1. Clinical use of RANKL Inhibitor in Osteoporosis
Thawee Songpatanasilp, M.D.,M.Sc.,Ph.D.
Associate Professor in Orthopaedics
Phramongkutklao College of Medicine

2. Disclosures
Songpatanasilp T. has received research grants, consultancies, and/or speaker’s honoraria from
GSK, Eli Lilly, MSD, Novartis, Pfizer, Servier, J&J, Roche,Takeda and Actavis

4. Osteoporosis Treatment 2015:
We have many effective drugs
Many Limitations:
Real or perceived intolerance
Concerns about safety, especially the long-term safety of bisphosphonates
Inconvenient or awkward dosing regimens
Poor adherence to therapy
No agent restores skeletal structure or strength to normal levels
i.e., no “cure” for osteoporosis

5. RANK Ligand is an Essential Mediator of Osteoclast Formation, Function and Survival
RANK Ligand (RANKL)
Signaling protein expressed by osteoblasts/bone lining cells1
Binds to RANK and promotes osteoclast formation, function and survival2
RANK
Expressed by osteoclasts and their precursors1
Activated by RANK Ligand binding1
Osteoprotegerin (OPG)
Protein secreted by osteoblasts/bone lining cells1
Natural inhibitor of RANK Ligand2
Blocks RANK Ligand signaling to balance bone remodeling2
1. Boyle WJ, et al. Nature 2003;423:337–342.
2. Kostenuik PJ. Curr Opin Pharmacol 2005;5:618–625.

6. Many factors stimulate osteoblast expression of RANK Ligand
CFU-M
RANKL
RANK
Glucocorticoids
PTH
Prefusion Osteoclast
PGE2
Vitamin D
IL-11
IL-6
Multinucleated Osteoclast
IL-1
PTHrP
TNF-
Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, PTH, TNF, IL-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss.1-3
Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity.1,2
RANK ligand is a key factor regulating osteoclastogenesis and bone resorption.1,2
Consistent with this are the following observations:
Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption.2
Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures.1,2
The anti-osteoclast effects of osteoprotegerin (OPG), the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models.2
This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand.2
TNF- = tumour necrosis factor-alpha
PTHrP = parathyroid hormone-related peptide
PTH = parathyroid hormone
IL-1, IL-6, IL-11 = interleukins-1, 6, and 11
PGE2 = prostaglandin E2
References:
Boyle WJ, et al. Osteoclast differentiation and activation. Nature. 2003;423:
Kostenuik PJ, Shalhoub V. Osteoprotegrin: a physiological and pharmacological inhibitor of bone resorption. Curr Pharm Des. 2001;7:
Hofbauer LC, Schoppet M. Clinical Implications of the Osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA. 2004;292:
Activated Osteoclast
Estrogen
Osteoblast
CFU-M = colony-forming unit macrophage
Adapted from Boyle WJ, et al. Nature. 2003;423:
Hofbauer LC, Schoppet M. JAMA. 2004;292: 6

7. OPG Is a Decoy Receptor That Prevents RANK Ligand Binding to RANK and Inhibits Osteoclast Formation, Function, and Survival
RANKL
RANK
OPG
CFU-GM
Prefusion Osteoclast
Hormones Growth Factors
Cytokines
Osteoclast Formation, Function, and Survival Inhibited
The body naturally produces a protein called OPG to neutralize the effects of RANK Ligand and defend against bone loss.1,2 When RANK Ligand is bound and neutralized by OPG, osteoclasts cannot form,3,4 function,3 or survive.5
OPG, a natural endogenous inhibitor of RANK Ligand, acts as a decoy receptor by binding with RANK Ligand, thereby inhibiting osteoclastogenesis and the survival of preexisting osteoclasts.1,2,6,7
OPG, a member of the TNF receptor family, binds to RANK Ligand and neutralizes its effects, thereby inhibiting bone resorption.1,2,6,7
OPG is an important inhibitor of the terminal differentiation and function of osteoclasts.1,2,6,7
Boyle WJ, et al. Nature. 2003;423:
Simonet WS, et al. Cell. 1997;89:
Fuller K, et al. J Exp Med. 1998;188:
Yasuda H, et al. Proc Natl Acad Sci U S A. 1998;95:
Lacey DL, et al. Am J Pathol. 2000;157:
Lacey DL, et al. Cell. 1998;93:
Bekker PJ, et al. J Bone Miner Res. 2001;16:
Osteoblasts
Bone Resorption Inhibited
Bone Formation
Adapted from Boyle WJ, et al. Nature. 2003;423:
Hofbauer LC, Schoppet M. JAMA. 2004;292:

8. Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function, and Survival
OPG Denosumab
CFU-GM
Prefusion Osteoclast
Hormones Growth Factors
Cytokines
Osteoclast Formation, Function, and Survival Inhibited
Denosumab is the first fully human monoclonal antibody in clinical development that specifically targets RANK Ligand, an essential mediator of osteoclast formation, function, and survival.1,2
Lewiecki EM. Exper Opin Biol Ther. 2006;6:
McClung ER, et al. N Engl J Med. 2006;354:
Osteoblasts
Bone Resorption Inhibited
Bone Formation
Adapted from Boyle WJ, et al. Nature. 2003;423:
Hofbauer LC, Schoppet M. JAMA. 2004;292:

10. Bone type affinity Trabecular >>> Cortical Bisphosphonates
Differences in Pharmacokinetics & Pharmacodynamics
Bone type affinity
Bisphosphonates
50%-70% in circulation are uptake by bone
Surface dependent
Remodeling dependent
Interchanging between bone surface-blood determine bony surface half life
Trabecular >>> Cortical

11. Bone type affinity Denosumab Cortical = Trabecular No bone uptake
Differences in Pharmacokinetics & Pharmacodynamics
Bone type affinity
Denosumab
No bone uptake
Reached everywhere that blood vessels going to
Cortical = Trabecular
Key Points1:
Context: Antiresorptives differ in the extent to which they suppress remodeling. Since remodeling is surface dependent, the degree to which antiresorptives suppress remodeling could be due, in part, to differences in their accessibility to bone surfaces.
Hypothesis: Differences in distribution and mechanism of action between denosumab and alendronate will result in a greater reduction in intracortical porosity with denosumab.
Study Population: Postmenopausal women aged 61±5 years were randomized double-blind to denosumab 60 mg Q6M (N=83), alendronate 70 mg QW (N=82), or placebo (N=82) for 12 months.
Methods: Trabecular bone volume fraction (BV/TV) and porosity in both the compact and the trabecularized cortex (outer and inner transitional zones) were measured from HRpQCT distal radius images obtained at baseline, 6 months, and 12 months using Strax 1.0 software.
Results: Both denosumab and alendronate improved trabecular BV/TV compared with placebo at 6 and 12 months. Alendronate reduced porosity at month 6 in the compact and trabecularized cortex compared with placebo; however, at month 12 there was no evidence of a difference with alendronate relative to placebo in any of these cortical compartments. Denosumab reduced porosity at both 6 and 12 months in all cortical compartments compared with baseline and placebo.
Conclusions: Access to cortical bone by therapeutic agents is a challenge because of its surface/bone volume configuration. The broader distribution of denosumab compared with alendronate is associated with greater and more uniform reductions in porosity throughout the cortex.
Reference:
1. Zebaze RM, Libanati C, Austin M, Bilezikian JP, Seeman E. Antiresorptive Action Is Dependent on Access to Remodeling Upon Cortical and Trabecular Surfaces: Comparison of Denosumab and Alendronate. American Society For Bone and Mineral Research, Minneapolis, Minnesota; October 12–15, Poster Presentation FR 0389 and SA 0389.
Adapted from Zebaze RM et al. Bone. 2014;59:173–179.

