2. OUTLINE

3. Decrease in skeletal morbidity

4. Prevalence of Skeletal-Related Events in Clinical Trials In the placebo-controlled trials of pamidronate and zoledronic acid, the placebo arm provides an accurate picture of the extent to which patients suffer these various skeletal complications Radiation to bone and pathologic fractures are the most common events, reflecting the burden of bone pain and the fragility of patients’ bones Patients with breast cancer have the highest incidence of skeletal complications—approximately half the patients in the placebo arm experienced a fracture over the 2 years on study, and 11% of patients required orthopedic surgery Therefore, there is a great need to provide effective therapy to reduce the risk of these painful and debilitating skeletal complications In the placebo-controlled trials of pamidronate and zoledronic acid, the placebo arm provides an accurate picture of the extent to which patients suffer these various skeletal complications Radiation to bone and pathologic fractures are the most common events, reflecting the burden of bone pain and the fragility of patients’ bones Patients with breast cancer have the highest incidence of skeletal complications—approximately half the patients in the placebo arm experienced a fracture over the 2 years on study, and 11% of patients required orthopedic surgery Therefore, there is a great need to provide effective therapy to reduce the risk of these painful and debilitating skeletal complications

5. Pamidronate vs Zoledronic acid Breast Cancer and Multiple Myeloma This was an international, multicenter, double-blind, randomized, phase III trial involving 1,648 patients Patients were randomized to receive either ZOMETA® (4 or 8 mg) or pamidronate disodium (90 mg) every 3 to 4 weeks for 25 months Patients also received supplemental calcium (500 mg) and vitamin D (400 International Units) open-label and were instructed to take 1 dose each day with food Core analysis of the study results was at 13 months (after patients had received 12 months of therapy), and the final analysis detailed here was performed at 25 months Approximately 60% of patients (n = 606) completed the 12-month core phase and were given the option of continuing to receive study medication during an additional 12-month extension phase Of these patients, 350 completed 24 months of treatment Adverse events and death were the most frequent reasons for discontinuation, and the percentage of patients who did not complete the study was similar across all treatment groups. Final analyses were performed at 25 months This trial was designed to show noninferiority of ZOMETA compared with pamidronateThis was an international, multicenter, double-blind, randomized, phase III trial involving 1,648 patients Patients were randomized to receive either ZOMETA® (4 or 8 mg) or pamidronate disodium (90 mg) every 3 to 4 weeks for 25 months Patients also received supplemental calcium (500 mg) and vitamin D (400 International Units) open-label and were instructed to take 1 dose each day with food Core analysis of the study results was at 13 months (after patients had received 12 months of therapy), and the final analysis detailed here was performed at 25 months Approximately 60% of patients (n = 606) completed the 12-month core phase and were given the option of continuing to receive study medication during an additional 12-month extension phase Of these patients, 350 completed 24 months of treatment Adverse events and death were the most frequent reasons for discontinuation, and the percentage of patients who did not complete the study was similar across all treatment groups. Final analyses were performed at 25 months This trial was designed to show noninferiority of ZOMETA compared with pamidronate

6. Proportion of Patients With SRE (–HCM) at Month 13 by Stratum and Treatment (Intent-to-Treat) Adapt. from Rosen et al., Cancer J 2001

7. Multiple event analysis demonstrated that 4 mg ZOMETA significantly decreased the risk of developing an SRE compared with pamidronate (ie, hazard ratio and 95% CI < 1) In the overall population, ZOMETA reduced the risk of developing an SRE by 16% compared with pamidronate (hazard ratio = 0.841; 95% CI, 0.719, 0.983; P = .030) In the breast cancer subpopulation, ZOMETA reduced the risk of developing an SRE by 20% (hazard ratio = 0.799; 95% CI, 0.657, 0.972;P = .025). In multiple myeloma patients, 4 mg ZOMETA was equivalent to pamidronate in reducing the risk of developing an SRE (hazard ratio = 0.955; 95% CI = 0.736, 1.240; P = .731) The hazard ratio reflects the risk of experiencing an SRE for patients treated with ZOMETA relative to patients treated with pamidronate; a hazard ratio < 1 indicates a decreased risk for patients treated with ZOMETA. If the upper boundary of the 95% CI is < 1, the reduction in risk is statistically significant To ensure the independence of skeletal events analyzed, a 21-day window was used to count SREs, such that any event that occurred within 21 days of a previous event was not included in the calculations. This prevented linked events, such as surgery to repair a fracture, from being counted as separate events and thus inflating the incidence of eventsMultiple event analysis demonstrated that 4 mg ZOMETA significantly decreased the risk of developing an SRE compared with pamidronate (ie, hazard ratio and 95% CI < 1) In the overall population, ZOMETA reduced the risk of developing an SRE by 16% compared with pamidronate (hazard ratio = 0.841; 95% CI, 0.719, 0.983; P = .030) In the breast cancer subpopulation, ZOMETA reduced the risk of developing an SRE by 20% (hazard ratio = 0.799; 95% CI, 0.657, 0.972;P = .025). In multiple myeloma patients, 4 mg ZOMETA was equivalent to pamidronate in reducing the risk of developing an SRE (hazard ratio = 0.955; 95% CI = 0.736, 1.240; P = .731) The hazard ratio reflects the risk of experiencing an SRE for patients treated with ZOMETA relative to patients treated with pamidronate; a hazard ratio < 1 indicates a decreased risk for patients treated with ZOMETA. If the upper boundary of the 95% CI is < 1, the reduction in risk is statistically significant To ensure the independence of skeletal events analyzed, a 21-day window was used to count SREs, such that any event that occurred within 21 days of a previous event was not included in the calculations. This prevented linked events, such as surgery to repair a fracture, from being counted as separate events and thus inflating the incidence of events

