34-1（見本英3）

　Original Contribution
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, Kazushige Hayakawa,2 Shiro Baba1 1 Department of Urology, Kitasato University School of Medicine2 Department of Radiology and Radiation Oncology, Kitasato University School of Medicine3 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, 2.5-5.5 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
long-term ADT,4 and continuous ADT decreases bone Introduction
mineral density (BMD) and increases the risk of bone urrent data from the Prostate Strategic Urologic Bisphosphonates are agents that inhibit the Epidemiology and End Results-Medicare database of the proliferation and differentiation of osteoclasts and repress United States show an increase in recent years in the bone resorption by osteoclasts. Bisphosphonates, such proportion of patients with localized and advanced as alendronate, pamidronate, risedronate, and zoledronic prostate cancer who receive androgen deprivation therapy acid, have already been used as first-line treatment for (ADT).1,2 Data on current prostate cancer treatment from osteoporosis and have also been reported to prevent the the Japan Study Group of Prostate Cancer (J-CaP) shows bone loss caused by ADT.7-9 In addition, studies reporting that primary ADT is chosen to treat localized and 7 and 10 years of experience with risedronate and advanced prostate cancer for 59.0% of patients.3 alendronate, respectively, suggest that long-term Possible adverse events of ADT, which involves treatment with these agents appears to be safe, with no gonadotropin-releasing hormone (GnRH) agonists, are increased risk of fracture or other adverse effects at doses generally related to changing levels of hormones and include hot flushes, loss of muscle mass, erectile Although the long-term efficacy and safety of dysfunction, fatigue, anemia, and osteoporosis.
bisphosphonates have been investigated and documented, Osteoporosis is a particularly serious complication of an increasing number of recent reports draw attention to Received 28 November 2011, accepted 5 January 2012Correspondence to: Masaomi Ikeda, Department of Urology, Kitasato University School of Medicine1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, JapanE-mail: [email protected] a possible correlation between long-term alendronate and mmol of Cr.22 We therefore used urinary NTx of <13.0 the occurrence of atypical insufficiency fractures owing nmol BCE/mmol・Cr as a marker for SSBT (SSBTM).
to what is known as severely suppressed bone turnover The non-SSBTM was defined as having 13.0 nmol BCE/ (SSBT).14-19 In experimental animals, bisphosphonates have been shown to inhibit normal repair of microdamagearising from marked suppression of bone turnover, which, in turn, results in accumulation of microdamage.20 BMD of the posteroanterior lumbar spine and proximal We investigated the incidence of an SSBT marker femur was determined by DXA using a Hologic QDR (SSBTM) associated with long-term risedronate treatment 4500A/SL densitometer (Hologic, Waltham, MA, USA) for patients with prostate cancer receiving ADT. In in all patients. The DXA device was standardized and addition, predictive factors were analyzed in the patients calibrated using the Anthropomorphic Spine Phantom (Hologic). In vivo precision assessment was performedaccording to the International Society for ClinicalDensitometry recommendation.23 By determining Materials and Methods
precision error (0.012 g/cm2) and least significant change (0.034 g/cm2 at 95% confidence interval [95% CI]), it Study participants were recruited at Kitasato University was confirmed that sufficiently precise assessment was Hospital, and all patients had prostate cancer and had not done in our hospital. Serum concentrations of testosterone previously received any hormonal therapy (hormone (SRL, Tokyo) were measured by radioimmunoassay.
naïve). From April 2004 to April 2007, 38 patients who Urine concentrations of NTx (SRL) were measured by had received risedronate (2.5 mg/d) simultaneously with ADT (combined GnRH agonist and antiandrogen We monitored for adverse events every 3 months treatment or monotherapy with a GnRH agonist) for more through physical examination as well as assays for serum than 3 years were enrolled in this study. Men with creatinine/calcium and other chemical variables. Adverse metabolic bone disease, history of treatment for events were scored using the National Cancer Institute osteoporosis, a serum calcium level <8.4 mg/dL or >10.6 Common Terminology Criteria for Adverse Events, mg/dL, or a serum creatinine (Cr) concentration >1.5 mg/dL were excluded. BMD of the posteroanteriorlumbar spine (L2-4) and proximal femur was determined by dual-energy x-ray absorptiometry (DXA). T score The primary study endpoint was to confirm patients with was calculated from a Japanese male reference database.21Patients with a T score of ≤2.5 were excluded. All patientsprovided written informed consent.