12. FREEDOM
Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months
Phase 3 RCT
Postmenopausal women age (mean 73 yrs) with lumbar or total hip T-score < -2.5 and >= -4.0
Mean T-score: spine -2.8; hip -1.8
Prevalent vertebral fracture 23%
Denosumab 60 mg q 6 months vs. placebo
Endpoints
Primary: new vertebral fractures at 36 months
Secondary: time to first hip and non vertebral fractures
Cummings SR, et al. N Engl J Med 2009;361:756-65

13. Denosumab Reduced Risk of Vertebral, Non-vertebral and Hip Fractures at 36 Months
FREEDOM Trial
RRR = 20% P = 0.01
RRR = 68% P < 0.001
Placebo
Denosumab
Incidence at Month 36 (%) .
RRR = 40% P = 0.04
(Primary Endpoint)
(Secondary Endpoint)
(Secondary Endpoint)
RR = risk reduction
Adapted from: Cummings SR, et al. N Engl J Med 2009;361:756–765.

14. (Subset from FREEDOM)

16. Denosumab Compared With Zoledronic Acid in Postmenopausal Women With Osteoporosis Previously Treated With Oral Bisphosphonates: Efficacy and Safety Results From a Randomized Double-blind Study* PD Miller,1 N Pannacciulli,2 JP Brown,3 E Czerwinski,4 BS Nedergaard,5 MA Bolognese,6 J Malouf,7 HG Bone,8 JY Reginster,9 A Singer,10 C Wang,
* present in ASBMR 2015, Seattle

18. Percentage change in Total hip BMD in head to head study vs various BPs

19. Denosumab: Safety and Tolerability
Overall, no increased risk of adverse events or serious adverse events in clinical trials
Increased incidence of (FREEDOM trial-3 years)
skin rash (1.3% vs 0.7%)
cellulitis (12/3808 vs 1/3805)
No renal or cardiovascular effects noted
Deaths: 90 in placebo group; 70 with DMab (p=0.06)
Less than 1% of patients developed binding antibodies over 2-8 years; none have developed neutralizing antibodies
Cummings SR, McClung MR et al. N Engl J Med. 2009;361:

20. Denosumab with Impaired Renal Function
Differences in Clinical Outcomes
Denosumab with Impaired Renal Function
Post-hoc analysis of FREEDOM study
Treatment response evaluated in subgroups of renal function
73 women had an eGFR of 15 to 29 ml/min (Gr 4)
2817 between 30 to 59 ml/min (Gr 3)
4069 between 60 to 89 ml/min (Gr 2)
842 had an eGFR ≥ 90ml/min (Gr 1)
Treatment efficacy did not differ by kidney function.
Bisphosphonates should not be used in patients with eGFR below 30 ml/min
Jamal S, McClung, Miller PD et al. J Bone Miner Res. 2011;26:

21. Long-term antiresorptive therapy: Rare complications
Osteonecrosis of the jaw
Atypical femoral fractures
Estimated market exposure to denosumab was 1,960,405 patient-years as of May 10, 2014 and there were1
47 spontaneous reports adjudicated as consistent with ONJ
5 spontaneous reports adjudicated as consistent with AFF
Osteonecrosis of the jaw:
Range of incidence reported on treatment is:2
Oral bisphosphonates per 100,000 patient-years
IV bisphosphonates 0-90 per 100,000 patient-years
Denosumab per 100,000 patient-years.
Key points:
Osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFFs) can potentially occur after long-term treatment with potent antiresorptive therapy such as bisphosphates and denosumab1
Estimated market exposure to denosumab was 1,960,405 patient-years as of May 10, 2014 and there were2
– 47 spontaneous reports adjudicated as consistent with osteonecrosis of the jaw (ONJ)
– 5 spontaneous reports adjudicated as consistent with atypical femoral fractures (AFF)
Osteonecrosis of the jaw:
The majority of cases (>90%) have occurred in cancer patients receiving a six-to-ten-fold higher doses of BPs than that used to treat osteoporosis.3 The incidence in the osteoporotic population is only slightly higher than the frequency observed in the general population.3
Range of incidence reported on treatment is:3
oral bisphosphonates per 100,000 patient-years
IV bisphosphonates 0-90 per 100,000 patient-years
denosumab per 100,000 patient-years.
Atypical femoral fractures:
Cases of atypical femoral fractures (AFFs) have been reported in patients with osteoporosis taking bisphosphonates and denosumab.1
However, they also occur in patients with no exposure to these medications and although there is thought to be an association between there use and AFF, a direct causal relationship has not yet been demonstrated.1
References:
Shane E, Burr D, Abrahamsen B et al. J Bone Miner Res. 2014;29:1-23.
Geller M et al. Poster. ASBMR 2014 Annual Meeting, Houston, TX; September 12–15, 2014
Khan AA, et al. J Bone Miner Res 2014 [Epub ahead of print] .
1. Geller M et al. Poster presented at: American Society of Bone and Mineral Research Meeting; September 12– ; Houston, US.
2. Khan AA, et al. Can Fam Physician. Jul 2008; 54(7): 1019–1021

