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
digest bone within a
sealed resorption vacuole
Resorption
Bone
Reversal
Resting
Bone
Apoptotic
osteoclasts
Bone
Preosteoblasts
Mature osteoblasts
building osteoid
tissue
Mineralization
Bone
Formation
Illustration Copyright ©2009 Nucleus Medical Art, All rights reserved. www.nucleusinc.com
Many Factors Regulate Bone Remodeling
Resorption
Formation
GM-CSF
IL-1
IL-6
RANKL
PGE2
TNF-
Bone
Reversal
Resting
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
NF-B, c-Fos
Pu.1
GM-CSF
Multipotent
Progenitor
RANK–
Macrophage
NFAT
Promonocyte
RANK+
RANKL
Mononuclear
Osteoclast
Precursor
Mature
Osteoclast
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
Colony-Forming
Unit-Macrophage
Osteoclast Precursor
Multinucleated
Osteoclast
RANKL
RANK
PTH
PGE2
Glucocorticoids
Vitamin D
IL-11
IL-6
IL-1
PTHrP
TNF-
+mCSF
Osteoblasts
and
Bone Marrow
Stromal Cells
Activated
Osteoclast
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
Colony-Forming
Unit-Macrophage
Osteoclast
Precursor
Multinucleated
Osteoclast
RANKL
RANK
Hormones
Growth Factors
Cytokines
Osteoblasts
Activated
Osteoclast
Bone Formation
Boyle WJ, et al. Nature. 2003;423:337-342.
Bone Resorption
3. Osteoprotegerin Prevents RANKL Binding
to RANK and Inhibits Osteoclast Activity
Osteoclast
Precursor
Colony-Forming
Unit-Macrophage
X
Multinucleated
Osteoclast
RANKL
RANK
OPG
Hormones
Growth Factors
Cytokines
Boyle WJ, et al. Nature. 2003;423:337-342.
X
Osteoblasts
X
Bone Resorption
Activated
Osteoclast
Physiologic Impact of the
RANK/RANKL/OPG Pathway

Mouse studies
–
RANK and RANKL knockouts

–
OPG knockout


No osteoclasts, severe osteopetrosis (lymph node agenesis)
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
Mesenchymal
Cell
Proliferation
Pre-Osteoblast
CBFA1
Glucocorticoids
Vitamin D3
PGE2
PTH
TGF-
IGF-I, II
Mature
Osteoblast
CBFA1
Msx-2
PTH
TGF-
IGF-I, II
Vitamin D3
c-fos
CBFA1
BMPs
TGFs
Proliferation
Osteoprogenitor
Proliferation
Commitment
No Turning Back
CBFA1
Dlx-5
fra-2/jun-D
Osteocyte
Mineralization
Lian JB, et al. In Osteoporosis. 2nd ed. Marcus R, et al, eds. Stanford, CA: Academic Press, 2001.
Dkk
WIF
Sclerostin
Wnt
sFRP
Liganded
State
Frizzled
axin
Dsh
Frat-1
APC
Gsk3
-Catenin
-Catenin
-Catenin
SMRT/
NCoR
Nucleus
OSTEOBLAST
With permission from
Shoback D. J Clin Endocrinol Metab.
2007;92:747-753.
-Catenin
Tcf/Ldf
p300/CBP
Nuclear
Localization
Altered
Transcription
of Genes
BONE
FORMATION
~Pathway Dead~
Dkk
Sclerostin
WIF
Wnt
Unliganded
State
sFRP
Liganded
State
Frizzled
Frizzled
axin
Dsh
Frat-1
APC
axin
APC
Gsk3
P
-Catenin
Gsk3
-Catenin
LRP
(No New
Bone
Made)
Proteosomal
Degradation
OSTEOBLAST
With permission from
Shoback D. J Clin Endocrinol Metab.
2007;92:747-753.
-Catenin
SMRT/
NCoR
Nucleus
-Catenin
Tcf/Lef
-Catenin
p300/CBP
Nuclear
Localization
Altered
Transcription
of Genes
BONE
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 osteoporosispseudoglioma 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
Cell
Tph1
Bone
Abbreviation: Creb, cyclic AMP-responsive element-binding protein.
With permission from Yadav VK, et al. Cell. 2008;135:825-837.
Decreased
Osteoblast
Proliferation
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*
Mature
Osteoblasts
X
Pre-Osteoblast
Lining Cells
Mesenchymal
Stem Cells
X
New Bone
Osteocyte
Bone
Ott SM. J Clin Endocrinol Metab. 2005;90:6741-6743. Semenov MV, et al. J Biol Chem. 2006;281:3827638284. Semënov M, et al. J Biol Chem. 2005;280:26770-26775. Li X, et al. J Biol Chem. 2005;280:1988319887. Graphic courtesy of Dr. Dolores Shoback.
Sclerostin MAb Binds Sclerostin—
Endogenous Inhibitor of Bone Formation
WITHOUT Sclerostin Antibody
WITH Sclerostin Antibody
Mesenchymal
Stem Cell
Mesenchymal
Stem cell
Osteoprogenitor
Cell
Osteoprogenitor
Cell
Pre-Osteoblast
Pre-Osteoblast
Scl-MAb
Sclerostin
Bone
Osteocyte
Graphic courtesy of Dr. Dolores Shoback.
Osteocyte
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 deficiencyinduced 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
Bisphosphonates
SERMs
Calcitonin
Estrogen
Teriparatide
Calcium and
vitamin D
Abbreviation: SERMs, selective estrogen receptor modulators.
McClung MR, et al. Bone. 2006;38(2 suppl 2):S13–17.
Falls
Injury
prevention
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
microarchitecture
Increase BMD
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
microarchitecture
Increase BMD
Decrease in fracture risk
Graphic courtesy of Dr. Paul Miller.
Available Bisphosphonates for
Osteoporosis

