Department of Urology, Kitasato University School of Medicine 2

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1 Original Contribution Kitasato Med J 2012; 42: The impact of urinary cross-linked N-telopeptide of type I collagen in patients with prostate cancer receiving long-term risedronate treatment and androgen-deprivation therapy Masaomi Ikeda, 1 Takefumi Satoh, 1 Ken-ichi Tabata, 1 Kazumasa Matsumoto, 1 Hiromichi Ishiyama, 2 Yusuke Inoue, 3 Kazushige Hayakawa, 2 Shiro Baba 1 1 Department of Urology, Kitasato University School of Medicine 2 Department of Radiology and Radiation Oncology, Kitasato University School of Medicine 3 Depertment of Diagnostic Radiology, Kitasato University School of Medicine Objective: To investigate predictive factors and the incidence of a marker for severely suppressed bone turnover (SSBT) associated with long-term risedronate treatment for patients with prostate cancer receiving androgen deprivation therapy (ADT). Methods: From April 2004 to April 2007, 38 patients who had received risedronate (2.5 mg/d) simultaneously with ADT for more than 3 years were enrolled in this study. Baseline assessments in all patients included urinary cross-linked N-telopeptide of type I collagen (NTx) and bone mineral density, with measurements repeated every 6 months. Urinary NTx falling to <13.0 nmol bone collagen equivalents per mmol of creatinine was used as a marker for SSBT (SSBTM). Results: SSBTM was confirmed in 4 patients (11%). The mean time from beginning the risedronate treatment to detectable SSBTM was 4.5 years (range, years). The mean (SD) age was 69.5 (1.2) years in the SSBTM group compared with 75.1 (6.4) years in the non-ssbtm group (P = 0.039). Conclusions: SSBTM associated with long-term treatment with risedronate for patients with prostate cancer receiving ADT was confirmed. The results suggest that careful monitoring of bone turnover markers is needed during long-term bisphosphonate treatment, especially in younger patients. Key words: prostate cancer, androgen deprivation therapy, bone turnover marker Introduction C urrent data from the Prostate Strategic Urologic Research Endeavour (CaPSURE) and the Epidemiology and End Results-Medicare database of the United States show an increase in recent years in the proportion of patients with localized and advanced prostate cancer who receive androgen deprivation therapy (ADT). 1,2 Data on current prostate cancer treatment from the Japan Study Group of Prostate Cancer (J-CaP) shows that primary ADT is chosen to treat localized and advanced prostate cancer for 59.0% of patients. 3 Possible adverse events of ADT, which involves gonadotropin-releasing hormone (GnRH) agonists, are generally related to changing levels of hormones and include hot flushes, loss of muscle mass, erectile dysfunction, fatigue, anemia, and osteoporosis. Osteoporosis is a particularly serious complication of long-term ADT, 4 and continuous ADT decreases bone mineral density (BMD) and increases the risk of bone fracture. 5,6 Bisphosphonates are agents that inhibit the proliferation and differentiation of osteoclasts and repress bone resorption by osteoclasts. Bisphosphonates, such as alendronate, pamidronate, risedronate, and zoledronic acid, have already been used as first-line treatment for osteoporosis and have also been reported to prevent the bone loss caused by ADT. 7-9 In addition, studies reporting 7 and 10 years of experience with risedronate and alendronate, respectively, suggest that long-term treatment with these agents appears to be safe, with no increased risk of fracture or other adverse effects at doses used to treat osteoporosis Although the long-term efficacy and safety of bisphosphonates have been investigated and documented, an increasing number of recent reports draw attention to Received 28 November 2011, accepted 5 January 2012 Correspondence to: Masaomi Ikeda, Department of Urology, Kitasato University School of Medicine Kitasato, Minami-ku, Sagamihara, Kanagawa , Japan ikeda.masaomi@grape.plala.or.jp 51

2 Ikeda, et al. a possible correlation between long-term alendronate and the occurrence of atypical insufficiency fractures owing to what is known as severely suppressed bone turnover (SSBT) In experimental animals, bisphosphonates have been shown to inhibit normal repair of microdamage arising from marked suppression of bone turnover, which, in turn, results in accumulation of microdamage. 