Efectos de Teriparatida y Denosumab sobre el Hueso

Cortical

Cesar E. Bogado Instituto de Investigaciones Metabólicas

26/10/2011

Effect of Teriparatide on non-vertebral fracture risk

* P = 0.02 vs. Placebo** P = 0.01 vs. Placebo

5

6

7

% o

f Wom

en

RR 0.46 (95% CI, 0.25 to 0.86)**

RR 0.47 (95% CI, 0.25 to 0.88)*

0

1

2

3

4

Placebo(n=544)

TPTD20(n=541)

TPTD40(n=552)

% o

f Wom

en

30 14 14

53% 54%

No. of women who had > 1 fragility fracture

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

FREEDOM: Denosumab (Prolia® ) redujo el riesgo de fractura en todo el esqueleto

Denosumab (Prolia ® ) redujo significativamente el riesgo de fractura osteoporótica en las vértebras, la cadera y las zona s no vertebrales* 1

INC

IDE

NC

IA D

E F

RA

CT

UR

AS

(%

)

de reducciónP < 0.001

de reducciónP < 0.01

1. Cummings SR et al. N Engl J Med 2009;361:756–765 .

*Todas las fracturas no vertebrales. Sin embargo, las fracturas de cráneo, cara, mandíbula, metacarpianos, dedos o dedos de los pies fueron excluidas debido a que no se asocian a disminución de la densidad mineral

ósea. Las fracturas patológicas y las asociadas a traumatismo severo también fueron excluidas.

VERTEBRALES NUEVAS CADERA NO VERTEBRALES*

INC

IDE

NC

IA D

E F

RA

CT

UR

AS

(%

)

de reducciónP < 0.04

The aging cortex

2020 4040 6060 8080 100100AgeAge

Instability ThresholdInstability Threshold

Cortex too thin for diameterCortex too thin for diameter

30

25

20

FEMALES

PO

RO

SIT

Y (

%)

30

25

20

MALES

PO

RO

SIT

Y (

%)

Aging increases cortical porosity

15

10

5

010-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89

TEN-YEAR AGE GROUPS

PO

RO

SIT

Y (

%)

15

10

5

010-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89

TEN-YEAR AGE GROUPS

PO

RO

SIT

Y (

%)

Bousson V, et al. J Bone Miner Res 2001; 16: 1308-1317

Temporal Effects of Teriparatide on Bone Microarchitecture Assessed by High Resolution

Peripheral Quantitative Computerized Tomography and Paired Bone Biopsies in

Postmenopausal Women with Osteoporosis

Cesar E. Bogado1, Jose R. Zanchetta1, Hua Zhou2, David Dempster2, Thomas Kohler3, Ralph Müller3, Cecilia Fosser4, Theresa Tuthill4, Thomas Kohler3, Ralph Müller3, Cecilia Fosser4, Theresa Tuthill4, David Thompson4, David Fryburg4, Tony M. Keaveny5, Urszula

Masiukiewicz4

1Instituto de Investigaciones Metabolicas, Buenos Aires, Argentina; 2 Columbia University, New York, NY and Helen Hayes Hospital, West Haverstraw, NY; 3 Institute for

Biomechanics, ETH Zurich, Zurich, Switzerland; 4 Pfizer, Inc. New London, CT; 5 UC Berkeley and O.N. Diagnostics, Berkeley, CA

Acknowledgement: This study was funded by Pfizer Inc.

Exploratory Clinical Study

• Single-center, open label, 12 month pilot methodology study.

• To explore and compare the ability of different methodologies to assess the effects of teriparatide on bone quality and strength estimators.bone quality and strength estimators.

• To explore the tempo of the response to treatment

• Twenty postmenopausal women aged 55-70 years with lumbar spine T-score ≤≤≤≤ -2.5 ≥≥≥≥ -3.5.

