Bisfosfonaten in de Oncologie
Dr. H.P. Sleeboom
Hagaziekenhuis Den Haag
Botmetastasen
Trabecular Bone Destroyed by Osteoclasts
Due to Tumor Osteolysis
Figure from
L Mosekilde
Disease prevalence, Bone mets. Median
U.S. (in thousands) incidence (%) survival (mo)
Myeloma 75 - 100 70 - 95 24
Renal 19...
Osteolysis in Multiple Myeloma
Osteoblastic Vertebral Metastases
Increased
bone
resorption
Hypercalcaemia
Fracture
Bone pain
Clinical Consequences of Increased
Bone Resorption
Bone
The Burden of Skeletal Complications in
Metastatic Bone Disease
% of patients affected in placebo arms of
bisphosphonate t...
Treatment of Bone Metastases
Traditional treatments
 Radiotherapy/radionuclides
 Endocrine treatment
 Chemotherapy
 Or...
“ Skeletal Related Events”
 (dreigende) fracturen: chirurgie, radiotherapie
 myelumcompressie
 hypercalciëmie
 pijnsco...
 Meeste studies: systemische therapie +/- bisfosfonaat
 Weinig grote vergelijkende studies tussen amino – en niet -
amin...
Werking
Bisfosfonaten
Impact of Changes in Bone Remodelling
Coupled and
balanced
Bone
Uncoupled but
balanced
Bone
Coupled but
imbalanced
Bone
Un...
 Gemetastaseerde maligniteiten
 Niet – gemetastaseerde maligniteiten
Prostaatcarcinoom
(–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)
S...
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...
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)
P...
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
F...
Prostate Cancer
Time to First SRE
Significant delay onset of skeletal complications by > 5 months
*After start of study dr...
Prostate Cancer
Time to First Pathologic Fracture
Significant delay onset of fractures by > 6 months
0
20
40
60
80
100
0 1...
Prostate Cancer
Survival
0
20
40
60
80
100
0 120 240 360 480 600 720 840 960
Days*
Percentsurviving
Median,
days P value
Z...
Mammacarcinoom
Oral ibandronate study MF 4434
 Randomized, double-blind,
placebo-controlled phase III study
 Treatment group (one table...
Patient disposition
Entered study
443 patients*
Number evaluable
435 patients
Placebo
143 patients
20mg ibandronate
144 pa...
Primary endpoint events
All new bone events
Placebo
(n=143)
20mg
ibandronate
(n=144)
50mg
ibandronate
(n=148) p-value
Mean...
Breast Cancer and Multiple Myeloma
Strata*
zoledronic acid pamidronate
4 mg 90 mg
N = 561 N = 555
Breast cancer 378 388
Ch...
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
Zol...
Zoledronic acid in Patients With Breast Cancer and
Osteolytic Lesion(s)
Time to First Skeletal Complication
0
10
20
30
40
...
Zoledronic acid in Patients With Breast Cancer and
Osteolytic Lesion(s)
Multiple-Event Analysis
Zoledronic acid significan...
Overview
Multiple-Event Analysis
Relative risk (zole 4 mg versus placebo)
P value
.010
.028
.151
Other
solid
tumors
NSCLC
...
Bijwerkingen
 Osteonecrosis of the jaw
Preventie Botmetastasen
Randomized, placebo controlled trial of
Clodronate in patients with primary
operable breastcancer
...
Clodronaat 1600 mg per dag oraal –
versus placebo gedurende 2 jaar.
Mediane follow up 2007 dagen
Powles T et al. J.Clin. O...
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
...
Clodronaat
N = 530 %
Placebo
N = 539 % P
patiënt met
extra ossale
metastasen
112 21.1 128 23.7 0.257
medicatie
periode
38 ...
Conclusie:
Significante reductie botmetastasen
tijdens behandeling
Significante reductie mortaliteit
Asco 2008
Adjuvant ovarian suppression combined with tamoxifen
or anastrozole, alone or in combination with zoledronic
aci...
Studie Gnant
 1801 vrouwen
 Gosereline
 Anastrozole versus Tamoxifen
 +/- Zoledroninezuur: 4 mg iv/ 6 maanden
Studie Gnant
 60 maanden mediane follow-up
 Disease free survival:
* Zoledroninezuur behandelde groep
reductie van 36 %
...
