Mechanisms of Anabolic Therapy John P. Bilezikian, MD, PhD (hon) - - PowerPoint PPT Presentation

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Mechanisms of Anabolic Therapy

John P. Bilezikian, MD, PhD (hon) Silberberg Professor of Medicine College of Physicians and Surgeons Columbia University New York, NY Osteoporosis CME 2018: New Insights in Research, Diagnosis, and Clinical Care July 12-13, 2018

John P. Bilezikian, MD, PhD (hon) Disclosures:

Abiogen (Consultant) Amgen (Consultant, Advisory Board) Shire Pharmaceuticals (Consultant) Radius Pharmaceuticals (Consultant, Advisory Board)

Regeneron (DSMB) Ultragenyx (Consultant)

6-18

• 1. Bone turnover
• 2. Architecture
• 3. Mineralization
• 4. Bone size and shape
• 5. Damage accumulation
• 6. Matrix quality

+

Bone strength

How antiresorptive agents improve bone strength

=

Bone density Bone quality

Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001): 785-95

 Bone Remodeling

Therapeutic Goals

Stabilize or increase BMD Maintain trabecular architecture Increase mineralization density of bone matrix

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THE HOLY GRAIL? The chronology of the development of therapies for osteoporosis: irony #1 For the first 20 years or so, the field was dominated by drugs that prevent microstructural deterioration, add mineral content to bone, but do not help to reconstruct the skeleton The chronology of the development of therapies for osteoporosis: irony #2

The attempt to improve skeletal microstructure as a treatment for

• steoporosis began with the

development of a drug that was thought to do the opposite!

Parathyroid Hormone?

“Parathyroid hormone is bad for bones”

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PHPT IN THE EARLY YEARS, 1929-1970 The captain (1929-1933) and The lady (1970)

70 80 90 100 Lumbar Spine Femoral Neck Radius

The densitometric signature of primary hyperparathyroidism in the modern era

Bone Mineral Density: % of Expected * * *Differs from radius, p<.05

Silverberg, Bilezikian et al. JBMR, 1989

Pledging allegiance to the proposition that BMD predicts fracture risk….the expectation in PHPT was: Vertebral sites Non-vertebral sites Fracture Risk in Primary Hyperparathyroidism

Khosla et al, J Bone Min Res 14:1700-1707, 1999

Vertebral Distal Forearm Rib All

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5 10 15 20 25 30 35 40

Fractured cases (%)

P=0.15 P<0.0001 P<0.0001

Symptomatic (n=41) Asymptomatic (n=109) Controls (n=300)

Patients Vignali E, Viccica G, Diacinti D et al. Morphometric Vertebral Fractures In Postmenopausal Women with Primary Hyperparathyroidism J Clin Endocrinol Metab 2009;94:2306-2309

5 10 15 20 25 30 35 40

P<0.0001

Asymptomatic Surg. Criteria Met (n=64) Surg. Criteria Not Met (n=45) Controls (n=300)

P=0.03 P=NS

• 3-D stack of 110 high

resolution slices

• ~ 3 min scan time
• <4 µSv radiation
• Reproducibility:
• Density: 0.7-1.8%
• Structure: 1.2-5.2%

HRpQCT (Xtreme CT)

Non-dominant distal radius and tibia Radius Tibia

Boutroy et al. JCEM 2005. 90(12):6508-15

Trabecular microstructural abnormalities in PHPT by HRpQCT (Hansen S et al. J Bone Miner Res 2012;27:1150-1158) Baseline data: PHPT vs Controls (p<0.05) Index RADIUS TIBIA TV BMD Cort BMD Trab BMD Trab BV/TV Tb.N

• Tb. Th
• Tb. Sp

Strength Failure Load

HRpQCT Parameters

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

# # #

Stein E, Silva BC et al. HRpQCT in PHPT, J Bone Miner Res, 2013

Trabecular and cortical indices are reduced at radius and tibia in Asymptomatic PHPT Matched Control PHPT

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Individual Trabecular Segmentation Analysis in PHPT

Stein E, Silva BC J Bone Miner Res, 2013

Matched Control Primary Hyperparathyroidism Green: horizontal plates (more competent) Red: vertical plates (less competent) Deteriorated Trabecular Microstructure by Trabecular Bone Score in Postmenopausal PHPT (Silva et al, J Clin Endo Metab, 2013)

Characteristics PHPT (n=22) TBS 1.24 ± 0.02 L1-L4 T-Score

• 1.0 ± 0.4

Total hip T-Score

• 1.1 ± 0.3

Femoral neck T-Score

• 1.4 ± 0.3

1/3 radius T-Score

• 1.3 ± 0.4

Osteoporosis at any site 11 (50%)

Microarchitecture partially degraded <1.2= degraded 1.2 – 1.35= partially degraded >1.35= normal

L1-L4 T-score classification n (%) Osteoporosis 3 (14) Osteopenia 7 (32) Normal 12 (53) L1-L4 TBS classification n (%) Degraded 8 (36) Partially degraded 8 (36) Normal 6 (27)

The inescapable conclusion

Even when presenting as an

asymptomatic disorder Primary hyperparathyroidism is BAD FOR BONES!

