New Tools for the Urologist in the Management of Patients with Bone Metastases

european urology supplements 6 (2007) 689 694 available at www.sciencedirect.com journal homepage: www.europeanurology.com New Tools for the Urologist in the Management of Patients with Bone Metastases Bob Djavan * Department of Urology, University Hospital Vienna, AKH, Urologie, Ebene 8D, Währinger Gürtel 18 20, 1090 Vienna, Austria Article info Keywords: Androgen-deprivation therapy Bone metastases Bone scan Prostate cancer Prostate-specific antigen Abstract Objectives: Bone metastases are common among patients with hormone-refractory prostate cancer and advanced renal cell carcinoma. Moreover, androgen-deprivation therapy (ADT) in patients with early prostate cancer has been associated with bone loss. Current guidelines for monitoring and managing bone health in patients with prostate cancer are evolving to optimize patient screening and treatment. Methods: Medline keyword searches and reviews of presentations from recent international symposia were performed to identify new tools for screening for bone metastases. In addition, guidelines and consensus recommendations were reviewed to identify bone health issues and their management in patients with genitourinary cancers. Results: Malignant bone disease contributes heavily to the burden of disease in patients with advanced prostate cancer. Furthermore, fractures are associated with decreased survival. The introduction of zoledronic acid has extended the skeletal health benefits of bisphosphonate therapy to the genitourinary cancer setting. Diagnosis of bone metastases while patients are still asymptomatic could allow the initiation of therapy before skeletal complications occur, thereby possibly delaying their onset. Recent analyses have identified risk factors for metastasis to bone, allowing urologists to better mobilize potentially limited resources for bone scans in their clinics. Moreover, algorithms for monitoring and treating bone loss in patients undergoing ADT may allow early detection and treatment of bone mineral density declines, thereby preserving patients functional independence throughout the continuum of care. Conclusions: The introduction of zoledronic acid and updated monitoring and treatment algorithms may aid in the maintenance of bone health in patients with genitourinary cancers. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel. +43 1 40400/2615; Fax: +43 1 4089966. E-mail address: bdjavan@hotmail.com. 1569-9056/$ see front matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2007.03.002

690 european urology supplements 6 (2007) 689 694 1. New tools for the urologist in the management of patients with bone metastases Monitoring and treating patients during androgendeprivation therapy (ADT) after initial treatment with curative intent poses several challenges to the treating urologist. Maintenance of bone health during ADT is an emerging concern. Although the optimal detection methodologies for recurrent disease and implementation of additional therapies have yet to be established, it is becoming increasingly apparent that early detection and treatment of bone loss and bone metastases may be feasible and beneficial [1]. It is now recognized that patients receiving ADT may experience a progressive decrease in bone mineral density (BMD) that results in an increased risk of fractures [2 6] (Fig. 1 [6]). Recommendations from multidisciplinary expert panels have outlined monitoring strategies for BMD loss during ADT [7 9], which may allow optimal utilization of limited resources such as dual-energy X-ray absorptiometry scanning (Fig. 2 [7]). However, there is currently no consensus on the optimal therapeutic approach for patients who experience ADT-associated bone loss. Behavioral modification and dietary supplementation are important first steps for all patients experiencing bone loss, but these measures alone may not be sufficient to maintain BMD in some patients undergoing ADT [7], and antiresorptive therapy with bisphosphonates may be needed to preserve bone health. Currently there is no consensus on optimal treatment selection; however, among bisphosphonates tested, zoledronic acid (4 mg via 15-min infusion) has demonstrated the most consistent efficacy, not only preventing bone loss but also substantially increasing BMD above baseline values in multiple clinical trials in patients receiving ADT for nonmetastatic prostate cancer or prostate cancer with bone metastases [9 11]. Moreover, the increased bone metabolism associated with ADT has also been associated with an increased risk of metastasis to bone in an animal model, and treatment with zoledronic acid significantly reduced bone metabolism and the incidence of bone metastasis in this setting [12]. A clinical study is currently under way to explore whether early use of zoledronic acid can prevent metastasis to bone in patients with prostate cancer (as discussed by Dr Petrylak on pages 677 682). Results from this study are eagerly awaited, especially in light of recent data from a pilot study [13] in patients with high-risk solid tumors (N = 40) wherein zoledronic acid significantly prolonged bone metastasis-free survival compared with placebo ( p < 0.0005; Fig. 3). The widespread availability of prostate-specific antigen (PSA) testing has allowed the detection of recurrent disease while it is still at an asymptomatic stage. Locating the site of recurrence, however, may be challenging. In addition to the absolute PSA value, assessment of PSA kinetics is becoming a widely recognized tool [14,15]. For example, slow and linear increases in PSA levels suggest that disease recurrence is localized, whereas rapid and exponential kinetics suggest that metastasis has occurred [16]. Metastasis to bone is relatively common among patients whose PSA levels increase beyond 10 ng/ml or show rapid kinetics after initial treatment with curative intent [17]. On the basis of this and other recent studies, the current guidelines from the European Association of Urology recommend screening for metastatic disease be performed in patients with biochemical relapse if their PSA levels are >20 ng/ml, their PSA velocity is >20 ng/ml/yr, or if they have any symptoms of metastatic disease Fig. 1 Patients with prostate cancer (PC) undergoing androgen-deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) agonist have an increased risk of bone fractures. Data from Smith MR et al [6].

