Established Benefits of Bisphosphonates; Focus on Breast and Prostate Cancers Prof. Mohamed Abdulla, Department of Clinical Oncology, Kasr El-Aini School of Medicine, Cairo University. “Tanta Cancer Center- April, 13th,2009”

Bone as a Dynamic Structure: Normal Turnover

Bone as a Dynamic Structure: Normal Turnover Osteoblast RANKL Osteoclast Bone

Annual turnover rate of about 25% in cancellous bone and 2-3% in cortical bone The process takes about 4-6 months. 1 osteoclast resorbs what 100 osteoblasts build.

The Vicious Cycle of Bone Destruction PTHrP released by tumor cells Tumor Cells PTHrP Osteoclastic resorption stimulated BMP PDGF FGFs IGFs TGF-β Peptides (eg, TGF-β) released by bone resorption Tumor cell production of PTHrP increased More bone resorption Osteoclast Tumor cell proliferation Bone Mundy GR, Yoneda T. N Engl J Med.1998;339:398-400.

Metastatic Bone Disease Is Prevalent 5-year world prevalence, thousands1 Incidence of bone metastases in cancers2 Median survival, months2-4 Myeloma 144 70 - 95 6 - 54 Renal 480 20 - 25 12 Melanoma 533 14 - 45 6 Bladder 1,000 40 6 - 9 Thyroid 475 60 48 Lung 1,394 30 - 40 6 - 7 Breast 3,860 65 - 75 19 - 25 Prostate 1,555 12 - 53 More lytic More blastic 1. Parkin DM, et al. Int J Cancer. 2001;94(2):153-156; 2. Coleman RE. Cancer Treat Rev. 2001;27(3):165-176; 3. Coleman RE. Cancer. 1997;80(8):1588-1594; 4. Zekri J, et al. Int J Oncol. 2001;19(2):379-382.

Bone Complications and Quality of Life Increased medical costs[1] Increased medical costs[1] Increased medical costs[1] Increased medical costs[1] Impaired mobility[6] Impaired mobility[6] Impaired mobility[6] Skeletal complications Diminished quality of life[2-4] Diminished quality of life[2-4] Diminished quality of life[2-4] Diminished quality of life[2-4] Negative impact on survival[5] Negative impact on survival[5] Negative impact on survival[5] 1. Groot MT, et al. Eur Urol. 2003;43:226-232. 2. Weinfurt KP, et al. ESMO 2002. Abstract 662P. 3. Weinfurt KP, et al. Med Care. 2004;42:164-175. 4. Saad F, et al. Eur Urol. 2004;46:731-740. 5. Oefelein MG, et al. J Urol. 2002;168:1005-1007. 6. Riggs BL, et al. Bone. 1995;17:505S-511S.

Pathologic Fractures Negatively Affect Survival Risk increase P value 1.29 Prostate cancer 29% .04 1.52 Breast cancer 52% < .01 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Hazard ratio Decreased mortality Increased mortality Data from Saad F, et al. Cancer. 2007;110(8):1860-1867.

FDA Accepts Composite Endpoints to Evaluate Therapy Benefit Composite endpoints based on occurrence of skeletal-related events (SREs) defined as Radiation to bone for bone pain or to treat or prevent pathologic fractures or spinal cord compression Pathologic fracture Spinal cord compression Surgery to bone Johnson JR, et al. J Clin Oncol. 2003;21:1404-1411.

Patients With Bone Metastases Are at High Risk for Developing Skeletal-Related Events SREs Placebo arms of large randomized studies Any Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression Patients With SRE, % Breast1 24 Months Prostate2 24 Months Cancer Type SRE, skeletal-related event. 1. Lipton A, et al. Cancer. 2000;88(5):1082-1090; 2. Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.

Ionizing External Beam Rth: Used over a Century for Palliation of Bone Mets. Related Effects. Bone Relief in The Majority of Patients. Reducing The Rate of Bone Destruction. 6-12 Months of Pain Control. Disadvantages: Myelosuppression. Dose to Surrounding Critical Structures.

