Mechanisms of Anabolic Therapies for Osteoporosis...Postmenopausal Women with Osteoporosis Neer RM,...
Transcript of Mechanisms of Anabolic Therapies for Osteoporosis...Postmenopausal Women with Osteoporosis Neer RM,...
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Mechanisms of Anabolic Therapies for Osteoporosis
Clifford Rosen MD
MMC: Portland Maine
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Conflicts of Interest
Associate Editor- UpToDate NEJM
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Outline
-Anabolics– How do they work?
• Work of the osteoblast?• Formation> Resorption• Increase osteoblast progenitors
PTH, PTHrp, Romosozumab– Drugs:
• PTH• Abaloparatide-PTHrp• Romosozumab• Others????
PTH1R Agonists That Activate the Anabolic Program
PTHrp
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OC OB
H+
FormationResorption20 Days 100 Days
RANK-L(OPGL)
OsteocalcinBSAP
PICP
M-CSF
120 Days
Collagen
Proteases
Osteocalcin
Matrix
CTxNTx
D-PyrRANK OPG
PTH and Bone Remodeling
IGFsIGF-BPsTGFs
αvβ3
IGF-IIGFBPs
LRP5,6
Osteocyte
Sclerostin
-Tgf-β
COOHBMP,S1P
Wnt 10b
PTH
Effect of PTH (1-34) on lumbar spine BMD
Placebo
PTH 20 mcg
PTH 40 mcg
Months
% C
hang
e (±
SE
)
02468
10121416
0 3 6 12 18
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***
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***
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*** p < 0.001 vs. Placebo
~ 7%
Neer et al. N Engl J Med. 2001;344:1434-1441
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Effect of Teriparatide on Incidence of Vertebraland Non-Vertebral Fractures in Postmenopausal Women with Osteoporosis
Neer RM, et al. N Engl J Med. 2001;344:1434-41
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2
4
6
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10
12
14
16
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Non-vertebral fractures
Patie
nts
(%) w
ith fr
actu
re
P< 0.01
53%
20 g PTH0
2
4
6
8
10
12
14
16
18
20
New vertebral fracture
Patie
nts
(%) w
ith f
ract
ure
P< 0.01
65%
20 g PTH PlaceboPlacebo
B3D-MC-GHACUCSF - Jiang
Patient 1124
Baseline Follow-up
Female, age 65Duration of therapy: 637 days (approx 21 mos)
BMD Change:Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%)Total Hip: +5.2% (group mean = 2.6 ± 4.9%)
How do Anabolic Agents Increase the Work of the Osteoblast?
Jiang Y et al. J Bone Miner Res. 2003;18:1932–1941
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Major Clinical Trials With Teriparatide
• Reduction in vertebral (65%) and non-vertebral (53%) fractures (Neer et al. N Eng J Med. 2001)
• As effective in women with mild or severe previous fragility fractures (Gallagher et al. 2004)
• As effective in women with 1, 2 or more previous fragility fractures (Gallagher et al. 2004)
• Reduced back pain (McClung et al. 2005; Miller et al. 2006)
PTH Light!!
Does once weekly PTH work?
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PTH once Weekly Increases L-S BMD-2%
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2
3
4
0 3 6 9 12Mea
n ch
ange
Spi
ne a
BM
D (%
)
Month
POWR
Placebo
2.1%
-2
-1
0
1
2
3
4
0 3 6 9 12
Mea
n ch
ange
Tra
becu
lar S
pine
vB
MD
(%)
Month
POWR
Placebo
3.8%
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0
1
2
3
4
0 3 6 9 12
Mea
n ch
ange
Hip
aB
MD
(%)
Month
POWR
Placebo
0.04%
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0
1
2
3
4
0 3 6 9 12
Mea
n ch
ange
Inte
gral
Fem
ur v
BMD
(%)
Month
POWR
Placebo
-0.4%
-50
-40
-30
-20
-10
0
10
20
0 3 6 9 12
Mea
n C
hang
e C
TX (%
)
Month
POWR
Placebo
-40
0
40
80
120
0 3 6 9 12
Mea
n C
hang
e P
1NP
(%)
Month
POWR
Placebo
Biochemical Markers of Bone Turnover with PTH once weekly
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PTH once weekly Fracture Trial-56ug: 1-34
Nakumara, 2012
PTH once weeklyReduces vertfractures by more than 50%
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Fracture Efficacy for Abaloparatide
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How Does PTH or PTHrp Work?
