Efficacy and Safety of Denosumab for the Treatment of Bone Metastases in Patients with Advanced Cancer

Review Articles Jpn J Clin Oncol 2012;42(8)663 669 doi:10.1093/jjco/hys088 Advance Access Publication 13 June 2012 Efficacy and Safety of Denosumab for the Treatment of Bone Metastases in Patients with Advanced Cancer Takayasu Kurata * and Kazuhiko Nakagawa Department of Medical Oncology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan *For reprints and all correspondence: Takayasu Kurata, Department of Medical Oncology, Kinki University School of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan. E-mail: t-kurata@med.kindai.ac.jp Received February 15, 2012; accepted May 15, 2012 Bone metastases are known to be caused by all types of cancer. Cancer metastasis to bone has been said to considerably compromise patients quality of life and adversely affect lifetime prognosis. Although progress in cancer treatment has prolonged survival significantly, this may make increased numbers of patients suffer from bone metastases. Until now, as for the treatment of bone metastases, local therapies, including radiation therapy and surgery, were performed mainly as palliative therapies. However, bisphosphonate-based therapies have recently become available and are frequently administered to delay or prevent skeletal-related events, which include pathologic bone fracture, spinal cord compression, radiologic treatment for bone lesions, surgical procedures for bone lesions and hypercalcemia. Moreover, denosumab, the first fully human monoclonal antibody to receptor activator of nuclear factor k-b ligand, was approved in the USA because of its evidence-supported clinical effects. Denosumab was effective for prolonging the time to skeletal-related events and inhibiting the onset of pain via the suppression of osteoclast activation. Denosumab has been shown to have a greater effect compared with zoledronic acid, most notably in patients with breast or prostate cancer. In this article, the efficacy and safety of denosumab for the treatment of bone metastases in patients with various advanced cancers are discussed. Key words: bone metastasis denosumab bisphosphonate skeletal-related event INTRODUCTION All types of cancers can metastasize to bones. Cancers that frequently metastasize to bone include breast cancer, prostate cancer, thyroid cancer and lung cancer. The incidence of bone metastasis is particularly high, ranging from 65 to 75% in patients with metastatic breast cancer and those with metastatic prostate cancer (1). Although the direct impact of bone metastasis on lifetime prognosis may be limited in patients with prostate cancer, patients experience significant declines in physical, functional and emotional well-being due to radiation and pathologic fractures (2). According to a recent report, there is an association between the development of pain and reduction in survival rate in patients with bone metastasis from breast cancer (3). With the advent of molecular-targeted drugs and progress in chemotherapy, prolonged survival rates can be expected. As a result, we predict that the incidence of bone metastases from cancers that formerly were unlikely to metastasize to bones may increase in the near future (4). Therefore, treating bone metastases becomes increasingly important in the management of cancer patients. Skeletal-related event (SRE) is a general term referring to consequences of cancer metastasis to bone. SREs include pathologic bone fracture, spinal cord compression, radiologic treatment for bone lesions, surgical procedures for bone lesions and hypercalcemia. Palliative therapies for bone metastases, such as radiological or surgical therapy, target the symptomatic site or the # The Author 2012. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