Radioactive Isotopes: Radio-nuclide Carrier Ligand Half Life (Days) ß Energy (MeV) Gamma Energy (MeV) Max. Range mm 89St Chloride 50.5 1.46 - 7.0 153Sm EDTMP 1.9 0.81 0.103 2.5 186Re HEDP 3.8 1.07 0.137 4.5 188Re 0.7 2.12 0.155 11.0

Radioactive Isotopes: 40-90% Effective Pain Relief. Onset of Action: 1 week. Duration of Response: 18 months. Repeated Doses. Potentiation of Analgesic Effect When Combined with Cth (Platinum). Tumoricidal Effect (-- spots in B/S) Thrombocytopenia & Neutropenia.

Mechanism of action of bisphosphonates Inhibit osteoclast formation and migration, and osteolytic activity; promote apoptosis Modulate signaling from osteoblasts to osteoclasts Local release during bone resorption Concentrated in newly mineralizing bone and under osteoclasts

Osteoclastic activation New molecular insights RANK/RANKL/Osteoprotogerin (members of TNF family) Receptor expressed on mature Osteoclasts and precursors Cytokine expressed by osteoblasts, stromal cells, some tumour cells and myeloma cells leading to osteoclastic activation Natural antagonist of RANK ligand secreted by bone lining cells (Decoy/scavenger receptor) RANK RANK Ligand (= Trance) Osteoprotegerin

Theriault ,Expert Rev.Anticancer Ther.,2003 Bisphosphonates: All bind with high affinity to hydroxyapetit crystals in bones “Half life in bones = 300 days”. Inhibit physiologic and pathologic bone resorption. All have common final effect: Inhibition of Osteoclastic Function Reduced Bone Turnover & Resorption. Increased Production of Osteoprotegerin by Osteoblasts. Theriault ,Expert Rev.Anticancer Ther.,2003

The Goal of Bisphosphonate Therapy Preserve patient’s functional independence and quality of life by . . . Preventing skeletal-related events (SREs) Prevent first and subsequent SREs Delay the onset of the first SRE Palliating and controlling bone pain Reduce the need for analgesics and palliative radiotherapy

Classes of Bisphosphonates1,2 etidronate pamidronate risedronate zoledronic acid clodronate alendronate tiludronate ibandronate 1. Thurlimann B. Bisphosphonates in Clinical Oncology: Focus on Pamidronate. 1999. 2. Fleisch H. Endocr Rev. 1998.

Bisphosphonate Indications—Focus on BC Prevention of SREs HCM Multiple myeloma Breast cancer Prostate cancera Other solid tumors Clodronate (oral)  Pamidronate (IV) Zoledronic acid (IV) Ibandronate (oral and IV)  = European Registration  = Worldwide Registration BC, breast cancer; SRE, skeletal-related event; HCM, hypercalcemia of malignancy; IV, intravenous. a In the United States, prostate cancer must have progressed despite hormone therapy. Prescribing information for pamidronate and zoledronic acid is available at: www.pamidronate.com and www.zometa.com. Further information for clodronate and ibandronate is available at www.bayer.nl/ebbsc/cms/nl/healthcare/bayer_schering_pharma and www.roche.com.

SRE Risk Reduction in BC—Results From an Independent Meta-analysis P value 0.59 ZOL 4 mg 41% .001 (Kohno 2005) 0.77 PAM 90 mg 23% < .001 (Aredia study 18 and 19) 0.82 Ibandronate 6 mg 18% .04 (Body 2003) 0.86 Ibandronate 50 mg 14% .08 (Body 2004) Oral clodronate 1,600 mg (Kristensen 1999) 31% (Paterson 1993) 17% (Tubiana-Hulin 2001) 8% 0.69 0.83 .03 (pooled) 0.92 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Cochrane database comparing placebo-controlled trials in breast cancer setting. ZOL, zoledronic acid; PAM, pamidronate. Adapted from Pavlakis N, et al. Cochrane Database Syst Rev. 2005:CDC003474.

Zoledronic Acid Reduced All Types of SREs at 1 Year in Patients With Bone Metastases From BC Zoledronic acid 4 mg (n = 114) Placebo (n = 113) SRE, skeletal-related event; BC, breast cancer; SCC, spinal cord compression; HCM, hypercalcemia of malignancy. Adapted from Kohno N, et al. J Clin Oncol. 2005;23(15):3314-3321.