The chronology of the development of therapies for osteoporosis: irony #3 During the time that the symptomatic phenotype of PHPT was being well characterized (1930-1960), another set of

• bservations was leading to another

conclusion:

Parathyroid Hormone is not always bad for bone

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Parathyroid Hormone is not always bad for bones

• Rats will gain enormous amounts of bone (Bauer, Aub,

Albright, 1929; Pugsley and Selye, 1932 )

• DXA, even though it proved to be misleading in

PHPT, did give the idea that under certain circumstances, PTH might be advantageous to bone under certain circumstances (Silverberg, Bilezikian,

et al. 1986- )

• The visionaries who were listening to a different

drummer (Parsons , Neer & Potts, 1971)

Parsons, Reeve, Potts, Slovik, Neer, Hodsman, Dobnig et al.

(circa 1969-1997)

• All demonstrated an anabolic effect of PTH under certain

circumstances

• A common cautionary note: PTH alone might serve an

anabolic function on trabecular bone but a catabolic function at cortical bone (“borrowing from Peter to pay Paul”)

• Use of either an active Vitamin D analogue or an

antiresorptive was thought to be important in demonstrating a true anabolic effect of PTH, namely an increase in total bone mass (subsequently shown not to be the

case- Neer et al. N Eng J Med 2001) 10 20 30 40 Osteoblast Osteoclast Vehicle 1 hour/day Continuous

PTH Mode of Administration, Timing and Dose Determine whether PTH is anabolic or catabolic in the rat skeleton

*p<.01 vs vehicle **p<.001 vs vehicle

*

Dobnig H, Turner RT. Endocrinology. 1997;138(11):4607-4612.

Cell Abundance (% Trabecular Bone Perimeter) **

Anabolic Daily (low dose) Catabolic Continuous (high dose)

EFFECT MODE

PTH dose and timing determine its effect on bone

Dobnig H, et al. Endocrinology 1997;138:4607-12.

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Anabolic Activity of PTH: Putative Mechanisms

• Cellular

– Recruitment of new osteoblasts – Activation of lining cells – Increased osteoblast life span and activity – Increased function of periosteal cells or their progenitors – Shift from adipocyte to

• steoblast differentiation

– Increased osteocyte function

• Regulatory

– RANK ligand-

• steoprotegerin system

– Sequences in the PTH molecule – Intracellular signaling pathways – Activation of specific genes – Post receptor mechanisms (IGF I, Wnt signaling, sclerostin) – Increased secretion of local factors (IGF-I)

Osteocyte – the mechanosensor Osteocyte – the mechanosensor

Marotti G, 1996 Marotti G, 1996

SOST

Wnt Wnt

CtBP Tcf -catenin CtBP Tcf -catenin

BMP BMP

Smad4

P

TFs R

• S

m a d s

PTH

Runx2-expressing

• steoblast progenitor

cAMP/PKA

P

CREB

P

CREB RANKL OPG

Catabolism

Anabolism

Intermittent

Three keys to the anabolic potential of PTH

• Low dose
• Intermittent administration
• Pulsatility with rapid “on” and “off”

kinetics Under these conditions…..

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10 20 30 40 50 60 70 80 1 2 3 4 5 6 Osteocalcin n-telopeptide

PTH is anabolic:

Lindsay R, et al. Lancet. 1997;350(9077):550-555.

Time (Months) Mean % Change in Turnover Marker

Bone Formation Markers increase before Bone Resorption Markers

Teriparatide Control

Quadruple Labels in Teriparatide-treated and Control Subjects

Dempster et al. 2003

Initial Cellular Mechanisms of PTH

PTH stimulates bone formation directly first and then stimulates the remodeling process PTH stimulates bone formation directly first and then stimulates the remodeling process

PTH as an Anabolic Agent for Bone: A Kinetic Model

Months Index of Bone Turnover

Peak

Bone formation markers

Early increase in bone formation also seen in dynamic histomorphometic indices by transiliac bone biopsy

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PTH as an Anabolic Agent for Bone: A Kinetic Model

