Osteoporosis: Targeting

Pathways that Lead to

Osteoporosis and Fractures

Dolores M. Shoback, MD
Professor of Medicine
Department of Medicine
University of California
San Francisco Veterans Affairs Medical Center
San Francisco, California
 Pathways Control Bone Remodeling
 Bone remodeling
– Resorption
 RANK, RANKL, OPG
– Formation
 Wnt/LRP5/ß-catenin
– Control of remodeling
 Connections between bone and brain,
gut and metabolism
 Imbalances of bone remodeling
– Lead to osteoporosis
– Offer potential targets for therapy

Abbreviations: LDL, low-density lipoprotein receptor-related protein; OPG, osteoprotegerin; RANK,

receptor activator for nuclear factor kappaB; RANKL, RANK-ligand.
 Bone Remodeling Cycle in Normal Bone
Osteoclasts
Resorption digest bone within a
sealed resorption vacuole

Bone

Resting Reversal

Apoptotic
Bone osteoclasts Bone

Preosteoblasts

Mature osteoblasts
Bone
building osteoid
tissue
Formation
Mineralization

Illustration Copyright ©2009 Nucleus Medical Art, All rights reserved. www.nucleusinc.com
 Many Factors Regulate Bone Remodeling
Resorption
Formation

GM-CSF RANKL
IL-1 PGE2
IL-6 TNF- Bone

Resting Reversal

Bone Bone

Formation
Resorption

Bone
Abbreviations: GM-CSF, granulocyte macrophage colony-stimulating factor; OPG
IL, interleukin; OPG, osteoprotegerin; RANKL, RANK-ligand, TGF-
PGE2, prostaglandin E2; TGF, transforming growth factor; Estrogen
TNF, tumor necrosis factor.
Illustration Copyright ©2009 Nucleus Medical Art, All rights reserved. www.nucleusinc.com
 Why Bone Remodeling?

Allows skeleton to
 Respond to mechanical loading
 Repair and prevent microdamage (“wear &
tear”)
– Maintains quality control
 Release growth factors and minerals
(calcium and phosphate) stored in matrix
into circulation

All bone cells participate in remodeling

Considerable energy expended to remodel the skeleton
Critical Checkpoint in Control
of Bone Remodeling

Regulation of osteoclast
 Formation
 Number
 Activity
 Lifespan
 Osteoclast Development

Monocyte Macrophage

NF-B, c-Fos
Pu.1
GM-CSF NFAT RANKL

Multipotent Pro- Mono- Mature

Progenitor monocyte nuclear Osteoclast
Osteoclast
RANK– RANK+
Precursor

Abbreviations: GM-CSF, granulocyte macrophage colony-stimulating factor; NF-κB, nuclear factor kappaB;
NFAT, nuclear factor of activated T-cells; RANK, receptor activator for nuclear factor kappa B.
Horowitz MC, et al. Immunol Rev. 2005;208:141-153.
 Osteoclast Structure and Function
 Function – bone resorption
 Highly specialized cytoskeletal structures
– “Ruffled border”
– “Sealing zone”
– Attach to and dissolve bone matrix
 Produce tartrate-resistant acid phosphatase
(TRAP), lysosomal enzymes, cathepsin K,
and integrins
 Express calcitonin receptors and RANK

Major therapeutic target in osteoporosis

Critical Checkpoint in Control
of Bone Remodeling
Regulation of osteoclast
 Formation
 Number
 Activity
 Lifespan

RANK/RANKL/OPG Pathway
 1. Many Factors Stimulate Osteoblast
Expression of RANK-Ligand1,2
Osteoclast Precursor
Colony-Forming
Unit-Macrophage Multinucleated
Osteoclast RANKL

RANK

PTH
PGE2
Glucocorticoids
+mCSF
Vitamin D
IL-11
IL-6 Activated
IL-1 Osteoblasts Osteoclast
PTHrP and
TNF- Bone Marrow
Stromal Cells

