ostéoporose faut-il se fier aux nouvelles thérapeutiques · altération de la microarchitecture...
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OstéoporoseFaut-il se fier aux nouvelles thérapeutiques
UCL 31.05. 2013
Y. Boutsen
Maladie générale du squelette caractérisée par une masse osseuse basse et une altération de la microarchitecture du tissu osseux conduisant à une augmentation de la fragilitéosseuse et un risque accru de fractures.
OstOstééoporose: Doporose: Dééfinitionfinition
FREQUENT ?
Risque de fractures Risque de fractures àà partir de 50 ans partir de 50 ans
Fracture de la colonne vertébrale :femme : 1 sur 6 (16%) homme : 1 sur 20 (5%)
Fracture du col de fémur :femme : 1 sur 6 (17.5%)homme : 1 sur 17 (6%)
Fracture du poignet :femme : 1 sur 6 (16%)homme : 1 sur 40 (2.5%)
Melton et al. Journal of Bone and Mineral Research 1992; 7 : 1005-1010
Une femme de race blanche a 50% de risque d’avoir au moins une fracture durantsa vie.
Meunier et al. Clinical Therapeutics, 1999; 21(6) : 1025-1044
0
500
1000
1500
2000
2500
3000
3500
35 40 45 50 55 60 65 70 75 80 85
Inci
denc
e/10
0.00
0 pe
rson
nes-
an
Age
fémur
colonne
poignet
Cooper et al. Trends Endocrinol Metab 1992; 3: 224-229.
Incidence de fractures par tranche dIncidence de fractures par tranche d’’âge âge (femmes)(femmes)
SEVERE ?
ConsConsééquences de la fracture de hanchequences de la fracture de hanche
Dans l’année qui suit la fracture de hanche :
• 20% de mortalité chez les femmes • 36% de mortalité chez les hommes
• 27% des personnes atteintes vont entrer pour la 1ère fois dans une maison de convalescence
• 40% ne peuvent plus marcher sans assistance
• 60% ont des difficultés dans des gestes essentiels de la vie courante (ex : faire sa toilette, cuisiner, s’habiller)
• 80% ont des difficultés dans d’autres activités quotidiennes (ex: courses, voiture)
Cooper.Am.J.Med. 1997;103: 12S-19S
Traitements de l’ostéoporose• Antirésorbeurs
CalciumŒstrogènes ± progestatifsModulateurs récepteurs oestrogénique: Raloxifène, …Tibolone CalcitoninesBisphosphonates: Etidronate, Pamidronate, Alendronate,
Risédronate, Ibandronate, Zolédronate….
• Denosumab
• OstéoformateursFluorures: Fluorure de sodium, Monofluorophosphate, PTH
• DiversAnabolisants, Vitamine D et dérivés, Diurétiques, Ipriflavone, Strontium
Importance de la Microarchitecture
Mosekilde, Bone Miner 10: 13-35 (1990)
Low Incidence of Anti-OsteoporosisTreatment After Hip Fracture
By Véronique Rabenda, MSc, Johan Vanoverloop, MSc, Valérie Fabri, MD, Raf Mertens, MD, François Sumkay, PhD,Carine Vannecke, MD, PhD, André Deswaef, PhD, Gert A.Verpooten, MD, PhD, and Jean-Yves Reginster, MD, PhD
Month 3 Month 6 Month 9 Month 12 After Month 12
Alendronate 311(1.34%) 534 (2.3%) 655(2.83%) 735 (3.18%) 1.053 (4.5%)
Risedronate 42 (0.18%) 64(0.28%) 79 (0.34%) 94 (0.41%) 163 (0.7%)
Raloxifene 30 (0.13%) 68 (0.29%) 88 (0.38%) 106 (0.46%) 160 (0.7%)
Total 383 (1.65%) 666 (2.88%) 822(3-55%) 935 (4.04%) 1.376 (6%)
Cumulative Number of Patients with Hip Fracture According to Type of Treatment at Progressive Time Periods
Rabenda V. et al. JBJS Am 2008;90:2142-8.
