1. Bisfosfonaten in de Oncologie
Dr. H.P. Sleeboom
Hagaziekenhuis Den Haag

2. Botmetastasen

3. Trabecular Bone Destroyed by Osteoclasts
Due to Tumor Osteolysis
Figure from
L Mosekilde

4. 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
Clinical Importance and Prognosis of
Bone Metastases
NCI, 1997; International Myeloma Foundation, 2001.

5. Osteolysis in Multiple Myeloma

6. Osteoblastic Vertebral Metastases

7. Increased
bone
resorption
Hypercalcaemia
Fracture
Bone pain
Clinical Consequences of Increased
Bone Resorption
Bone

8. The Burden of Skeletal Complications in
Metastatic Bone Disease
% of patients affected in placebo arms of
bisphosphonate trials
Disease Breast Myeloma Prostate Others
Observation time 12 months 9 months 15 months 9 months
Radiation to bone 33 22 29 32
Fractures 41 30 22 21
Hypercalcaemia
of malignancy 9 6 1 3
Surgery to bone 8 5 3 4
Spinal cord
compression 2 3 7 4

9. Treatment of Bone Metastases
Traditional treatments
 Radiotherapy/radionuclides
 Endocrine treatment
 Chemotherapy
 Orthopaedic intervention
 Analgesics
Complementary approach
 Osteoclast inhibition

10. “ Skeletal Related Events”
 (dreigende) fracturen: chirurgie, radiotherapie
 myelumcompressie
 hypercalciëmie
 pijnscore, kwaliteit van leven
 nieuwe botmetastasen

11.  Meeste studies: systemische therapie +/- bisfosfonaat
 Weinig grote vergelijkende studies tussen amino – en niet -
aminobisfosfonaten
 Hypercalciëmie behandeling: snelheid normaliseren
serumcalcium en duur response

12. Werking
Bisfosfonaten

13. Impact of Changes in Bone Remodelling
Coupled and
balanced
Bone
Uncoupled but
balanced
Bone
Coupled but
imbalanced
Bone
Uncoupled and
imbalanced
Bone

14.  Gemetastaseerde maligniteiten
 Niet – gemetastaseerde maligniteiten

15. Prostaatcarcinoom

16. (–HCM) at 6 months—Protocols 032 and INT05
Total N = 378
0
0.1
0.2
0.3
0.4
Total
24% 24%
P = 1.0
ProportionwithSRE(–HCM)
SRE SMR
MeanSMR(–HCM)
0
0.2
0.4
0.6
0.8
Total
Pam 90 mg
Placebo
P = .942
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.

17. Placebo q 3 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
Zoledronic acid 4 mg* q 3 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
Prostate Cancer
Trial Design
0 15 months
Core analysis
24 months
Final analysis
RR
AA
NN
DD
OO
MM
II
ZZ
EE
DD
N = 214
N = 208
• Stratification based on presence or absence of any distant
metastases at initial diagnosis of cancer
• 221 patients were randomized to receive zoledronic acid 8 mg and then
reduced to 4 mg; no efficacy conclusions drawn from 8/4 mg group

18. Prostate Cancer
Percentage of Patients With an SRE
38
49
0
10
20
30
40
50
60
Zoledr acid 4mg (N = 214) Placebo (N = 208)
Percentofpatients
P = .028
Significantly fewer patients (22% relative reduction) experienced
an SRE
 Zoledronic acid 4 mg versus placebo remained
significant when asymptomatic fractures were excluded

19. Prostate Cancer
Percentage of Patients With Each SRE
26
17
4
6
2
0
33
25
8 7
4
1
0
5
10
15
20
25
30
35
Radiation to
bone
Fractures Spinal cord
compression
Antineoplastic
therapy
Surgery to
bone
Hypercalcemia
Percentofpatients
Zoledr acid 4 mg (N = 214) Placebo (N = 208)
Zoledronic acid consistently reduces all types of SREs

20. Prostate Cancer
Time to First SRE
Significant delay onset of skeletal complications by > 5 months
*After start of study drug.
0
20
40
60
80
100
0 120 240 360 480 600 720
Days*
Percentwithoutevent
Median,
days P value
Zoledr acid 4 mg 488 .009
Placebo 321

21. Prostate Cancer
Time to First Pathologic Fracture
Significant delay onset of fractures by > 6 months
0
20
40
60
80
100
0 120 240 360 480 600 720
Days*
Percentwithoutevent
Median,
days P value
Zoledr acid 4 mg NR .020
Placebo NR
*After start of study drug.
NR = not reached

22. Prostate Cancer
Survival
0
20
40
60
80
100
0 120 240 360 480 600 720 840 960
Days*
Percentsurviving
Median,
days P value
Zoledr acid 4 mg 546 .103
Placebo 469
*Time after start of study drug.

