It describes the pathophysiology, molecular biology and management of bone related problem among prostate cancer patients.

1. PROSTATE CANCER:
BONE HEALTH INTEGRITY:
WHY IMPORTANT?
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Janssen Cilag – Prostate Cancer Day
Intercontinental Cairo Semiramis
01-10-2015

2. Speaker Disclosures
Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen
Cilag, Merck Serono, Novartis, Pfizer.
Speaker Disclosures:

3. Cancer Related Bone Disease:
The Pessimist Layout:
• Cancer Related Bone Disease:
• Effect of Treatment.
• Effect of Metastases.
• Prostate Cancer  60% Bone Metastases.
• Improved Survival  more disease and therapy related events.
• SRE:
1. Pain
2. Pathological Fracture
3. Spinal cord compression
4. Radiation therapy treatment
5. Life threatening hypercalcemia
• Heavy Burden:
Medical, Psychological, Social and Economic.
Yong et al. Curr Opin Oncol 2014, 26:274 – 283
Loss of BMD
 QoL & Survival

4. Cancer Related Bone Disease:
The Pessimist Layout:
Danish Observational Study (1999 – 2007):
23087 Incidental Prostate Cancer Patients
Bone Metastases:
• 3% at diagnosis.
• 11.5% at 2.2
years.
No B.M. B.M. B.M. + SRE
Mortality
Rate Ratio
4.7
Mortality
Rate Ratio
10.2
Norgaard et al. J Urol 2010; 184:162 – 167.

5. • SRE require High Health Resource Utilization and
Cost.
• The cost is directly related to:
1. In- or out-patient care.
2. Surgical intervention (Fixation versus Decompression).
3. Radiation Therapy (yes or no).
4. Number of episodes of care (once or repeated).
• The Mean Costs in Observational Trials:
• US Data:
• USD 12469 in 2006 Dollars.
• Repeated SRE: USD 26384.
• One Type: USD 8484.
• European Data: Euro 1485 – 15267.
Cancer Related Bone Disease:
The Economic Burden:
Lage et al. Am J Manag Care 2008; 14:317–322.
Body et al. J Med Econ 2013; 16:539 – 546.

6. Cancer Related Bone Disease:
The Old Dogma:
Palliative Radiation Therapy
> 15 Years Ago

7. Cancer Related Bone Disease:
The New Insight:
Dynamic Structure
Bone Turnover
Resorption
Formation
Total
Volume
of Bone
Time
Percent/Year
Bone Remodeling
Calcium
Homeostasis
Skeletal
Integrity
Parfitt AM. Bone. 2004; 35(1):1-3.
Fazzalari NL. Semin Cell Dev Biol. 2008; 19(5):467-72.

8. Normal Bone Physiology:
O.Blast O.BlastO.Blast
Bone Formation
O.Clast
Precursor
Cells
RANKL
Differentiated
O.Clast
Mature
Multinucleated
O.Clast
Bone Resorption
H+ En
z
OPG
Rana et al. Hematol Oncol Clin N Am 27 (2013) 1261–1283 Ca++, Cytokines, NTX
Vit D
PTH
PGE2
IL1
E2

9. • Estrogen + Osteoblast = Osteoprotegerin.
• Osteoprotegerin + RANKL =  RANK.
•  RANK  Arrest of Osteoclast Differentiation 
Apoptosis  NO BONE LOSS.
Normal Bone Physiology:
• Females:
• Premenopausal  Preservation of skeletal integrity.
• Postmenopausal & Endocrine Therapy (Breast Cancer) 
Osteoporosis.
• Males:
• Androgens –Aromatase Estrogen  Bone Preservation.
• Orchiectomy & ADT   Androgens  Estrogen  Bone Loss.
Boyle WJ, et al. Nature 2003; 423:337-42..

10. 1Kanis JA. In: Kanis JA, ed. Osteoporosis. London, 1997; 22-57; 2Eastell R, et al. J Bone Miner Res 2002; 17(suppl 1):S165;
3Lee WY, et al. J Clin Endocrinol Metab 2002; 87:329-35;4Maillefert JF, et al. J Urol 1999; 161:1219-22;
5Gnant M, et al. Breast Cancer Res Treat 2002; 76(suppl 1):S31, Abstract 12;6Shapiro CL, Manola J, Leboff M. J Clin Oncol 2001; 19:3306-
331..
Estrogen / Androgen DeprivationAssociated Bone Loss
Premenopausal women
Normal men1
Early menopausal women1
Late menopausal women1
AI therapy in post menopausal women2
Androgen deprivation therapy agonist4
AI therapy plus GnRH agonist5
Ovarian failure secondary to
chemotherapy6
AI, aromatase inhibitor;
GnRH, gonadotropin-releasing hormone;
BMD, bone mineral density.
Lumbar spine BMD loss at 1 year (%)
7.7%
7.0%
4.6%
2.6%
2.0%
1.0%
0.5%
0 2 4 6 8

11. ADT-related fracture risk
Shahinian VB, et al. N Engl J Med 2005; 352:154-164.
Years After Diagnosis
Unadjustedfracture-free
survival(%)
2 3 4 5 6 7 8 9 101
0
100
90
80
70
60
50
40
30
20
10
Over a 4-year period
 19.4% fractures on ADT
 12.6% fractures not on ADT
No ADT (N=32,931)
GnRH Agonist, 1- 4 doses (N = 3763)
GnRH Agonist, 5 - 8 doses (N = 2171)
GnRH Agonist, 9 doses (N = 5061)
Orchiectomy (N = 3399)
GnRH, gonadotropin-releasing hormone;
ADT, androgen deprivation therapy.