Studie Gnant
 Relapse free survival
* zoledroninezuur behandelde groep
reductie van 35 %
H R 0.65 95 % CI 0.46 – 0.92
p =...
Studie Gnant
 Geen verschil overall survival
* H R 0.60 95% C I 0.60 - 1.11
p= 0.10
Bisfosfonaten bij
aromataseremmers
14
Tumor cellTumor cell
NucleusNucleus
AndrostenedioneAndrostenedioneAndrostenedione
Intracellular Aromatase
Androstenedio...
Normal Bone
Osteoporosis
A skeletal disorder characterized by compromised
bone strength predisposing a person to an increa...
Therapy-Induced Bone Loss May Increase
Fracture Risk in Breast Cancer Patients
1. Coleman RE, et al. J Clin Oncol. 2006;24...
Zofast studie
 Zoledroninezuur bij letrozole
upfront of delayed
bij adjuvante behandeling
mammacarcinoom
Zofast studie
 BMD after 12 month
upfront delayed
 L2 – L4 + 4.39 % - 4.9 %
 Hip + 1.89 % - 3.52 %
p= < 0.0001
Proposed Trt Algorithm for AI-induced
bone loss
T-score < -2.0
Monitor BMD
every 2 years
Bisphosphonate
therapy
(e.g.zoled...
Tenslotte….
Adapted from Roodman D. N Engl J Med. 2004;350:1655.
Osteoblasts
Activated
Osteoclast
RANKL
RANK
Cytokines and
Growth Fact...
RANK Ligand is Implicated in Bone Loss
Across a Broad Range of Conditions
Post-
Menopausal
Osteoporosis
Male
Osteoporosis
...
Seminar 15-01-2009 - bisfosfonaten en kanker
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Seminar 15-01-2009 - bisfosfonaten en kanker

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  • 10 July 2013
  • 10 July 2013 Add change in antineoplastic therapy to speakers notes
  • Include 11% absolute reduction and 22% relative reduction in speakers notes
  • Note that the curves appear to have separated and the data are trending toward a survival benefit for the ZOMETA group. However, the data to not achieve statistical significance.
  • 10 July 2013
  • 10 July 2013
  • 10 July 2013
  • Emphasize that the trial was a non-inferiority trial and was not designed to show the superiority of ZOMETA compared with pamidronate.
  • Leo, I did not add the Ns because it would be too confusing. The N should really be for the entire stratum, but we’ve deleted the 8/4 mg group. Basically, half of these patients had NSCLC. The other half have “other solid tumors” predominantly renal cell carcinoma, small cell lung cancer, colon/rectum/ intestinal cancer, bladder cancer, or cancer of unknown primary.
  • Leo, I did not add the Ns because it would be too confusing. The N should really be for the entire stratum, but we’ve deleted the 8/4 mg group. Basically, half of these patients had NSCLC. The other half have “other solid tumors” predominantly renal cell carcinoma, small cell lung cancer, colon/rectum/ intestinal cancer, bladder cancer, or cancer of unknown primary.