8. Intravenous ibandronate significantly reduces skeletal morbidity

9. BPs in Prostate Cancer - Multiple Event Analysis - Multiple event analysis provides a sensitive measure of skeletal morbidity because it accounts for all events as well as the time to and between events The hazard ratio reflects the risk of experiencing an SRE; a hazard ratio of < 1 indicates a decreased risk for patients treated with 4 mg ZOMETA. If the upper boundary of the 95% CI is < 1, the reduction in risk is statistically significant (P < .05) ZOMETA treatment decreased the risk of developing a skeletal complication by 36% compared with placebo. The hazard ratio comparing 4 mg ZOMETA with placebo at 24 months was 0.64 (95% CI 0.485 to 0.845; P = .002) Including HCM as an SRE did not affect the analysis To ensure the independence of skeletal events analyzed, a 21-day window was used to calculate both the skeletal morbidity rate and the multiple-event analysis, such that any event that occurred within 21 days of a previous event was not included in the calculations. This prevented linked events, such as surgery to repair a fracture, from being counted as separate events and thus inflating the incidence of events The multiple event analysis was performed using the Andersen-Gill methodology Reference Andersen PK, Gill RD. Cox’s regression model for counting processes: a large sample study. The Annals of Statistics. 1982;10:1100-1120 Multiple event analysis provides a sensitive measure of skeletal morbidity because it accounts for all events as well as the time to and between events The hazard ratio reflects the risk of experiencing an SRE; a hazard ratio of < 1 indicates a decreased risk for patients treated with 4 mg ZOMETA. If the upper boundary of the 95% CI is < 1, the reduction in risk is statistically significant (P < .05) ZOMETA treatment decreased the risk of developing a skeletal complication by 36% compared with placebo. The hazard ratio comparing 4 mg ZOMETA with placebo at 24 months was 0.64 (95% CI 0.485 to 0.845; P = .002) Including HCM as an SRE did not affect the analysis To ensure the independence of skeletal events analyzed, a 21-day window was used to calculate both the skeletal morbidity rate and the multiple-event analysis, such that any event that occurred within 21 days of a previous event was not included in the calculations. This prevented linked events, such as surgery to repair a fracture, from being counted as separate events and thus inflating the incidence of events The multiple event analysis was performed using the Andersen-Gill methodology Reference Andersen PK, Gill RD. Cox’s regression model for counting processes: a large sample study. The Annals of Statistics. 1982;10:1100-1120

10. Analgesic effects

11. Pilot study of intravenous ibandronate in patients with opioid-resistant metastatic bone pain Design Open-label pilot study conducted in 18 patients with moderate-to-severe opioid-resistant bone pain 12 women, 6 men (breast cancer n=10, other tumor types n=8) Received non-standard, intensive ibandronate therapy: 4mg given as a 2-hour infusion for 4 consecutive days (16mg total dose) Efficacy assessed on days 0, 7, 21, and 42 (or until death) Adverse events monitored over 6-week study period

12. Effects on pain (VAS) and MEDD(mean ± SEM)

13. Safety Issues

14. Renal toxicity of bisphosphonates

15. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases

16. Systematic review: bisphosphonates and osteonecrosis of the jaws

18. Individualization of therapy ?

19. Bisphosphonates for metastatic breast cancer- ? WHEN TO START? -

20. ? WHEN TO STOP ?

21. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid

22. Analysis limited to breast cancer patients

23. Zoledronic Acid Reduced Ntx Levels at Month 3 in Patients With Elevated Baseline Ntx

24. Relative Risk of Clinical Events in BC Patients With Persistently Elevated NTX Versus Normalized NTX

25. Use of Bone Resorption Markers to Direct Zoledronic Acid Therapy—BISMARK

26. Bisphosphonates for breast cancer metastatic to bone

29. Mortality Is Increased in BC Patients with Persistently Elevated NTx Various data on markers of bone resoprtion – some of which will be discussed later today - show that elevation of bone markers is associated with worse outcome. These data show reduced survival in BC patients with elevated NTx at baseline. They also show that normalization of NTx improves survival compared with persistent elevation.Various data on markers of bone resoprtion – some of which will be discussed later today - show that elevation of bone markers is associated with worse outcome. These data show reduced survival in BC patients with elevated NTx at baseline. They also show that normalization of NTx improves survival compared with persistent elevation.

30. Comparative effects of oral ibandronate and zoledronic acid on bone turnover markers