664 Denosumab for treatment of bone metastases site at which neuroparalysis is likely to occur. Recently, drug therapy for the prevention or delay of SREs in asymptomatic, as well as symptomatic, cases has attracted attention. Researchers report that among these drugs, zoledronic acid, a bisphosphonate preparation, is more effective for treating a large variety of cancers (5 7). The mechanism of action of zoledronic acid involves the inhibition of bone resorption by osteoclasts in the bone. Several new drugs with different mechanisms of action have been developed, including the prevention of cancer cell uptake by bone, prevention of cancer cell stimulation of osteoblasts or inhibition of osteoclasts activation. These drugs have been studied for their usefulness in the clinical setting (8). Denosumab, a molecular-targeted drug that inhibits osteoclast activation, was approved by the US Food and Drug Administration (FDA) in November 2010 because of abundant evidence supporting its efficacy and potentially remarkable SRE inhibition (9). Denosumab has also been approved by the FDA for use in post-menopausal women at risk for osteoporosis. In this article, on the basis of the latest findings, we overview the efficacy and safety of denosumab for the treatment of bone metastases in patients with various advanced cancers. transforming growth factor-b and insulin-like growth factor. These growth factors are released in the process of bone resorption by osteoclasts and further promote cancer cell proliferation. In this manner, the interaction among cancer cells, osteoblasts and osteoclasts forms a negative cycle that accelerates bone destruction (11,12). Denosumab is the world s first fully human monoclonal antibody to RANKL developed by Amgen in the USA. As previously mentioned, the RANKL RANK system is deeply involved in the establishment of bone metastases. Thus, control of bone metastases appears to depend largely on the inhibition of the RANKL RANK system. Osteoprotegerin (OPG), a RANKL decoy receptor, can bind to RANKL to block RANKL RANK binding and inhibit osteoclast activation. Denosumab has a marked ability to bind to RANKL, as demonstrated by the dissociation constant (K d ¼ 3 10 212 ). Like OPG, denosumab seems to bind to RANKL, blocking RANKL RANK binding, resulting in the inhibition of osteoclast activation. Denosumab is thought to inhibit the establishment of bone metastases through this mechanism (11,12) (Fig. 1). Moreover, once-monthly administration of denosumab appears to be effective because of its long biologic half-life and effective duration of action. CANCER METASTASIS TO BONE, AND MECHANISM OF ACTION OF DENOSUMAB Bone metastases are classified into the following three categories: osteolytic metastasis occurs when osteoclast function is excessive. Osteoblastic metastasis is characterized by excessive bone formation due to increased osteoblast activation. Mixed metastasis is a combination of osteolytic metastasis and osteoblastic metastasis. The frequency of bone metastases from breast cancer and prostate cancer is particularly high. According to imaging studies, bone metastases from breast cancer are classified either as osteolytic or as mixed metastases, while bone metastases from prostate cancer are classified as osteoblastic metastases. The establishment of metastatic bone lesions involves bone destruction mediated by bone resorption resulting from osteoclast activation. For example, in the case of bone metastasis from prostate cancer, the bone resorption marker often increases even in the process of osteoblastic metastasis (10). For this reason, irrespective of the type of cancer or bone metastasis, bone metastases can be prevented by intensive control of bone resorption. Cancer cells release osteoclast-activating factors, including parathyroid hormone-related peptide, prostaglandin E and interleukin-6. The osteoclast-activating factors do not directly activate osteoclasts, but stimulate osteoblasts and promote expression of receptor activator of nuclear factor kappa-b (NFkB) ligands (RANKLs). RANKL binds to receptor activator of NFkB (RANK). This binding allows differentiation of osteoclast precursors into mature osteoclasts and acceleration of bone resorption. Bone matrix contains abundant PHARMACOLOGY OF DENOSUMAB Non-clinical studies using animal models have been conducted to evaluate the pharmacology of denosumab. Inhibition of bone resorption by denosumab was examined in young male and female uncastrated cynomolgus monkeys. The animals were given denosumab at doses of 1, 10 and 50 mg/kg once a month for up to 12 months. In this experiment, the level of type I collagen cross-linked N-telopeptide (NTx), a bone resorption marker, in the urine (creatinine