  • 10 July 2013
  • The vicious cycle hypothesis of bone lesion progression in multiple myeloma involves the increased expression of RANK Ligand and the inhibition of the expression of OPG. The mechanism by which lytic bone lesions are established in patients with multiple myeloma is somewhat different compared with the establishment of osteolytic and osteoblastic bone metastases. Multiple myeloma cells have been shown to affect osteoclasts by two different pathways: Tumor cells can directly activate osteoclasts by expressing RANK Ligand. 1 Tumor-expressed RANK Ligand can directly interact with RANK on the surface of osteoclasts. Also, tumor cells can also interact with osteoblasts, thus increasing osteoblast expression of RANKL and decreasing expression of OPG. 2,3,4 Myeloma cell lines in culture could activate stromal cells to express RANK Ligand and inhibit the expression of OPG. 5,6 In addition, myeloma cells downregulated expression of OPG in cocultured preosteoblasts and stromal cells. 3-7 Myeloma cells from 22 experiments in 9 patients could induce the differentiation of preosteoclasts into multinucleated bone-resorbing osteoclasts by a RANK Ligand-mediated mechanism. 7 Direct contact between myeloma cells and osteoclasts increased myeloma cell viability and decreased their apoptotic rate. 7 MIP-1  (macrophage inflammatory protein-1 alpha) produced by myeloma cells can stimulate osteoclasts and enhanced interactions between myeloma cells and marrow stromal cells, leading to increases in RANK Ligand expression. 8 Farrugia AN, et al. Cancer Res. 2003;63:5438-5445. De Leenheer E, et al. Curr Opin Pharmacol . 2004;4:340-346. Roux S, Mariette X. Leuk Lymphoma. 2004;45:1111-1118. Sezer O, et al. Blood. 2003;101:2094-2098. Pearse RN, et al. Proc Natl Acad Sci USA . 2001;98:11581-11586. Giuliani N, et al. Blood. 2001;98:3527-3533. Yaccoby S, et al. Cancer Res . 2004;64:2016-2023. Terpos E, Dimopoulos MA. Ann Oncol . 2005;16:1223-1231.
  • References 1 Hofbauer LC et al. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004; 292: 490–495 2 Boyle WJ et al. Osteoclast differentiation and activation. Nature 2003; 423: 337–342
  • Seminar 15-01-2009 - bisfosfonaten en kanker

    1. 1. Bisfosfonaten in de Oncologie Dr. H.P. Sleeboom Hagaziekenhuis Den Haag
    2. 2. Botmetastasen
    3. 3. Trabecular Bone Destroyed by Osteoclasts Due to Tumor Osteolysis Figure from L Mosekilde
    4. 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. 5. Osteolysis in Multiple Myeloma
    6. 6. Osteoblastic Vertebral Metastases
    7. 7. Increased bone resorption Hypercalcaemia Fracture Bone pain Clinical Consequences of Increased Bone Resorption Bone
    8. 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. 9. Treatment of Bone Metastases Traditional treatments  Radiotherapy/radionuclides  Endocrine treatment  Chemotherapy  Orthopaedic intervention  Analgesics Complementary approach  Osteoclast inhibition
    10. 10. “ Skeletal Related Events”  (dreigende) fracturen: chirurgie, radiotherapie  myelumcompressie  hypercalciëmie  pijnscore, kwaliteit van leven  nieuwe botmetastasen
    11. 11.  Meeste studies: systemische therapie +/- bisfosfonaat  Weinig grote vergelijkende studies tussen amino – en niet - aminobisfosfonaten  Hypercalciëmie behandeling: snelheid normaliseren serumcalcium en duur response
    12. 12. Werking Bisfosfonaten
    13. 13. Impact of Changes in Bone Remodelling Coupled and balanced Bone Uncoupled but balanced Bone Coupled but imbalanced Bone Uncoupled and imbalanced Bone
    14. 14.  Gemetastaseerde maligniteiten  Niet – gemetastaseerde maligniteiten
    15. 15. Prostaatcarcinoom
    16. 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. 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. 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. 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. 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. 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. 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. 23. Mammacarcinoom
    24. 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. 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. 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. 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. 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. 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. 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. 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. 32. Bijwerkingen  Osteonecrosis of the jaw
    33. 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. 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. 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. 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. 37. Conclusie: Significante reductie botmetastasen tijdens behandeling Significante reductie mortaliteit
    38. 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. 39. Studie Gnant  1801 vrouwen  Gosereline  Anastrozole versus Tamoxifen  +/- Zoledroninezuur: 4 mg iv/ 6 maanden
    40. 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. 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. 42. Studie Gnant  Geen verschil overall survival * H R 0.60 95% C I 0.60 - 1.11 p= 0.10
    43. 43. Bisfosfonaten bij aromataseremmers
    44. 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. 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. 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. 47. Zofast studie  Zoledroninezuur bij letrozole upfront of delayed bij adjuvante behandeling mammacarcinoom
    48. 48. Zofast studie  BMD after 12 month upfront delayed  L2 – L4 + 4.39 % - 4.9 %  Hip + 1.89 % - 3.52 % p= < 0.0001
    49. 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. 50. Tenslotte….
    51. 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. 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

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