1. 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”

2. Bone as a Dynamic Structure: Normal Turnover

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

4. 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.

5. 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:

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

7. 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: Weinfurt KP, et al. ESMO Abstract 662P. 3. Weinfurt KP, et al. Med Care. 2004;42: Saad F, et al. Eur Urol. 2004;46: Oefelein MG, et al. J Urol. 2002;168: Riggs BL, et al. Bone. 1995;17:505S-511S.

8. 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):

9. 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:

10. 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): ; 2. Saad F, et al. Eur Urol Suppl. 2007;6(11):

12. 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.

13. 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

14. 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.

15. 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

16. 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

17. 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

18. 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

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

20. 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: and Further information for clodronate and ibandronate is available at and

21. SRE Risk Reduction in BC—Results From an Independent Meta-analysis
P value
0.59
ZOL 4 mg 41%
(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:CDC

22. 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):

23. 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.

24. 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: 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): ; 2. Body J-J, et al. Ann Oncol. 2003;14(9): Reprinted from Kohno N, et al. J Clin Oncol. 2005;23(15):

25. 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:
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):

26. 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

27. Ovarian Suppression Plus TAM or ANA +/- ZA: ABCSG-12 Trial Design
Accrual
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 Abstract LBA4.

28. 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 Abstract LBA4.

29. 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 (0.46 to 0.92), P = .014
No ZA 82
events vs No ZA, P Value
No. of Events Hazard ratio (95 % CI)
ZA (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 Abstract LBA4.

30. 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 Abstract LBA4.
Gnant M, et al. ASCO Abstract LBA4.

31. 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 Abstract 512.

32. ≤40 yrs; stages I-III; last menstrual period ≤ 6 mos prior to entry
Effect of Zoledronic Acid on BMD: CALGB 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
Randomize
Stratifications
Stage
Tamoxifen
ZA 4 mg IV Q3Mos
Calcium/Vit D
Calcium/Vit D
“Late”
Shapiro CL, et al. ASCO Abstract 512.

33. CALGB 79809 Mean Percent Change in BMD +/- Tamoxifen at 12 Months4
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 Abstract 512.

34. 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
≥ nmol/L
n = 197
Sufficient
72 nmol/Ln
n = 123 HR
(95% CI)
1.94
( )
1.37
( )
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 Abstract 511.

35. 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

36. 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

37. ZO-FAST Primary Endpoint Mean Change in BMD from Baseline6 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

38. 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

39. 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 had both a clinical and radiographic fx
^Patients and Patient had both a clinical and radiographic fx

40. 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= ) 70 60
Disease-Free Survival (%) 50 40 30 20
Upfront ZOL
Delayed ZOL 10 5 10 15 20 25 30 35
Study Month

41. 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

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

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

44. 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)

45. 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

46. 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

47. 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: and Further information for clodronate and ibandronate is available at and

48. 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 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 , JNCI durable benefits

49. 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.

50. 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
Placebo
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 < With Perrmission from Saad F, et al. BJU Int. 2006;96:

51. 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):

52. 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): ; 2. Saad F, et al. J Natl Cancer Inst. 2004;96(11): ; 3. Rosen LS, et al. Cancer. 2004;100(12): ; 4. Lipton A, et al. Cancer. 2003;98(5):

53. Thank you