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PA-1
Pathophysiology of Metastatic Bone Disease and the
Role of Bisphosphonates
Prof. Robert Coleman, MD, FRCPCancer Research Centre
Weston Park HospitalSheffield, England
C
PA-2
Disease prevalence, Disease prevalence, Bone mets. Bone mets. MedianMedianU.S. (in thousands)U.S. (in thousands) incidence (%)incidence (%) survival (mo) survival (mo)
MyelomaMyeloma 75 - 100 75 - 100 70 - 9570 - 95 2424RenalRenal 198 198 20 - 2520 - 25 1212MelanomaMelanoma 467 467 14 - 4514 - 45 66BladderBladder 582 582 4040 6 - 96 - 9ThyroidThyroid 207 207 6060 4848LungLung 386 386 30 - 4030 - 40 77BreastBreast 1,993 1,993 65 - 7565 - 75 2424ProstateProstate 984 984 65 - 7565 - 75 3636
Clinical Importance and Prognosis of Bone Metastases
C
NCI, 1997; International Myeloma Foundation, 2001.
PA-3
Skeletal Complications in Metastatic Bone Disease Are Significant
% of patients affected in PLACEBO arms of:
Pamidronate trials ZOMETA® trials
Disease Breast Myeloma Prostate OthersObservation time 12 months 9 months 15 months 9 months
Radiation to bone 33 22 29 32
Fractures 41 30 22 21
Hypercalcaemiaof malignancy 9 6 1 3
Surgery to bone 8 5 3 4
Spinal cordcompression 2 3 7 4
C
PA-4
Role of the osteoclast in bone pathology
Growthfactors
Osteoclast activity
Osteolysis Direct bone destruction
Bone
Bone secondariesPrimary
Local factorsSystemic factors
Tumour cells
Bony complications
Pathophysiology of Bone Metastases
C
Activatedosteoclast
PA-5
Cancer and Bone Cell Interactions
C
Osteolytic bone disease Osteoblastic bone disease
Osteoclast
Osteoblast
UnknownGFs
TGF-
PA-6
Bone RemodellingCancer Effects
C
Coupled andbalanced
Bone
Uncoupled butbalanced
Bone
Coupled butimbalanced
Bone
Uncoupled andimbalanced
Bone
PA-7
Lytic Blastic MixedX-ray pattern
Bo
ne
-sp
ec
ific
alk
alin
e p
ho
sp
hat
as
e (
ng
/mL
)
N-t
elo
pe
pti
de
(BC
E/M
Cr)
Bone Markers in Osteolytic and Bone Markers in Osteolytic and Osteosclerotic Metastatic Bone DiseaseOsteosclerotic Metastatic Bone Disease
0
10
30
20
40
50
60
Lytic Blastic MixedX-ray pattern
0
100
300
200
400
500
C
Lipton A. Semin Oncol. 2001;28:54-59.
PA-8
Increasedbone
resorption
Hypercalcaemia
Fracture
Bone pain
Consequences of Increased Bone Resorption
C
Bone
PA-9
Treatment of Bone Metastases
Traditional treatmentsTraditional treatments Radiotherapy/radionuclides
Endocrine treatment
Chemotherapy
Orthopaedic intervention
Analgesics
Complementary approachComplementary approach
Osteoclast inhibition
C
PA-10
Bisphosphonate Pharmacology
Proposed mode of actionProposed mode of action
Aminobisphosphonates Bisphosphonates
Bisphosphonates
Precursorcells
Matureosteoclasts
Accession
Tumourcells
Prostaglandinsand other
factors
C
PA-11
§Not placebo-controlled.
