testosterone (T, normal range 212 742 ng/dl). A 2-h fasting morning urine sample was collected at the same time for measurements of calcium (<0.525 mmol), creatinine (0.10 0.18 mmol), and deoxypyridinoline (DPD, normal range 3 21 pmol/mmol urinary creatinine). Ca and P were determined by automatic routine procedures. PTH, E2, T and B-ALP were measured by enzyme immunoassays. DPD and 25-OHD were determined by HPLC. 2.4. Statistical analysis Statistical analyses were performed using StatSoft software (release 4.5). All values were expressed as mean S.D. The

C. Magno et al. / European Urology 47 (2005) 575 581 577 significance of percent changes in biochemical parameters and in BMD from baseline was evaluated by Student s t-test for paired observation. The comparison of changes between groups was evaluated by analysis of variance (ANOVA) for repeated measure and then by Student s t-test for unpaired observation. All p values are two-sided, and values of less than 0.05 were considered to indicate statistical significance. 3.Results The biochemical parameters of all patients are shown in Table 1. At the beginning of the study, there were no significant differences between the treatment groups. Due to ADT, the serum concentrations of T and E2 decreased significantly in A group (p < 0.001 for each comparison with baseline value). In particular serum concentrations of testosterone at 6, and 12 months in all patients were in the range of those for castrated men (<50 ng/dl). Patients treated with bicalutamide had no change of testosterone plasma levels while 17-beta-estradiol increased significantly (p < 0.001 for each comparison with the baseline value). During the study period, there were no significant changes in serum Ca, P, PTH and 25-OHD concentrations in the four groups. BMI increased but not significantly during the study period in both groups of patients (data not shown). 3.1. Biochemical bone markers During treatment period, DPD levels significantly increased in A1 group from baseline after 6 and 12 months and were not significantly modified in A2 subgroup. Observed changes in A1 subgroup were also statistically significant with respect to the A2 subgroup. DPD levels had no significant changes in B1 subgroup from baseline after 6, and 12 months and Table 1 Biochemical parameters at the beginning of the study, at 6 and at 12 months Length of treatment (months) Group A1 (MAB) Calcium and cholecalciferol Group A2 (MAB) Calcium and cholecalciferol plus Neridronate Group B1 (Bicalutamide) Calcium and cholecalciferol Group B2 (Bicalutamide) Calcium and cholecalciferol plus Neridronate Ca (mg/dl) 0 9.6 0.8 9.4 0.6 9.4 0.7 9.3 0.6 6 9.9 0.5 9.5 0.7 9.6 0.6 9.4 0.8 12 9.8 0.8 9.6 0.7 9.8 0.5 9.6 0.7 P (mg/dl) 0 3.4 0.7 3.1 0.6 3.2 0.5 3.3 0.4 6 3.1 0.5 3.4 0.4 3.4 0.3 3.1 0.6 12 3.2 0.5 3.4 0.6 3.2 0.5 3.3 0.7 PTH (pg/ml) 0 45 10 40 13 65 15 46 10 6 40 12 41 15 50 14 45 12 12 39 16 48 14 43 18 40 16 25-OHD (ng/ml) 0 51.9 19.8 54.5 22.5 54.9 17.8 56.3 17.8 6 59.8 25.1 62.5 18.6 63.8 22.2 62.8 25.1 12 61.1 18.2 64.2 25.6 64.1 15.2 67.1 16.2 T (ng/dl) 0 372 35 380 40 472 35 472 35 6 32 6 a 33 4 a 374 22 327 16 12 38 4 a 36 5 a 380 33 318 18 E2 (pg/ml) 0 28 4 27 5 31 3 31 5 6 6 4 a 7 3 a 36 6 37 6 12 5 3 a 6 4 a 43 4 42 5 DPD (pmol/mmol urinary creatinine) 0 15.1 3.9 16.2 5.1 14.7 4.9 14.2 4.8 6 24.8 4.7 a 15.8 3.9 b 14.8 3.3 11.5 3.3 a,c 12 26.1 5.5 a 14.6 4.6 b 15.5 5.5 9.5 3.5 a,c B-ALP (IU/L) 0 23.7 4.7 26.3 5.6 24.7 3.7 25.4 4.1 6 28.3 4.5 a 24.7 3.9 b 25.3 3.5 21.5 3.5 a,c 12 30.0 6.6 a 22.8 4.3 b 26.0 4.6 20.0 3.6 a,c Data are expressed as mean S.D. a Significant comparison with basal values (p < 0.05). b Significant comparison between group A1 and A2 (p < 0.05). c Significant comparison between group B1 and B2 (p < 0.05).

