Post on 04-Oct-2018
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