12. RANKL is the KEY Player in CTIBL

13. Molecular Basis of Bone Metastases in
Prostate Cancer:
• Bone microenvironment is the ideal soil for cancer cells 
Enriched by resorption and growth factors.
• Tumor cell  Induce osteoclast bone destruction.
Mundy GR (ed). Cellular mechanisms of bone resorption. In: Bone Remodeling and Its Disorders. 2nd ed. London, England: Martin
Dunitz Ltd; 1999;23-25.

14. Molecular Basis of Bone Metastases in
Prostate Cancer:
Bone Resorption
Products.
Cancer
Cell
O.Blast
RANKL
O.Clast
++
Osteolytic Factors
Bone Resorption
Osteolytic
Osteoblastic
Factors
O.Blast
++
New Bone
Osteoblastic
Armstrong AP, et al. Prostate 2008; 68:92-104.

15. RANKL Beyond its Bone Resorption
Effect:
Osteoblasts
RANKL
Bone matrix
Circulating Cancer cells
expressing RANK
RANKL may act as a
chemotactic factor which
attracts circulating cancer
cells expressing RANK to
migrate into the bone
Armstrong AP, et al. Prostate 2008; 68:92-104.
RANK

16. Targets to Avoid Bone Loss:
1. Osteoclasts.
Bisphosphonates
2. RANKL.
Denosumab
3. Tumor related osteolytic & Osteoblastic factors
Investigational
Mechanistically
Different

17. Management of Bone – Related Problems
in Prostate Cancer
Prostate Cancer
Therapy Related Bone Loss (ADT Therapy)
Prevention of SRE Due to Bone Metastases
Treatment of Symptomatic Bone Metastases

18. 1. Treatment of Symptomatic Bone
Metastases of Prostate Cancer (Pain):
1. External Beam Radiation Therapy:
Treatment of Choice for 1 or limited number of sites.
2. Bone Targeted Pharmaceuticals:
Radium – 223 ALSYMPCA Trial: (CRPC): Multiple Bones, No Visceral
1. Bisphosphonates:
If Rth failed to control pain. Not approved in US for this indication.
2. Surgery: Fractures and spinal cord compression.
3. Analgesics.
4. Systemic Treatments: ADT in HSPC, Abiraterone,
Enzalutamide and Cytotoxics in CRPC.
RADIUM -
223
BSC HR
OAS 14.9 ms 11.3 ms 0.70
TIME TO 1ST
SRE
15.6 ms 9.8 ms 0.60

19. 2. Prevention/Delay of SRE due to Bone
Metastases: CRPC:
• Zoladronic acid (Most potent Bisphosphonates) &
Denosumab: Highly effective in:
•  SRE.
•  Time to 1st SER.
•  Pain and analgesic scores.
• No survival impact.
• Zoladronic Acid versus Denosumab:
Zoladronic Denosumab Significance
Time to 1st SER 20.7 ms 17.1 ms HR = 0.82
OAS 19.4% 19.8% HR = 1.03
ONJ 2.3% 1.3% N.S.
Hypocalcemia 13% 6% Highly Sig.

20. • CALGB 90202: Zoladronic versus Placebo: No Effect
2. Prevention/Delay of SRE due to Bone
Metastases: Castrate Sensitive:
Denosumab  No Data

21. 3. Prevention of ADT-Bone Loss in Non
Metastatic Disease:
Significant Increase of
BMD and decreased
Fractures
Zoladronic Acid 4 mg/3
months IV/Year
Denosumab 60 mg/6
months SC
Approved
Smith et al. J Urol. 2003;169(6):2008
Smith et al. N Engl J Med. 2009;361(8):745.
Both are not approved for
non metastatic CRPC to
Prevent/Delay BM

22. Considerations Prior to Osteoclast
Inhibitor Therapy:
• Dental Care (Initial & Follow up) to avoid ONJ.
• Correction of Hypocalcemia and vitamin D deficiency.

23. Take Home Message:
• Osteoblastic bone lesions in axial skeleton are the most
frequent sites in advanced prostate cancer.
• Systemic treatment is an important component in
controlling symptoms.
• External beam radiation therapy is still of interest for
single and limited sites bone disease.
• CRPC with Bone Only Wide Spread should be considered
for treatment with Radium-223.
• CRPC with Bone Metastases  The use of Osteoclast
Inhibitors are associated with decreased SRE.
• In HSPC; the use of osteoclast inhibitors will counteract
the ADT – Associated Bone Loss, however their role in
management of Bone Metastases are less appreciated.

25. Thank You