Table 1. Patient characteristics (n = 38)
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 ALP, alkaline phosphatase; BMD, bone mineral density; SD, According to the Japanese Osteoporosis Society standard deviation; PSA, prostate-specific antigen; NTx, cross- guidelines, the normal range of urinary NTx in males is linked N-telopeptide of type I collagen; BCE, bone collagen 13.0-66.2 nmol bone collagen equivalents (BCE) per Urinary NTx of long-term risedronate treatment SSBTM based on the defining criteria. Statistical analyses mmol・Cr, a statistically significant difference (P = 0.021).
were performed by the Mann-Whitney test using The mean BMD and T score of the posteroanterior lumbar StatView, version 5.0 (SAS Institute, Cary, NC, USA).
spine and the femoral neck were not significantly different All P values were 2-sided, and P < 0.05 was considered between the baseline and SSBT. The mean time from statistically significant. Values are reported as mean ± beginning of the risedronate treatment to SSBTM standard deviation (SD) unless otherwise specified.
detection was 4.5 years (range, 2.5-5.5 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 The clinical characteristics of all entry patients are listed years in the SSBTM group compared with 75.1 ± 6.4 in Table 1. Of the 38 patients, the mean age was 74.5 years in the non-SSBTM group (P = 0.039). The mean years (range, 56-86 years), and the mean PSA was 51.2 PSA was 101.5 ± 158.6 ng/mL in the SSBTM group ± 82.9 ng/mL. The mean administering duration of and 45.3 ± 71.2 ng/mL in the non-SSBT group. These risedronate was 4.2 years (range, 3.0-4.8 years). The differences did not reach statistical significance (P = mean urinary NTx at the baseline was 26.3 ± 14.2 nmol 0.642). Moreover, treatment duration of risedronate, BCE/mmol・Cr. The mean BMD of the posteroanterior hemoglobin, ALP, calcium, and serum testosterone were lumbar spine and femoral neck was 1.002 ± 0.25 g/cm2 not statistically significant factors between the groups.
and 0.876 ± 0.15 g/cm2, respectively.
During treatment, adverse events related to risedronate Among the 38 patients, SSBTM was confirmed in 4 were never higher than grade 3 (NCI-CTCAE v.3.0).
patients (11%) based on the defining criterion. The Neither severe gastrointestinal complaints nor outcome data comparison between baseline and SSBTM osteonecrosis of the jaw were reported in any of the detection are listed in Table 2. Of 4 patients, the mean patients. There were no cases of insufficiency fracture in urinary NTx at the baseline was 18.8 ± 3.24 nmol BCE/ the patients who had confirmed SSBTM. However, 2 mmol・Cr and with SSBT was 9.8 ± 2.86 nmol BCE/ 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 )
SSBTM, marker for severely suppressed bone turnover; NS, not significant Table 3. Comparison of predictive factors between SSBTM group and non-SSBTM group
due to adverse events, were similar between eachtreatment and its respective control arm. However, recentreports suggested a link between long-term alendronate Discussion
therapy and the development of atypical insufficiency Prostate cancer is the second most frequently diagnosed fractures.14-19 This is thought to be due to SSBT leading cancer and the sixth leading cause of male cancer death to impaired bone remodeling, accumulation of in the world, accounting for 14% (903,500) of the total microdamage in bone and increased skeletal fragility.
new cancer cases in 2008.24 Incidence rates vary by Odvina et al.19 reported on 9 patients who had sustained more than 25-fold worldwide, with the highest rates spontaneous, nontraumatic and nonpathologic fractures recorded primarily in the developed countries of Oceania, while receiving long-term alendronate therapy (>3 years).
Europe, and North America, largely because of the wide Furthermore, Goh et al.18 and Kwek et al.17 reported 17 utilization of PSA testing that detects clinically important patients receiving long-term alendronate therapy tumors. In addition, incidence of prostate cancer and (average, 4.8 years) with low-energy subtrochanteric related mortality are rapidly increasing in Japan.
