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Nuevos fármacos:
DenosumabAdolfo Díez PérezHospital del Mar -Institut Municipal
d’Investigacions Mèdiques
U BUniversitat Autònoma
de Barcelona
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Regulación del remodelamiento
Harada S and Rodan GA. Nature. 2003;423:349-55.
BMP LRP5/Wnt
Intermittent PTHβ-blockers
AndrogensMechanical
load
SOST β-adrenergic
LeptinImmobilisation
Ageing
Bone mass
Oestrogen deficiency Immobilisation
Oestrogen
SERMsBisphosphonates
Calcitonin
CalciumVitamin D
Low Ca (PTH)
Bone formation
Bone resorption
Novel EST Sequence Identified in a Rat Foetal Intestinal cDNA Library
Tissue Distribution of OPG• Human:
– lung, heart, placenta, kidney, osteoblasts
• Mouse:– Embryo: placenta, skin, major arteries,
gastrointestinal tract, bone, cartilage – Adult: lung, liver, kidney, brain, testis,
articular cartilage
Ribs
Mandible
Maxilla
Palate Skin
Major arteriesVertebraeAbdominalaorta
GI tract
La ausencia de actividad OPG causafracturas por fragilidad
Radiografía de un ratón de 1 mes de edad OPG knockout con fracturas espontáneas por fragilidad
RatRatóónnOPG OPG Knockout Knockout
Bucay N, et al. Genes Dev. 1998;12:1260-1268.
Efecto de los niveles de OPG en la regulación de la densidad ósea
Radiografías de fémur de ratón
Ratón knockout OPG: no producciónnatural de OPG
Ratón transgénicoOPG: producciónaumentada de OPG
Bolon B, et al. Arthritis Rheum. 2002;46:3121-3135.
Efecto de RANK y Ligando RANK en la regulación de la densidad mineral
Normal Ausencia deLigando RANK1
Ausencia deRANK2
Aumento de BMD
1 Kong YY et al. Nature 1999; 397: 315–323; 2 Li J et al. Proc Natl Acad Sci USA 2000; 97: 1566–1571
RANKL como mediador esencial de la formación, función y supervivencia del
osteoclastoPre-FusionOsteoclast
CFU-M
OsteoblastsActivated Osteoclast
MultinucleatedOsteoclast
HormonesGrowth factorsCytokines
RANKLRANKOPG
Bone Formation
Bone ResorptionAdapted from Boyle WJ, et al. Nature. 2003;423:337-342.
In the presence of M-CSFCFU-M=colony forming unit macrophageM-CSF=macrophage colony stimulating factor
Provided as an educational resource. Do not copy or distribute.© 2007 Amgen. All rights reserved.
Inhibición de OPG y estimulación de RANKL por glucocorticoides
hOB lineage cells
Hofbauer LC et al. Endocrinology 1999; 140: 4382–4389
Los estrógenos estimulan la expresión génica y producción protéica de OPG por hOB
Dose TimeDose
Time
OPG protein secretion by 17β-E2 in FOB/ER-9 cells
OPG nRNA levels by 17β-E2 in FOB/ER-9 cells
Hofbauer LC et al. Endocrinology 1999; 140: 4367-70
Boyle WJ et al. Nature 2003; 423: 337-42
Diferenciación de células precursoras hematopoyéticas a osteoclasto
RANKL como mediador esencial de la formación, función y supervivencia del
osteoclastoPre-FusionOsteoclast
CFU-M
OsteoblastsActivated Osteoclast
MultinucleatedOsteoclast
HormonesGrowth factorsCytokines
RANKLRANKOPG
Bone Formation
Bone ResorptionAdapted from Boyle WJ, et al. Nature. 2003;423:337-342.
In the presence of M-CSFCFU-M=colony forming unit macrophageM-CSF=macrophage colony stimulating factor
Provided as an educational resource. Do not copy or distribute.© 2007 Amgen. All rights reserved.