0 13 26 39 52 65 78 91 104 117 130 143 156
Weeks of follow-up
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
Pers
iste
nt p
atie
nts
Persistence with treatment in the total population of patients who began alendronate treatment (including the daily group, weekly group, and switch group) after the occurrence of a hip fracture
Rabenda V. et al. JBJS Am 2008;90:2142-8.
Excess RANK Ligand Can Increase Bone Resorption Leading to Osteoporosis
Bone Formation
Bone Resorption
Activated Osteoclast
CFU-GM PrefusionOsteoclast
MultinucleatedOsteoclast
Osteoblasts
RANKL
RANK
OPG
Decreased Estrogen Leads to Increased RANK Ligand
Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.
Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function, and Survival
RANKL
RANK
OPG
Denosumab
Bone Formation Bone Resorption Inhibited
Osteoclast Formation, Function, and Survival Inhibited
CFU-GM PrefusionOsteoclast
Osteoblasts
HormonesGrowth FactorsCytokines
Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.
Phase 1 Single-Dose Study of Denosumab in Healthy Postmenopausal Women: Serum
Levels of Denosumab
Study Month10–1
100
101
102
103
104
Den
osum
ab S
erum
Con
cent
ratio
n (n
g/m
L) (M
ean
±SE
M)
1 3 5 90 2 4 6
EC50
7 8
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)
Adapted from: Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.
Effect of 4 Years of Denosumab Treatment on Lumbar Spine BMD
Phase 2: Postmenopausal Women With Low BMD
*P < 0.001 for 60-mg Q6M group vs placebo.Note: Graph depicts only the 60-mg Q6M group from baseline through 48 months.McClung MR, et al. N Engl J Med. 2006;354:821-831.Adapted from Miller PD, et al. Bone. 2008;43:222-229.
−4
−2
0
2
4
6
8
10
12
14
0 6 12 18 24 36 48
Months
Perc
ent C
hang
e(L
S M
ean
±SE
)
Continued Treatment at 60 mg Q6M
Placebo60 mg Q6M
**
*
*
The Percent Change in Bone Mineral Density Over 36 Months With Denosumab
Phase 3: The FREEDOM Trial
Denosumab 60 mg Q6MPlacebo
Bone Mineral Density Substudy n = 441
Lumbar Spine
Study Months
−2
0
2
4
6
8
10
12
0 6 12 24 36
**
**
*
Mea
n Pe
rcen
t Cha
nge
in B
MD Total Hip
Study Months
36−2
0
2
4
6
8
10
12
0 6 12 24
**
**
*
Mea
n Pe
rcen
t Cha
nge
in B
MD
9.2%
6.0%
†
†
Intent-to-treat, last observation carried forward analysis*P < 0.001 for denosumab vs placebo† denosumab group relative increase in BMD vs placebo at month 36Cummings SR, et al. N Engl J Med. 2009;361:756-765. Copyright © 2009 Massachusetts Medical Society. All rights reserved.
The Effect of Denosumab on Fracture Risks at 36 Months
Phase 3: The FREEDOM Trial
ARR = absolute risk reduction; RRR = relative risk reductionCummings SR, et al. N Engl J Med. 2009;361:756-765.
7.2%
8.0%
1.2%
6.5%
0.7%
2.3%
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
New Vertebral Nonvertebral Hip
Inci
denc
e at
Mon
th 3
6 (%
)PlaceboDenosumab
ARR = 0.5%RRR = 40%P = 0.04
ARR = 1.5%RRR = 20%P = 0.01ARR = 4.8%
RRR = 68%P < 0.001
Primary Endpoint
Adverse Events Over 36 Months Phase 3: The FREEDOM Trial
Adverse events, n (%)Placebo
(n = 3,876)
Denosumab 60 mg Q6M(n = 3,886) P value
All adverse events 3,607 (93.1) 3,605 (92.8) 0.91
Serious adverse events 972 (25.1) 1,004 (25.8) 0.61
Deaths 90 (2.3) 70 (1.8) 0.08
AEs leading to study discontinuation 81 (2.1) 93 (2.4) 0.39
AEs leading to discontinuing the study drug 202 (5.2) 192 (4.9) 0.55
AEs = adverse eventsAdapted from: Cummings SR, et al. N Engl J Med. 2009;361:756-765.