PTHPPR
SOST RANKL
bone formation bone resorptio
pHDAC4/5
Gs
Mef2c
HDAC4/5
CREB
CRTC2
pCRTC2
SIK2
cAMP, PKA
Wein et al, Nature Communications, 2
Silk inducible kinase
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Sost?
HSCs
The Bone Marrow Niche: Mesenchymal and Hematopoietic Vitality
Adipocytes
Osteocyte
Long et al, 2014
OB Choices for Fuel Utilization
AMPK
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Aerobic glycolysis in bone: lactate production and gradients in calvaria- PTH induces glycolysis
W. F. Neuman, M. W. Neuman, R. BrommageAmerican Journal of Physiology - Cell Physiology Jan 1978
What happens if we reduce or prevent PTH1R activation?
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Prx1cre;PTH1Rfl/flPTH1Rfl/flA
D
C
PTH1Rfl/flPrx1Cre;PTH1Rfl/fl
B
Prx1cre;PTH1Rfl/flPTH1Rfl/fl
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Runx2 Osx Alp Col1α1 Ocn
Fold
ove
r con
trol
0.0
0.5
1.0
1.5
Prx1cre;PTH1Rfl/flPTH1Rfl/fl
PTH1R deletion in pre- OBs
Fan et al Cell Metabolism 2017
PTH Reduces Bone Marrow Adiposity
Fan et al, Cell Metabolism, 2017
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Hypoparathyroidism- High BMAT and Decreases with PTH
MSC Fate in the Marrow Niche
mesenchymalstromal cell (mMSC)
pre‐adipocytePref‐1
osteoblast
adipocyte
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PDGFRC/EBPsZfp423Zfp467Prx1
PTH in the Marrow Niche
Pre-OBOcy
???
PTH
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PTH Summary- Part 1
• PTH and PTHrp stimulate bone formation and resorption- Super-remodelers
• Fracture efficacy established for both• PTH stimulates progenitor
differentiation and glycolysis via actions on IGF-I, SOST, and Sik2
• PTH inhibits adipocyte differentiation
Antibodies to Sclerostin: The Next New Anabolic?
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Sclerosteosis
Sclerostin (SOST)A member of Dan/Cerb family
• Expressed in Bone…limited synthesis in non skeletal tissue– Osteocytes– Increased by BMP and during osteoblast
differentiation• PTH down regulates• High affinity for BMP 6, 7 not 2 or 4• A BMP and Wnt antagonist (binds
LRP5)
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Increased bone mass throughout skeleton.
Good quality, fracture resistant bone.
Photo: Janssens and Van Hul.Hum Mol Genet. 2002;11:2385‐93.
Normal
Sclerosteosis /van Buchem’s
Wild Type Mouse
Scl‐KO Mouse
Sclerostin
Osteocyte
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LRP5 signaling pathway: Inactivation by Dkk proteins
GSK-3bAPC
p
Frizzled
LRP5
b-catenin
dvlaxin
X
Dkk1
P
Internalization
Degradation
Dkk1
Kremen
LRP5 signaling pathway for osteogeneiss: Canonical Pathway; SOST Blocks WNT-Lrp5 signaling
GSK-3bAPC
Osteoblastdifferentiation
Frizzled
WntLRP5
b-catenin
sFRPDkk1
dvlaxin
TCF-LEF
Frat1
SOST
nucleusReduced Osteoclast
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Monoclonal to Sclerostin vs Alendronate and PTH
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Romozsozumab Reduces Fractures
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Summary: New Anabolic Treatments
• PTH builds bone by suppressing SOST, stimulating glycolysis and shifting progenitors towards OBs
• Abaloparatide enters the market as a PTH like agent at lower cost and possibly greater benefit?
• Monoclonal antibodies to sclerostin increase bone mass by enhancing the work of bone formation
• Romosozumab works but safety has not been fully established due to potential cardiovascular risk