22. FREEDOM Extension Study Design International, multicenter, open-label, single-arm study
Year 1 2 3 4 5 6 7 8 9 10 R A N D O M I Z T
Denosumab 60 mg
SC Q6M
(N = 3902)
Denosumab 60 mg
SC Q6M
(N = 2343)
Long-term
Denosumab
Treatment
Calcium and Vitamin D
Placebo
SC Q6M
(N = 3906)
Denosumab 60 mg
SC Q6M
(N = 2207)
Cross-over
Denosumab
Treatment
Year 1 2 3 4 5 6 7
Key Inclusion Criteria for the Extension:
Completed the FREEDOM study (completed the 3-year visit, did not discontinue investigational product, and did not miss > 1 dose)
Not receiving any other osteoporosis medications
Amgen Corporate Template

23. Effects of Denosumab Treatment on L-Spine and Total-hip BMD Through 10 Years (All Participants)
Long-term Denosumab (N = 2210)
Placebo
Cross-over Denosumab (N = 2089)
Long-term Denosumab (N = 2210)
Placebo
Cross-over Denosumab (N = 2089)
L-Spine
Total-Hip
All Participants
All Participants
FREEDOM
Extension
FREEDOM
Extension
21.7%c
9.2%c b b b
16.5%c b b b b
7.4%c b b b b b a
Percentage Change From Baseline b b a
Percentage Change From Baseline a b b a b a b a a b b a a a a a a a a a
Study Year 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10
Study Year
BMD data are LS means and 95% confidence intervals. *Subjects who completed the year-10 visit and missed ≤ 1 dose in FREEDOM and ≤ 1 dose in the Extension, and had an Extension baseline and ≥ 1 post-baseline BMD measurement during the Extension. aP < 0.05 vs FREEDOM baseline.
bP < 0.05 vs FREEDOM and Extension baselines. cPercentage change while on denosumab treatment.

24. Effects of Denosumab Treatment on Femoral Neck and 1/3 Radius BMD Through 10 Years
Placebo
Cross-over Denosumab
Long-term Denosumab
Femoral Neck
1/3 Radius
FREEDOM
Extension
9.0%d
FREEDOM
Extension b b b a b
7.1%d b a b
2.7%d b b a a a b a c
Percentage Change From Baseline a
Percentage Change From Baseline b a c
2.3%d a b c a b a a a a a a a a a
Study Year 1 2 3 4 5 6 7 8 9 10
Study Year 1 2 3 4 5 6 7 8 9 10
BMD data are LS means and 95% confidence intervals. aP < 0.05 vs FREEDOM baseline. bP < 0.05 vs FREEDOM and Extension baselines.
cP < 0.05 vs Extension baseline. dPercentage change while on denosumab treatment.

25. Cumulative Subject Incidence of New Vertebral and Nonvertebral Fractures: Long-term Denosumab Group
Placebo
Virtual Twin Placebo
Long-term Denosumab
New Vertebral
Nonvertebral
RR (95% CI) =
0.62 (0.47–0.80)
RR (95% CI) =
0.54 (0.43–0.68) n
264 86
149 N
3691
3702
2116 n
293
238
172 N
3606
3902
2343
n = number of subjects with ≥ 1 fracture.
N = number of randomized (FREEDOM) or enrolled (Extension) subjects.
Percentages are Kaplan-Meier estimates.
RR < 1 favors long-term denosumab over virtual twin placebo.
n = number of subjects with ≥ 1 fracture.
N = number of subjects with an evaluation.
RR < 1 favors long-term denosumab over virtual twin placebo.