• Daily teriparatide 20 µg s.c. plus Ca and Vit D to assure a total daily intake of 1200-1500 mg Ca and 800 IU Vit D

Subjects Characteristics at Baseline

N = 20

Age 62 (4.1)

BMI 25.5 (3.6)BMI 25.5 (3.6)

Lumbar Spine T- score -3.1 (0.3)

Total hip T- score -1.2 (0.9)

Data presented as mean (SD)

Efficacy Assessments

Day 0 Day 7 Month 1 Month 3 Month 6 Month 12

DXA (spine, hip and wrist) X X X X

BTM (OC, BSAP, PINP, CTx) X X X X X X

QCT (spine) X X X X

QCT (hip) X X

HR-pQCT (tibia and wrist) X X X X

Bx (Baseline n= 15, Month 12 n= 11) X X

Micro-CT (Bone Biopsy) X X

MicroMRI (wrist) X X X X

FEA of spine QCT scans X X X X

FEA of hip QCT scans X X

Temporal Changes in Integral Bone (Trabecular + Cortical) Volumetric BMD Measured by HR-

pQCT at the Ultradistal Radius and Tibia95

% C

I

All changes not statistically significant

Mea

n ±

95%

CI

Temporal Changes in Cortical vBMD Measured by HR-pQCT at the Ultradistal

Radius and Tibia

-1

0

1

Radius Tibia

% C

hang

e fr

om B

asel

ine

95%

CI

∗∗∗∗

-5

-4

-3

-2

% C

hang

e fr

om B

asel

ine

Mea

n ±

95%

CI

∗∗∗∗ p< 0.05 vs baseline

Month 3 Month 6 Month 12

∗∗∗∗

∗∗∗∗ ∗∗∗∗

∗∗∗∗ ∗∗∗∗

Percent Change in Cortical Thickness at Month 12 Compared to Baseline

30

40

50∗∗∗∗

∗∗∗∗ p< 0.05 vs. baseline

% c

hang

e fr

om b

asel

ine

95%

CI

-10

0

10

20

RadiusHR-pQCT

TibiaHR-pQCT

Iliac CrestHistomorphometry

Iliac CrestMicroCT

∗∗∗∗ ∗∗∗∗

% c

hang

e fr

om b

asel

ine

Mea

n ±

95%

CI

Temporal Changes in Cortical Thickness measured by HR-pQCT at the Ultradistal

Radius and Tibia

5

6

7

Bas

elin

e

Radius

Tibia

95%

CI ∗∗∗∗ ∗∗∗∗

∗∗∗∗

∗∗∗∗

0

1

2

3

4

0 3 6 9 12 15% C

ha

ng

e fr

om

Bas

elin

e

Month

Mea

n ±

95%

CI

∗∗∗∗ ∗∗∗∗

∗∗∗∗ p< 0.05 vs baseline

Conclusions

• Twelve months treatment with teriparatide consistently increased cortical thickness at all skeletal sites evaluated.

• Using HR-pQCT, this effect can be detected in-vivo as early as 3 months after treatment initiation.early as 3 months after treatment initiation.

• The observed trend to a positive effect of teriparatide on trabecular microarchitecture at the tibia as compared to the other skeletal sites evaluated requires further exploration

Effects of 12 months treatment with teriparatideon volumetric bone mineral density and structural

parameters at the femoral neck assessed by quantitative computerized tomography in

postmenopausal women with osteoporosis.

CE Bogado1, JK Brown2, TM Keaveny3, D CE Bogado , JK Brown , TM Keaveny , D Dempster4, D. Thompson5, JR Zanchetta1, U

Masiukiewicz5

Instituto de Investigaciones Metabolicas, Buenos Aires, Argentina; 2- Mindways Software, Austin, USA; 3- University

of California, Berkeley, USA; 4- Columbia University, New York, USA; 5- Pfizer Inc., New London, USA

Geometric Measures Derived from QCT Cross-Sectional Images

• Cross-Sectional Images from:

– Femoral Neck– Intertrochanter– Femoral Shaft

Multi-Slice Analysis

• 11 Images

• Central Image at • Central Image at “Optimum” location

• 5 Images either side at 1 mm intervals

QCT ROI at Femoral Neck

% cambio (Media) 95% CI PInt vBMD (g/cm3) 2.12 1.08; 3.15 0.0004

Ct vBMD (g/cm3) -1.66 -2.90; -0.42 0.0113

Tb vBMD (g/cm3) 4.21 2.02; 6.39 0.0007

Perim (cm) 0.0006 -1.54; 1.55 0.9994

Cambios porcentuales luego de 12 mesesde tratamiento con Teriparatida

Ct CSA (cm2) 3.19 1.71; 4.68 0.0002

Ct Th (mm) 4.19 2.47; 5.91 0.0001

CSMI (cm4) 4.89 1.90; 7.89 0.0029

W-CSMI (mg cm) 3.08 0.91; 5.25 0.0077

Buckling ratio -5.41 -7.68; -3.15 0.0001

Conclusions

• The positive changes in bone strength estimators (CSMI, W-CSMI and buckling ratio) and structural parameters (Ct CSA and Ct Th) are in line with our previous observation of an increase in femoral neck bone strength induced by teriparatide.