Although ADT is usually given to patients with locally Clinically, SSBT is characterized by spontaneous or advanced prostate cancer or metastasis not only in Japan atraumatic fractures involving the skeletal areas that are but also in the United States, the frequency of ADT being rich in cortical bone, with fractures occurring at atypical used to treat localized disease is also increasing in clinical sites for patients with osteoporosis, such as the femoral practice.3 Furthermore, several randomized controlled shaft, pubis, or ischium, during long-term alendronate trials show an overall survival benefit of neoadjuvant therapy. SSBT is histologically defined by a reduced and adjuvant ADT, and this combination treatment has osteoblastic surface and an osteoclastic surface with had a large impact.25-27 Therefore, the number of patients decreased or absent tetracycline labeling.19 These undergoing ADT may increase worldwide.
histomorphometric findings are similar to those of Recent studies suggest that starting ADT earlier in adynamic bone disease in patients with renal failure.33 the course of prostate cancer may improve survival, but Most patients displayed low urinary NTx and serum this approach will also prolong the hypogonadal state osteocalcin, but serum bone-specific ALP was and could thus increase the risk of osteoporosis. With long-term ADT, osteoporosis is an important clinical issue In the present study, SSBTM was revealed in 4 of the for men. Men are estimated to lose BMD at a rate of 38 patients (11%) with prostate cancer who received long- ≤1% annually with advancing age, and 1 in 8 men >50 term risedronate treatment with ADT during a follow-up years old will experience an osteoporosis-related fracture of more than 3 years. The mean age in the SSBTM group in their lifetime.8 Shahinian et al.6 reported that of men and non-SSBTM group was 69.5 ± 1.2 years and 75.1 surviving ≥5 years after the diagnosis of prostate cancer, ± 6.4 years, respectively (P = 0.039). To our knowledge, 19.4% of those who received ADT had a fracture this is the first report to find a high risk of SSBTM in compared with 12.6% of those not receiving ADT. The benefit of bisphosphonate therapy for male osteoporosis The present study was limited by the data on SSBTM has been suggested by previous reports.28 A second- not being from a randomized trial. Additional limitations generation intravenous bisphosphonate (pamidronate) include the small sample size, lack of bone biopsy and was shown to inhibit the decrease of BMD in prostate relatively short follow-up. However, around 10% of cancer patients receiving ADT,9 while a third-generation patients with prostate cancer had SSBTM during ADT intravenous bisphosphonate (zoledronic acid) actually with long-term risedronate treatment. Thus, we must not reversed BMD decline.29 Another third-generation oral only take care of osteoporosis, but also monitor a patient's bisphosphonate (risedronate) was shown to recover bone bone turnover. This may be critical given the potential loss in patients with prostate cancer undergoing ADT.8 for a long life span in patients with prostate cancer.
T h e l o n g - t e r m t o l e r a b i l i t y a n d s a f e t y o f In conclusion, SSBTM associated with long-term bisphosphonates have been widely studied and risedronate treatment for patients with prostate cancer documented.10,11,30-32 After long-term treatment with receiving ADT was confirmed. These results suggest alendronate, risedronate, or zoledronic acid, the incidence that careful monitoring of bone turnover markers is of overall adverse events, serious adverse events, or drug- needed during long-term bisphosphonate treatment.
related adverse events, as well as the withdrawal rates Urinary NTx of long-term risedronate treatment 12. Ensrud KE, Barrett-Connor EL, Schwartz A, et al.
Acknowledgments
Randomized trial of effect of alendronate continuation We thank Yukitoshi Ohta, R.T., Erina Sato, C.R.C., and versus discontinuation in women with low BMD: Mineko Uemae, R.T. for their helpful data management.
results from the Fracture Intervention Trial long-termextension. J Bone Miner Res 2004; 19: 1259-69.
13. Bone HG, Hosking D, Devogelaer JP, et al. Ten References
years' experience with alendronate for osteoporosisin postmenopausal women. N Engl J Med 2004; 1. Kawakami J, Cowan JE, Elkin EP, et al. Androgen- deprivation therapy as primary treatment for localized 14. Park-Wyllie LY, Mamdani MM, Juurlink DN, et al.
prostate cancer: data from Cancer of the Prostate Bisphosphonate use and the risk of subtrochanteric Strategic Urologic Research Endeavor (CaPSURE).
or femoral shaft fractures in older women. JAMA 2. Shahinian VB, Kuo YF, Freeman JL, et al. Increasing 15. Sayed-Noor AS, Sjoden GO. Case reports: two use of gonadotropin-releasing hormone agonists for femoral insufficiency fractures after long-term the treatment of localized prostate carcinoma. Cancer alendronate therapy. Clin Orthop Relat Res 2009; 3. Hinotsu S, Akaza H, Usami M, et al. Current status 16. Visekruna M, Wilson D, McKiernan FE. Severely of endocrine therapy for prostate cancer in Japan suppressed bone turnover and atypical skeletal analysis of primary androgen deprivation therapy on fragility. J Clin Endocrinol Metab 2008; 93: 2948- the basis of data collected by J-CaP. Jpn J Clin 17. Kwek EB, Goh SK, Koh JS, et al. An emerging 4. Holzbeierlein JM, Castle EP, Thrasher JB.