26. Nonvertebral Fracture (%)
Yearly Subject Incidence of Nonvertebral Fractures: Long-term Denosumab Group
Long-term Denosumab
Virtual Twin Placebo
RR (95% CI) =
0.58 (0.35–0.89)
RR (95% CI) =
0.44 (0.25–0.71)
RR (95% CI) =
0.62 (0.36–1.00)
RR (95% CI) =
0.50 (0.26–0.84)
RR (95% CI) =
0.27 (0.12–0.52)
RR (95% CI) =
0.31 (0.13–0.61)
RR (95% CI) =
0.55 (0.22–1.17)
Nonvertebral Fracture (%)
Subject Incidence of
1.8
1.9
1.5
1.6
1.2
1.1
0.8 n 34 27 28 14 16 N
2343
2244
2067
1867
1743
1585
1451
For Extension participants (N = 2343).
n = number of subjects with ≥ 1 fracture; N = number of randomized subjects who remained on study at the beginning of each period.
RR < 1 favors long-term denosumab over virtual twin placebo.

27. Exposure-adjusted Subject Incidence of Adverse Events (Rates per 100 Subject-years)
Extension Years 1–7
Cross-over Denosumab (N = 2206)
Long-term Denosumab (N = 2343)
Year 1 2 3 4 5 6 7
Serious infections
1.6
1.5
1.1
1.3
2.2
2.1
1.2
1.7
2.4
2.6
Malignancies
1.9
2.8
2.7
2.5
FREEDOM Years 1–3
Extension Years 1–7
Placebo
(N = 3883)
Cross-over Denosumab (N = 2206)
Long-term Denosumab
(N = 2343)
All AEs
156.1
96.8
97.0
Infections
30.7
20.7
19.9
Malignancies
1.6
2.0
Eczema
0.6
0.9
Hypocalcemia
< 0.1
Pancreatitis
Serious AEs
10.4
10.1
10.3
1.3
1.4
1.5
Cellulitis or erysipelas
Fatal AEs
0.8
Osteonecrosis of the jaw
Atypical femoral fracture
N = number of subjects who received ≥ 1 dose of investigational product. Treatment groups are based on the original randomized treatments received in FREEDOM. AEs coded using MedDRA v Cumulative osteonecrosis of the jaw cases: 6 cross-over, 7 long-term. Cumulative atypical femoral fracture cases: 1 cross-over, 1 long-term.
Amgen Corporate Template

32. Over all summary
What are the “good” points of denosumab over other agents now?
Best compliance : only sc. injection q. 6 months
Low side effects : compared to others
Excellent efficacy : BMD gain / fracture reduction…….best for cortical bone
Kidney’s friend : can use with safety and efficiency in CKD 4

33. Indication registered to Thai FDA
Denosumab is indicated for
Treatment of osteoporosis in postmenopausal women
Treatment of osteoporosis in men at risk of fracture
Treatment of Bone Loss in Patients Undergoing Hormone Ablation for Cancer (men and women)
(Cancer-treatment induced bone loss, CTIBL)
Naive
Existing oral BP pt

34. Osteoporosis Who should be treated with Denosumab? Naive Switch
high risk PMwomen & men
BPs drug holiday period
Trend to AE of BPs
intolerance to BPs
Renal impairment
non-responders
Trend to low compliance
to improve adherence/convenience
after hip fracture
after TPTD
CTIBL
Patient

35. Guideline recommendation
First-line recommendation
US: American Association of Clinical Endocrinologist (AACE) recommended Prolia as first line for the treatment of osteoporosis in postmenopausal women 1
UK: National Institute for Health and Clinical Excellence (NICE) recommended Prolia as first line for the treatment of osteoporosis in postmenopausal women who has risk of fracture.2
Canada: recommended Prolia as first line for the treatment of osteoporosis in postmenopausal women for reduced risk of hip, vertebral, non-vertebral fracture 3
1.Sutton EE, Riche DM. Ann Pharmacother ;46:1000-9
2. Moen MD, Keam SJ. Denosumab: Drugs Aging Jan 1;28(1):63-82
3. Josse R, Khan A, Ngui D, Shapiro M. Curr Med Res Opin Mar;29(3):205-16

36. Thank You For Your Attention