correction) was measured over time. In weeks 13, 25 and 37, NTx decreased significantly in the 10 mg/kg denosumab group compared with the control group (P, 0.05). In the 50 mg/kg denosumab group, NTx decreased significantly throughout the 52-week administration period (P, 0.05) (13). In experiments using mouse models with various cancer metastases, the inhibitory effects of denosumab mediated by RANKL inhibition, including suppression of bone lesions and reduction in tumor tissue volume in the bone, were evaluated. In these experiments, recombinant OPG fused to the Fc portion of the immunoglobulin heavy chain (OPG-Fc) was used in place of denosumab, which does not bind to mouse RANKL. In one experiment using mouse models of bone metastases from breast cancer (14), OPG-Fc was administered subcutaneously twice a week at a dose of 0.3 or 3.0 mg/kg at 0 21 days after tumor implantation. Twenty-five days after tumor implantation, the inhibition of osteolytic lesion formation in the hind-limb bones was observed, along with a reduction in the number of osteoclasts both in the OPG-Fc 0.3 mg/kg group and in the OPG-Fc 3.0 mg/kg group. These inhibitory effects were dependent on

Jpn J Clin Oncol 2012;42(8) 665 Figure 1. Establishment of cancer metastasis to bone and the site of action of denosumab. PTHrP, parathyroid hormone-related peptide; PGE 2, prostaglandin E 2 ; IL-6, interleukin-6; TGF-b, transforming growth factor-b; IGF, insulin-like growth factor. Figure 2. Area of osteolytic lesion in the posterior limbs 25 days after tumor transplantation (bone metastasis mouse model of human breast cancer). the dosage of OPG-Fc, and a significant difference in inhibition was observed between the treatment groups and the control group (P ¼ 0.0014 and,0.0001) (Fig. 2). In an experiment using mouse models of bone metastasis from prostate cancer (15), OPG-Fc was administered subcutaneously three times a week at a dose of 3.0 mg/kg at 11 28 days after tumor implantation. Additionally, 11 and 18 days after implantation, docetaxel was administered intraperitoneally at a dose of 5 or 10 mg/kg, either alone or in combination with OPG-Fc. Twenty-seven days after implantation, this treatment resulted in a significant reduction in osteolytic lesions in the femur and tibia in the OPG-Fc monotherapy group and the OPG-Fc þ docetaxel (10 mg/kg) combination therapy group compared with the control group (P, 0.0001 and,0.0001). Similar results were obtained in the measurement of tumor tissue volume in the hind-limb bone. In an experiment using mouse models of bone metastasis from lung cancer (16), OPG-Fc was subcutaneously administered three times a week at a dose of 3.0 mg/kg at 7 23 days after tumor implantation. At 7 and 14 days after implantation, docetaxel was administered intraperitoneally at a dose of 15 mg/kg, either alone or in combination with OPG-Fc. Twenty-three days after implantation, this treatment resulted in a significant reduction in bone lesions in the femur and tibia in the OPG-Fc monotherapy group and the OPG-Fc þ docetaxel combination therapy group compared with the control group (P, 0.0001 and,0.0001). Consequently, denosumab inhibited bone resorption in healthy cynomolgus monkey models and exerted its inhibitory effects by RANKL inhibition, resulting in suppression of bone lesions and reduction in tumor tissue volume in mouse models of bone metastases from breast cancer, prostate cancer and lung cancer. DENOSUMAB CLINICAL RESULTS EFFICACY AND SAFETY OF DENOSUMAB FOR THE TREATMENT OF BONE METASTASIS FROM BREAST CANCER Lipton et al. (17) conducted a randomized Phase II study examining the efficacy and safety of denosumab in 255