Oral
–
–
–
–
–

Intravenous
–
–

Etidronate (not US)
Chlordronate (not US)
Alendronate (daily, weekly)
Risedronate (daily, weekly, monthly)
Ibandronate (daily, monthly)
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
effects on osteoclasts
Binding to bone mineral
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

Low binding affinity
–
Uptake: avid
–
Uptake: weaker
–
Diffusion in bone: low
–
Diffusion in bone: greater
–
Detachment: low
–
Detachment: higher
–
Re-attachment: high
–
Re-attachment: lower
–
Examples
–
Example

Zoledronate

Alendronate
Nancollas GH, et al. Bone. 2006;38:617-627.

Risedronate
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
% of Women with
Incident Vertebral Fractures
MORE Trial—3 Years
25
20
30%
15
10
RR 0.5a
(95% CI = 0.3–0.7)
5
55%
0
a
Placebo
Raloxifene 60 mg/d
RR 0.7a
(95% CI = 0.6–0.9)
Without Pre-Existing
Vertebral Fracture
With Pre-Existing
Vertebral Fracture
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
% of Patients with ≥1 Fracture
16
14
12
10
8
65% 
6
4
2
0
a
RR 0.35 (95% CI = 0.22–0.55)a
Placebo
P <.001 vs placebo.
Neer RM, et al. N Engl J Med. 2001;344:1434-1441.
Graphic courtesy of Dr. Paul Miller.
Teriparatide 20 µg
Nonvertebral and Hip Fractures
20
Teriparatide
Percent with New Fractures
Control
Teriparatide 20 µg
15
10
RR = 0.5 (0.3,0.9)
5
NS
0
Nonvertebral 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.
Hip Fractures
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
Prevention
GIO (Women, Men)
Treatment
Estrogen

Alendronate PO


Risedronate PO


Ibandronate PO















Calcitonin IN
Raloxifene PO
Treatment

Ibandronate IV
Zoledronate IV
Prevention
Men

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)

Denosumab

Odanacatib

Lasofoxifene

Bazedoxifene

CE/bazedoxifene

New delivery systems – oral
salmon calcitonin
Osteo-anabolic (bone-forming)




Sclerostin inhibitor
Variations of PTH
Endogenous PTH
stimulation – calcium
sensing receptor
antagonist (calcilytic)
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)
Serum Level (ng/mL)
4
10
3
10
2
10
1
EC50
10
0
0
1
2
3
6
5
4
Study Month
With permission from Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.
9
Dmab Mechanism of Action
RANKL
RANK
CFU-M
OPG
Dmab
Pre-Fusion
Osteoclast
Multinucleated
Osteoclast
Growth Factors
Hormones
Cytokines
Osteoclast
Osteoblast
Lineage
Bone
Abbreviation: CFU-M, colony forming unit macrophage.
FREEDOM Results

68% decrease in vertebral fractures
–

140% decrease in hip fractures
–


0.7% vs 1.2%, P = .036
20% decrease in nonvertebral fractures
–

2.3% vs 7.2%, P <.000
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

Efficacy
–
–
–
–
–

Increases BMD
Reduces BTMs
Decreases risk of VFs and NVFs
Decreases risk of ER+ breast
cancer
Improves signs and symptoms of
vulvovaginal atrophy
Safety
–
Bazedoxifene


Efficacy
–
Increases BMD
–
Reduces BTMs
–
Decreases risk of VFs
Safety
–
Increases risk of VTEs, hot
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
BMD (g/cm 2)
0.32
0.30
0.28
0.26
0.24
0.22
0.20
Lumbar Spine
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.
Tibia-Femur
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?
Strontium
ranelate
BONE
FORMATION
Pre-OB
BONE
RESORPTION
+
REPLICATION
Pre-OC
Strontium
-
ranelate
OB
DIFFERENTIATION
OB
OB
OC
Strontium
ranelate
+ BONE-FORMING
ACTIVITY
-
- BONE RESORBING
ACTIVITY
BONE MATRIX
With permission from Marie PJ, et al. Calcif Tiss Int. 2001;69:121-129.
Strontium Reduces VF Risk in SOTI
Trial
% Patients with Morphometric VFs
Spinal Osteoporosis Therapeutic Intervention
35
30
32.8
Placebo
Strontium
25
20.9
20
15
10
5
12.2
 41%
6.4
(P <.001)
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
% Patients with NVF
12
12.9
11.2
Placebo
10
Strontium
8
High Risk: age 74+ and
FN T-score -3.0 or less
6.4
6
16%
4.3
(P = .04)
4
36%
2
0
(P = .046)
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