20 We investigated the incidence of an SSBT marker (SSBTM) associated with long-term risedronate treatment for patients with prostate cancer receiving ADT. In addition, predictive factors were analyzed in the patients who had a confirmed SSBTM. Materials and Methods Patients Study participants were recruited at Kitasato University Hospital, and all patients had prostate cancer and had not previously received any hormonal therapy (hormone naïve). From April 2004 to April 2007, 38 patients who had received risedronate (2.5 mg/d) simultaneously with ADT (combined GnRH agonist and antiandrogen treatment or monotherapy with a GnRH agonist) for more than 3 years were enrolled in this study. Men with metabolic bone disease, history of treatment for osteoporosis, a serum calcium level <8.4 mg/dl or >10.6 mg/dl, or a serum creatinine (Cr) concentration >1.5 mg/dl were excluded. BMD of the posteroanterior lumbar spine (L2-4) and proximal femur was determined by dual-energy x-ray absorptiometry (DXA). T score was calculated from a Japanese male reference database. 21 Patients with a T score of 2.5 were excluded. All patients provided written informed consent. mmol of Cr. 22 We therefore used urinary NTx of <13.0 nmol BCE/mmol Cr as a marker for SSBT (SSBTM). The non-ssbtm was defined as having 13.0 nmol BCE/ mmol Cr. Study evaluation BMD of the posteroanterior lumbar spine and proximal femur was determined by DXA using a Hologic QDR 4500A/SL densitometer (Hologic, Waltham, MA, USA) in all patients. The DXA device was standardized and calibrated using the Anthropomorphic Spine Phantom (Hologic). In vivo precision assessment was performed according to the International Society for Clinical Densitometry recommendation. 23 By determining precision error (0.012 g/cm 2 ) and least significant change (0.034 g/cm 2 at 95% confidence interval [95% CI]), it was confirmed that sufficiently precise assessment was done in our hospital. Serum concentrations of testosterone (SRL, Tokyo) were measured by radioimmunoassay. Urine concentrations of NTx (SRL) were measured by enzyme immunoassay. We monitored for adverse events every 3 months through physical examination as well as assays for serum creatinine/calcium and other chemical variables. Adverse events were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (NCI-CTCAE v.3.0). Statistical analysis The primary study endpoint was to confirm patients with Table 1. Patient characteristics (n = 38) Study design Eligible patients received risedronate (2.5 mg/d) simultaneously with the initiation of ADT. At baseline, the BMD of all patients was assessed by DXA and urinary cross-linked N-telopeptide of type I collagen (NTx) was measured; tests were repeated every 6 months. Serum testosterone and prostate-specific antigen (PSA) were measured at baseline. Serum calcium, alkaline phosphatase (ALP) and other chemical variables were monitored every 3 months. Urine samples for measurement of bone turnover markers were obtained in the morning. Definition According to the Japanese Osteoporosis Society guidelines, the normal range of urinary NTx in males is nmol bone collagen equivalents (BCE) per 52 Characteristics Mean ± SD Age, years (range) 74.5 (56-86) PSA, ng/ml 51.2 ± 82.9 Hemoglobin, g/dl 13.5 ± 1.1 ALP, IU/L 231 ± 68 Calcium, mg/dl 9.2 ± 0.4 Serum testosterone, ng/ml 4.80 ± 1.47 Urinary NTx, nmol BCE/mmol Cr 26.3 ± 14.2 BMD, g/cm 2 Posteroanterior lumbar spine ± 0.25 Femoral neck ± 0.15 T score Posteroanterior lumbar spine ± 1.97 Femoral neck ± 1.08 ALP, alkaline phosphatase; BMD, bone mineral density; SD, standard deviation; PSA, prostate-specific antigen; NTx, crosslinked N-telopeptide of type I collagen; BCE, bone collagen equivalents; Cr, creatinine

3 Urinary NTx of long-term risedronate treatment SSBTM based on the defining criteria. Statistical analyses were performed by the Mann-Whitney test using StatView, version 5.0 (SAS Institute, Cary, NC, USA). All P values were 2-sided, and P < 0.05 was considered statistically significant. Values are reported as mean ± standard deviation (SD) unless otherwise specified. Results The clinical characteristics of all entry patients are listed in Table 1. Of the 38 patients, the mean age was 74.5 years (range, years), and the mean PSA was 51.2 ± 82.9 ng/ml. The mean administering duration of risedronate was 4.2 years (range, years). The mean urinary NTx at the baseline was 26.3 ± 14.2 nmol BCE/mmol Cr. The mean BMD of the posteroanterior lumbar spine and femoral neck was ± 0.25 g/cm 2 and ± 0.15 g/cm 2, respectively. Among the 38 patients, SSBTM was confirmed in 4 patients (11%) based on the defining criterion. The outcome data comparison between baseline and SSBTM detection are listed in Table 2. Of 4 patients, the mean urinary NTx at the baseline was 18.8 ± 3.24 nmol BCE/ mmol Cr and with SSBT was 9.8 ± 2.86 nmol BCE/ mmol Cr, a statistically significant difference (P = 0.021). The mean BMD and T score of the posteroanterior lumbar spine and the femoral neck were not significantly different between the baseline and SSBT. The mean time from beginning of the risedronate treatment to SSBTM detection was 4.5 years (range, years). A comparison of the factors related to SSBTM is shown in Table 3. Of the factors evaluated, only the age differed significantly. The mean age was 69.5 ± 1.2 years in the SSBTM group compared with 75.1 ± 6.4 years in the non-ssbtm group (P = 0.039). The mean PSA was ± ng/ml in the SSBTM group and 45.3 ± 71.2 