In favor of zoledronic acid In favor of pamidronate Breast Cancer—Benefits of ZOL Are Beyond Those of PAM and Continue After the Onset of SREs ZOL reduced the risk of experiencing any SRE on study or after the first SRE by ~30% vs PAMa in a large, double-blind, phase III trial Risk reduction P value All SREs (n = 766) .015 0.711 29% 0.690 Excluding first SRE 31% .045 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Relative risk In favor of zoledronic acid In favor of pamidronate a As determined by Andersen-Gill multiple event analysis. ZOL, zoledronic acid (4 mg q 3-4 wks); PAM, pamidronate (90 mg q 3-4 wks); SRE, skeletal-related event. Adapted from Zheng M, et al. Poster presented at: 9th International Conference on Primary Therapy of Early Breast Cancer; January 26-29, 2005; St. Gallen, Switzerland. Poster 104.

BPI Mean Change From Baseline Zoledronic Acid Significantly Reduces Mean Composite Brief Pain Inventory (BPI) Score ZOL 4 mg q 4 wk Placebo Increased pain *P < .05 BPI Mean Change From Baseline * * Decreased pain * * * * * * * * * * * Zoledronic Acid Significantly Reduces Mean Composite BPI Pain Score Ongoing antineoplastic or hormonal therapy was permitted Zoledronic acid also consistently reduced BPI composite pain scores from baseline and compared with the placebo group throughout the study (P < .05) At every time point, patients in the placebo group had either no change or an increase from baseline in their mean pain score, whereas patients in the zoledronic acid group had a statistically significant decrease from baseline in their mean pain score at every time point throughout the study, except for week 2 REFERENCES Kohno N, Aogi K, Minami H, et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol. 2005;23:3314-3321. 2 4 8 12 16 20 24 28 32 36 40 44 48 52 Time on Study, Weeks Similar results observed in trials of IV pamidronate (90 mg q 3-4 wk)1 and IV ibandronate (6 mg q 3-4 wk)2 Patients continued to receive chemotherapy or standard treatment for breast cancer. IV, intravenous. 1. Lipton A, et al. Cancer. 2000;88(5):1082-1090; 2. Body J-J, et al. Ann Oncol. 2003;14(9):1399-1405. Reprinted from Kohno N, et al. J Clin Oncol. 2005;23(15):3314-3321.

ZOL Significantly Improves Most Quality-of-Life Measures in Patients With Bone Metastases From BC * * * * Zoledronic Acid Significantly Improves Most Quality-of-Life Measures in Breast Cancer Patients With Bone Metastases Wardley et al demonstrated a significant median improvement of 8.3% in overall global health at study end (P = .013)1 Physical, emotional, and social functioning also showed significant overall improvement (P = .013; P = .005; P = .043) Furthermore, physical, role, and social functioning showed significantly greater improvements after treatment in the community setting compared with the hospital crossover setting (P = 0.018, P = 0.001, and P = 0.026, respectively) REFERENCES Wardley A, Davidson N, Barrett-Lee P, et al. Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration. Br J Cancer. 2005;92:1869-1876. Graph depicts overall mean change from baseline quality-of-life scores reported at final visit after 9 infusions. ZOL, zoledronic acid; BC, breast cancer; EORTC QLQ, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire. *P < 0.05 compared with baseline values. Reprinted from Wardley A, et al. Br J Cancer. 2005;92(10):1869-1876.

Cell viability (% control) after 4 days of treatment Zoledronic Acid—Anti-tumour Potential Reduces the viability of human breast cancer cells in vitro1 zoledronic acid pamidronate clodronate 100 Cell viability (% control) after 4 days of treatment 50 1 10 100 1000 Bisphosphonate concentration (µM) * These points have reached statistical significance. 1. Senaratne SG, et al. Br J Cancer. 2000.

Ovarian Suppression Plus TAM or ANA +/- ZA: ABCSG-12 Trial Design Accrual 1999-2006 1,803 premenopausal breast cancer patients Endocrine-responsive (ER and/or PR positive) Stage I & II, <10 positive nodes No chemotherapy except neoadjuvant Treatment duration: 3 years Tamoxifen 20 mg/d Tamoxifen 20 mg/d + Zoledronic acid 4 mg Q6Mos Anastrozole 1 mg/d Anastrozole 1 mg/d + Zoledronic acid 4 mg Q6Mos Surgery (+RT) Goserelin 3.6 mg Q28D Randomize 1:1:1:1 Gnant M, et al. ASCO 2008. Abstract LBA4.