• Moreover, the increase in Ct Th is in agreement with our • Moreover, the increase in Ct Th is in agreement with our previous results on the effects of teriparatide at the distal radius and tibia and iliac crest biopsy samples in this same group of patients.

• The increase in Ct Th and Ct CSA in the absence of change in periosteal perimeter might suggest endostealapposition of new bone. This preliminary observation requires further investigation.

The Decrease in Cortical Bone Volumetric Mineral Density Induced by Teriparatide in Postmenopausal

Women with Osteoporosis is Associated With an Increase in Cortical Porosity as Assessed by High Resolution Peripheral Quantitative Computerized

Tomography (HR-pQCT)

Bogado C.E.1, Silveira F.1, Dempster D.2, Zhou H. 2, Zanchetta J.R.1,Fosser C.3, Masiukiewicz U.3

1- Instituto de Investigaciones Metabolicas, Buenos Aires, Argentina; 2-Columbia University, New York, NY and Helen Hayes Hospital, West

Haverstraw, NY; 3- Pfizer Inc., Groton, CT

Cortical Porosity as Estimated by HR-pQCT

Temporal Changes in Biochemical Bone Markers and Cortical Porosity

Bogado CE et al ASBMR 2011

Biochemical Bone Markers changes are depicted as %/10

Cortical Porosity at Baseline and Month 12

Bogado CE et al ASBMR 2011

Temporal Changes in Cortical vBMD Measured by HR-pQCT at the Ultradistal

Radius and Tibia

-1

0

1

Radius Tibia

% C

hang

e fr

om B

asel

ine

95%

CI

∗∗∗∗

-5

-4

-3

-2

% C

hang

e fr

om B

asel

ine

Mea

n ±

95%

CI

∗∗∗∗ p< 0.05 vs baseline

Month 3 Month 6 Month 12

∗∗∗∗

∗∗∗∗ ∗∗∗∗

∗∗∗∗ ∗∗∗∗

Correlation between Changes in Cortical Porosity and vBMD

Bogado CE et al ASBMR 2011

Conclusion

Our results suggest that the decrease in cortical vBMDinduced by teriparatide is related to an increase in induced by teriparatide is related to an increase in

cortical porosity and that those changes in porosity can be estimated by non-invasive imaging techniques like

HR-pQCT.

Resumen

Ct vBMD Ct Thickness Ct Porosity

PTH

Effects of Denosumab and Alendronate on Skeletal

MicroarchitectureE. Seeman1, P.D. Delmas2, D.A. Hanley3,

D. Sellmeyer4, A.M. Cheung5, E. Shane6, A. Kearns7, T. Thomas8, C. Bogado9, S. Boutroy2, S.K. Boyd3,

S. Majumdar10, M. Fan11, C. Libanati11, S. Majumdar10, M. Fan11, C. Libanati11, and J. Zanchetta9

1Austin Health, University of Melbourne, Melbourne, Australia; 2INSERM U831 and University of Lyon, Lyon, France; 3University of Calgary, Calgary, AB, Canada; 4Johns Hopkins University, Baltimore, MD; 5University

Health Network and University of Toronto, Toronto, ON, Canada; 6Columbia Presbyterian Medical Center, New York, NY USA; 7Mayo Clinic, Rochester, MN, USA; 8INSERM U890 and University Hospital, Saint-Etienne,

France; 9Instituto de Investigaciones Metabólicas, Buenos Aires, Argentina; 10UCSF, San Francisco, CA, USA; 11Amgen Inc., Thousand Oaks, CA, USA

Study Design• Multi-center, RDBPC, pilot phase 2, active-controlled, double-dummy, 1-year study