ng/ml in the non-ssbt group. These differences did not reach statistical significance (P = 0.642). Moreover, treatment duration of risedronate, hemoglobin, ALP, calcium, and serum testosterone were not statistically significant factors between the groups. During treatment, adverse events related to risedronate were never higher than grade 3 (NCI-CTCAE v.3.0). Neither severe gastrointestinal complaints nor osteonecrosis of the jaw were reported in any of the patients. There were no cases of insufficiency fracture in the patients who had confirmed SSBTM. However, 2 patients received palliative radiation therapy to treat pain Table 2. Outcome data comparison between baseline and urinary NTx of <13.0 nmol BCE/mmol Cr as a SSBTM (n = 4 ) Variable Baseline Mean ± SD SSBTM Mean ± SD P value NTx, nmol BCE/mmol Cr 18.8 ± ± BMD, g/cm 2 Posteroanterior lumbar spine ± ± 0.15 NS Femoral neck ± ± 0.13 NS T score Posteroanterior lumbar spine 0.95 ± ± 2.11 NS Femoral neck 0.15 ± ± 0.97 NS SSBTM, marker for severely suppressed bone turnover; NS, not significant Table 3. Comparison of predictive factors between SSBTM group and non-ssbtm group Variable SSBTM (n = 4) non-ssbtm (n = 34) Mean ± SD Mean ± SD P value Age 69.5 ± ± Treatment duration of risedronate 4.2 ± ±0.4 NS PSA ± ±71.2 NS Hemoglobin 13.3 ± ±1.2 NS ALP 176 ± ±67 NS Calcium 9.1 ± ±0.4 NS Serum testosterone 4.21 ± ±1.53 NS 53

4 Ikeda, et al. relief for bone metastases. Discussion Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of male cancer death in the world, accounting for 14% (903,500) of the total new cancer cases in Incidence rates vary by more than 25-fold worldwide, with the highest rates recorded primarily in the developed countries of Oceania, Europe, and North America, largely because of the wide utilization of PSA testing that detects clinically important tumors. In addition, incidence of prostate cancer and related mortality are rapidly increasing in Japan. Although ADT is usually given to patients with locally advanced prostate cancer or metastasis not only in Japan but also in the United States, the frequency of ADT being used to treat localized disease is also increasing in clinical practice. 3 Furthermore, several randomized controlled trials show an overall survival benefit of neoadjuvant and adjuvant ADT, and this combination treatment has had a large impact Therefore, the number of patients undergoing ADT may increase worldwide. Recent studies suggest that starting ADT earlier in the course of prostate cancer may improve survival, but this approach will also prolong the hypogonadal state and could thus increase the risk of osteoporosis. With long-term ADT, osteoporosis is an important clinical issue for men. Men are estimated to lose BMD at a rate of 1% annually with advancing age, and 1 in 8 men >50 years old will experience an osteoporosis-related fracture in their lifetime. 8 Shahinian et al. 6 reported that of men surviving 5 years after the diagnosis of prostate cancer, 19.4% of those who received ADT had a fracture compared with 12.6% of those not receiving ADT. The benefit of bisphosphonate therapy for male osteoporosis has been suggested by previous reports. 28 A secondgeneration intravenous bisphosphonate (pamidronate) was shown to inhibit the decrease of BMD in prostate cancer patients receiving ADT, 9 while a third-generation intravenous bisphosphonate (zoledronic acid) actually reversed BMD decline. 29 Another third-generation oral bisphosphonate (risedronate) was shown to recover bone loss in patients with prostate cancer undergoing ADT. 8 The long-term tolerability and safety of bisphosphonates have been widely studied and documented. 10,11,30-32 After long-term treatment with alendronate, risedronate, or zoledronic acid, the incidence of overall adverse events, serious adverse events, or drugrelated adverse events, as well as the withdrawal rates due to adverse events, were similar between each treatment and its respective control arm. However, recent reports suggested a link between long-term alendronate therapy and the development of atypical insufficiency fractures This is thought to be due to SSBT leading to impaired bone remodeling, accumulation of microdamage in bone and increased skeletal fragility. Odvina et al. 19 reported on 9 patients who had sustained spontaneous, nontraumatic and nonpathologic fractures while receiving long-term alendronate therapy (>3 years). Furthermore, Goh et al. 18 and Kwek et al. 17 reported 17 patients receiving long-term alendronate therapy (average, 4.8 years) with low-energy subtrochanteric fractures of similar configuration. Clinically, SSBT is characterized by spontaneous or atraumatic fractures involving the skeletal areas that are rich in cortical bone, with fractures occurring at atypical sites for patients with osteoporosis, such as the femoral shaft, pubis, or ischium, during long-term alendronate therapy. SSBT is histologically defined by a reduced osteoblastic surface and an osteoclastic surface with decreased or absent tetracycline labeling. 