Mechanisms of Anabolic Therapies for Osteoporosis Clifford Rosen MD - - PDF document

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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

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OC

OB H+

Formation Resorption

20 Days 100 Days RANK-L(OPGL) Osteocalcin BSAP PICP M-CSF 120 Days Collagen Proteases

Osteocalcin

Matrix

CTx NTx D-Pyr RANK OPG

PTH and Bone Remodeling

IGFs IGF-BPs TGFs

αvβ3

IGF-I IGFBPs

LRP5,6

Osteocyte

Sclerostin

• Tgf-β

COOH

BMP,S1P

Wnt 10b

PTH

Effect of PTH (1-34) on lumbar spine BMD

Placebo PTH 20 mcg PTH 40 mcg Months

% Change (±SE)

2 4 6 8 10 12 14 16 3 6 12 18

*** *** *** *** *** *** *** ***

*** p < 0.001 vs. Placebo

~ 7%

Neer et al. N Engl J Med. 2001;344:1434-1441

4 Effect of Teriparatide on Incidence of Vertebral and Non-Vertebral Fractures in Postmenopausal Women with Osteoporosis

Neer RM, et al. N Engl J Med. 2001;344:1434-41

2 4 6 8 10 12 14 16 18 20

Non-vertebral fractures

Patients (%) with fracture P< 0.01

53%

20 g PTH

2 4 6 8 10 12 14 16 18 20

New vertebral fracture

Patients (%) with fracture

P< 0.01

65%

20 g PTH Placebo Placebo

B3D-MC-GHAC UCSF - Jiang

Patient 1124

Baseline Follow-up

Female, age 65 Duration 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

1 2 3 4 3 6 9 12 Mean change Spine aBMD (%) Month

POWR Placebo

2.1%

• 2
• 1

1 2 3 4 3 6 9 12 Mean change Trabecular Spine vBMD (%) Month

POWR Placebo

3.8%

• 2
• 1

1 2 3 4 3 6 9 12 Mean change Hip aBMD (%) Month

POWR Placebo

0.04%

• 2
• 1

1 2 3 4 3 6 9 12 Mean change Integral Femur vBMD (%) Month

POWR Placebo

• 0.4%
• 50
• 40
• 30
• 20
• 10

10 20 3 6 9 12

Mean Change CTX (%) M

• nth

POW R Placebo

• 40

40 80 120 3 6 9 12

Mean Change P1NP (%) Month POW R 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 weekly Reduces vert fractures by more than 50%

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9 Fracture Efficacy for Abaloparatide

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How Does PTH or PTHrp Work?

PTH PPR 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. Brommage

American Journal of Physiology - Cell Physiology Jan 1978 What happens if we reduce or prevent PTH1R activation?

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Prx1cre;PTH1Rfl/fl PTH1Rfl/fl

A D C

PTH1Rfl/fl Prx1Cre;PTH1Rfl/fl

B

Prx1cre;PTH1Rfl/fl PTH1Rfl/fl

5 5

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* *** * * Runx2 Osx Alp Col1α1 Ocn Fold over control 0.0 0.5 1.0 1.5

Prx1cre;PTH1Rfl/fl PTH1Rfl/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

mesenchymal stromal cell (mMSC) pre‐adipocyte Pref‐1

• steoblast

adipocyte

• PDGFR

C/EBPs Zfp423 Zfp467 Prx1

PTH in the Marrow Niche

Pre-OB

Ocy ??

?

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

19 LRP5 signaling pathway: Inactivation by Dkk proteins

GSK-3b

A P C p

Frizzled LRP5

b-catenin

dvl

axin

X

Dkk1 P

Internalization Degradation

Dkk1 Kremen

LRP5 signaling pathway for osteogeneiss: Canonical Pathway; SOST Blocks WNT-Lrp5 signaling

GSK-3b

A P C

Osteoblast differentiation

Frizzled

Wnt

LRP5

b-catenin

sFRP

Dkk1 dvl

axin

TCF-LEF Frat1

SOST nucleus

Reduced 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