Abbreviations: IL, interleukin; mCSF, macrophage colony-stimulating factor; PTH, parathyroid hormone;
PTHrP, parathyroid hormone-related protein.
1. Boyle. WJ, et al. Nature. 2003;423:337-342. 2. Hofbauer LC, et al. JAMA. 2004;292:490-495.
 2. RANK-Ligand Expression Mediates
Osteoclast Formation, Function, and Survival
Osteoclast
Colony-Forming Precursor
Unit-Macrophage
Multinucleated RANKL
Osteoclast
RANK

Hormones
Growth Factors Activated
Cytokines Osteoblasts Osteoclast

Bone Formation
Bone Resorption
Boyle WJ, et al. Nature. 2003;423:337-342.
 3. Osteoprotegerin Prevents RANKL Binding
to RANK and Inhibits Osteoclast Activity
Osteoclast
Precursor

Colony-Forming Multinucleated
Unit-Macrophage Osteoclast RANKL

X RANK

OPG

Hormones
Growth Factors
X Activated
Osteoclast
Cytokines Osteoblasts

Boyle WJ, et al. Nature. 2003;423:337-342.

X
Bone Resorption
 Physiologic Impact of the
RANK/RANKL/OPG Pathway
 Mouse studies
– RANK and RANKL knockouts
 No osteoclasts, severe osteopetrosis (lymph node agenesis)
– OPG knockout
 Unchecked resorption, osteoporosis, fractures, bone
quantity/quality, vascular calcifications

 Human mutations
– RANK – constitutional activating mutations
 Familial expansile osteolysis, familial early-onset Paget’s
disease, expansile skeletal hyperphosphatasia
– OPG – autosomal recessive inactivating mutations
 Juvenile Paget’s disease
 Life Cycle of Osteoblasts
BMPs
TGF-s
Stem Cell Stromal
Proliferation Mesenchymal
Cell
CBFA1
CBFA1
BMPs Proliferation
Pre-Osteoblast Msx-2
TGFs
PTH
TGF- Osteoprogenitor
IGF-I, II
Vitamin D3
CBFA1 c-fos
Glucocorti- Commitment
coids Proliferation No Turning Back
Vitamin D3
PGE2
PTH
TGF- CBFA1
IGF-I, II Dlx-5
fra-2/jun-D Osteocyte

Mature Mineralization
Osteoblast

Lian JB, et al. In Osteoporosis. 2nd ed. Marcus R, et al, eds. Stanford, CA: Academic Press, 2001.
 WIF sFRP
Dkk Sclerostin Wnt
Liganded
State

Frizzled
axin
Dsh
Frat-1

APC

Gsk3
-Catenin -Catenin

-Catenin
SMRT/ Nuclear
NCoR Localization
Nucleus
Altered
OSTEOBLAST -Catenin p300/CBP
Transcription
With permission from
Shoback D. J Clin Endocrinol Metab. Tcf/Ldf of Genes BONE
2007;92:747-753. FORMATION
 ~Pathway Dead~
WIF sFRP
Dkk Sclerostin Wnt
Unliganded Liganded
State State

Frizzled Frizzled
axin
Dsh
Frat-1

APC APC
Gsk3 P
axin -Catenin
Gsk3
LRP -Catenin -Catenin
Proteosomal
Degradation -Catenin
(No New Nuclear
SMRT/
Bone NCoR Localization
Made) Nucleus
Altered
OSTEOBLAST -Catenin p300/CBP
Transcription
With permission from
Tcf/Lef of Genes BONE
Shoback D. J Clin Endocrinol Metab.
2007;92:747-753. FORMATION
 Wnt/LRP5/-Catenin Pathway in Bone
Formation

 Genetic disorders and mouse models

– Loss of function mutations in LRP5 (severe
osteoporosis and fractures – OPPG)
– Gain of function mutations in LRP5 (high bone
mass “trait”)
 Wnt/LRP5/-catenin pathway is essential
– Osteoblast proliferation, differentiation, and
survival
– Activity (work done) during a phase of bone
formation
Abbreviations: LRP, LDL receptor-related protein; OPPG, osteoporosis pseudoglioma syndrome.
Ott SM. J Clin Endocrinol Metab. 2005;90:6741-6743.
 Role of LRP5 in Bone Formation
Mechanism

