Ostéoporose Faut-il se fier aux nouvelles thérapeutiques. UCL Y. Boutsen

Transcription

1 Ostéoporose Faut-il se fier aux nouvelles thérapeutiques UCL Y. Boutsen

2 Ostéoporose: DéfinitionD 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 fragilité osseuse et un risque accru de fractures.

3 FREQUENT?

4 Risque de fractures à 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%) Une femme de race blanche a 50% de risque d avoir au moins une fracture durant sa vie. Fracture du poignet : femme : 1 sur 6 (16%) homme : 1 sur 40 (2.5%) Meunier et al. Clinical Therapeutics, 1999; 21(6) : Melton et al. Journal of Bone and Mineral Research 1992; 7 :

5 Incidence de fractures par tranche d âge d (femmes) Incidence/ personnes-an fémur colonne poignet Age Cooper et al. Trends Endocrinol Metab 1992; 3:

6 SEVERE?

7 Conséquences 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 1 ère 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

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9 Traitements de l ostéoporose Antirésorbeurs Calcium Œstrogènes ± progestatifs Modulateurs récepteurs oestrogénique: Raloxifène, Tibolone Calcitonines Bisphosphonates: Etidronate, Pamidronate, Alendronate, Risédronate, Ibandronate, Zolédronate. Denosumab Ostéoformateurs Fluorures: Fluorure de sodium, Monofluorophosphate, PTH Divers Anabolisants, Vitamine D et dérivés, Diurétiques, Ipriflavone, Strontium

10 Importance de la Microarchitecture Mosekilde, Bone Miner 10: (1990)

11 Low Incidence of Anti-Osteoporosis Treatment 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 Cumulative Number of Patients with Hip Fracture According to Type of Treatment at Progressive Time Periods Month 3 Month 6 Month 9 Month 12 After Month 12 Alendronate 311(1.34%) 534 (2.3%) 655(2.83%) 735 (3.18%) (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%) (6%) Rabenda V. et al. JBJS Am 2008;90:

12 Persistent patients Weeks of follow-up 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:

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14 Excess RANK Ligand Can Increase Bone Resorption Leading to Osteoporosis CFU-GM Prefusion Osteoclast Multinucleated Osteoclast RANKL RANK OPG Decreased Estrogen Leads to Increased RANK Ligand Osteoblasts Activated Osteoclast Bone Formation Adapted from: Boyle WJ, et al. Nature. 2003;423: Bone Resorption

15 Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function, and Survival CFU-GM Prefusion Osteoclast RANKL RANK OPG Denosumab Hormones Growth Factors Cytokines Osteoclast Formation, Function, and Survival Inhibited Osteoblasts Bone Formation Bone Resorption Inhibited Adapted from: Boyle WJ, et al. Nature. 2003;423:

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17 Phase 1 Single-Dose Study of Denosumab in Healthy Postmenopausal Women: Serum Levels of Denosumab Denosumab Serum Concentration (ng/ml) (Mean ± SEM) Study Month 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) EC 50 Adapted from: Bekker PJ, et al. J Bone Miner Res. 2004;19:

18 Effect of 4 Years of Denosumab Treatment on Lumbar Spine BMD Phase 2: Postmenopausal Women With Low BMD Percent Change (LS Mean ± SE) Months *P < 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: Adapted from Miller PD, et al. Bone. 2008;43: * * Continued Treatment at 60 mg Q6M * * Placebo 60 mg Q6M

19 The Percent Change in Bone Mineral Density Over 36 Months With Denosumab Phase 3: The FREEDOM Trial Bone Mineral Density Substudy n = 441 Placebo Denosumab 60 mg Q6M Mean Percent Change in BMD * * Lumbar Spine * * 9.2% * Mean Percent Change in BMD * * * Total Hip * 6.0% * Study Months Study Months Intent-to-treat, last observation carried forward analysis *P < for denosumab vs placebo denosumab group relative increase in BMD vs placebo at month 36 Cummings SR, et al. N Engl J Med. 2009;361: Copyright 2009 Massachusetts Medical Society. All rights reserved.

20 The Effect of Denosumab on Fracture Risks at 36 Months Incidence at Month 36 (%) 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% 7.2% Phase 3: The FREEDOM Trial ARR = 4.8% RRR = 68% P < % ARR = 1.5% RRR = 20% P = % 6.5% ARR = 0.5% RRR = 40% P = % New Vertebral Nonvertebral Hip Primary Endpoint Placebo Denosumab 0.7% ARR = absolute risk reduction; RRR = relative risk reduction Cummings SR, et al. N Engl J Med. 2009;361:

21 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 events Adapted from: Cummings SR, et al. N Engl J Med. 2009;361:

22 Adverse Events Over 36 Months (continued) Phase 3: The FREEDOM Trial Placebo (n = 3,876) Denosumab 60 mg Q6M (n = 3,886) Adverse events, n (%) Adverse events Infection 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 0.05 Eczema 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 fracture Adapted from: Cummings SR, et al. N Engl J Med. 2009;361:

23 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 events Malignancy 125 (3.2) 144 (3.7) 0.28 Infection 133 (3.4) 159 (4.1) 0.14 Cardiovascular events 178 (4.6) 186 (4.8) 0.74 Stroke 54 (1.4) 56 (1.4) 0.89 Coronary heart disease 39 (1.0) 47 (1.2) 0.41 Peripheral vascular disease 30 (0.8) 31 (0.8) 0.93 Atrial fibrillation 29 (0.7) 29 (0.7) 0.98 Serious adverse events occurring with 0.1% incidence and P 0.01 Cellulitis (includes erysipelas) 1 (< 0.1) 12 (0.3) Concussion 11 (0.3) 1 (< 0.1) Adapted from: Cummings SR, et al. N Engl J Med. 2009;361:

24 BOONEN S. JCEM 2011

25 BOONEN S. JCEM 2011

26 BOONEN S. JCEM 2011

27 Jönsson et al OI 2010

28 Jönsson et al OI 2010

29 Denosumab Re-treatment and Changes to Serum CTx and BSAP Levels Phase 2: Postmenopausal Women With Low BMD Serum CTx BSAP Placebo 30 mg Q3M Median ng/ml (Q1, Q3) Discontinued Treatment Re-treatment 60 mg Q6M Median mcg/l (Q1, Q3) Discontinued Treatment Re-treatment 60 mg Q6M Months Months Adapted from Miller PD, et al. Bone. 2008;43:

30 Denosumab Re-treatment and Changes in Lumbar Spine and Total Hip BMD Phase 2: Postmenopausal Women With Low BMD Placebo 30 mg Q3M Percent Change (LS Mean ± SE) Lumbar Spine Months Discontinued Treatment Re-treatment 60 mg Q6M Percent Change (LS Mean ± SE) Total Hip Months Discontinued Treatment Re-treatment 60 mg Q6M Adapted from Miller PD, et al. Bone. 2008;43:

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