666 Denosumab for treatment of bone metastases female patients with bone metastases from breast cancer observed by diagnostic imaging. A total of 212 patients received denosumab subcutaneously every 4 weeks, and 43 patients received a bisphosphonate preparation intravenously. At 13 weeks after the start of the study, the median decrease in NTx was 71% in the denosumab group and 79% in the bisphosphonate group. The percentage of patients who achieved a 65% or more decrease in urine NTx/creatinine (Cr) ratio was 74% in the denosumab group and 63% in the bisphosphonate group, showing a stronger inhibitory effect on bone resorption in the denosumab group than in the bisphosphonate group. The incidence of SREs was 9% in the denosumab group and 16% in the bisphosphonate group. There was no onset of serious or fatal adverse reactions associated with denosumab, and the safety profile of the patients was similar to that of patients with advanced breast cancer undergoing systemic therapy. Stopeck et al. (18) conducted a randomized controlled Phase III study evaluating denosumab in 2046 female patients with breast cancer diagnosed as having one or more bone metastases. A total of 1026 patients received 120 mg denosumab subcutaneously every 4 weeks and 1020 patients received 4 mg of zoledronic acid intravenously every 4 weeks, followed by a comparative review of the delayed onset of SREs or the inhibitory effect on the onset of SREs. Compared with the zoledronic acid group, the time to the first on-study SRE was significantly prolonged in the denosumab group [hazard ratio (HR) ¼ 0.82, 95% confidence interval (CI) 0.71 0.95, P ¼ 0.001 (non-inferiority test) and P ¼ 0.01 (superiority test)] (Table 1). This effect persisted throughout the study period. While the time to the on-study SRE (median) was 26.4 months in the zoledronic acid group, patients in the denosumab group did not achieve the median level. In addition, the time to first and subsequent on-study SREs was also significantly prolonged in the denosumab group (rate ratio ¼ 0.77, 95% CI 0.66 0.89, P ¼ 0.001). No significant difference in overall survival or disease progression was noted between the groups. There was also no difference in the incidence of adverse reactions or serious adverse reactions between the groups. At 13 weeks after the start of the study, the urine NTx/Cr ratio decreased by 80% in the denosumab group and by 68% in the zoledronic acid group, showing a significant decrease in the former group (P, 0.001). In the zoledronic acid group, many adverse events related to renal function and acute phase reactions developed, while frequent occurrences of hypocalcemia were observed in the denosumab group. In addition, jaw osteonecrosis developed in 2.0% of the patients in the denosumab group and 1.4% in the zoledronic acid group, with no significant difference between the groups (P ¼ 0.39). Denosumab showed better outcomes with respect to the delayed onset of SREs and the inhibitory effect on the onset of SREs than zoledronic acid, suggesting that denosumab was well tolerated by the majority of patients (Table 1) (19). Pain was reported by 90% or more of the patients with bone metastases (20). Pain has been suggested as a predicator of lifetime prognosis in breast cancer patients with bone metastases (2). Cleeland et al. (21) weighed the impact of monthly subcutaneous administration of 120 mg denosumab and monthly intravenous administration of 4 mg zoledronic acid on pain in a randomized Phase III study in female patients with breast cancer diagnosed as having bone metastases. When compared with the zoledronic acid group, the denosumab group had a shorter time to improvement of movement restriction due to pain (70 days in the denosumab group versus 86 days in the zoledronic acid group, P ¼ 0.09) and a prolonged time to aggravation of pain (394 days in the denosumab group versus 310 days in the zoledronic acid Table 1. Summary of randomized Phase III studies of denosumab and zoledronic acid Breast cancer Prostate cancer Advanced cancer or multiple myeloma excluding breast and prostate cancer D Z D Z D Z Time to first on-study SRE Median (months) NR 26.4 20.7 17.1 20.6 16.3 HR (95% CI) 0.82 (0.71 0.95) 0.82 (0.71 0.95) 0.84 (0.71 0.98) NSCLC: 0.84 (0.64 1.10) Multiple myeloma: 1.03 (0.68 1.57) Superiority or non-inferiority Superiority, P ¼ 0.01 Superiority, P ¼ 0.008 Non-inferiority, P ¼ 0.0007 Jaw osteonecrosis (%) 2.0 1.4 2 1 1.1 1.3 Renal adverse events (%) 4.9 8.5 15 16 8.3 10.9 Hypocalcemia (%) 5.5 3.4 13 6 10.8 5.8 Acute phase reaction (%) 10.4 27.3 8 18 6.9 14.5 D, denosumab; Z, zoledronic acid; SRE, skeletal-related event; HR, hazard ratio; NR, not reached; NSCLC, non-small cell lung cancer. Acute phase reaction: common cold-like symptoms including fever, chills, bone pain, joint pain and muscle pain within 3 days after administration of the drugs.

