Metastatic bone disease is a challenging condition that places a heavy burden on patients. New insights into the cellular and molecular mechanisms have led to improved treatments. Cancer cells interact with the bone microenvironment through factors like RANKL, RANK, and osteoprotegerin, inducing a "vicious cycle" of bone destruction. Emerging therapies target these interactions by inhibiting RANKL with drugs like denosumab. Radiopharmaceuticals like radium-223 also show promise by targeting areas of new bone growth in metastases. While radiation remains important for pain relief, combination therapies offer the potential for improved outcomes in metastatic bone disease.

1. METASTATIC BONE
DISEASE:
AN OLD DOGMA
& NEW INSIGHT
MOHAMED ABDULLA M.D.
PROF. OF CLINICAL ONCOLOGY
CAIRO UNIVERSITY
Tanta University – 17/02/2015

2. Bone Metastases: The Old
Dogma:
 Cancer Related Bone Disease:
 Effect of Treatment.
 Effect of Metastases.
 Improved Survival  more disease and
therapy related events.
 Breast Cancer  50% Bone Metastases
 Prostate Cancer  60% Bone Metastases.
 Heavy Burden: Medical, Psychological, Social
and Economic.

3. Decision of Treatment:
 Diagnosis.
 Osseous +/- visceral crisis
 Performance status.
 Number and location
 Outcome of every modality and when
combined.
 Availability of newer therapeutic modalities.
 Expected life span.
 What do we need to achieve?

4. The FRAX Tool: Assessing
Fracture Risk
http://www.sheffield.ac.uk/FRAX

5. Cellular and molecular physiology of
bone
The most peculiar feature of bone physiology is
Bone Remodeling
Continuous interplay
between
Osteoblasts:
Laying down new bones
Osteoclasts:
Dissolving old bones
● Continuous maintenance program in order to provide a
mechanism for self-repair and renewal
● The old bone matrix is replaced by a new one
● The process takes about 4-6 months.

6. MMP H+
CATH H+
Osteoclasts (Derived From
Haematopoietic System (GM-CFU))
Bone resorption ● H+
Dissolve bone mineral
Digestion of organic
matrix
Ca++ release
Cytokines & growth factors (TGFß, IGF)
Degradation products of type I bone
collagen (serve as biochemical marker
of bone resorption NTX in urine
Adapted from Roodman GD. J Clin Oncol 2001; 19: 3562–71.
Bone
resorption
products
Proteolytic enz (MMP, Cathepsins)
● Osteoclasts attach to bone surface and secrete acid and hydrolytic
enzymes

7. Formation and Activation of
Osteoclasts
 Receptor activator of NF-kB
 Receptor expressed on mature
Osteoclasts and precursors
Osteoprotegerin
Molecular insights
RANK/RANKL/Osteoprotegerin (members of TNF family)
RANK Ligand
RANK
● Cytokine expressed by osteoblasts, stromal cells,
some tumour cells leading to osteoclastic activation
● Natural antagonist of RANKL secreted by bone
lining cells (decoy/scavenger receptor)

8. 1,25D3
PTH/
PTHrP
PGE2
IL-11
Stromal cell/
Osteoblast
OCL
Precursor
Activated
OCL
RANK
RANKL
PTH-rP, PTH, TNF, IL-1 Induce Osteoclastic Bone
Resorption via Transactivation of RANKL Gene on
Stromal/Osteoblastic Cells
Kitazawa S and Kitazawa R. J Pathol 2002 Oct;198(2):228-36.

9. Estrogen & Bone Health:
Estrogen
Receptors:
• BM Stromal
Cells
• Osteoblasts
• Osteoclasts
++
OPG
Estroge
n
RANK
L

10. Boyle WJ, et al. Nature 2003; 423:337-42..
Estrogen
Osteoblasts
Bone formation
Estrogen Limits RANKL Expression
and Stimulates OPG Production
Bone
resorption
Osteoclasts
Androgen
OPG, osteoprotegerin;
RANKL, receptor activator for nuclear factor κ B ligand.
AROMATASE
Apoptotic
osteoclasts

11. Fractures with Adjuvant Aromatase
Inhibitors
Trial Mean F/U Fx w/AI Fx w/Tam
ATAC1 68 mo. 11% 7.7%
(p<0.0001)
BIG 1-982 51 mo. 8.6% 5.8%
(p<0.001)
IES3 55.7 mo. 7.0 4.9
(p=0.003)
1Forbes JF et al. Lancet Oncol. 2008;9(1):45-53; 2Crivellari D et al. J Clin Oncol. 2008;26(12):1972-9;
3Coombes RC et al. N Engl J Med. 2004;350(11):1081-92;

12. 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.