european urology supplements 6 (2007) 689 694 691 Fig. 2 Guidance from an expert panel for bone health monitoring and treatment during androgen-deprivation therapy. * Rule out pathologic fracture from bone metastases. ADT: androgen-deprivation therapy; BMD: bone mineral density; DEXA: dual-energy X-ray absorptiometry; CT: computed tomography. Adapted with permission from Diamond TH et al [7]. [18]. However, use of these PSA cut-off values may lead to underdiagnosis of bone metastases, especially in the case of PSA-negative relapse, which typically has a greater osteolytic component compared with PSA-expressing tumors [19]. Indeed, a small retrospective evaluation reported that bisphosphonate treatment in patients with PSAnegative recurrent disease not only reduced pain but also produced a radiographic response in the bone lesions [20]. The introduction of metabolic-labeling agents such as 11 C-acetate (AC) and image fusion technologies may provide imaging specialists with sensitive tools for the detection of visceral metastases [21]. Fig. 3 Zoledronic acid prolonged bone metastasis-free survival (BMFS) in a pilot study in patients with high-risk solid tumors. Adapted with permission from Mystakidou Ketal[13]. Such imaging technologies have increased the sensitivity of screening for recurrent tumors throughout the body. However, traditional bone scans remain a sensitive and reliable method for the detection of sites of possible metastasis on the skeleton [18,21]. Furthermore, bone scans are relatively inexpensive compared with the emerging methodologies for the detection of visceral metastases. In prostate cancer, as with other solid tumors, the skeleton is the most common target site for tumor metastasis [22]. Prostate cancer appears to have a predilection for metastasizing to bone, especially in the lumbar spine [23], which may place patients at risk for painful and potentially debilitating spinal cord compression [24]. Therefore, bone scans could be a first step in screening for metastatic disease in patients with rising PSA levels after initial radical prostatectomy. Moreover, levels of biochemical markers of bone metabolism are often perturbed in patients with malignant bone disease [25 28], and bone marker assessment may one day assist in the early identification and monitoring of bone metastases. Bisphosphonates have become an integral component of therapy for patients with bone lesions from multiple myeloma or breast cancer [29], but early-generation bisphosphonates demonstrated limited efficacy in patients with bone metastases from genitourinary malignancies [1]. Within the past 5 yr, the new-generation bisphosphonate zoledronic acid has demonstrated efficacy in the prevention of skeletal morbidity in patients with bone metastases secondary to solid tumors other than breast cancer, and has received international

692 european urology supplements 6 (2007) 689 694 Table 1 Recommendations from a multidisciplinary expert panel on the use of bisphosphonates in patients with prostate cancer Patient s condition Bone scan negative * in hormone-sensitive patients Bone scan negative * in hormone-refractory patients Bone scan positive * in hormone-sensitive patients Bone scan positive * in hormone-refractory patients IV bisphosphonate No Use of bisphosphonate at physician s discretion; monitor patient closely IV bisphosphonate therapy should be strongly considered Yes * At any point that the patient has bone loss, consider a bisphosphonate. IV: intravenous. Adapted with permission from Carroll PR et al [37]. regulatory approval for the treatment of bone metastases secondary to a broad range of solid tumors [30 34], thereby extending the benefits of bisphosphonate therapy to patients with hormonerefractory prostate cancer (HRPC) and other genitourinary tumors. On radiographs bone metastases can appear osteoblastic (characterized by increased bone formation; typical of metastases secondary to prostate cancer), osteolytic (characterized by increased bone resorption; typical of metastases secondary to renal cell carcinoma [RCC]), or mixed (typical of bone metastases from other solid tumors) in appearance, but all malignant bone disease is associated with increases in osteolytic bone destruction and increased risk of skeletal-related events (SREs) [22]. These complications include pathologic fracture, severe bone pain requiring palliative radiotherapy (external beam or radiopharmaceuticals) or palliative change in the chemotherapeutic regimen (for patients with HRPC), the requirement for orthopedic surgery to bone, and spinal cord compression [30]. Osteolytic disease is also associated with hypercalcemia of malignancy, a potentially life-threatening event [22]. Zoledronic acid (4 mg via 15-min infusion every 3 wk for up to 2 yr) significantly delayed the onset of SREs and reduced the ongoing risk of SREs in randomized placebocontrolled trials in patients with bone metastases from HRPC, and in patients with bone metastases from lung cancer and other solid tumors, including RCC ( p < 0.05) [30 34]. Use of bisphosphonates has been widely recommended for patients with bone metastases from prostate cancer [18,35 37], and the utility of bisphosphonates throughout the disease continuum has been reviewed (Table 1 [37]). However, many of the patients who enrolled in the zoledronic acid phase 3 studies had already experienced potentially disabling SREs. Detection and treatment of bone metastases before the onset of SREs could therefore slow the erosion in quality of life and functional independence that may occur in patients with advanced cancer. Indeed, exploratory analyses suggest that earlier treatment of bone metastases before the onset of bone pain or SREs may even be more efficacious than later treatment in reducing the incidence of SREs (as discussed by Dr Saad on pages 683 688). In the past, treatment of bone metastases was viewed as mainly palliative therapy. Recent evidence, however, suggests that the extent of bone metastases and skeletal morbidity may play an important role in the disease course [22,38 40]. In a correlative study [38] in patients with bone metastases from HRPC (N = 56), the percentage of the skeletal surface area that was affected by metastatic bone disease was the only significant covariate for decreased survival (risk ratio = 2.6 for patients with >4.6% of their skeleton affected versus patients with <4.6% of their skeleton affected; p = 0.016); and survival curves reflected sustained differences in survival during 4 yr of observation (Fig. 4). Furthermore, although no causal relationship has been established, in two separate retrospective analyses Fig. 4 Percentage of the skeleton affected by bone disease (<4.6% or >4.6%) inversely correlates with survival in patients with prostate cancer. Adapted with permission from Macmillan Publishers Ltd: Noguchi M et al. Br J Cancer 2003;88:195 201, copyright 2003 [38].