Disease-free survival, % Time since randomization, mos Disease-Free Survival: ZA Vs No ZA 100 90 80 70 60 Disease-free survival, % 50 40 No. of Events Hazard ratio (95% CI) events vs no ZA, P Value 30 ZA 0.643 (0.46 to 0.91), P = .011 54 20 No ZA 83 10 12 24 36 48 60 72 84 Time since randomization, mos Number at risk 904 838 735 565 441 265 161 60 No ZA ZA 899 851 744 573 434 270 131 59 Gnant M, et al. ASCO 2008. Abstract LBA4.

Secondary Endpoints: ZA Vs No ZA RFS OS 100 100 90 90 80 80 70 70 60 60 Recurrence-free survival, % 50 Overall survival, % 50 No. of Events Hazard ratio (95 % CI) ZA 54 0.653 (0.46 to 0.92), P = .014 No ZA 82 events vs No ZA, P Value No. of Events Hazard ratio (95 % CI) ZA 16 0.595 (0.32 to 1.11), P = .101 No ZA 26 events vs No ZA, P Value 40 40 30 30 20 20 10 10 12 24 36 48 60 72 84 12 24 36 48 60 72 84 Time since randomization, months Time since randomization, months Number at risk 899 904 832 846 730 714 538 555 403 414 257 241 145 123 47 54 904 838 735 565 441 265 161 60 No ZA ZA 899 851 744 573 434 270 131 59 Gnant M, et al. ASCO 2008. Abstract LBA4.

Direct antitumor activity ZA-Mediated Mechanisms Contributing to Improved Disease-Free Survival ZA-Mediated Mechanisms Contributing to Improved Disease-Free Survival Direct antitumor activity Immune activation Bone mets recurrence Non-bone mets recurrence Contralateral recurrence Locoregional mets recurrence Disease-free survival Gnant M, et al. ASCO 2008. Abstract LBA4. Gnant M, et al. ASCO 2008. Abstract LBA4.

CALGB 79809 Study Rationale: Chemotherapy Decreases Bone Density Chemo-induced OF 50-70% of women Increasing age Distinct from amenorrhea that reverses No standard definition Bone loss due to estrogen deprivation 1.0 None Chem Only 0.8 Horm Only Both 0.6 Estimated Probability 0.4 0.2 0.0 25 30 35 40 45 50 55 Age at Diagnosis Shapiro CL, et al. ASCO 2008. Abstract 512.

≤40 yrs; stages I-III; last menstrual period ≤ 6 mos prior to entry Effect of Zoledronic Acid on BMD: CALGB 79809 Trial Design “Early” ZA 4 mg IV Q3Mos Calcium/Vit D Calcium/ Vit D Premenopausal women ≤40 yrs; stages I-III; last menstrual period ≤ 6 mos prior to entry Mos 1 12 24 36 Randomize Stratifications Stage Tamoxifen ZA 4 mg IV Q3Mos Calcium/Vit D Calcium/Vit D “Late” Shapiro CL, et al. ASCO 2008. Abstract 512.

CALGB 79809 Mean Percent Change in BMD +/- Tamoxifen at 12 Months 4 2.0 2.2 2 ZA-TAM Control-TAM -2 ZA % ∆ Control -4 4.3 -6 -8 -10 9.5 -12 Shapiro CL, et al. ASCO 2008. Abstract 512.

Distant Disease-Free Survival Distant Disease-Free Survival by Vitamin D Level in EBC Distant Disease-Free Survival Deficient < 50 nmol/L n = 192 Insufficient ≥ 50-72 nmol/L n = 197 Sufficient 72 nmol/Ln n = 123 HR (95% CI) 1.94 (1.16-3.25) 1.37 (0.80-2.33) 1.0 5 Yr 82% 85% 88% 10 Yr 69% 79% 83% 1.0 Sufficient 0.8 Insufficient Deficient 0.6 Proportion distant disease-free 0.4 0.2 P = .02 0.0 2 4 6 8 10 12 Yrs since diagnosis Goodwin PJ, et al. ASCO 2008. Abstract 511.