23. Mammacarcinoom

24. Oral ibandronate study MF 4434
 Randomized, double-blind,
placebo-controlled phase III study
 Treatment group (one tablet per day
before breakfast)
– placebo
– 20mg ibandronate
– 50mg ibandronate
 Duration: up to 96 weeks
 Companion study of similar design
completed and under analysis

25. Patient disposition
Entered study
443 patients*
Number evaluable
435 patients
Placebo
143 patients
20mg ibandronate
144 patients
50mg ibandronate
148 patients
Completed
54 patients
Withdrawn
89 patients
Completed
55 patients
Withdrawn
89 patients
Completed
63 patients
Withdrawn
85 patients
PWFU data
additional
69 patients
PWFU data
additional
56 patients
PWFU data
additional
56 patients
*Australia/New Zealand, Russia, South Africa, USA

26. Primary endpoint events
All new bone events
Placebo
(n=143)
20mg
ibandronate
(n=144)
50mg
ibandronate
(n=148) p-value
Mean number of events
per patient
2.23 1.36
p=0.001
1.43
p=0.014
0.017
Mean number of
measurement periods
with events per patient
1.27 0.79
p=0.002
0.84
p=0.014
0.017
Total number of periods
with events
182 114
p=0.002
125
p=0.014
0.017
Percentage of patients
with events
61.5 46.5
p=0.011
52.0
p=0.102
0.036

27. Breast Cancer and Multiple Myeloma
Strata*
zoledronic acid pamidronate
4 mg 90 mg
N = 561 N = 555
Breast cancer 378 388
Chemotherapy 178 181
Hormonal therapy 200 207
Multiple myeloma 183 167
*ITT population.

28. Breast Cancer and Multiple Myeloma
Trial Design
0 13 months
Core analysis
25 months
Final analysis
R
A
N
D
O
M
I
Z
E
D
Zoledronic acid 4 mg* q 3 to 4 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
Pamidronate q 3 to 4 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
N = 564
N = 558
• Stratification based on multiple myeloma, breast cancer patients receiving
chemotherapy, and breast cancer patients receiving hormonal therapy
• 526 patients were randomized to receive zoledronic acid 8 mg and then
reduced to 4 mg; no efficacy conclusions drawn from 8/4 mg group

29. Zoledronic acid in Patients With Breast Cancer and
Osteolytic Lesion(s)
Time to First Skeletal Complication
0
10
20
30
40
50
60
70
80
90
100
0 50 100 150 200 250 300
Days*
Percentwithoutevent
Zole 4 mg 310 .013
Pam 90 mg 174
Median time,
days P value
Zoledronic acid delays the onset of skeletal complications
by 4.5 months in patients with osteolytic lesions
*After start of study drug.

30. Zoledronic acid in Patients With Breast Cancer and
Osteolytic Lesion(s)
Multiple-Event Analysis
Zoledronic acid significantly reduces the risk of developing a
skeletal complication in patients with osteolytic lesions
Relative risk (zole 4 mg versus pam)
In favor of zole In favor of pamidronate
P value
Osteolytic
lesions
.010
All
patients
.037
0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 20
No
osteolytic
lesions
.760

31. Overview
Multiple-Event Analysis
Relative risk (zole 4 mg versus placebo)
P value
.010
.028
.151
Other
solid
tumors
NSCLC
Other
In favor of zole In favor of placebo
Prostate
cancer .002
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
P value
Relative risk (zole 4 mg versus pam)
Total
In favor of zole In favor of pam
Multiple
myeloma
0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 20
Zoledronic acid decreases the risk of a skeletal
complication
Breast
cancer
.059
.731
.042

32. Bijwerkingen
 Osteonecrosis of the jaw

33. Preventie Botmetastasen
Randomized, placebo controlled trial of
Clodronate in patients with primary
operable breastcancer
Powles T et al. J.Clin. Oncology. 2002 : 3219 - 3224

34. Clodronaat 1600 mg per dag oraal –
versus placebo gedurende 2 jaar.
Mediane follow up 2007 dagen
Powles T et al. J.Clin. Oncology. 2002 : 3219 - 3224

35. Clodronaat
N = 530 %
Placebo
N = 539 % P
patiënt met
botmeta.
63 11.9 80 14.8 0.127
medicatie
periode
12 2.3 28 5.2 0.016
follow up
periode
51 9.6 52 9.7 0.732

36. Clodronaat
N = 530 %
Placebo
N = 539 % P
patiënt met
extra ossale
metastasen
112 21.1 128 23.7 0.257
medicatie
periode
38 7.2 39 7.2 1.0
follow up
periode
74 14.0 89 16.5 0.139
metastasen 139 26.2 145 26.9
overleden 98 18.5 129 23.9 0.047

37. Conclusie:
Significante reductie botmetastasen
tijdens behandeling
Significante reductie mortaliteit

38. Asco 2008
Adjuvant ovarian suppression combined with tamoxifen
or anastrozole, alone or in combination with zoledronic
acid, in premenopausal women with hormone
responsive, stage I and II breast cancer: First efficacy
results from ABGSG-12
M.Gnant et al.