 Mouse genetics (KOs, Tgs)

 Showed etiology of altered bone cell
function in LRP5 “knockout” and “gain of
function” models
 Endocrine—not paracrine—mechanisms
 Cell responsible (“driver”) is not a bone cell
– Bone receiving signals from the gut (small
intestine) that dictate bone formation

Abbreviations: KO, knockout; Tg, transgenic.

Yadav VK, et al. Cell. 2008;135:825-837.
 Role of LRP5 in Bone Formation
Mechanism
 Innovative experiments/genetic
manipulations in mice
 Studies of patients with known mutations
in the LRP5 gene
Serotonin made in the gut is the key to the
control of bone formation mediated by the
Wnt/LRP5/-catenin pathway

Stimulation or inhibition of bone formation

via Wnt signaling (genetic cases) is mediated via
serotonin receptors in bone
Yadav VK, et al. Cell. 2008;135:825-837.
 Observations
 Enzyme that regulates production of serotonin (Tph1) is
strongly upregulated in the duodenum in LRP5(-/-) mice
 Upregulation produces increased circulating serotonin levels
originating from duodenum, not central nervous system
 Confirmed in mice and patients with osteoporosis-
pseudoglioma syndrome (loss-of-function mutations in LRP5)
 Confirmed that serotonin levels in patients with high bone mass
(gain-of-function mutations in LRP5) are decreased by ~50%
 Postulated & showed serotonin acting via receptors (subtype
Htr1b) inhibits bone formation
 Loss of serotonin signaling or production
– +++Net bone remodeling effect
– High bone mass

Abbreviations: Htr1b, human serotonin receptor 1b; Tph1, tryptophan hydroxylase-1.

Yadav VK, et al. Cell. 2008;135:825-837.
 Bone – Gut Connection
Mechanism
Duodenum
Htr1b

Creb Osteoblast

LRP5
Serotonin

Enterochromaffin Tph1
Cell
Decreased
Osteoblast
Bone Proliferation

Abbreviation: Creb, cyclic AMP-responsive element-binding protein.

With permission from Yadav VK, et al. Cell. 2008;135:825-837.
 Natural Inhibitors of the
Wnt/LRP5/-Catenin Pathway

 Dickkopf (Dkk) – made by myeloma

cells
 Soluble decoy receptors, proteins –
WIF, sFRP
 Sclerostin (SOST) – product of
osteocytes

Abbreviations: sFRP, secreted frizzled-related protein; WIF, Wnt inhibitory factor.

 Sclerostin Secreted by Osteocytes
Negatively Regulates Bone Formation
Sclerostin*
Mesenchymal
Mature Stem Cells
Pre-Osteoblast
Osteoblasts Lining Cells
X X
New Bone

Osteocyte
Bone
Ott SM. J Clin Endocrinol Metab. 2005;90:6741-6743. Semenov MV, et al. J Biol Chem. 2006;281:38276-
38284. Semënov M, et al. J Biol Chem. 2005;280:26770-26775. Li X, et al. J Biol Chem. 2005;280:19883-
19887. Graphic courtesy of Dr. Dolores Shoback.
 Sclerostin MAb Binds Sclerostin—
Endogenous Inhibitor of Bone Formation
WITHOUT Sclerostin Antibody WITH Sclerostin Antibody

Mesenchymal Mesenchymal
Stem Cell Stem cell

Osteoprogenitor Osteoprogenitor
Cell Cell

Pre-Osteoblast Pre-Osteoblast

Scl-MAb
Sclerostin

Bone Osteocyte
Osteocyte

Graphic courtesy of Dr. Dolores Shoback.