Zoledronic acid 4 mg IV q6mo ZO-FAST Design IMMEDIATE Eligibility: ER+/PgR+ early breast cancer Postmenopausal T score ≥ –2 Stratification: Adjuvant CT T score Established vs recent postmenopausal Letrozole 2.5 mg/d R A N D O M I Z E Zoledronic acid 4 mg IV q6mo DELAYED† Letrozole 2.5 mg/d Add zoledronic acid if: BMD T score below 2 or clinical or asymptomatic fracture at 36 months 5 years 1065 pts in 128 centers in Asia Pacific, Central and South America, Egypt, and Europe

ZO-FAST Study Objectives Primary objective Percent change in lumbar spine (L2-L4) BMD at 12 m Key secondary objectives Incidence of fractures at 3 years Time to disease recurrence/relapse Overall survival General safety of the two treatment arms

ZO-FAST Primary Endpoint Mean Change in BMD from Baseline 6 4 4.39 2 1.89 1.89 Immediate BMD change (%) 4.39 -4.9 -3.52 Delayed -3.52 -2 -4.9 -4 -6 Lumbar Spine Hip P<0.0001 P<0.0001 Mean Percent Change in BMD from Baseline to 36 Months

Shift in LS T Score Distribution at 36 Months in Patients with Baseline BMD between -1 and -2 (Osteopenic) T Score > -1 T Score -1 to -2 T Score < -2 100 80 60 Patients (%) 40 20 P<0.001 Immediate (N=146) Delayed (N=139) 44.5 % in the immediate arm and 38.1 % in the delayed arm had missing data due to early discontinuations at month 36 or missing central reader BMD values at baseline

Immediate group: 26 patients (5.0%)* All Fractures at 36 Months Immediate group: 26 patients (5.0%)* Clinical: 24 (4.6%) Radiological Fx detected at Month 36 X-ray: 3 (0.6%) Delayed group: 32 patients (6.0%)^ Clinical: 26 (4.9%) Radiological Fx detected at Month 36 X-ray: 8 (1.5%) Fisher’s exact test for difference between arms; p=0.502 *Patient 661-00002 had both a clinical and radiographic fx ^Patients 0152-00009 and Patient 0304-00022 had both a clinical and radiographic fx

Disease-Free Survival (%) ZO-FAST 36-mo : Disease-Free Survival 100 90 80 Upfront zoledronic acid significantly decrease the risk of DFS events by 41% (HR= 0.588, P= 0.0314) 70 60 Disease-Free Survival (%) 50 40 30 20 Upfront ZOL Delayed ZOL 10 5 10 15 20 25 30 35 Study Month

Sites of Disease Recurrence at Month 36 Immediate N=532 No. of Patients (%) Delayed Local 2 (0.4) 10 (1.9) Distant* Bone Brain Lymph node Liver Lung Skin Other 20 (3.8) 9 (1.7) 4 (0.8) 5 (0.9) 7 (1.3) 30 (5.6) 17 (3.2) 3 (0.6) 6 (1.1) 12 (2.3) *Patient could have multiple sites reported

ZO-FAST (36 mo) : Recurrences at the Breast No of Patients (%) (n = 532) (n = 532)

ZO-FAST (36 mo) : Sites of Disease Recurrences No of Patients (%) (n = 532) (n = 532)

AEs Occurring in > 10% of Patients No. of Patients (%) Immediate (N=524) Delayed (N=536) Arthralgia 236 (45.1) 228 (42.6) Hot flashes 140 (26.8) 153 (28.6) Fatigue 90 (17.1) 84 (15.7) Bone pain 85 (16.3) 59 (11.0) Pyrexia 78 (14.9) 16 (3.0) Headache 70 (13.4) 53 (9.9) Myalgia 66 (12.6) 67 (12.5) Pain in extremity 59 (11.3) 63 (11.8) Back pain 57 (10.9) Weight increase 39 (7.4) 54 (10.0)

Safety Results Renal disorders No cases of renal impairment were related to study drug administration Immediate: 1 patient (not related, received 3 doses of zoledronic acid prior to onset) Delayed: 3 patients (none had received any doses of zoledronic acid) Osteonecrosis of the jaw Immediate: 1 patient (0.2%) (mandibular involvement; received 6 doses of zoledronic acid prior to onset) Delayed: none