13. Molecular basis of Bone
Metastases
 Bone is mainly
composed of a hard
mineralized tissue
 It is more resistant to
invasion and destruction
by cancer cells than other
organs
 On their own: Cancer cells
can not destroy
mineralized bone
Hamdy A. Azim , Nermine S. Kamal , Hatem A. Azim Jr: Bone metastasis in breast cancer : The story
of RANK-Ligand JENCI 43 ,June 2012

14. The pivotal role of osteoclasts in
cancer induced bone destruction
 Osteoclasts are the only cells capable of
resorbing mineralised bone
 In order to grow in bones, cancer cells must
possess the capability to induce osteoclastic
bone destruction
Roodman GD. J Clin Oncol 2001; 19: 3562–71.
Tumour Cell / Bone Microenvironment
Interaction

15. Tumor cell – Bone microenvironment interactions:
 Collagen fragments ,TGFb, and IGFs are
chemotactic for tumour cells
Mundy GR (ed). Cellular mechanisms of bone resorption. In: Bone Remodeling and Its Disorders. 2nd ed. London, England: Martin Dunitz Ltd; 1999;23-25.
 Ca++, TGF
Stimulate tumour
cells to produce PTH-rP
 TGF, IGF
Stimulate tumour
cell growth
Bone
resorption
products
Bone microenvironment is a kind of fertile soil which can attract
and support the growth of circulating tumour cells (seeds)

16. Bone-derived
growth factors
IGF, TGF
Tumour cell –Bone microenvironment Interactions:
The Vicious Circle in Breast Cancer
Cancer cells
Osteoclasts
Osteoblasts
Osteolytic factors
PTHrP, IL-11
RANKL
Most of osteolytic
factors act via
osteoblast
production of
RANKL
Mineralised bone matrix
The Soil and Seed Theory

17. Tumour cell –Bone microenvironment Interactions:
the Vicious Circle in Prostate Cancer
Osteoblastic
factors
Adrenomedullin
ET-1,
Bone-derived
growth factors
IGF, TGF
New bone
Cancer cells
Osteoclasts Mineralised bone matrix
Osteoblasts
Osteolytic factors
PTHrP,RANKL, IL-11
RANKL
The Soil and Seed Theory

18. Osteoblasts
RANKL
Bone matrix
RANKL and Chemotactic Migration of Circulating Cancer Cells
to Bone
Tumour Cell / Bone Microenvironment Interactions
Circulating Cancer cells
expressing RANK
RANKL may act as a
chemotactic factor which
attracts circulating cancer
cells expressing RANK to
migrate into the bone
Adapted by Hamdy Azim from Armstrong AP, et al. Prostate 2008; 68:92-104.

19. Treatment of bone metastases:
cellular and molecular based
therapy Target osteoclasts : Bisphosphonates
 Target PTHrP: monoclonal antibodies
 Target RANKL:
– Recombinant osteoprotogerin:(AMGN-0007)
– Anti-RANKL monoclonal antibodies (AMG 162)
 Target TGF:
Inhibitors of TGF signaling in tumour cells (MAP kinase pathway) ???
x
x
Desonumab

20. Histologic Response to
Denosumab
Pre-treatment Week 13 post-treatment
Giant cells No giant cells
Irregular bone trabeculae (ovals)
Osteoid (arrows)
Biopsy of the sacrum
Thomas D, et al. J Clin Oncol. 2008;26:553S. Abstract 10500 and oral presentation.