• Ambulatory postmenopausal women, age 50 to 70 yrs, no fractures

• Lumbar spine or total hip T-scores between –2.0 and –3.0

• Randomization 1:1:1 (calcium and vitamin D for all)

• vBMD, Cortical Thickness and Porosity assessed using HR-pQCT (Scanco)

BA

Placebo (N = 82) END

SCREENING Denosumab 60 mg Q6M (N = 83)

ASELINE

VISIT

Alendronate 70 mg QW (N = 82)Randomization

1:1:1

12 Months0 – 35 Days

Seeman E et al. JBMR. 2010;25:1886 N = number of women randomized

D

OF

TREATME

NT

Age (yrs)* 60.3 (5.9)60.7 (5.2)60.8 (5.2)

Denosumab60 mg Q6M

(N = 83)

Alendronate70 mg QW

(N = 82)Placebo(N = 82)

Baseline Characteristics

* mean (SD)

–2.4 (0.4)–2.5 (0.3)–2.4 (0.3)Lumbar spine BMD T-score*

–1.4 (0.8)–1.4 (0.7)–1.1 (0.7)Total hip BMD T-score*

13.6 (7.6)13.1 (8.0)12.8 (6.2)Years post menopause*

Body mass index (kg/m2)* 27.2 (4.3)26.4 (4.4)26.9 (5.0)

Discontinued study, n (%)

Completed study, n (%)

9 (10.8)13 (15.9) 8 (9.8)

74 (89.2)69 (84.1)74 (90.2)

Total vBMD at the Distal Radius

ALN

DMAb

0

1.0

2.0

P = 0.0244 vs ALN

Per

cent

Cha

nge

Fro

m B

asel

ine

Placebo

–3.0

–2.0

–1.0

0 6 12

Month

Data are least squares means with 95% CIs

P < 0.0001 vs Placebo

Per

cent

Cha

nge

Fro

m B

asel

ine

Cortical vBMD at the Distal Radius

0.5

0

0.5

ALN

DMAbP

erce

nt C

hang

e F

rom

Bas

elin

e

P = 0.0229 vs ALN

P < 0.0001 vs Placebo

Data are least squares means with 95% CIs

–2.0

–1.5

–1.0

0 6 12

Month

Placebo

Per

cent

Cha

nge

Fro

m B

asel

ine

-1

0

1

2

3

4

5

Por

cent

aje

de c

ambi

o de

sde

bas

al

Med

ia (

95%

CI)

Porcentaje de Cambios desde el Basal del Espesor Cortical en el Radio

AlendronatoDenosumab

Placebo

-3

-2

-1

0 6 12Meses

Por

cent

aje

de c

ambi

o de

sde

bas

al

-3

-2

-1

0

1

2

3

4

5

Por

cent

aje

de c

ambi

o de

sde

basa

l M

edia

(95

% C

I)

Dife

renc

ia c

on D

enos

umab

Med

ia (

95%

CI)Alendronato

Denosumab

Placebo

-1

0

1

2

3

4

5

6

7

Alendronato

Placebo

2

3

4

5

6

7

8

Por

cent

aje

de c

ambi

ode

sde

basa

l M

edia

(95

% C

I)

Porcentaje de Cambios desde el Basal del Espesor Cortical en la Tibia

AlendronatoDenosumab

Placebo

0

1

0 6 12Meses

Por

cent

aje

0

1

2

3

4

5

6

7

8

Por

cent

aje

de c

ambi

ode

sde

basa

l M

edia

(95

% C

I) Alendronato

Denosumab

Placebo

Alendronato

Placebo

-1

0

1

2

3

4

5

6

Dife

renc

iaco

n D

enos

umab

Med

ia (

95%

CI)

Cortical Porosity at the Distal Radius

6

8

10Placebo ALN DMAb

P < 0.01

P = 0.47

P = 0.06

Per

cent

Cha

nge

Fro

m B

asel

ine

Data are means with 95% CIs

–8

–6

–4

–2

0

2

4

6

Month 12

Per

cent

Cha

nge

Fro

m B

asel

ine

Resumen

Ct vBMD Ct Thickness Ct Porosity

PTH

Dmab

Resumen

Ct vBMD Ct Thickness Ct Porosity

PTH

Dmab