Efecto de la OPG recombinante sobreOsteoclastos y Mineralización
Rapid but reversible reductions in OC.N. and increases in Bone Mineralization in Intact Rats
*Significantly different from vehicle, P < 0.05 OcS%BS = osteoclast surface
***
Osteoclast Surface in Proximal Tibia
rhOPG(5mg/kg)
Vehicle
***
0 3015 20 25105Time (Days After Treatment)
OcS
%B
S
6
8
4
0
12
2
10
von Kossa Staining of Proximal Tibia
Capparelli C, et al. J Bone Miner Res. 2003;18:852–858
Denosumab se une al Ligando RANK e Inhibe la Formación, Función y Supervivencia del Osteoclasto
RANKLRANKOPGDenosumab
Bone Formation
HormonesGrowth factorsCytokines
Bone ResorptionInhibited
Osteoclast Formation, Function, and Survival Inhibited
CFU-M Pre-FusionOsteoclast
In the presence of M-CSFCFU-M=colony forming unit macrophageM-CSF=macrophage colony stimulating factor
Provided as an educational resource. Do not copy or distribute.© 2007 Amgen. All rights reserved.
Osteoblasts
Propiedades Farmacológicas de Denosumab
• Isotipo de inmunolobulinaIgG2
• Alta afinidad por el LigandoRANK humano
• Alta especificidad por el Ligando RANK
– No unión detectable a TNFα, TNFβ, TRAIL, or CD40L
• No se han detectadosanticuerpos neutralizantes
Denosumab
TNF = tumor necrosis factor; TRAIL = TNFα-related apoptosis-inducing Ligand.
Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. Elliott R, et al. Osteoporos Int.2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med. 2006;354:821-31.
Cambios en Hueso Cortical (Masa, Area y vBMD) en Monos OVX
Data: Mean ± SE*P< 0.05 vs. OVX-Veh^P< 0.05 vs. Sham-Veh
SHAM ControlOVX ControlOVX + 25 mg/kg DMABOVX + 50 mg/kg DMAB
Tibial Cortical AreaRadial Cortical Area
pQCT TibialDiaphysis
Ominsky et al. JBMR 2007 (Suppl 1) abstract 1082 Months of TreatmentMonths of Treatment
Tibial Cortical vBMDRadial Cortical vBMD
0 3 6 9 12 15
-3
-2
-1
0
1 *^*
Months of Treatment
% C
hang
e fr
om B
asel
ine
0 3 6 9 12 15-10
-8
-6
-4
-2
0
2**
**^
* *
Months of Treatment
**
0 3 6 9 12 15-6-5-4-3-2-1012
**
**^^
** **^^
**
**^^^
0 3 6 9 12 15-5
-4
-3
-2
-1
*******
* *
^
*
^
% C
hang
e fr
om B
asel
ine
Study Month
10–1
100
101
102
103
104
Den
osum
abSe
rum
Con
cent
ratio
n (n
g/m
L)(M
ean ±
SEM
)
Denosumab 0.01 mg/kg (n = 6)Denosumab 0.03 mg/kg (n = 6)Denosumab 0.1 mg/kg (n = 6)Denosumab 0.3 mg/kg (n = 6)Denosumab 1.0 mg/kg (n = 6)Denosumab 3.0 mg/kg (n = 6)
1 3 5 90 2 4 6
EC50
7 8
Denosumab Fase 1 en MujeresSanas Postmenopáusicas
Serum Levels of Denosumab
Dosis s.c. de 60 mg cada 6 meses
Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.
aP < 0.001 vs placebo
McClung MR, et al. N Engl J Med. 2006;354:821-831.