578 C. Magno et al. / European Urology 47 (2005) 575 581 were significantly decreased in B2 subgroup. The changes in B1 subgroup were statistically significant towards the B2 subgroup. Changes in B-ALP levels were similar to those recorded for pyridinium crosslinks. In fact, in A1 subgroup, B-ALP increased from baseline at 6 and 12 months, whereas in A2 subgroup it was substantially unmodified from baseline. These changes in A1 subgroup were also statistically significant with respect to the A2 subgroup. In B1 subgroup, B-ALP showed no significant changes from baseline at 6, and 12 months, whereas in B2 subgroup it was significantly decreased from baseline at 6, and 12 months. These changes in B1 subgroup were also statistically significant with respect to the B2 subgroup. (Fig. 1). 3.2. Bone mineral density All patients showed a T-score less than 2.5 S.D. at baseline. In A1 subgroup, after 12 months, BMD significantly decreased from baseline at the lumbar spine ( 4.9 2.5%, p = 0.002) and total hip ( 1.9 1.5%, p = 0.04). BMD did not significantly change at lumbar spine (p = ns), or at total hip (p = ns) from baseline for patients treated with neridronate (A2 subgroup). Changes in A1 subgroup, at lumbar spine and total hip, were also statistically significant with Fig. 2. Changes in Bone Mineral Density at 12 months of therapy in patients no treated (A1, B1) or treated (A2, B2) with neridronate. #p < 0.05 for comparisons with basal values. respect to the A2 subgroup (p < 0.05). In B1 subgroup, after 12 months, BMD slightly decreased not reaching significance at lumbar spine ( 1.5 1.0%, p = ns) and total hip ( 1.0 0.8%, p = ns). BMD significantly changed at lumbar spine (+2.5 1.2%, p < 0.05), or at total hip (+1.6 0.6%, p < 0.05) in patients treated with neridronate (B2 subgroup). Changes in B1 subgroup, BMD at lumbar spine and total hip, were also statistically significant with respect to B2 subgroup (p < 0.05). In A1 subgroup, after 12 months, BMD decreased both at lumbar spine and total hip, lower than in B1 subgroup (p < 0.001). In B2 subgroup, treated with bicalutamide, calcium, cholecalciferol and neridronate, BMD significantly increased with respect to A2 subgroup (p < 0.001). (Fig. 2). 3.3. Adverse events No relevant side effects due to neridronate were recorded during our study. A transient flu-like syndrome, not requiring treatment, was observed in 3/30 patients (10%) treated with neridronate after the first administration. 4.Discussion Fig. 1. Mean changes in urinary excretion of deoxypyridinoline and serum concentrations of bone alkaline phosphatase in patients no treated (A1, B1) or treated (A2, B2) with neridronate. Measurements of the biochemical bone markers (DPD and B-ALP) at baseline, at 6 months, and at 12 months. Bone loss commonly occurs in men with prostate cancer treated with ADT, and its rate seems to exceed that associated with menopause in women. In patients treated with ADT, markers of bone turnover (DPD and B-ALP) significantly increased and total hip and vertebral BMD markedly decreased [25,26]. Bisphosphonates currently seem to be the most promising therapy in this type of osteoporosis with enhanced turnover. They represent a logical therapy in men who have low BMD at baseline or who develop bone loss during the course of therapy. Two recent papers review the role of

