Pathophysiology of Metastatic Bone Disease and the Role of Bisphosphonates

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  • 04/07/10 07:07 Please add text for each treatment day
  • Pathophysiology of Metastatic Bone Disease and the Role of Bisphosphonates

    1. 1. Pathophysiology of Metastatic Bone Disease and the Role of Bisphosphonates C
    2. 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.
    3. 3. Skeletal Complications in Metastatic Bone Disease Are Significant <ul><li> % of patients affected in PLACEBO arms of: </li></ul><ul><li> Pamidronate trials ZOMETA ® trials </li></ul><ul><li>Disease Breast Myeloma Prostate Others Observation time 12 months 9 months 15 months 9 months </li></ul><ul><li>Radiation to bone 33 22 29 32 </li></ul><ul><li>Fractures 41 30 22 21 </li></ul><ul><li>Hypercalcaemia of malignancy 9 6 1 3 </li></ul><ul><li>Surgery to bone 8 5 3 4 </li></ul><ul><li>Spinal cord compression 2 3 7 4 </li></ul>C
    4. 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. 5. Cancer and Bone Cell Interactions C Osteolytic bone disease Osteoblastic bone disease Osteoclast Osteoblast Unknown GFs TGF- 
    6. 6. Bone Remodelling Cancer Effects C Coupled and balanced Bone Uncoupled but balanced Bone Coupled but imbalanced Bone Uncoupled and imbalanced Bone
    7. 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. 8. Consequences of Increased Bone Resorption Increased bone resorption Hypercalcaemia Fracture Bone pain C Bone
    9. 9. Treatment of Bone Metastases <ul><li>Traditional treatments </li></ul><ul><li>Radiotherapy/radionuclides </li></ul><ul><li>Endocrine treatment </li></ul><ul><li>Chemotherapy </li></ul><ul><li>Orthopaedic intervention </li></ul><ul><li>Analgesics </li></ul><ul><li>Complementary approach </li></ul><ul><li>Osteoclast inhibition </li></ul>C
    10. 10. Bisphosphonate Pharmacology Proposed mode of action Aminobisphosphonates Bisphosphonates Bisphosphonates Precursor cells Mature osteoclasts Accession Tumour cells Prostaglandins and other factors C
    11. 11. Prevention of Skeletal-Related Events Phase III Pamidronate Studies <ul><li>Breast cancer </li></ul><ul><li>Conte, 1996 (N = 295) - chemotherapy § </li></ul><ul><ul><li>Increased time to progression - 249 versus 168 days ( P = .02) </li></ul></ul><ul><li>Hultborn, 1996 (N = 401) - chemotherapy § </li></ul><ul><ul><li>Increased time to progression - 14 versus 9 months ( P < .01) </li></ul></ul>§Not placebo-controlled. C <ul><li>Theriault, 1999 (N = 374) - endocrine </li></ul><ul><ul><li>Reduced proportion of SREs - 47% versus 57% ( P = .057) </li></ul></ul><ul><li>Hortobagyi, 1996 (N = 382) - chemotherapy </li></ul><ul><ul><li>Reduced proportion of SREs - 43% versus 56% ( P = .008) </li></ul></ul><ul><li>Myeloma </li></ul><ul><li>Berenson, 1996 (N = 377) - first and second-line therapy </li></ul><ul><ul><li>Reduced proportion of SREs - 24% versus 41% ( P < .001) </li></ul></ul>
    12. 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. 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
    14. 14. Total Number of SREs Recorded During Randomised Clinical Trials of Pamidronate <ul><li>Breast Breast Myeloma Protocol 19 Protocol 18 Protocol 12 24 mo 24 mo 21 mo </li></ul> Pam Pam Pam SRE 90 mg Placebo 90 mg Placebo 90 mg Placebo All SRE (+HCM) 387 630 475 648 307 376 Pathologic fracture 251 349 331 403 170 189 Vertebral fracture 103 148 115 143 96 123 Nonvertebral fracture 148 201 216 260 74 66 Radiation to bone 105 207 114 192 97 129 Surgery to bone 14 28 15 24 15 25 Spinal cord compression 4 7 7 8 2 8 Hypercalcaemia 13 39 8 21 23 25 C
    15. 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
    16. 16. Prostate Cancer and Other Tumours <ul><li>Increased bone resorption with osteosclerotic metastases </li></ul><ul><li>Useful pain relief from acute high-dose bisphosphonate treatment </li></ul><ul><li>No previous randomised trial evidence for bisphosphonate effects on SREs </li></ul>C