Time (Months)
a
Total Hip Distal 1/3 Radius
Denosumab 60 mg (N = 46)
Placebo (N = 46)Denosumab 14 mg (N = 53)
Open-label alendronate (N = 46)Denosumab 210 mg (N = 46)Denosumab 100 mg (N = 41)
Mea
n Pe
rcen
t Cha
nge
from
Bas
elin
e
Lumbar Spine
-2
-1
0
1
2
3
4
5
6
0 2 4 6 8 10 12-3 -3
-2
-1
0
1
2
3
0 2 4 6 8 10 12
4
5
6
a
-2
-1
0
1
2
3
4
0 2 4 6 8 10 12-3
5
6
a
Fase II Mujeres Postmenopáusicascon Baja DMO
Lumbar Spine Hip, and Distal 1/3 Radius BMD at 12 months
Efecto de 4 Años de Tratamientocon Denosumab en DMO Lumbar
Placebo 6 mg Q3M 14 mg Q3M 14 mg Q6M 100 mg Q6M60 mg Q6M
-4
-2
0
2
4
6
8
10
12
14
0 6 12 18 24 36 48
Per
cent
Cha
nge
(LS
Mea
n ±
SE
)
Months
Miller PD et al Bone 2008;doi:10.1016/j.bone.2008.04.007
Efecto de 4 Años de Tratamiento con Denosumab Sobre CTX y BSAP
Placebo 6 mg Q3M 14 mg Q3M 14 mg Q6M 100 mg Q6M60 mg Q6M
Bone-specific Alkaline Phosphatase
Med
ian
ng/m
L(Q
1, Q
3)
Med
ian µg
/L (Q
1, Q
3)
Serum C-telopeptide
0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30 36 42 480
4
8
12
16
20
0 6 12 18 24 30 36 42 48Months Months
Miller PD et al Bone 2008;doi:10.1016/j.bone.2008.04.007
CTX Sérico a los 5 Años con Denosumab
0.00.10.20.30.40.50.60.70.80.91.0
Seru
m C
TX (n
g/m
l)
BL 1 month 6 months 12 months 24 months 36 months 48 months 60 months
Each box-and-whisker plot shows the middle 80% of the observations (deleting the top and bottom 10% of the data). Horizontal lines represent the premenopausal range from the BONTURNO study Reference Range Study: 0.11 to 0.51 ng/mL for CTX )
Adami et al Calcif Tissue Int. 2008 May;82(5):341-7
Estudio fase III: FREEDOM
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Cummings SR et al. N Engl J Med 2009; 361: 756-65
Efecto de Denosumab sobre el Riesgo de Fractura Vertebral
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Cummings SR et al. N Engl J Med 2009; 361: 756-65
Risk Ratio0,32
(0,26-0,41)P<0,001
Efecto de Denosumab sobre el Riesgo de Fractura No-vertebral
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Hazard Ratio0,80
(0,67-0,95)P=0,01
Cummings SR et al. N Engl J Med 2009; 361: 756-65
Efecto de Denosumab sobre el Riesgo de Fractura de Fémur
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Hazard Ratio0,60
(0,37-0,97)P=0,04
Cummings SR et al. N Engl J Med 2009; 361: 756-65
Efecto sobre los Marcadores Bioquímicos de Remodelamiento
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Cummings SR et al. N Engl J Med 2009; 361: 756-65
CTx y BSAP tras Interrupción de Denosumab o Alendronato
*P < 0.001 at month 36 and = 0.05 at month 48 vs placebo†P = 0.008 at month 36 vs placebo
Miller P, et al. Bone 2008;43:222-9.
Discontinued Treatment
–100
–50
0
50
100
†
Discontinued Treatment
–100
–50
0
50
100*
Perc
ent C
hang
e(M
edia
n [Q
1, Q
3])
Time (months) Time (months)
Denosumab 210 mg Q6MOpen-label alendronate
0 12 24 36 48 0 12 24 36 48
Serum CTx BSAP
Reversibilidad del Efecto de Denosumab sobre el Remodelamiento
DiscontinuationStudy
FREEDOM study
STAND study
CTXDenosumab
treatment studiesDiscontinuation
biopsy study
Baseline Month 12 Noof study treatment
0.00.10.20.30.40.50.60.70.80.9
Seru
m C
TX le
vels
, med
ian
(IQR
)-
ng/m
L
Denosumab discontinued for 24 months
Brown J. et al. ASBMR 2010
Acontecimientos Adversos de Denosumab vs. Placebo
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* NA denotes not applicable.P values are based on the log-rank test, except for between-group comparisons of deaths and cardiovascular events,
which were based on the Cox proportionalhazards model with adjustment for the baseline cardiovascular risk score.