Prevention of Skeletal-Related Events Phase III Pamidronate Studies
Breast cancer Conte, 1996 (N = 295) - chemotherapy§
– Increased time to progression - 249 versus 168 days (P = .02) Hultborn, 1996 (N = 401) - chemotherapy§
– Increased time to progression - 14 versus 9 months (P < .01)
C
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)
PA-12
Proportion of Patients Having SREsPooled Breast Cancer Clinical Trials (N = 756)
45
20
35
56
3341
0
20
40
60
80
100
All SREs(–HCM)
Radiationto bone
Fractures
Pe
rce
nt
of
pa
tie
nts
51
29
40
64
4352
0
20
40
60
80
100
All SREs(–HCM)
Radiationto bone
Fractures
Pe
rce
nt
of
pa
tie
nts
Pam 90 mg Placebo
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
PA-13
Proportion of Patients Having SREsMultiple Myeloma (N = 377)
2414 17
41
2230
0
20
40
60
80
100
All SREs(–HCM)
Radiationto bone
Fractures
Per
cen
t o
f p
atie
nts
38
2531
51
34 37
0
20
40
60
80
100
All SREs(–HCM)
Radiationto bone
FracturesP
erce
nt
of
pat
ien
ts
Pam 90 mg Placebo
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
PA-14
Total Number of SREs Recorded During Randomised Clinical Trials of Pamidronate
Breast Breast MyelomaProtocol 19 Protocol 18 Protocol 12
24 mo 24 mo 21 mo
Pam Pam PamSRE 90 mg Placebo 90 mg Placebo 90 mg Placebo
All SRE (+HCM)All SRE (+HCM) 387387 630630 475475 648648 307307 376376
Pathologic fracturePathologic fracture 251251 349349 331331 403403 170170 189189
Vertebral fractureVertebral fracture 103103 148148 115115 143143 9696 123123
Nonvertebral fractureNonvertebral fracture 148148 201201 216216 260260 7474 6666
Radiation to boneRadiation to bone 105105 207207 114114 192192 9797 129129
Surgery to boneSurgery to bone 1414 2828 1515 2424 1515 2525
Spinal cord compressionSpinal cord compression 44 77 77 88 22 88
HypercalcaemiaHypercalcaemia 1313 3939 88 2121 2323 2525
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PA-15
Effects of Pamidronate on Pain and Analgesic Consumption
Breast cancerBreast cancerChemotherapyChemotherapy
24 mo24 mo
Breast cancerBreast cancerEndocrine
24 mo
MultipleMultiplemyelomamyeloma
9 mo9 mo
1.52 1.55
0.590.74
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Pain scoreRTOG
AnalgesicscoreRTOG
P = .028 P = .009
1.38
2.28
0.24
0.9
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Pain scoreRTOG
AnalgesicscoreRTOG
P = .011 P = < .001
0.180.55
-0.46-0.09
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Pain scoreRTOG
AnalgesicscoreRTOG
P = .089 P = .050
Pamidronate Placebo
Pain and analgesic scores at the last measurement mean change from baseline
C
PA-16
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
C
PA-17
(–HCM) at 6 months—Protocols 032 and INT05Total N = 378
0
0.1
0.2
0.3
0.4
Total
24% 24%
P = 1.0
Pro
po
rtio
n w
ith
SR
E (
–HC
M)
SRE SMR
Mea
n S
MR
(–H
CM
)
0
0.2
0.4
0.6
0.8
Total
Pam 90 mgPlacebo
P = .942
17
0.30 0.29
Pamidronate in Prostate CancerNo Effect on Proportion of Patients With SRE and Mean SMR
Lipton A, et al. Cancer Invest. 2001;20:45-47.
PA-18
Adverse Events Profile of Pamidronate
Acute phase response
– Fever, myalgia, arthralgia
Anaemia
Mineral disorders
Renal effects
– Dose and infusion time related
PA-19
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;9:745-751.Green JR, et al. Pharmacol Toxicol. 1997;80:225-230.
C
PA-20
ZOMETA® Key Preclinical Properties
In vitroIn vitro Potently inhibits osteoclast formation and bone
resorption regardless of pathogenetic stimulus
C
In vivoIn 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
PA-21
ZOMETA®
Key Clinical Pharmacology Properties
Similar to other bisphosphonates Similar to other bisphosphonates in vitroin vitro
Low protein binding; no uptake by red blood cells
No interaction with CYP450 metabolising enzymes
Similar to other bisphosphonates Similar to other bisphosphonates in vivoin 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)
39
§Berenson J, et al. J Clin Pharmacol. 1997;37:285.
PA-22
Mild to moderate renal impairment (CLcr 30 - 80 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 30 - 80 mL/min) are not needed
Treatment cycle
1 2 3
AU
C0-
24h, n
g/m
L•h
100
200
300
400
500
600
700
800
900
Normal Mild Moderate/Severe
ZOMETA®
Key Clinical Pharmacology Properties
PA-23
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
PA-24Urinary 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
Med
ian
% c
han
ge
fro
m
bas
elin
e
ZOMETA 0.4 mg ZOMETA 2 mg
ZOMETA 4 mg Pam 90 mg
PA-25
Pooled Protocols 036 and 037—complete response rate: normalisation of corrected serum calcium 10.8 mg/dL ( 2.7 mmol/L)
Co
mp
lete
res
po
nd
ers
(%)
*Denotes statistical significance versus pamidronate. Major P, et al. J Clin Oncol. 2001;19:558-567.
Efficacy in Hypercalcaemia of Malignancy
0
20
40
60
80
100
Day 0 Day 4 Day 7 Day 10
ZOMETA® 4 mg (n = 86)
ZOMETA 8 mg (n = 90)
Pamidronate 90 mg (n = 99)
83.3%P = .010*
56%P = .021*
88%P = .002*
87%P = .015*82.6%
P = .005*
45%
33%
64%70%
C
PA-26
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 limitedrange of activity
ZOMETA® is a potent inhibitor of osteoclast activity and provides a bone-specific treatment
C