Months Index of Bone Turnover

Peak

Bone formation markers Bone resorption markers

“Anabolic Window” Believed to limit the osteoanabolic potential of PTH

Dynamic mechanisms utilized by

• steoanabolic drugs
• Modeling-based bone formation
• Remodeling based bone formation
• Overflow remodeling-modeling-based

bone formation Three Types of Bone Formation

RBF = Remodeling- based formation MBF = Modeling- based formation

• MBF = Overflow

Modeling-based formation

Dempster DW et al Longitudinal Effects of Teriparatide or Zoledronic Acid on Bone Modeling- and Remodeling-Based Formation in the SHOTZ Study. J Bone Miner Res. 2017 Nov 30. 10.1002/jbmr.3350. [Epub ahead of print]

RBF: bone formation over remodeled surfaces MBF: bone formation over quiescent surfaces

• MBF : bone

formation beyond the boundaries of the BRU

Osteoanabolic Mechanisms

Remodeling-based Formation (RBF) Scalloped cement Line Modeling-based Formation (MBF) Smooth cement line Overflow modeling-based Formation (oMBF) Double-labels extend beyond the boundaries of the scalloped cement line

Dempster DW et al Longitudinal Effects of Teriparatide or Zoledronic Acid on Bone Modeling- and Remodeling-Based Formation in the SHOTZ Study. J Bone Miner Res. 2017 Nov 30. 10.1002/jbmr.3350. [Epub ahead of print]

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Clinical Trials

Teriparatide Abaloparatide The chronology of the development of therapies for osteoporosis: irony #4 TERIPARATIDE DOESN’T EXIST AS A HORMONE OR AS A METABOLIC PRODUCT!

His Glu Ser Gly

Human Parathyroid Hormone

1 10 20 30 Ser Val Ile Gln Leu Met Asn Leu Lys His Leu Asn Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His Asn Phe

• COOH

H2N

Gly

Teriparatide

Intact PTH (1-84)

Improved Trabecular Connectivity After hPTH (1-34) Therapy

Dempster DW, et al. J Bone Miner Res. 2001;16(10):1846-1853.

After CD: 4.6/mm3 Before CD: 2.9/mm3

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Teraparatide Why do we want to do better?

• Needs to be refrigerated
• Daily injectable
• Limited period of therapy
• The ‘anabolic window’ is

relatively small

• Safety concerns

Safety of PTH

• No oncogenic signals after 15 years of

human use, worldwide (well over 2 million patient

exposures)

• The likelihood that osteosarcoma is a

human toxicity when PTH is used in the way it is being used would appear to be remote.

• Nevertheless, surveillance (and the black

box) continues

– Such concerns are also applied to abaloparatide

Clinical Trials

Teriparatide Abaloparatide Emergence of a new osteoanabolic Abaloparatide, an analogue of PTHrP

Hattersley G, Bilezikian JP, Kumar P et al. The Endocrine Society 94th Annual Mtg Houston, 2012

44

22 30 34

100% hPTHrP

38% hPTHrP

Teriparatide hPTHrP1-34 Abaloparatide

100% hPTHrP 38% hPTHrP

22 34

based on amino acid replacements between residues 22-34

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Taking advantage of basic mechanisms to develop a PTH/PTHrP analogue that has greater osteoanabolic activity Hypothesis: Abaloparatide will bind more selectively bind to the transient RG configuration of the PTH/PTRrP receptor

R0 conformation of the PTH1R (Associated with more prolonged binding of the ligand)

[Ligand] Log M

125I-PTH(1-34) bound (%)

RG conformation of the PTH1R (Associated with a more transient binding of the ligand)

125I-M-PTH(1-15) bound (%)

Abaloparatide Teriparatide Abaloparatide Teriparatide

• 11
• 10
• 9
• 8
• 7
• 6
• 5

100 75 50 25 100 75 50 25

• 11
• 10
• 9
• 8
• 12

[Ligand] Log M

Donovan, Cremers and Bilezikian. Pharmacokinetics of PTH and analogues Brit J Clin Pharmacol, 2018 (in press)

Binding properties of abaloparatide and teriparatide Relative ligand binding states Transient/prolonged state of the PTH/PTHrP receptor: Abaloparatide>> Teriparatide

cAMP release Time cAMP release Time

RG conformation R0 conformation

G

s

Osteocytes/osteoblasts Ligand More transient cAMP signal More prolonged cAMP signal

HIGHER ratio anabolic/catabolic pathways LOWER ratio anabolic/catabolic pathways

Abaloparatide Teriparatide

Donovan, Cremers and Bilezikian. Pharmacokinetics of PTH and analogues Brit J Clin Pharmacol, 2018 (in press)

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*P < 0.01 vs. placebo; †P 0< 0.05 abaloparatide vs. teriparatide. Error bars indicate median interquartile ranges.