Adverse Events Over 36 Months (continued)Phase 3: The FREEDOM Trial
Adverse events, n (%)Placebo
(n = 3,876)
Denosumab60 mg Q6M(n = 3,886)
Adverse eventsInfection 2,108 (54.4) 2,055 (52.9)Malignancy 166 (4.3) 187 (4.8)Injection site reaction 26 (0.7) 33 (0.8)Hypocalcemia 3 (0.1) 0 (0)Delayed fracture healing 4 (0.1) 2 (0.05)Femoral shaft fracture 3 (0.1) 0 (0)Humerus nonunion fracture 1 (0.03) 0 (0)Osteonecrosis of the jaw 0 (0) 0 (0)Adverse events occurring with ≥ 2% incidence and P ≤ 0.05Eczema 65 (1.7) 118 (3.0)Fall* 219 (5.7) 175 (4.5)Flatulence 53 (1.4) 84 (2.2)
*Excludes falls occurring on the same day as a fractureAdapted from: Cummings SR, et al. N Engl J Med. 2009;361:756-765.
Adverse Events Over 36 Months (continued)Phase 3: The FREEDOM Trial
Adverse events, n (%)Placebo
(n = 3,876)
Denosumab 60 mg Q6M(n = 3,886) P value
Serious adverse eventsMalignancy 125 (3.2) 144 (3.7) 0.28Infection 133 (3.4) 159 (4.1) 0.14Cardiovascular events 178 (4.6) 186 (4.8) 0.74
Stroke 54 (1.4) 56 (1.4) 0.89Coronary heart disease 39 (1.0) 47 (1.2) 0.41Peripheral vascular disease 30 (0.8) 31 (0.8) 0.93Atrial fibrillation 29 (0.7) 29 (0.7) 0.98
Serious adverse events occurring with ≥ 0.1% incidence and P ≤ 0.01Cellulitis (includes erysipelas) 1 (< 0.1) 12 (0.3) 0.002Concussion 11 (0.3) 1 (< 0.1) 0.004
Adapted from: Cummings SR, et al. N Engl J Med. 2009;361:756-765.
BOONEN S. JCEM 2011
BOONEN S. JCEM 2011
BOONEN S. JCEM 2011
Jönsson et al OI 2010
Jönsson et al OI 2010
Denosumab Re-treatment and Changes to Serum CTx and BSAP Levels
Phase 2: Postmenopausal Women With Low BMD
Adapted from Miller PD, et al. Bone. 2008;43:222-229.
Re-treatment60 mg Q6M
DiscontinuedTreatment
Placebo30 mg Q3M
Serum CTx BSAP
Months
00.20.40.60.81.01.21.41.6
0 6 12 18 24 30 36 42 48
Med
ian
ng/m
L (Q
1, Q
3)
Months
0
5
10
15
20
25
0 6 12 18 24 30 36 42 48M
edia
n m
cg/L
(Q1,
Q3)
Re-treatment60 mg Q6M
DiscontinuedTreatment
Denosumab Re-treatment and Changes in Lumbar Spine and Total Hip BMD
Phase 2: Postmenopausal Women With Low BMD
Adapted from Miller PD, et al. Bone. 2008;43:222-229.
Lumbar Spine Total Hip
Perc
ent C
hang
e(L
S M
ean
±SE
)
Months
-6
-4
-2
0
2
4
6
8
Months
0 6 12 18 24 36 48-4-202468
101214
0 6 12 18 24 36 48
Re-treatment60 mg Q6M
DiscontinuedTreatment
Re-treatment60 mg Q6M
DiscontinuedTreatment
Placebo30 mg Q3M
Perc
ent C
hang
e(L
S M
ean
±SE
)