21. Denosumab or Zoladronic Acid?
Parameter Denosumab Zoladronic Acid
Mechanism RANKL Inhibitor Mechanical Inhibition of Osteoclasts
Administration SC IV Infusion
Elimination RES Renal
Immunogenic
Reaction
No Yes
ONJ +++ +
Anti-Tumor Effect Prostate Breast & Prostate

22. Denosumab vs Zoledronic Acid: Double-
Blind, Placebo-Controlled Phase III Trial
Patients with CRPC and bone
metastases, and no
current or past IV
bisphosphonate treatment
(N = 1901)
*Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine clearance and
subsequent dose intervals determined by serum creatinine.
No SC dose adjustments made due to increased serum creatinine.
Denosumab 120 mg SC +
Placebo IV* q4w
(n = 950)
Zoledronic acid 4 mg IV* +
Placebo SC q4w
(n = 951)
 Calcium and vitamin D supplemented in both treatment groups
 Primary endpoint: time to first on-study SRE (fracture, radiation or surgery to
bone, spinal cord compression)
Fizazi K, et al. Lancet. 2011;377:813-822.

23. Zoledronic acid 951 733 544 407 299 207 140 93 64 47
Denosumab 950 758 582 472 361 259 168 115 70 39
Patients at Risk, n
Study Mo
0
1.00
ProportionofSubjectsWithoutSRE
0 3 6 9 12 15 18 21 24 27
0.25
0.50
0.75
KM Estimate of
Median Mos
Denosumab
Zoledronic acid
20.7
17.1
HR: 0.82 (95% CI: 0.71-0.95;
P = .0002, noninferiority;
P = .008, superiority)
18%
Risk
reduction
Time to First On-Study SRE
Fizazi K, et al. Lancet. 2011;377:813-822.

24. Radium-223 Targets Bone
Metastases
 Radium-223
functions as a
calcium mimic
 Targets sites of
new bone growth
within and
around bone
metastases
 Excreted by the
small intestine
Ra
Ca
Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

25. Parker C, et al. ASCO GU 2012. Abstract 8.
Patients with symptomatic
CRPC and ≥ 2 bone
metastases with no
known visceral
metastases, either
post-docetaxel or unfit
for docetaxel
(N = 921)
 Primary endpoint: OS
 Secondary endpoints: time to first SRE, time to total ALP progression, total ALP
response, ALP normalization, time to PSA progression, safety, QoL
Radium-223 50 kBq/kg +
BSC
Placebo (saline) +
BSC
Stratified by total ALP, previous docetaxel, and
bisphosphonate use; randomized 2:1
Up to 6 treatments at 4-wk intervals
ALSYMPCA: Phase III Trial of
Radium-223 in Symptomatic
Prostate Cancer

26. ALSYMPCA: Overall Survival
Radium-223 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0
Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.
OS(%)
Radium-223 (n = 541)
Median OS: 14.0 mos
Placebo (n = 268)
Median OS: 11.2 mos
HR: 0.695 (95% CI: 0.552-0.875;
P = .00185)
3 6 9 12 15 18 21 24 27
MosPts at Risk, n
0
10
20
30
40
50
60
70
80
90
100
0

27. ALSYMPCA: Time to First SRE
Radium-223 541 379 214 111 51 22 6 0
Placebo 268 159 74 30 15 7 2 0
0
10
20
30
40
50
60
70
80
90
100
PatsWithoutSRE(%)
HR: 0.610 (95% CI: 0.461-0.807;
P = .00046)
Radium-223 (n = 541)
Median: 13.5 mos
Placebo (n = 268)
Median: 8.4 mos
0 3 6 9 12 15 18 21
Pts at Risk, n Mos
Sartor O, et al. ASCO GU 2012. Abstract 9.

28. EBRT: ASTRO Task-Force
Guidelines:

29. EBRT: ASTRO Task-Force
Guidelines:
 Continues to be, the mainstay for the
treatment of painful, uncomplicated bone
metastases.
 Many schedules and fractionation.
 SBRT  special situation clinically.
 Combination with other bone directed
therapies.

30. Take Home Message:
 Metastatic bone disease is a highly
challenging and treatable disease.
 Effective pain relief with radiation therapy.
 Surgical correction is an option.
 Radiopharmaceuticals.
 Systemic Therapies

31. Thank you