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Prof. Robert Coleman, MD, FRCP Cancer Research Centre
Pathophysiology C 4/19/2017 1:42 AM Pathophysiology of Metastatic Bone Disease and the Role of Bisphosphonates Prof. Robert Coleman, MD, FRCP Cancer Research Centre Weston Park Hospital Sheffield, England
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Clinical Importance and Prognosis of Bone Metastases
Disease prevalence, Bone mets. Median U.S. (in thousands) incidence (%) survival (mo) Myeloma Renal Melanoma Bladder Thyroid Lung Breast 1, Prostate NCI, 1997; International Myeloma Foundation, 2001.
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Skeletal Complications in Metastatic Bone Disease Are Significant
% of patients affected in PLACEBO arms of: Pamidronate trials ZOMETA® trials Disease Breast Myeloma Prostate Others Observation time 12 months 9 months 15 months 9 months Radiation to bone Fractures Hypercalcaemia of malignancy Surgery to bone Spinal cord compression
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Pathophysiology of Bone Metastases
C Pathophysiology of Bone Metastases Role of the osteoclast in bone pathology Tumour cells Primary Bone secondaries Systemic factors Local factors Osteoclast activity Osteolysis Growth factors Direct bone destruction Activated osteoclast Bone Bony complications
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Cancer and Bone Cell Interactions
Osteolytic bone disease Osteoblastic bone disease TGF- Unknown GFs Osteoblast Osteoclast
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Bone Remodelling Cancer Effects
Coupled and balanced Bone Coupled but imbalanced Bone Uncoupled but balanced Bone Uncoupled and imbalanced Bone
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Bone Markers in Osteolytic and Osteosclerotic Metastatic Bone Disease
60 500 50 400 40 300 Bone-specific alkaline phosphatase (ng/mL) 30 N-telopeptide (BCE/M Cr) 200 20 100 10 Lytic Blastic Mixed Lytic Blastic Mixed X-ray pattern X-ray pattern Lipton A. Semin Oncol. 2001;28:54-59.
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Consequences of Increased Bone Resorption
Hypercalcaemia Increased bone resorption Fracture Bone pain Bone
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Treatment of Bone Metastases
C Treatment of Bone Metastases Traditional treatments Radiotherapy/radionuclides Endocrine treatment Chemotherapy Orthopaedic intervention Analgesics Complementary approach Osteoclast inhibition
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Bisphosphonate Pharmacology
Proposed mode of action Aminobisphosphonates Bisphosphonates Mature osteoclasts Precursor cells Prostaglandins and other factors Accession Tumour cells Bisphosphonates
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Prevention of Skeletal-Related Events Phase III Pamidronate Studies
C Prevention of Skeletal-Related Events Phase III Pamidronate Studies Breast cancer Conte, 1996 (N = 295) - chemotherapy§ Increased time to progression versus 168 days (P = .02) Hultborn, 1996 (N = 401) - chemotherapy§ Increased time to progression - 14 versus 9 months (P < .01) Theriault, 1999 (N = 374) - endocrine Reduced proportion of SREs - 47% versus 57% (P = .057) Hortobagyi, 1996 (N = 382) - chemotherapy Reduced proportion of SREs - 43% versus 56% (P = .008) Myeloma Berenson, 1996 (N = 377) - first and second-line therapy Reduced proportion of SREs - 24% versus 41% (P < .001) §Not placebo-controlled.
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39 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 Pam 90 mg Placebo Lipton A, et al. Cancer. 2000;88: Novartis. Data on file.
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Proportion of Patients Having SREs Multiple Myeloma (N = 377)
39 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 Pam 90 mg Placebo Berenson JR, et al. N Engl J Med. 1996;334: Berenson JR, et al. J Clin Oncol. 1998;16:
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C Total Number of SREs Recorded During Randomised Clinical Trials of Pamidronate Breast Breast Myeloma Protocol 19 Protocol 18 Protocol mo 24 mo 21 mo Pam Pam Pam SRE 90 mg Placebo 90 mg Placebo 90 mg Placebo All SRE (+HCM) Pathologic fracture Vertebral fracture Nonvertebral fracture Radiation to bone Surgery to bone Spinal cord compression Hypercalcaemia
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Effects of Pamidronate on Pain and Analgesic Consumption
Pain and analgesic scores at the last measurement mean change from baseline 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 Pamidronate Placebo
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Prostate Cancer and Other Tumours
Increased bone resorption with osteosclerotic metastases Useful pain relief from acute high-dose bisphosphonate treatment No previous randomised trial evidence for bisphosphonate effects on SREs
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Proportion with SRE (–HCM)
17 Pamidronate in Prostate Cancer No Effect on Proportion of Patients With SRE and Mean SMR (–HCM) at 6 months—Protocols 032 and INT05 Total N = 378 SRE SMR P = 1.0 24% 24% Mean SMR (–HCM) P = .942 Proportion with SRE (–HCM) 0.30 0.29 Lipton A, et al. Cancer Invest. 2001;20:45-47.