19 These histomorphometric findings are similar to those of adynamic bone disease in patients with renal failure. 33 Most patients displayed low urinary NTx and serum osteocalcin, but serum bone-specific ALP was inconsistent. In the present study, SSBTM was revealed in 4 of the 38 patients (11%) with prostate cancer who received longterm risedronate treatment with ADT during a follow-up of more than 3 years. The mean age in the SSBTM group and non-ssbtm group was 69.5 ± 1.2 years and 75.1 ± 6.4 years, respectively (P = 0.039). To our knowledge, this is the first report to find a high risk of SSBTM in younger patients. The present study was limited by the data on SSBTM not being from a randomized trial. Additional limitations include the small sample size, lack of bone biopsy and relatively short follow-up. However, around 10% of patients with prostate cancer had SSBTM during ADT with long-term risedronate treatment. Thus, we must not only take care of osteoporosis, but also monitor a patient's bone turnover. This may be critical given the potential for a long life span in patients with prostate cancer. In conclusion, SSBTM associated with long-term risedronate treatment for patients with prostate cancer receiving ADT was confirmed. These results suggest that careful monitoring of bone turnover markers is needed during long-term bisphosphonate treatment. 54

5 Urinary NTx of long-term risedronate treatment Acknowledgments We thank Yukitoshi Ohta, R.T., Erina Sato, C.R.C., and Mineko Uemae, R.T. for their helpful data management. References 1. Kawakami J, Cowan JE, Elkin EP, et al. Androgendeprivation therapy as primary treatment for localized prostate cancer: data from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). Cancer 2006; 106: Shahinian VB, Kuo YF, Freeman JL, et al. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005; 103: Hinotsu S, Akaza H, Usami M, et al. Current status of endocrine therapy for prostate cancer in Japan analysis of primary androgen deprivation therapy on the basis of data collected by J-CaP. Jpn J Clin Oncol 2007; 37: Holzbeierlein JM, Castle EP, Thrasher JB. Complications of androgen-deprivation therapy for prostate cancer. Clin Prostate Cancer 2003; 2: Wadhwa VK, Weston R, Parr NJ. Frequency of zoledronic acid to prevent further bone loss in osteoporotic patients undergoing androgen deprivation therapy for prostate cancer. BJU Int 2010; 105: Shahinian VB, Kuo YF, Freeman JL, et al. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352: Satoh T, Kimura M, Matsumoto K, et al. Single infusion of zoledronic acid to prevent androgen deprivation therapy-induced bone loss in men with hormone-naive prostate carcinoma. Cancer 2009; 115: Izumi K, Mizokami A, Sugimoto K, et al. Risedronate recovers bone loss in patients with prostate cancer undergoing androgen-deprivation therapy. Urology 2009; 73: Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgendeprivation therapy for prostate cancer. N Engl J Med 2001; 345: Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Longterm Extension (FLEX):a randomized trial. JAMA 2006; 296: Mellstrom DD, Sorensen OH, Goemaere S, et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int 2004; 75: Ensrud KE, Barrett-Connor EL, Schwartz A, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension. J Bone Miner Res 2004; 19: Bone HG, Hosking D, Devogelaer JP, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004; 350: Park-Wyllie LY, Mamdani MM, Juurlink DN, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA 2011; 305: Sayed-Noor AS, Sjoden GO. Case reports: two femoral insufficiency fractures after long-term alendronate therapy. Clin Orthop Relat Res 2009; 467: Visekruna M, Wilson D, McKiernan FE. Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab 2008; 93: Kwek EB, Goh SK, Koh JS, et al. An emerging pattern of subtrochanteric stress fractures: a longterm complication of alendronate therapy? Injury 2008; 39: Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 2007; 89: Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005; 90: Li J, Mashiba T, Burr DB. Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage. Calcif Tissue Int 2001; 69: Orimo H, Hayashi Y, Fukunaga M, et al. Diagnostic criteria for primary osteoporosis: year 2000 revision. J Bone Miner Metab 2001; 19: Fukunaga M, Sone T, Tomomitsu T, et al. Reference ranges for markers of bone turnover: gender and age. Osteoporos Jpn 2001; 9: (in Japanese). 23. Baim S, Wilson CR, Lewiecki EM, et al. Precision assessment and radiation safety for dual-energy X- ray absorptiometry: position paper of the International Society for Clinical Densitometry. J Clin Densitom 2005; 8: Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 61: Roach M, 3rd, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG J Clin Oncol 2008; 26:

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