Jpn J Clin Oncol 2012;42(8) 667 group, P ¼ 0.09), although these differences were not statistically significant. Based on the above findings, denosumab is considered to be useful for the treatment of breast cancer patients with bone metastases. Therefore, the use of denosumab is recommended along with pamidronic acid and zoledronic acid by the American Society of Clinical Oncology (ASCO) guidelines for the treatment of patients with metastatic breast cancer (22). However, because jaw osteonecrosis rarely induced by these drugs can be serious, the guidelines state that patients receiving drugs that suppress osteoclast activity should have a dental check-up and receive preventive dental treatment before starting cancer treatment. EFFICACY AND SAFETY OF DENOSUMAB IN THE TREATMENT OF BONE METASTASES FROM PROSTATE CANCER Patients with prostate cancer are known to suffer decreased bone mineral density (BMD) and increased risk of bone fracture due to androgen ablative therapy. Smith et al. (23) conducted a randomized controlled Phase III study to examine the impact of denosumab on BMD and bone fracture in 1468 patients with non-metastatic hormone-sensitive prostate cancer during androgen ablative therapy. In this study, the patients were assigned to receive 60 mg denosumab monthly (n ¼ 734) or placebo (n ¼ 734) and followed for 36 months. After 24 months, BMD of the lumbar spine increased by 5.6% in the denosumab group and decreased by 1.0% in the placebo group (P, 0.001). In addition, the effect was maintained for 36 months until completion of the observation period. The risk of vertebral fracture after 36 months was significantly lower at 62% in the denosumab group (relative risk ¼ 0.38, 95% CI 0.19 0.78, P ¼ 0.006). There was no difference in the incidence of adverse events between the groups. Fizazi et al. (24) conducted a randomized controlled Phase III study to examine the inhibitory effect of denosumab on SREs in castration-resistant prostate cancer patients with one or more bone metastases observed with X-ray, who had no prior history of intravenous bisphosphonate therapy. A total of 951 patients received 120 mg denosumab subcutaneously every 4 weeks and 953 patients received 4 mg zoledronic acid intravenously every 4 weeks. The median time to the first on-study SRE was 20.7 months in the denosumab group and 11.2 months in the zoledronic acid group, showing a significant difference favoring the denosumab group [HR ¼ 0.82, 95% CI 0.71 0.95, P ¼ 0.0002 (noninferiority test) and P ¼ 0.008 (superiority test)] (Table 1). The median time to first and subsequent on-study SREs was also significantly prolonged in the denosumab group (rate ratio ¼ 0.82, 95% CI 0.71 0.94, P ¼ 0.008). There was no inter-group difference in overall survival or disease progression. Serious adverse events were observed in 63% of the denosumab group and 60% of the zoledronic acid group, with jaw osteonecrosis in 2% of the denosumab group and 1% of the zoledronic acid group; however, there was no significant inter-group difference. This study investigated that the prolonged time to on-study SREs and inhibitory effect of denosumab on the onset of SREs exceeded that of zoledronic acid. There was no difference in the overall safety profile between the groups (Table 1). EFFICACY AND SAFETY OF DENOSUMAB FOR THE TREATMENT OF BONE METASTASES FROM OTHER CANCERS Body et al. (25) conducted a randomized controlled Phase III study to compare the therapeutic effects of denosumab and zoledronic acid in 29 breast cancer patients and 25 multiple myeloma patients with bone metastases observed by imaging. In this study, 24 breast cancer patients and 20 multiple myeloma patients were randomized to one of four denosumab groups, 0.1, 0.3, 1.0 and 3.0 mg/kg, subcutaneous; 5 breast cancer patients and 5 multiple myeloma patients were randomized to 90 mg intravenous pamidronic acid. All patients were followed for 84 days. The results showed that urine and serum NTx/Cr ratios decreased on the day of denosumab administration, and the decrease was maintained throughout the follow-up period in the