39. Studie Gnant
 1801 vrouwen
 Gosereline
 Anastrozole versus Tamoxifen
 +/- Zoledroninezuur: 4 mg iv/ 6 maanden

40. Studie Gnant
 60 maanden mediane follow-up
 Disease free survival:
* Zoledroninezuur behandelde groep
reductie van 36 %
H R 0.64 95 % C I 0.46 – 0.91
p = 0.01

41. Studie Gnant
 Relapse free survival
* zoledroninezuur behandelde groep
reductie van 35 %
H R 0.65 95 % CI 0.46 – 0.92
p = 0.015

42. Studie Gnant
 Geen verschil overall survival
* H R 0.60 95% C I 0.60 - 1.11
p= 0.10

43. Bisfosfonaten bij
aromataseremmers

44. 14
Tumor cellTumor cell
NucleusNucleus
AndrostenedioneAndrostenedioneAndrostenedione
Intracellular Aromatase
AndrostenedioneAndrostenedioneAndrostenedione
Human Breast
Adipose
Fibroblasts
Human BreastHuman Breast
AdiposeAdipose
FibroblastsFibroblasts
A
R
O
M
A
T
A
S
E
AA
RR
OO
MM
AA
TT
AA
SS
EE
A
R
O
M
A
T
A
S
E
AA
RR
OO
MM
AA
TT
AA
SS
EE
Letrozole
Anastrozole
LetrozoleLetrozole
AnastrozoleAnastrozole
Hamster
Ovarian
Tissue
HamsterHamster
OvarianOvarian
TissueTissue
Endocrine
cell
Endocrine
cell

45. Normal Bone
Osteoporosis
A skeletal disorder characterized by compromised
bone strength predisposing a person to an increased
risk of fracture.
National Institutes of Health (USA)
Consensus Development Panel on Osteoporosis Prevention,
Diagnosis, and Therapy, 2001.
Osteoporosis

46. Therapy-Induced Bone Loss May Increase
Fracture Risk in Breast Cancer Patients
1. Coleman RE, et al. J Clin Oncol. 2006;24(18S):5s. Abstract 511. 2. Baum M, et al. Cancer. 2003;98:1802-1810.
3. Howell A, et al. Lancet. 2005;365:60-62.
37 Months2
68 Months3
Anastrozole
Tamoxifen
Δ
Lumbar
Spine
BMD, %1
Year
Δ
Total
Hip
BMD, %1
Year
4
0
-4
-8
4
0
-4
-8
1 2 5
0
3
6
9
12
Fractures,
%
1 2 5
Data from the Arimidex®
, Tamoxifen, Alone or in Combination (ATAC) study.
N = 9366 postmenopausal women with localized breast cancer.
P < .001
P < .0001 P < .0001

47. Zofast studie
 Zoledroninezuur bij letrozole
upfront of delayed
bij adjuvante behandeling
mammacarcinoom

48. Zofast studie
 BMD after 12 month
upfront delayed
 L2 – L4 + 4.39 % - 4.9 %
 Hip + 1.89 % - 3.52 %
p= < 0.0001

49. Proposed Trt Algorithm for AI-induced
bone loss
T-score < -2.0
Monitor BMD
every 2 years
Bisphosphonate
therapy
(e.g.zoledronic acid
4 mg/6 months)
plus calcium and Vit. D
supplements
Calcium and
Vitamin D
Exercise?
Monitor risk status
and BMD
every 1-2 years
T-score ≥ -2.0
No additional
Risk factors
Any 2 of the following risk factors:
-T-score < -1.5
- age > 65 years
- low BMI
- Family history of hip fracture
- Personal history of fragility fracture
after age 50
- Oral corticosteroid use of > 6 months
- Smoking (current and history of)
Patient with breast cancer
initiating AI therapy
Hadji, Body, Aapro et al.; Ann Oncol 2008

50. Tenslotte….

51. Adapted from Roodman D. N Engl J Med. 2004;350:1655.
Osteoblasts
Activated
Osteoclast
RANKL
RANK
Cytokines and
Growth Factors
Growth
Factors
Cancer Cells in Bone
Metastasis
RANK Ligand is a Key Mediator in the ‘Vicious
Cycle’ of Bone Destruction in Metastatic Cancer
Bone
Resorption
Osteolytic Lesions

52. RANK Ligand is Implicated in Bone Loss
Across a Broad Range of Conditions
Post-
Menopausal
Osteoporosis
Male
Osteoporosis
Rheumatoid
Arthritis
Pathological Bone Loss
Glucocorticoid-
Induced
Osteoporosis
Therapy-
Related Bone
Loss
Treatment-Induced
Bone Loss
Gluco-
corticoids
Aromatase
Inhibitors
Androgen
Deprivation
Therapy
Bone
Metastases/
Multiple Myeloma
Cancer-
Related Bone
Destruction