 Target Sclerostin—Animal Studies
 Knockout mouse (SOST –/–)1
– >50% increase in BMD (lumbar spine, femur)
– Micro-CT: increased BV/TV in trabecular and cortical bone
– Histomorphometric analysis: >9-fold increase in
osteoblast surface (formation), NO change in osteoclast
surface (uncoupling)
– Mechanical testing: strength significantly increased
 Sclerostin MAb treatment of OVX rat at 6 months2
– Complete reversal of 1-year of estrogen deficiency-
induced bone loss
– Bone mass (and strength) increased to levels above
non-OVX controls
– Reversible

Abbreviations: BV/TV, trabecular bone volume; CT, computed tomography; OVX, ovariectomized.
1. Li X, et al. J Bone Miner Res. 2008;23:860-869. 2. Li X, et al. J Bone Miner Res. 2009;24:578-588.
 Micro-CT Images (Rat)
Region of Analysis Sham

OVX OVX + Sclerostin Ab

With permission from Li X, et al. J Bone Miner Res. 2009;24:578-588. …& mechanically strong
*
 Conclusion
 Osteoporosis: reduction in bone mass,
disruption in bone micro-architecture

CHANGES in BIOMECHANICAL
STRENGTH  FRACTURES
 “IMBALANCE” in bone remodeling
– Excessive RANKL/RANK signaling
– Inadequate OPG production
– Inadequate Wnt/LRP-5 activity
– “Excessive” inhibition of the pathway
How Do Current Therapies Impact
Osteoporosis and Fracture
Prevention?

Paul D. Miller, MD
Distinguished Clinical Professor of Medicine
University of Colorado Medical Center
Colorado Center for Bone Research
Lakewood, CO
 Strategies for Reducing Fracture Risk

Osteoporosis Falls

Bisphosphonates Injury
SERMs Calcium and
prevention
Calcitonin vitamin D
Estrogen
Teriparatide

Abbreviation: SERMs, selective estrogen receptor modulators.

McClung MR, et al. Bone. 2006;38(2 suppl 2):S13–17.
 Antiresorptive Agents

 Estrogen
 Calcitonin
 Bisphosphonates
 SERMs (selective estrogen receptor modulators)
 Anti-RANK ligand antibody (in development)
 Cathepsin K inhibitors (in development)
 Mechanism of Fracture Risk Reduction

Antiresorptive therapy

Reduce bone turnover

Stabilize or improve
Increase BMD
microarchitecture

Decrease in fracture risk

Graphic courtesy of Dr. Paul Miller.
 Anabolic Agents

 Teriparatide (rh 1-34 parathyroid hormone)

 rh 1-84 parathyroid hormone
(in development)
 Strontium ranelate (in development)
 Mechanism of Fracture Risk Reduction

Anabolic therapy

Increase bone turnover

Stabilize or improve
Increase BMD
microarchitecture

Decrease in fracture risk

Graphic courtesy of Dr. Paul Miller.
 Available Bisphosphonates for
Osteoporosis
 Oral
– Etidronate (not US)
– Chlordronate (not US)
– Alendronate (daily, weekly)
– Risedronate (daily, weekly, monthly)
– Ibandronate (daily, monthly)
 Intravenous
– Ibandronate (quarterly)
– Zoledronic acid (annual)
 Off-label
– Pamidronate (IV quarterly)
Why Parenteral Route of Administration
Has Appeal
 Oral bisphosphonates, as good as they are, have fastidious
absorption patterns
 Oral bisphosphonates may induce GI intolerability
 A physician may not want to give an oral bisphosphonate to
patients with GI diseases (achalasia, scleroderma, Barrett’s,
etc)
 In clinical practice, bisphosphonate blood levels cannot be
measured, creating uncertainties around bone bioavailability
in certain clinical management scenarios
 IV delivery requires patient adherence
 Bisphosphonates
 Biochemical analogs of naturally occurring pyrophosphates
 High affinity for bone at the calcium-phosphorus interface
(physiochemical) surface and stabilizes
the crystal
 Reduce osteoclast activity by inhibiting the enzyme farnesyl
pyrophosphate synthetase (FPPS)
 Differences among bisphosphonates are related to differences
in the physiochemical and cellular effects
 Bisphosphonates are not metabolized. The molecule released
(detachment) from bone retains
biologic activity
 What Determines Potency and
Duration of Action?
Physicochemical Effect
OH R1 OH
O P C P O