high-dose denosumab group. On the other hand, in the pamidronic acid group, although the NTx/Cr ratio decreased at drug initiation, the effect decreased over time. The patients in the denosumab group tolerated the drug favorably. Although not many patients were included in this study, denosumab showed a similar inhibitory effect to pamidronic acid on bone resorption in patients with bone metastases from multiple myeloma and breast cancer. The investigators suggested that the effect of denosumab was more stable than that of pamidronic acid. Henry et al. (26) conducted a randomized controlled Phase III study in 1779 patients with various cancers, excluding breast cancer and prostate cancer, with bone metastases. The patients were randomized to 120 mg subcutaneous denosumab monthly (n ¼ 886) or to 4 mg intravenous zoledronic acid monthly (n ¼ 890). The time to the first on-study SRE was compared between the groups. The median time to the first on-study SRE was 20.6 months in the denosumab group and 16.3 months in the zoledronic acid group, demonstrating the non-inferiority of denosumab relative to zoledronic acid (HR ¼ 0.84, 95% CI 0.71 0.98, P ¼ 0.0007) (Table 1). There was a tendency toward prolonged time to first and subsequent on-study SREs in the denosumab group compared with the zoledronic acid group, but the difference was not significant (rate ratio ¼ 0.90, 95% CI 0.77 1.04, P ¼ 0.14). There was no difference in overall survival or disease progression between the groups. The urine NTx/Cr ratio was decreased by 76% in the denosumab group and 65% in the zoledronic acid group, showing a significant difference between the groups (P, 0.001). Additionally, in a subgroup analysis of the time to the first on-study SRE by cancer type, HRs for non-small cell lung cancer, multiple myeloma and other solid cancers were 0.84, 1.03 and 0.79, respectively, demonstrating no significant interaction between cancer type and prolongation of the time to the first on-study SRE (P ¼ 0.5%). The incidence of hypocalcemia

668 Denosumab for treatment of bone metastases was high in the denosumab group. The incidence of jaw osteonecrosis was low in both groups, with no significant difference between them. Increased acute phase reactions after initial administration, renal-related adverse events and increased serum creatinine were observed in the zoledronic acid group compared with the denosumab group. As stated above, in patients with various cancers, including multiple myeloma, with bone metastases, denosumab is effective for inhibiting the onset of SREs and prolonging the time to SREs similar to or more effectively than zoledronic acid (Table 1). CONCLUSION In patients with bone metastases of various cancer types, denosumab was effective in prolonging the time to SREs and inhibiting the onset of pain via suppression of osteoclast activation. Denosumab has beenshowntohaveagreater effect compared with zoledronic acid, most notably in patients with breast or prostate cancer (Table 2). Bisphosphonate therapy has achieved satisfactory results in the treatment of bone metastases; however, renal function monitoring of patients with decreased renal function and concern for acute phase reaction after initial administration have been necessary. In addition, bisphosphonate preparations are administered intravenously while denosumab is administered subcutaneously (Table 2). The simpler administration method of denosumab could be an advantage in the USA and also in Japan. Although the direct cost of denosumab is higher than zoledronic acid for patients with bone metastases (27) (Table2), in assessments including prolongation of the time to SREs, a cost-effectiveness study performed in the USA reported that denosumab is more cost-effective than zoledronic acid (28). Therefore, the Table 2. Summary of an effect and safe difference between denosumab and zoledronic acid Denosumab Zoledronic acid Administration Subcutaneous injection Intravenous drip infusion Effect of bone modifying Greater (breast, prostate) Equal (other tumors) Risk of joint Similar osteonecrosis Renal adverse events Similar Hypocalcemia More Acute phase reactions More Long-term safety Unknown Satisfactory Direct cost 1650 US dollars/vial 895 US dollars/vial 45 155 Japanese Yen/vial 32 254 Japanese Yen/vial standard medical treatment for bone metastases is expected to change from bisphosphonate preparations to denosumab in the future. However, as stated in the ASCO guidelines (21), the risk of jaw osteonecrosis due to denosumab is comparable to that of bisphosphonate preparations. Conflict of interest statement None declared. References 1. Coleman RE. Skeletal complications of malignancy. Cancer 1997;80(8 Suppl):1588. 