Serum Biomarkers of Bone Turnover

Adapted from Miller et al. JAMA. 2016; 316:722-733.

“Anabolic window”

PTH/PTHrP analogues that stimulate bone formation to a greater extent than bone resorption: a time dependent model

Months Index of Bone Turnover

Peak

Bone Formation Markers Bone Resorption Markers

Effects of Abaloparatide on Major Osteoporotic Fracture Incidence in Postmenopausal Women with Osteoporosis- Results of the Phase 3 ACTIVE Trial Objective: Effect of Abaloparatide or Teriparatide on Major Osteoporotic Fractures (high or low trauma clinical fxs; upper arm, forearm, hip, shoulder, and/or spine) Results: Abaloparatide vs PBO (70% reduction: p=0004 ) Teriparatide vs PBO (no significant reduction) Abaloparatide vs Teriparatide (P < 0.05)

Miller et al. JAMA. 2016;316:722-733.

Summary: Teriparatide vs Abaloparatide

Characteristics Teriparatide Abaloparatide

Refrigeration Yes No Daily Injectable Yes Yes* Dose 20ug 80ug Limited period of approved therapy 2 years 2 years ‘Anabolic Window Narrow Wider Adverse Event Profile Similar Similar Safety Concerns Re Osteosarcoma in rats Yes Yes

*Transdermal preparation being developed

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Osteoanabolic therapy with PTH and PTHrP analogues

• Utilizes different therapeutic

mechanisms by which bone is accrued and fracture incidence is reduced.

• The mechanisms by which these

anabolics function lead to microstructural improvements.

THE FUTURE OF OSTEOANABOLIC THERAPY

• increased bone mass throughout

skeleton.

• very low fracture risk
• due to absence of sclerostin

(SOST) - an inhibitor of Wnt signaling and bone formation

Clues to a new therapeutic approach: Sclerosteosis & van Buchem’s Disease

Janssens and Van Hul. Hum Mol Genet. 2002;11:2385-93.

Heterozygous carriers of Sclerosteosis and van Buchem’s disease do not appear to have complications as seen in the homozygous subjects

• Higher bone density
• Increased markers of bone

formation

• Levels of sclerostin are

intermediate

• No long-term or progressive

sequellae

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Wnt

Wnt

Sclerostin

DS H

Frat1 GSK3β βcatenin

DS H

AXIN

βcatenin P

Proteosomal Degradation

βcatenin

Osteoblast differentiation, proliferation, and mineralization activity Osteoblast: Reduced activity

βcatenin

Sclerostin DKK1 DKK1

Wnt DSH Frat 1

βcatenin βcatenin

Sclerostin Sclerostin Antibody

βcatenin

DKK1 Antisclerostin Antibody Rx (Li et al, JBMR, 2009)

12 8 4 Sham Ovx Ovx + Scl-Ab

Periosteal BFR

Sham Ovx Ovx + Scl-Ab 5 4 3 2 1 Ob S/BS

Sham Ovx Ovx + Scl-Ab 10 8 6 4 2

Oc S/BS

Sham Ovx Ovx + Scl-Ab 5 4 3 2 1

Perio MS/BS

Sham Ovx Ovx + Scl-Ab 60 50 40 30 20 10 Sham Ovx Ovx + Scl-Ab 40 30 20 10

Intracort MS/BS

100 75 50 25

Endocort MS/BS

Sham Ovx Ovx + Scl-Ab

Cortical Endocortical BFR

Li et al, JBMR 2009

VEHICLE Scl-Ab (30 mg/kg IV) VEHICLE Scl-Ab (30 mg/kg IV) L2 VERTEBRA PROXIMAL TIBIA E F G H

Ominsky MS et al, J Bone Miner Res 2010;25:948-59

Sclerostin Antibody Increases Cancellous Bone Volume and Bone Formation

Cynomolgus monkeys treated for 10 weeks with sclerostin Ab Marked increase in modeling-based bone formation

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CLINICAL TRIALS AND MECHANISMS OF THERAPEUTICS: ANTISCLEROSTIN ANTIBODY

• Romosozumab
• Blosozumab (development ended, 2016)

Human Studies

Romosozumab: Changes in bone formation and bone resporption markers P1NP CTX Romo Dmab Romo Dmab

Cosman F et al. N Engl J Med 2016;375:1532-1543.

Romosozumab appears to be a mixed anabolic and antiresoprtive agent

CATEGORY RESORPTION FORMATION Anti-remodeling agents

• bisphosphonates, RANKL inhibitor

Osteoanabolics

• PTH and PTHrP analogues

‘Mixed osteoanabolic and antiresorptive:

• sclerostin inhibitors

Mechanisms of Therapeutics for Osteoporosis

Thank You!