OH R2 OH

Cellular and molecular

Binding to bone mineral
effects on osteoclasts

Both contribute
to in vivo potency
Bauss F, Russell RG. Osteoporos Int. 2004;15:423–433.
Graphic courtesy of Dr. Paul Miller.
 Bisphosphonates Have Different
Binding Affinities for Bone Mineral

Adsorption affinity constant (KL/106L mol-1)

 Hydroxyapatite1
– Zoledronic acid (3.47) > alendronate (2.94)
 Ibandronate (2.36) > risedronate (2.19)
 Etidronate (1.19) > clondronate (0.72)

 Octacalcium phosphate2
– Zoledronic acid > alendronate > ibandronate
 Risedronate > etidronate > clodronate

1. Nancollas GH, et al. Bone. 2006;38:617–627. 2. [TO COME FROM DR. MILLER]
 Effect of Binding Affinity on
Bisphosphonate Bone Surface Uptake
and Detachment
 High binding affinity
– Uptake: avid
– Diffusion in bone: low
– Detachment: low
– Re-attachment: high
– Examples
 Zoledronate
 Alendronate
 Low binding affinity
– Uptake: weaker
– Diffusion in bone: greater
– Detachment: higher
– Re-attachment: lower
– Example
 Risedronate

Nancollas GH, et al. Bone. 2006;38:617-627.

 Bisphosphonate Safety Issues

 “Over-suppression” of bone remodeling?

 Renal safety
 Osteonecrosis of the jaw
 Mid-shaft femoral fractures
 Known side effects: Upper GI (oral),
musculoskeletal pain; first phase reactions/iritis (IV)
 Bisphosphonate “Drug Holiday”

 Not a topic of discussion when bisphosphonates first launched

 Became a consideration after July 9, 2002
(WHI JAMA publication)
 Became more widely discussed after FLEX (Black et al, JAMA
2004) and the better science defining BP PK/PD became
available
 FRAXTM also drove the “drug holiday” discussion in women
(untreated) who had been at low risk before bisphosphonates
were started
 Not a standard of care in the United States

Miller PD. Best Prac Res Clin Endocrinol Metab. 2008;22:849–868.

 Calcitonin
 Derived from parafollicular cells of the thyroid gland
 Inhibits bone resorption
 Available in nasal, subcutaneous, and oral formulations
 Nasal formulation demonstrates reduction in vertebral fracture
only in the 200 IU/spray formulation; lower and higher doses
had no effect; nor has any dose available shown nonvertebral
fracture risk reduction
 Has excellent safety profile; ability to reduce pain with
formulations other than injectable uncertain
 Estrogen Receptor Shape Drives
Function
 The estrogen receptor (ER) is a nuclear transcription factor that
interacts with estrogen in the nucleus
 ER ligand binding sites anchor estrogen
 A conformational change occurs
 The new shape allows activating factors (AF-1 and AF-2) to dock with
specific coactivators, forming a gene transcription complex
 Transcription occurs at estrogen-responsive genes to produce effects
on different tissues
– Bone rebuilding
– Serum lipid reduction

Estrogen is locked into the molecule by a conformational folding of

the ER “like a stick jammed into jaws of a crocodile.”2
1. Jordan VC, et al. J Natl Cancer Inst. 2001;93:1449–1457. 2. MacGregor JI, Jordan VC.
Pharmacol Rev. 1998;50:151–196.
 Effect of Raloxifene in Women with or
Without Pre-Existing Fractures
MORE Trial—3 Years
25 RR 0.7a
Incident Vertebral Fractures
Placebo (95% CI = 0.6–0.9)
Raloxifene 60 mg/d
20
% of Women with