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Adverse Events Profile of Pamidronate
Acute phase response Fever, myalgia, arthralgia Anaemia Mineral disorders Renal effects Dose and infusion time related
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Zoledronic Acid Zoledronic acid is a new, highly potent bisphosphonate
Pathophysiology 4/19/2017 1:42 AM Zoledronic Acid Zoledronic acid is a new, highly potent bisphosphonate Heterocyclic nitrogen-containing bisphosphonate composed of A core bisphosphonate moiety An imidazole-ring side chain containing 2 critically positioned nitrogen atoms Green JR, et al. J Bone Miner Res. 1994;9: Green JR, et al. Pharmacol Toxicol. 1997;80:
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ZOMETA® Key Preclinical Properties
In vitro Potently inhibits osteoclast formation and bone resorption regardless of pathogenetic stimulus In vivo Potently inhibits bone resorption in a variety of models of benign and malignant bone disease irrespective of tumour types Preserves bone architecture and strength Novel anti-angiogenic and anti-pain effects Reduces the number and size of bone metastases in models of tumour-induced osteolysis
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ZOMETA® Key Clinical Pharmacology Properties
39 ZOMETA® Key Clinical Pharmacology Properties Similar to other bisphosphonates in vitro Low protein binding; no uptake by red blood cells No interaction with CYP450 metabolising enzymes Similar to other bisphosphonates in vivo Rapid postinfusion decline of plasma concentrations of drug; plasma drug concentrations are dose proportional Majority of drug is taken up by bone; remainder is rapidly eliminated into urine unchanged (ca. 40% of dose 0-24h) §Berenson J, et al. J Clin Pharmacol. 1997;37:285.
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ZOMETA® Key Clinical Pharmacology Properties
Mild to moderate renal impairment (CLcr mL/min) is associated with a small increase in AUC0-24h and Cmax, but has no effect on urinary excretion The increase in AUC0-24h and Cmax is not affected by cumulative dose Dose adjustments in renal impairment (CLcr mL/min) are not needed Normal Mild Moderate/Severe 900 800 700 600 AUC0-24h, ng/mL•h 500 400 300 200 100 1 2 3 Treatment cycle
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Phase II Study (007) Results Support ZOMETA® 4-mg Infusion Every 3 to 4 Wk
ZOMETA® given every 4 wk produced sustained effects on serum and urinary markers of bone resorption The 4-mg dose was most effective in suppressing markers of bone resorption Skeletal events and pathologic fractures occurred slightly less frequently in patients treated with 4 mg than 2 mg ZOMETA ZOMETA 0.4 mg was clearly ineffective compared with 2 mg and 4 mg Time to first skeletal event in breast cancer patients was almost 2 mo longer in the 4-mg versus 2-mg dose group
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Median % change from baseline
Urinary N-telopeptide/Creatinine Ratio After the First and Subsequent (q4 wk) Doses of ZOMETA® (Study 007) ZOMETA 0.4 mg ZOMETA 2 mg ZOMETA 4 mg Pam 90 mg -20 Median % change from baseline -40 -60 -80 Baseline Wk 1 Wk 4 Wk 12 Wk 24 Wk 40 ZOMETA dose
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Efficacy in Hypercalcaemia of Malignancy
Pathophysiology C 4/19/2017 1:42 AM Efficacy in Hypercalcaemia of Malignancy 88% P = .002* 83.3% P = .010* 87% P = .015* 82.6% P = .005* 56% P = .021* 70% 64% Complete responders (%) 45% 33% Please add text for each treatment day Pooled Protocols 036 and 037—complete response rate: normalisation of corrected serum calcium 10.8 mg/dL ( 2.7 mmol/L) *Denotes statistical significance versus pamidronate. Major P, et al. J Clin Oncol. 2001;19:
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Conclusions Metastatic bone disease is an important healthcare problem
Pathophysiology is similar across all tumour types Osteoclast activation accompanies all bone metastases Currently available bisphosphonates have a limited range of activity ZOMETA® is a potent inhibitor of osteoclast activity and provides a bone-specific treatment
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