    17. 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.
    18. 18. Adverse Events Profile of Pamidronate <ul><li>Acute phase response </li></ul><ul><ul><li>Fever, myalgia, arthralgia </li></ul></ul><ul><li>Anaemia </li></ul><ul><li>Mineral disorders </li></ul><ul><li>Renal effects </li></ul><ul><ul><li>Dose and infusion time related </li></ul></ul>
    19. 19. Zoledronic Acid <ul><li>Zoledronic acid is a new, highly potent bisphosphonate </li></ul><ul><li>Heterocyclic nitrogen-containing bisphosphonate composed of </li></ul><ul><ul><li>A core bisphosphonate moiety </li></ul></ul><ul><ul><li>An imidazole-ring side chain containing 2 critically positioned nitrogen atoms </li></ul></ul>Green JR, et al. J Bone Miner Res . 1994;9:745-751. Green JR, et al. Pharmacol Toxicol. 1997;80:225-230. C
    20. 20. ZOMETA ® Key Preclinical Properties <ul><li>In vitro </li></ul><ul><li>Potently inhibits osteoclast formation and bone resorption regardless of pathogenetic stimulus </li></ul>C <ul><li>In vivo </li></ul><ul><li>Potently inhibits bone resorption in a variety of models of benign and malignant bone disease irrespective of tumour types </li></ul><ul><li>Preserves bone architecture and strength </li></ul><ul><li>Novel anti-angiogenic and anti-pain effects </li></ul><ul><li>Reduces the number and size of bone metastases in models of tumour-induced osteolysis </li></ul>
    21. 21. ZOMETA ® Key Clinical Pharmacology Properties <ul><li>Similar to other bisphosphonates in vitro </li></ul><ul><li>Low protein binding; no uptake by red blood cells </li></ul><ul><li>No interaction with CYP450 metabolising enzymes </li></ul><ul><li>Similar to other bisphosphonates in vivo </li></ul><ul><li>Rapid postinfusion decline of plasma concentrations of drug; plasma drug concentrations are dose proportional </li></ul><ul><li>Majority of drug is taken up by bone; remainder is rapidly eliminated into urine unchanged (ca. 40% of dose 0-24h) </li></ul>39 §Berenson J, et al. J Clin Pharmacol. 1997;37:285.
    22. 22. ZOMETA ® Key Clinical Pharmacology Properties <ul><li>Mild to moderate renal impairment (CL cr 30 - 80 mL/min) is associated with a small increase in AUC 0-24h and C max , but has no effect on urinary excretion </li></ul><ul><li>The increase in AUC 0-24h and C max is not affected by cumulative dose </li></ul><ul><li>Dose adjustments in renal impairment (CL cr 30 - 80 mL/min) are not needed </li></ul>Treatment cycle 1 2 3 AUC 0-24h , ng/mL•h 100 200 300 400 500 600 700 800 900 Normal Mild Moderate/Severe
    23. 23. Phase II Study (007) Results Support ZOMETA ® 4-mg Infusion Every 3 to 4 Wk <ul><li>ZOMETA ® given every 4 wk produced sustained effects on serum and urinary markers of bone resorption </li></ul><ul><li>The 4-mg dose was most effective in suppressing markers of bone resorption </li></ul><ul><li>Skeletal events and pathologic fractures occurred slightly less frequently in patients treated with 4 mg than 2 mg ZOMETA </li></ul><ul><li>ZOMETA 0.4 mg was clearly ineffective compared with 2 mg and 4 mg </li></ul><ul><li>Time to first skeletal event in breast cancer patients was almost 2 mo longer in the 4-mg versus 2-mg dose group </li></ul>
    24. 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. 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
    26. 26. Conclusions <ul><li>Metastatic bone disease is an important healthcare problem </li></ul><ul><li>Pathophysiology is similar across all tumour types </li></ul><ul><li>Osteoclast activation accompanies all bone metastases </li></ul><ul><li>Currently available bisphosphonates have a limited range of activity </li></ul><ul><li>ZOMETA ® is a potent inhibitor of osteoclast activity and provides a bone-specific treatment </li></ul>C

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