30%

15

10
RR 0.5a
(95% CI = 0.3–0.7)
5
55%

0
Without Pre-Existing With Pre-Existing
Vertebral Fracture Vertebral Fracture
a
Women who completed the study and had evaluable radiographs at 36 months.
With permission from Ettinger B, et al. JAMA. 1999;282:637-645.
 Invasive Breast Cancer—Similar
Incidence Rates with Raloxifene and
Tamoxifen
Raloxifene
Tamoxifen

With permission from Vogel VG, et al. JAMA. 2006;295:2727-2741.

 Effect of Teriparatide on Risk of
Vertebral Fractures in Postmenopausal
Women
16 RR 0.35 (95% CI = 0.22–0.55)a
% of Patients with ≥1 Fracture

14

12

10

8
65% 
6

0
a Placebo Teriparatide 20 µg
P <.001 vs placebo.
Neer RM, et al. N Engl J Med. 2001;344:1434-1441.
Graphic courtesy of Dr. Paul Miller.
 Nonvertebral and Hip Fractures
Teriparatide
20
Control
Percent with New Fractures

Teriparatide 20 µg
15

10

RR = 0.5 (0.3,0.9)

5
NS

0
Nonvertebral Fractures Hip Fractures
5 fragility hip fractures (control + primary treatment group).
Nonvertebral fractures = fragility fractures, otherwise not specified.
Neer R, et al. N Engl J Med. 2001;344:1434–1441.
Graphic courtesy of Dr. Paul Miller.
 FDA Label Contraindications
to Teriparatide
 Unexplained hypercalcemia
 Unexplained elevated alkaline phosphatase
 Paget’s disease
 Prior skeletal (therapeutic) radiation
 Metastatic cancer
 Unfused epiphysis
 GFR <30 mL/min
 Basic Lab Tests Before Starting
Teriparatide
 Serum calcium
 Alkaline phosphatase
 25 hydroxy-vitamin D
 PTH
 Serum creatinine

Miller PD, et al. Endocrine Practice. 2004;10:139–148.

 FDA Indications for Osteoporosis

Drug PMO GIO (Women, Men) Men

Prevention Treatment Prevention Treatment
Estrogen 

Alendronate PO    

Risedronate PO     
Ibandronate PO  
Ibandronate IV 
Zoledronate IV     
Calcitonin IN 
Raloxifene PO  
Teriparatide SC   

Graphic courtesy of Dr. E. M. Lewiecki.

 Conclusions

 Antiresorptive and anabolic therapies are both available to

manage postmenopausal osteoporosis
 Antiresorptives: calcitonin, selective estrogen receptor
modulators, and bisphosphonates, all have unique mechanisms
to reduce fracture risk
 Bisphosphonates can reduce the risk for vertebral,
nonvertebral, and hip fractures and although individual clinical
trials show differences in efficacy, the lack of head-to-head
fracture trials precludes validation of any superiority of 1
bisphosphonate over another
 Conclusions

 Both oral as well as intravenous bisphosphonates

are available. Intravenous allows delivery without GI
side effects, and assures drug delivery to bone in
circumstances where absorption of oral
bisphosphonates is uncertain
 Teriparatide stimulates bone formation and is
especially useful in patients at high risk for
fractures or who do not “respond” to alternative
osteoporosis pharmacologic agents
Future Treatment and Prevention
of Osteoporosis and Fractures:
What Do the Data Show?

E. Michael Lewiecki, MD, FACP, FACE

Osteoporosis Director
New Mexico Clinical Research & Osteoporosis Center
Clinical Assistant Professor of Medicine
University of New Mexico School of Medicine
Albuquerque, New Mexico
 Ultimate Goal

To minimize fracture risk by achieving

“normal” bone strength with therapy that
is safe, well-tolerated, easy to administer,
and inexpensive

Courtesy of Dr. David Dempster

 How Do We Get There?