Keep in Mind: Immediate use of zoledronic acid (4 mg IV q6mo) prevents bone loss in women with early stage BC receiving adjuvant letrozole The difference in the number of fractures with immediate use of zoledronic acid versus delayed is not significant Disease free survival was significantly improved with the use of zoledronic acid upfront The safety results were as expected and consistent with the known safety profiles of each drug These results add to the growing body of evidence that zoledronic acid can provide anti-tumor effects and may prolong DFS in patients with early BC

Bisphosphonate Indications—Focus on PC Prevention of SREs HCM Multiple myeloma Breast cancer Prostate cancera Other solid tumors Clodronate (oral)  Pamidronate (IV) Zoledronic acid (IV) Ibandronate (oral and IV)  = European Registration  = Worldwide Registration PC, prostate cancer; SREs, skeletal-related events; HCM, hypercalcemia of malignancy; IV, intravenous. a In the United States, prostate cancer must have progressed despite hormone therapy. Prescribing information for pamidronate and zoledronic acid is available at: www.pamidronate.com and www.zometa.com. Further information for clodronate and ibandronate is available at www.bayer.nl/ebbsc/cms/nl/healthcare/bayer_schering_pharma and www.roche.com.

Bisphosphonates in the Treatment of Bone Metastases From Prostate Cancer Test drug N Results Reference Etidronate 57 Transient pain reduction Smith 1989, J Urol Clodronate 75 Only transient Elomaa 1992, symptomatic benefit Int Urol Nephrol Placebo-Controlled Studies Clodronate 311 No significant benefit Dearnaley 2003, JNCI Pamidronate 378 No significant benefit Small 2003, JCO Clodronate 209 No significant benefit Ernst 2003, JCO Zoledronic acid 643 Significant objective and Saad 2002-4, JNCI durable benefits

Spinal Cord Compression Change in Antineoplastic Therapy Zoledronic Acid Reduced All Types of SREs at 2 Years in Patients With Bone Metastases From PC P = .028 38 26 17 4 6 2 49 33 25 8 7 1 10 20 30 40 50 60 Any SRE Radiation to Bone Fractures Spinal Cord Compression Change in Antineoplastic Therapy Surgery to Bone HCM Zoledronic acid 4 mg (n = 214) Placebo (n = 208) Patients With SRE, % SRE, skeletal-related event; PC, prostate cancer; HCM, hypercalcemia of malignancy. Adapted from Saad F, et al. Poster presented at: 19th EAU Congress; March 24-27, 2004; Vienna, Austria. Poster 615.

Mean Change From Baseline in BPI Pain Score Zoledronic Acid Resulted in Better Control of Pain Versus Placebo Over 2 Years in Patients With PC Time on Study, Months Mean Change From Baseline in BPI Pain Score Mean n baseline BPI Zoledronic acid 4 mg 214 2.0 Placebo 208 2.1 0.2 0.4 0.6 0.8 1 1.2 3 6 9 12 15 18 21 24 * PC, prostate cancer; BPI, Brief Pain Inventory. *P < .05. With Perrmission from Saad F, et al. BJU Int. 2006;96:964-969.

Prostate Cancer—ZOL Reduced the Risk of SREs Regardless of Prior SRE History Risk reduction P value Before study entry 0.670 No prior SRE 33% .027 0.603 Prior SRE 40% .028 0.640 Overall trial population 36% .002 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Risk ratio (zoledronic acid 4 mg versus placebo) In favor of zoledronic acid In favor of placebo ZOL, zoledronic acid; SRE, skeletal-related event. Data from Saad F, et al. J Natl Cancer Inst. 2004;96(11):879-882.

Zoledronic Acid Significantly Reduced the Risk of SREs Across All Tumor Types Versus Placebo Risk reduction P value 41% .019 36% .002 31% .003 32% .016 58% .010 Breast1 Prostate2 Solid tumors3 Lung cancer3 RCC4 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Relative risk of SRE In favor of ZOL In favor of placebo SRE, skeletal-related event; RCC, renal cell carcinoma; ZOL, zoledronic acid. 1. Kohno N, et al. J Clin Oncol. 2005;23(15):3314-332; 2. Saad F, et al. J Natl Cancer Inst. 2004;96(11):879-882; 3. Rosen LS, et al. Cancer. 2004;100(12):2613-2621; 4. Lipton A, et al. Cancer. 2003;98(5):962-969.

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