C. Magno et al. / European Urology 47 (2005) 575 581 579 bisphosphonates: Saad et al. state that bisphosphonates act against osteoclasts which affect bone integrity [27], and Bae et al. recommend that bisphosphonate treatment is initiated in men who have osteopenia or osteoporosis [28] The present study shows that neridronate prevents bone loss in men undergoing treatment for prostate cancer with ADT. The markers of bone resorption and bone formation that increased in the group of patients treated with calcium and vitamin D alone, did not show any significant elevation in patients receiving neridronate plus calcium and vitamin D, during the study period remaining substantially stable. This data is different from data reported by Smith et al. [15] who evaluated the effect of two years of treatment with pamidronate in patients in ADT for prostate cancer. Serum B-ALP and osteocalcin concentrations initially decreased in patients treated with pamidronate then approached or returned to baseline levels by 48 weeks, whereas bone resorption markers, urinary DPD and N-Telopeptide initially decreased and then increased exceeding the baseline value after 12 weeks. Concerning BMD in our patients, neridronate was able to prevent bone loss due to ADT, not modifying BMD at any levels. Since low BMD is a determining factor for fracture risk [29], these findings suggest that neridronate may reduce this risk in subjects receiving ADT for treatment of prostate cancer. This data is in accordance with a previous report by Smith et al. [15], who demonstrated that pamidronate similarly prevents bone loss in androgen deprivated patients affected by prostate cancer. ADT can modify body composition. In fact, low levels of testosterone are associated with increase in total body fat and loss of lean body mass. In our study, we did not evaluate body composition, but only BMI. It increased but not significantly in both groups of patients. In patients over 65 years of age with low-normal serum testosterone concentrations, testosterone treatment as compared with placebo did not increase BMD in lumbar spine [30,31]. In uncontrolled studies of patients with congenital or acquired primary or secondary hypogonadism, testosterone-replacement therapy increased BMD [31,32]. To our knowledge, there is little data about prevention and/or treatment of osteoporosis in androgen deprivated patients affected by prostate cancer. Recent studies demonstrate the efficacy of several bisphosphonates such as pamidronate and zoledronic acid, in this condition. Smith et al. [15] reported prevention of bone loss with pamidronate in patients treated by LH-RH analogues for prostatic cancer. Recently, a random placebo controlled study showed that zoledronic acid, a third-generation bisphosphonate indicated for treatment of bone metastases from multiple myeloma and solid tumours, at the dosage of 4 mg intravenously every 3 months, not only prevented bone loss but also increased BMD during ADT for prostate carcinoma [16,17]. Alendronate is the only bisphosphonate approved for treatment of male osteoporosis. Oral alendronate increases BMD and helps to decrease vertebral fracture in subjects with osteoporosis and normal or near normal serum testosterone concentrations [18]. The efficacy of alendronate in hypogonadal men is not known. Neridronate, a bisphosphonate structurally similar to alendronate and pamidronate, has been used successfully in various clinical conditions. Quarterly and intravenously administered, it significantly increased BMD and lowered risk of clinical fracture in adults with osteogenesis imperfecta [23]. Treatment of postmenopausal osteoporosis with 50 mg intravenous neridronate bimonthly results in a clinically relevant increase in BMD, one amongst the largest so far observed using any other bisphosphonate [22]. Moreover, neridronate was effective in decreasing bone turnover parameters in Paget s disease [18 20]. For the first time, our study provides evidence that neridronate Intramuscularly, monthly given, is effective in preventing bone loss in castrated men for prostate cancer. Furthermore, treatment with neridronate was well-tolerated as confirmed by low frequency (5%) and no severity of adverse effects recorded. Our study it is somewhat limited in statistical power because of the small sample size. Larger, additional, prospective studies are needed to evaluate the longterm effects of this bisphosphonate for fracture risk and disease-related outcomes. Finally, as increased bone turnover and low bone density are associated with higher risk of osteoporotic fractures, we suggest that during ADT treatment patients should receive bisphosphonates, like neridronate, to prevent further bone loss and fractures. 5.Conclusion Even if this study is based on a relatively small series of patients, we can conclude that neridronate is an effective treatment in preventing bone loss in men receiving ADT for prostate cancer. We can also confirm in our investigation that bicatulamide does not cause bone loss during prolonged therapy in prostate cancer patients. Neridronate may be administered in patients treated by bicatulamide only in case of evidence of osteoporosis.

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[25] Mittan D, Lee S, Miller E, Perez RC, Basler JW, Bruder JM. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 2002;87:3656 61. [26] Preston DM, Torrens JI, Harding P, Howard RS, Duncan WE, McLeod DG. Androgen deprivation in men with prostate cancer is associated with an increased rate of bone loss. Prostate Cancer Prostatic Dis 2002;5:304 10. [27] Saad F, Schulman CC. Role of Bisphosphonates in Prostate Cancer. Eur Urol 2004;45:26 34. [28] Bae DC, Stein BS. The diagnosis and treatment of osteoporosis in men on androgen deprivation therapy for advanced carcinoma of the prostate. J Urol 2004 Dec;172(6 Pt 1):2137 44. [29] Cummings SR, Black DM, Nevitt MC, Browner WS, Cauley JA, Genant HK, et al. Appendicular bone density and age predict hip fracture in women. JAMA 1990;263:665 8. [30] Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999;84:1966 72. [31] Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 1996;81:4358 65. [32] Finkelstein JS, Klibanski A, Neer RM, Doppelt SH, Rosenthal DI, Segre GV, et al. Increases in bone density during treatment of men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1989;69:776 83. Editorial Comment Fred Saad, Montreal, Canada fredsaad@videotron.ca Bone health and prostate cancer: A new challenge for urologists Bone health related to prostate cancer has become an important area of research. Urologists and other specialists treating patients with prostate cancer need to be aware of the potential bone complications that can arise not only from bone metastases but

C. Magno et al. / European Urology 47 (2005) 575 581 581 also from the accelerated bone loss that may occur in patients treated with androgen deprivation. This is going to be a new challenge for urologists. They will have to become familiar with things like bone mineral density, words like osteopenia and osteoporosis and drugs that may prevent or correct bone loss such as bisphosphonates. Urologists need to be actively involved in this area if they want to continue to play a lead role in the management of prostate cancer. Bisphosphonates such as pamidronate and zoledronic acid have proven to be effective in ADT induced bone loss and other agents are presently being studied in large randomised trials. The authors of this paper have conducted a small study using a new monthly intra muscular bisphosphonate, neridronate, and have shown it to be effective in preventing bone loss in men on ADT. If the results are similar in larger studies this will become another interesting alternative for patients at risk of osteoporosis. With all this new information it will be essential, in the near future, to develop some consensus guidelines. This will eventually help urologists to better evaluate, follow and treat patients on ADT with regards to the question of bone health.