 Improving understanding of the regulators of bone

remodeling and mediators of bone resorption and
formation
 Developing new agents that prevent bone loss and/or
restore lost bone mass and bone quality that occurs
due to age and disease
 Modulating bone remodeling in ways that optimize
skeletal health
 Regulation of Bone Remodeling

 Bone formation: Wnt/β-catenin pathway

– Stimulation: Wnt signaling proteins bind
to the frizzled/LRP5/6 receptor
– Inhibition: Dkk1, sclerostin bind to
receptor to antagonize Wnt signaling
 Bone resorption: RANKL/RANK/OPG
pathway
– Stimulation: RANKL binds to RANK
– Inhibition: OPG decoy receptor for RANKL
 New and Emerging Treatments

Antiresorptive (anticatabolic) Osteo-anabolic (bone-forming)

 Denosumab  Sclerostin inhibitor
 Odanacatib
 Variations of PTH
 Lasofoxifene
 Endogenous PTH
 Bazedoxifene
stimulation – calcium
 CE/bazedoxifene sensing receptor
 New delivery systems – oral antagonist (calcilytic)
salmon calcitonin
 New delivery systems –
transdermal PTH

Strontium ranelate
Combinations of antiresorptive and anabolic
 Denosumab (Dmab)

 Fully human monoclonal antibody-IgG2 isotype

 High affinity and specificity for human RANK ligand
 Does not bind to TNFα, TNFβ, TRAIL, or CD40L
 Pharmacokinetics (SC): similar to other fully human IgG2
monoclonal antibodies
– Absorption is rapid and prolonged (Cmax ≈1–4 wks postdose)
– Long half-life ≈34 days with maximum dose
– Distribution ≈ intravascular volume
– Clearance ≈ reticuloendothelial system
– No kidney filtration or excretion of intact molecule

Abbreviations: TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand.

Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. Boyle WJ, et al. Nature. 2003;423:337-342.
 Dmab Serum Levels (1 mg/kg SC)

10
Serum Level (ng/mL)

10
2

10
1
EC50
10

0 0 1 2 3 4 5 6 9
Study Month

With permission from Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.
 Dmab Mechanism of Action
RANKL
RANK
OPG CFU-M
Dmab
Pre-Fusion
Osteoclast

Growth Factors Multinucleated

Hormones Osteoclast
Cytokines

Osteoclast

Osteoblast
Lineage Bone
Abbreviation: CFU-M, colony forming unit macrophage.
 FREEDOM Results

 68% decrease in vertebral fractures

– 2.3% vs 7.2%, P <.000
 140% decrease in hip fractures
– 0.7% vs 1.2%, P = .036
 20% decrease in nonvertebral fractures
– 6.5% vs 8.0%, P = .011
 Dmab increased BMD and reduced BTMs compared with placebo
 AEs and SAEs generally similar to placebo
– No increased risk of cancer, infection, cardiovascular disease,
delayed fracture healing, hypocalcemia, no osteonecrosis of the jaw
– Increased risk of cellulitis, eczema, flatulence; decreased risk of
falls, concussion

Cummings SR, et al. N Engl J Med. 2009;361:1-10.

 RANKL Inhibition with Dmab

 Increases BMD and reduces BTMs in postmenopausal women with low

BMD and osteoporosis1,2
 Effects on BMD and BTMs are reversible with discontinuation, with a
robust response to retreatment
 Reduces risk of vertebral, hip, and nonvertebral fractures in women
with PMO3
 In patients initiating treatment, those taking Dmab increase BMD and
decrease BTMs more than those taking ALN, with higher preference
and greater satisfaction for Dmab vs ALN4
 In patients previously treated with ALN, those switching to Dmab
increase BMD more than those continuing ALN5
 Good safety and tolerability1-5

1. McClung MR, et al. N Engl J Med. 2006;354:821-831. 2. Bone HG, et al. J Clin Endocrinol Metab. 2008;93:2149-2157.
3. Cummings SR, et al. N Engl J Med. 2009;361:756-765. 4. Brown JP, et al. J Bone Miner Res. 2009;24:153-161.
5. Kendler DL, et al. J Bone Miner Res. 2009. [epub]
Resorbing Osteoclast
 Weekly Dosing of Odanacatib

