This document summarizes metastatic bone disease and the role of bisphosphonates. It discusses how bisphosphonates like pamidronate and zoledronic acid inhibit osteoclast activity to prevent skeletal complications from bone metastases. Clinical trials showed bisphosphonates reduced skeletal complications, bone pain, and hypercalcemia compared to placebo in cancers like breast cancer and multiple myeloma. Zoledronic acid was found to be more potent than pamidronate in suppressing bone turnover based on markers and time to first skeletal event.

1. Pathophysiology of Metastatic Bone Disease and the Role of Bisphosphonates C

2. Clinical Importance and Prognosis of Bone Metastases Disease prevalence, Bone mets. Median U.S. (in thousands) incidence (%) survival (mo) Myeloma 75 - 100 70 - 95 24 Renal 198 20 - 25 12 Melanoma 467 14 - 45 6 Bladder 582 40 6 - 9 Thyroid 207 60 48 Lung 386 30 - 40 7 Breast 1,993 65 - 75 24 Prostate 984 65 - 75 36 C NCI, 1997; International Myeloma Foundation, 2001.

4. Pathophysiology of Bone Metastases Role of the osteoclast in bone pathology Growth factors Osteoclast activity Osteolysis Direct bone destruction Bone Bone secondaries Primary Local factors Systemic factors Tumour cells Bony complications C Activated osteoclast

5. Cancer and Bone Cell Interactions C Osteolytic bone disease Osteoblastic bone disease Osteoclast Osteoblast Unknown GFs TGF- 

6. Bone Remodelling Cancer Effects C Coupled and balanced Bone Uncoupled but balanced Bone Coupled but imbalanced Bone Uncoupled and imbalanced Bone

7. Bone Markers in Osteolytic and Osteosclerotic Metastatic Bone Disease Lytic Blastic Mixed X-ray pattern Bone-specific alkaline phosphatase (ng/mL) N-telopeptide (BCE/M Cr) 0 10 30 20 40 50 60 Lytic Blastic Mixed X-ray pattern 0 100 300 200 400 500 C Lipton A. Semin Oncol . 2001;28:54-59.

8. Consequences of Increased Bone Resorption Increased bone resorption Hypercalcaemia Fracture Bone pain C Bone

10. Bisphosphonate Pharmacology Proposed mode of action Aminobisphosphonates Bisphosphonates Bisphosphonates Precursor cells Mature osteoclasts Accession Tumour cells Prostaglandins and other factors C

12. Proportion of Patients Having SREs Pooled Breast Cancer Clinical Trials (N = 756) 12 months 24 months P = .002 P < .001 P = .078 P < .001 P < .001 P = .002 Lipton A, et al. Cancer . 2000;88:1082-1090. Novartis. Data on file. 39 Pam 90 mg Placebo

13. Proportion of Patients Having SREs Multiple Myeloma (N = 377) 9 months 21 months P < .001 P = .049 P = .004 P = .015 P = .060 P = .255 Berenson JR, et al. N Engl J Med. 1996;334:488-493. Berenson JR, et al. J Clin Oncol . 1998;16:593-602. 39 Pam 90 mg Placebo

15. Effects of Pamidronate on Pain and Analgesic Consumption Breast cancer Chemotherapy 24 mo Breast cancer Endocrine 24 mo Multiple myeloma 9 mo P = .028 P = .009 P = .011 P = < .001 P = .089 P = .050 Pain and analgesic scores at the last measurement mean change from baseline C Pamidronate Placebo

17. (–HCM) at 6 months—Protocols 032 and INT05 Total N = 378 24% 24% P = 1.0 Proportion with SRE (–HCM) SRE SMR Mean SMR (–HCM) P = .942 17 0.30 0.29 Pamidronate in Prostate Cancer No Effect on Proportion of Patients With SRE and Mean SMR Lipton A, et al. Cancer Invest . 2001;20:45-47.

24. Urinary N-telopeptide/Creatinine Ratio After the First and Subsequent (q4 wk) Doses of ZOMETA ® (Study 007) -80 -60 -40 -20 0 Baseline Wk 1 Wk 4 Wk 12 Wk 24 Wk 40 ZOMETA dose 1 2 3 4 5 6 7 8 9 Median % change from baseline ZOMETA 0.4 mg ZOMETA 2 mg ZOMETA 4 mg Pam 90 mg

25. Efficacy in Hypercalcaemia of Malignancy Pooled Protocols 036 and 037— complete response rate: normalisation of corrected serum calcium  10.8 mg/dL (  2.7 mmol/L) Complete responders (%) *Denotes statistical significance versus pamidronate. Major P, et al. J Clin Oncol. 2001;19:558-567. 83.3% P = .010* 56% P = .021* 88% P = .002* 87% P = .015* 82.6% P = .005* 45% 33% 64% 70% C