european urology supplements 6 (2007) 689 694 693 in patients with prostate cancer (N = 195 [39] and N = 643 [40]), patients with fractures had significantly decreased survival compared with patients who did not experience fractures ( p < 0.05). Further objective evidence for effects of bone-directed therapy on the disease course comes from an analysis of the RCC subset of the study in patients with bone metastases from lung cancer and other solid tumors, wherein 4 mg zoledronic acid significantly delayed the time to disease progression in bone compared with placebo [34]. These observations suggest that the interactions between tumor and bone can profoundly influence bone lesion progression, and the effects of bisphosphonates on malignant osteolysis can have meaningful effects. Therefore, earlier treatment may have benefits in addition to the preservation of physical functioning. 2. Conclusions With new diagnostic insights and the widespread availability of zoledronic acid, urologists are now equipped with multiple tools to aid in the maintenance of bone health in patients with genitourinary cancers. Ongoing clinical trials are investigating the use of biochemical markers of bone turnover in monitoring disease progression and response to therapy, the optimal timing and schedule of bisphosphonate therapy throughout the disease course in patients with prostate cancer and RCC, and whether use of zoledronic acid in patients with high-risk disease may reduce the risk of metastasis to bone. Authorship Dr. Djavan was responsible for the generation of this article, controlling the content from its inception, and gave final approval of the submitted version. ProEd Communications, Inc provided medical editorial assistance. Conflicts of interest Dr. Djavan has no potential conflicts of interest. Role of the funding source This article was supported by an unrestricted educational grant provided by Novartis Pharmaceuticals Corporation. Acknowledgements Funding for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. I thank Catherine Browning, PhD, ProEd Communications, Inc, for her medical editorial assistance with this manuscript. References [1] Saad F, Higano CS, Sartor O, et al. The role of bisphosphonates in the treatment of prostate cancer: recommendations from an expert panel. Clin Genitourin Cancer 2006;4:257 62. [2] Greenspan SL, Coates P, Sereika SM, et al. Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J Clin Endocrinol Metab 2005;90: 6410 7. [3] Krupski TL, Smith MR, Lee WC, et al. Natural history of bone complications in men with prostate carcinoma initiating androgen deprivation therapy. Cancer 2004;101:541 9. [4] Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:154 64. [5] Morote J, Orsola A, Abascal JM, et al. Bone mineral density changes in patients with prostate cancer during the first 2 years of androgen suppression. J Urol 2006;175:1679 83, discussion 1683. [6] Smith MR, Boyce SP, Moyneur E, et al. Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol 2006;175:136 9, discussion 139. [7] Diamond TH, Higano CS, Smith MR, Guise TA, Singer FR. Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies. Cancer 2004;100:892 9. [8] Smith MR. Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer. Drugs Aging 2003;20:175 83. [9] Eastham JA. Bone health in men receiving androgen deprivation therapy for prostate cancer. J Urol 2007;177: 17 24. [10] Ryan CW, Huo D, Demers LM, Beer TM, Lacerna LV. Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer. J Urol 2006;176:972 8, discussion 978. [11] Polascik TJ, Given RW, Metzger C, et al. Open-label trial evaluating the safety and efficacy of zoledronic acid in preventing bone loss in patients with hormone-sensitive prostate cancer and bone metastases. Urology 2005;66: 1054 9. [12] Padalecki SS, Carreon M, Grubbs B, Cui Y, Guise TA. Androgen deprivation enhances bone loss and prostate cancer metastases to bone: prevention by zoledronic acid. Oncology 2003;17(Suppl 3):32. [13] Mystakidou K, Katsouda E, Parpa E, et al. Randomized, open label, prospective study on the effect of zoledronic

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