2. Weinfurt KP, Li Y, Castel LD, et al. The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer. Ann Oncol 2005;16:579 84. 3. Koizumi M, Yoshimoto M, Kasumi F, Iwase T, Ogata E. Post-operative breast cancer patients diagnosed with skeletal metastasis without bone pain had fewer skeletal-related events and deaths than those with bone pain. BMC Cancer 2010;10:423. 4. Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350:1655. 5. Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001;7:377. 6. Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150. 7. Saad F, Gleason DM, Murray R, et al. A randomized, placebocontrolled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458. 8. Hayashi S, Hanamura T. Encounter of cancer cells with bone. Development of bone metastasis-specific targeting therapy. Clin Calcium 2011;21:389. 9. Bouganim N, Clemons MJ. Bone-targeted agents in the treatment of bone metastases: RANK outsider or new kid on the block? Future Oncol 2011;7:381. 10. Guise TA, Mohammad KS, Clines G, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res 2006;12:6213s. 11. Chayahara N, Minami H. Treatment of bone metastasis with anti-rankl antibody. Clin Calcium 2011;21:1217. 12. Ogata A, Kohno N. Current and future treatment of bone metastases in breast cancer. Jpn J Breast Cancer 2009;24:329. 13. Twelve-month non-clinical safety study using monkeys. Approved assessment material to Pharmaceutical and Medical Devices Agency, Japan (http://www.info.pmda.go.jp/shinyaku/p201200013/index.html). 14. Canon JR, Roudier M, Bryant R, et al. Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis 2008;25:119. 15. Miller RE, Roudier M, Jones J, et al. RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. Mol Cancer Ther 2008;7:2160. 16. Pharmacology of RANKL inhibition in H1299 non-small-cell lung cancer xenogeneic transplant mouse model. Approved assessment material to Pharmaceutical and Medical Devices Agency, Japan (http:// www.info.pmda.go.jp/shinyaku/p201200013/index.html). 17. Lipton A, Steger GG, Figueroa J, et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 2007;25:4431. 18. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132.

Jpn J Clin Oncol 2012;42(8) 669 19. Steger GG, Bartsch R. Denosumab for the treatment of bone metastases in breast cancer: evidence and opinion. Ther Adv Med Oncol 2011;3:233. 20. Smith HS. Painful osseous metastases. Pain Physician 2011;14:E373. 21. Cleeland CS, Patrick DL, Fallowfield L, et al. Comparing the effects of denosumab and zoledronic acid on pain interference with daily functioning in a randomized phase 3 trial of patients with breast cancer and bone metastases. The 33rd Annual San Antonio Breast Cancer Symposium (SABCS) 2010;P1-13-01. http://www.abstracts2view.com/ sabcs10/view.php?nu=sabcs10l_745. 22. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 2011;29:1221. 23. Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. NEnglJ Med 2009;361:745. 24. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377:813. 25. Body JJ, Facon T, Coleman RE, et al. A study of the biological receptor activator of nuclear factor-kappab ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 2006;12:1221. 26. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. JClin Oncol 2011;29:1125. 27. Analysource. Analysource Online. http://www.analysource.com (March 2012, date last accessed). 28. Xie J, Namjoshi M, Wu EQ, et al. Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases. J Manag Care Pharm 2011;17:621.