Ostéoporose Faut-il se fier aux nouvelles thérapeutiques · altération de la microarchitecture...

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

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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


(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


(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

Jönsson et al OI 2010

Denosumab Re-treatment and Changes to Serum CTx and BSAP Levels


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

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ng/m

L (Q

1, Q

3)

Months

0

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15

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0 6 12 18 24 30 36 42 48M

edia

n m

cg/L

(Q1,

Q3)



Denosumab Re-treatment and Changes in Lumbar Spine and Total Hip 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

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Months

0 6 12 18 24 36 48-4-202468

101214

0 6 12 18 24 36 48





Placebo30 mg Q3M

Perc

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e(L

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±SE

)

Ostéoporose Faut-il se fier aux nouvelles thérapeutiques · altération de la microarchitecture...

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