Cummings SR et al. N Engl J Med 2009; 361: 756-65
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* NA denotes not applicable.P values are based on the log-rank test, except for between-group comparisons of deaths and cardiovascular events,
which were based on the Cox proportionalhazards model with adjustment for the baseline cardiovascular risk score.
Cummings SR et al. N Engl J Med 2009; 361: 756-65
Acontecimientos Adversos Graves de Denosumab vs. Placebo
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* NA denotes not applicable.P values log-rank test, except for between-group comparisons of deaths and cardiovascular events, which were based
on the Cox proportionalhazards model with adjustment for the baseline cardiovascular risk score. ‡P≤0.05 for the between-group comparison (MedDRA). ¶ Excludes falls that occurred on the same day as a fracture.§ P≤0.01 for the between-group comparison.
Cummings SR et al. N Engl J Med 2009; 361: 756-65
Acontecimientos Adversos Poco frecuentes (< 1-2%)
Descubrimiento y desarrollo de la VíaRANK/RANKL/OPG y Denosumab
RANKL = RANK ligandOPG = osteoprotegerinOPGL = OPG Ligand (OPG-binding molecule)
1. Anderson DM, et al. Nature. 1997;390:175-179.2. Simonet WS, et al. Cell. 1997;89:309-319.3. Lacey DL, et al. Cell. 1998;93:165-176.4. Yasuda H, et al. Proc Natl Acad Sci U S A.
1998;95:3597-3602.5. Kong Y, et al. Nature. 1999;397:315-323.6. Kong Y, et al. Nature. 1999;402:304-309.7. Burgess TL, et al. J Cell Biol. 1999;145:527-538.
8. Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.9. Available at: www.clinicaltrials.gov. Accessed June 16, 2008.10. McClung MR, et al. N Engl J Med. 2006;354:821-831.11. Miller PD, et al. Bone. 2008;43:222-229.12. Bone HG, et al. J Clin Endocrinol Metab. 2008;93(6):2149-2157.13. Brown JP, et al. J Bone Miner Res. 2009;24:153-161.14. Kendler DL, et al. [Published online ahead of print July 13,
2009]. J Bone Miner Res. doi:10.1359/JBMR.090716.15. Cummings SR, et al. N Engl J Med. 2009 Aug 20;361(8):756-65.
2009
OPG is disclosed in patent filings as an important regulator of bone density
1995 1997 1999 2000 2001OPG protein enters human testing
OPG-Fc and Fc-OPG enter human testing
First dose of denosumabadministered in human on June 30th
Additional approaches to inhibiting RANKL are explored in humans
Identification and cloning of RANK/ RANKL and OPG publishedin Natureand Cell 1,2
Publicationsof scientific findings in journals including Nature and Journal ofCell Biology 5-7
1998
A molecule that binds to OPG was identified and referred to as OPGL; found to be identical to RANKL; OPG recognized as a decoy receptor3,4
2004 2006First single-dose study of denosumabin post-menopausal women published in JBMR8
Phase 2 trial in post-menopausal women with low BMD published in NEJM10
Phase 3 trials with denosumabin post-menopausal women initiated9
2008Key denosumabclinical data published:
Ph 2 PMO 4-year data in Bone11
Ph 3 DEFENDtrial inJCEM12
DECIDE Ph 3 trial in JBMR13
Key denosumabclinical data published:
Ph 3 STAND in JBMR14
Ph 3 FREEDOM in NEJM15
Conclusiones• El tratamiento con Ac monoclonalesanti-RANKL (Denosumab) en inyecciónsubcutánea cada 6 meses, es un supresor de la resorción:
• Potente• Altamente selectivo• Reversible
Conclusiones
• Denosumab es eficaz en reducirlas fracturas:
• Vertebrales• No vertebrales• De fémur
• La posología es muy adecuada• El tratamiento es seguro