Slide Not Available

See Clinical Pharmacology & Therapeutics 2009;Vol.86:175-182 for line graph-Figure 3A

 New SERMs for Postmenopausal
Osteoporosis
Lasofoxifene Bazedoxifene
 Efficacy  Efficacy
– Increases BMD
– Increases BMD
– Reduces BTMs
– Decreases risk of VFs and NVFs – Reduces BTMs
– Decreases risk of ER+ breast – Decreases risk of VFs
cancer
 Safety
– Improves signs and symptoms of
vulvovaginal atrophy – Increases risk of VTEs, hot
 Safety flushes, muscle cramps
– Increases risk of venous
thromboembolisms (VTEs), hot
flushes, muscle spasm, and
vaginal bleeding

Cummings SR, et al. J Bone Miner Res. 2008;23:S81. Silverman SL, et al. J Bone Miner Res.
2008;23:1923-1934. Eastell R, et al. J Bone Miner Res. 2008;23:S81.
 Wnt Signaling

With permission from Baron R, et al. Endocrinol. 2007;148:2633-2644.

 Sclerostin MAb Increases BMD in Rats
0.34 Sham Vehicle PTH Mab

0.32
0.30
BMD (g/cm 2)

0.28
0.26
0.24
0.22
0.20
Lumbar Spine Tibia-Femur

1.5-year-old rats 1 year post-ovariectomy

MAb 25 mg/kg 2x/wk x 5 wk
PTH 1-34 100 mcg/kg 5x/wk x 5 wk
Warmington K, et al. J Bone Miner Res. 2005;20(suppl 1):S22.
Li X, et al. J Bone Miner Res. 2009;24:578-588.
 Strontium

 Description
– Soft silvery white metallic element occurring naturally as
celestine or strontianite
– Atomic weight = 87.62
– Calcium atomic weight = 40.078
 History
– First found 1790 in lead mines near Strontian, Scotland
– Radioactive Sr-90 discovered 1940s (nuclear weapons)
Strontium Ranelate—Mechanism of Action?
BONE Strontium BONE
ranelate
FORMATION RESORPTION
+
Pre-OB REPLICATION Pre-OC

Strontium
ranelate
- DIFFERENTIATION

OB OB OB

Strontium OC
ranelate
+ BONE-FORMING - - BONE RESORBING
ACTIVITY
ACTIVITY

BONE MATRIX
With permission from Marie PJ, et al. Calcif Tiss Int. 2001;69:121-129.
 Strontium Reduces VF Risk in SOTI
Trial
Spinal Osteoporosis Therapeutic Intervention
% Patients with Morphometric VFs

35 32.8

30 Placebo Strontium

25
20.9
20
15 12.2
 41%
10 (P <.001)
6.4
5 49%
(P <.001)
0
12 Months 36 Months

With permission from Meunier PJ, et al. N Engl J Med. 2004;350:459-468.

 Strontium Reduces Nonvertebral Fractures
(NVFs) in TROPOS Trial
TReatment Of Peripheral Osteoporosis
5-year phase III study evaluating NVF risk in 5091 women with PMO
randomized to SR or placebo: 3-year data
14 12.9

12 11.2
% Patients with NVF

10 Placebo Strontium

8
6.4 High Risk: age 74+ and
16% FN T-score -3.0 or less
6
(P = .04) 4.3
4
36%
2 (P = .046)

0
All NVFs Hip Fracture
Entire Sample High Risk Subjects
Reginster JY, et al. J Clin Endocrinolo Metab. 2005;90:2816-2822.
 Summary

 Improved understanding of basic bone

physiology in health and disease
 New targets for therapeutic intervention
identified
 Promising agents are in development
 Challenges in clinical trial design,
regulatory requirements, and market
forces