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Mechanisms of Anabolic Therapies for Osteoporosis

Clifford Rosen MD

rosenc@mmc.org

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

3

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

***

***

***

***

***

***

***

***

*** 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

0

2

4

6

8

10

12

14

16

18

20

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%

-2

-1

0

1

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%

-2

-1

0

1

2

3

4

0 3 6 9 12

Mea

n ch

ange

Hip

aB

MD

(%)

Month

POWR

Placebo

0.04%

-2

-1

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

0

5

0

5

******

*

***

**

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

-

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