pattern of subtrochanteric stress fractures: a long- Complications of androgen-deprivation therapy for term complication of alendronate therapy? Injury prostate cancer. Clin Prostate Cancer 2003; 2: 147- 18. Goh SK, Yang KY, Koh JS, et al. Subtrochanteric 5. Wadhwa VK, Weston R, Parr NJ. Frequency of insufficiency fractures in patients on alendronate zoledronic acid to prevent further bone loss in therapy: a caution. J Bone Joint Surg Br 2007; 89: osteoporotic patients undergoing androgen deprivation therapy for prostate cancer. BJU Int 2010; 19. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication 6. Shahinian VB, Kuo YF, Freeman JL, et al. Risk of of alendronate therapy. J Clin Endocrinol Metab fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352: 154-64.
20. Li J, Mashiba T, Burr DB. Bisphosphonate treatment 7. Satoh T, Kimura M, Matsumoto K, et al. Single suppresses not only stochastic remodeling but also infusion of zoledronic acid to prevent androgen the targeted repair of microdamage. Calcif Tissue deprivation therapy-induced bone loss in men with hormone-naive prostate carcinoma. Cancer 2009; 21. Orimo H, Hayashi Y, Fukunaga M, et al. Diagnostic criteria for primary osteoporosis: year 2000 revision.
8. Izumi K, Mizokami A, Sugimoto K, et al. Risedronate J Bone Miner Metab 2001; 19: 331-7.
recovers bone loss in patients with prostate cancer 22. Fukunaga M, Sone T, Tomomitsu T, et al. Reference undergoing androgen-deprivation therapy. Urology ranges for markers of bone turnover: gender and age.
Osteoporos Jpn 2001; 9: 265-71 (in Japanese).
9. Smith MR, McGovern FJ, Zietman AL, et al.
23. Baim S, Wilson CR, Lewiecki EM, et al. Precision Pamidronate to prevent bone loss during androgen- assessment and radiation safety for dual-energy X- deprivation therapy for prostate cancer. N Engl J ray absorptiometry: position paper of the International Society for Clinical Densitometry. J Clin Densitom 10. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years 24. Jemal A, Bray F, Center MM, et al. Global cancer of treatment: the Fracture Intervention Trial Long- statistics. CA Cancer J Clin 2011; 61: 69-90.
term Extension (FLEX):a randomized trial. JAMA 25. Roach M, 3rd, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and 11. Mellstrom DD, Sorensen OH, Goemaere S, et al.
external-beam radiotherapy for locally advanced Seven years of treatment with risedronate in women prostate cancer: long-term results of RTOG 8610. J with postmenopausal osteoporosis. Calcif Tissue Int 26. D'Amico AV, Denham JW, Bolla M, et al. Short- vs 30. Devogelaer JP, Brown JP, Burckhardt P, et al.
long-term androgen suppression plus external beam Zoledronic acid efficacy and safety over five years radiation therapy and survival in men of advanced in postmenopausal osteoporosis. Osteoporos Int age with node-negative high-risk adenocarcinoma of the prostate. Cancer 2007; 109: 2004-10.
31. Sorensen OH, Crawford GM, Mulder H, et al. Long- 27. Bolla M, Collette L, Blank L, et al. Long-term results term efficacy of risedronate: a 5-year placebo- with immediate androgen suppression and external controlled clinical experience. Bone 2003; 32: 120- irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised 32. Ott SM. Long-term safety of bisphosphonates. J trial. Lancet 2002; 360: 103-6.
Clin Endocrinol Metab 2005; 90: 1897-9.
28. Saad F, Abrahamsson PA, Miller K. Preserving bone 33. Parfitt AM. Renal bone disease: a new conceptual health in patients with hormone-sensitive prostate f r a m e w o r k f o r t h e i n t e r p r e t a t i o n o f b o n e cancer: the role of bisphosphonates. BJU Int 2009; histomorphometry. Curr Opin Nephrol Hypertens 29. Smith MR, Eastham J, Gleason DM, et al.
Randomized controlled trial of zoledronic acid toprevent bone loss in men receiving androgendeprivation therapy for nonmetastatic prostate cancer.
J Urol 2003; 169: 2008-12.

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