Θεραπευτικά ζητήματα του οστικού μεταβολισμού Σπογγώδες και φλοιώδες οστό: η διαφοροποίηση του ιστού προαναγγέλλει και τη δράση της διαφοροποίησης των αντιοστεοπορωτικών φαρμάκων; Γεώργιος Παν. Καμπάκης Ρευματολόγος
Φλοιώδες Οστούν 80% του σκελετού 20% ενεργό σε κύκλο αναδιαμόρφωσης Σχέση επιφάνειας/ όγκο Οστεοκύτταρα σπάνια Διάρκεια κύκλου 7μήνες Porosity 10% Αντιστέκεται σε στρέψη και καμπύλ Σπογγώδες Οστούν 20% του σκελετού 80% ενεργό σε κύκλο αναδιαμόρφωση Σχέση επιφάνειας/ όγκο Διάρκεια κύκλου 3-4μήνες Porosity 50-90% Δυνάμεις συμπίεσης
Δομή των Οστών σπογγώδες σπογγώδες φλοιώδες φλοιώδες σπογγώδες φλοιώδες φλοιώδες σπογγώδες σπογγώδες
intracortical remodeling may be self perpetuating by creating intracortical porosity and so more bone surface for remodeling to occur upon, while remodeling upon the trabecular bone surface is self limiting because it removes trabeculae with their surface
Αντικαταγματική δράση Σπονδυλικά ΜηΣπονδυλικά Ισχίου Οιστρογόνα Καλσιτονίνη Ραλοξιφαίνη () Αλενδρονάτη Ρισεδρονάτη Ζολεδρονικό Ιμπανδρονάτη Τεριπαρατίδη Ρανελικό Στρόντιο () Denosumab
Τεριπαρατιδη
Διφωσφονικά
1
Schematic representation of the skeletal distribution of bisphosphonates Bisphosphonates are rapidly absorbed to bone surfaces at sites of bone turnover1,2 Alendronate (ALN) on bone surface in rodent3 ALN on bone surfaces at 24 hrs Trabecular bone 1. Baron R et al, Bone 2011;48 (4): 677-692. 2. Kimmel DB J Dent Res 86(11):1022-1033, 2007 3.Masarachia P, et al. Bone 1996;19:281-90. 2010 Amgen. All rights reserved.
Schematic representation of the skeletal distribution of denosumab Denosumab continuously circulates in blood and extracellular fluid1 Denosumab in blood vessels within bone tissue in rodent2 Control Denosumab Blood Vessel Tibial Cortex 1. Baron R et al, Bone 2011;48 (4): 677-692. 2. Kostenuik PJ, et al. J Bone Miner Res 2009;24:182-95 2010 Amgen. All rights reserved.
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Cortical Porosity 28-72%
Dmab prevents increases in distal radius cortical porosity (HRpQCT) Bone architecture pilot study Cortical Porosity (% change) Denosumab (n=82) -2.98 Alendronate (n=82) 2.86 Placebo (n=83) p=0.02 vs placebo 5.19-5 Boyd et al. ECTS congress 2011, abstract and poster PP264 2010 Amgen. All rights reserved. 0 5
Effect of 4 Years of Denosumab Treatment on Total Hip and Distal 1/3 Radius BMD Phase 2 Study in Women With Low BMD Placebo 60 mg Q6M Total Hip Distal 1/3 Radius 8 6 2 0 Percent Change (LS Mean ± SE) Percent Change (LS Mean ± SE) 4 2 0 2 2 4 6 4 0 6 12 18 24 36 48 Months P < 0.001 for 60-mg Q6M group vs placebo. Note: Graph depicts only the 60-mg Q6M group from baseline through 48 months. Adapted from Miller PD, et al. Bone. 2008;43:222-229. 2010 Amgen. All rights reserved. 4 6 0 6 12 18 24 Months 36 48
BMD at Month 12 for All Measured Skeletal Sites Phase 3: The DECIDE Trial 1.1% Percent Change From Baseline (%) in BMD Least Squares Mean (95% CI) 6 1.0% 5 Alendronate 70 mg QW Denosumab 60 mg Q6M 1.0% 4 0.6% 3 2 0.6% 1 0 Total Hip Lumbar Spine Trochanter Femoral Neck 1/3 Radius P 0.0001. Brown JP, et al. J Bone Miner Res. 2009;24:153-161. Brown JP, et al. Presented at: 35th Annual European Symposium on Calcified Tissues; May 24-28, 2008; Barcelona, Spain. Late breaking abstract LB2. 2010 Amgen. All rights reserved.
Effects of Treatment on BMD Over 12 Months Phase 3: The STAND Trial Alendronate 70 mg QW (n = 241) Total Hip (primary endpoint) Lumbar Spine (secondary endpoint) 1.90% Percent Change From Baseline (Least Squares Mean ± 95% CI) 2.4 Denosumab 60 mg Q6M (n = 246) (95% CI: 1.61%, 2.18%) 4 3.03% (95% CI: 2.63%, 3.44%) 2.0 3 1.6 1.2 2 0.8 1.05% (95% CI: 0.76%, 1.34%) 0.4 0.0 1.85% 1 (95% CI: 1.44%, 2.26%) 0 0 6 Study Month 12 n = number of patients who have a baseline and 1 postbaseline evaluation. P < 0.05; P < 0.01. CI = confidence interval Adapted from: Kendler DL, et al. J Bone Miner Res. 2010;25:72-81 2010 Amgen. All rights reserved. 0 6 Study Month 12
Effect of Time-on-Prior Alendronate on Total Hip BMD Changes Phase 3: The STAND Trial Percent Change in Total Hip BMD (Least Squares Mean ± 95% CI) 4 Alendronate 70 mg QW Denosumab 60 mg Q6M 3 2 1 0 6 to < 12 Months 2010 Amgen. All rights reserved. P < 0.05 P < 0.01 Adapted from: Kendler DL, et al. J Bone Miner Res. 2010;25:72-81 12 to 24 Months > 24 Months
The Effect of Denosumab on Fracture Risks at 36 Months Phase 3: The FREEDOM Trial 9% Incidence at Month 36 (%) 8% 7% Placebo Denosumab RR = 20% P = 0.01 RR = 68% P < 0.001 8,0% 7,2% 6,5% 6% 5% 4% 3% 2% RR = 40% P = 0.04 2,3% 1% 1,2% 0,7% 0% New Vertebral 2010 Amgen. All rights reserved. Primary Endpoint RR = risk reduction Cummings SR, et al. N Engl J Med. 2009;361:756-765. Nonvertebral Hip
The Effect of Denosumab on New Vertebral Fractures At Month 12, 24, and 36 Phase 3: The FREEDOM Trial 8,0% 7,0% RR = 68% P < 0.001 Placebo Denosumab 7,2% Crude Incidence (%) RR = 71% P < 0.0001 6,0% 5,0% 5,0% 4,0% 3,0% 2,0% RR = 61% P < 0.001 2,3% 2,2% 1,0% 1,4% 0,9% 0,0% 0 12 Months Intent-to-treat, last observation carried forward analysis Data on file, Amgen. 2010 Amgen. All rights reserved. 0 24 Months 0 36 Months
The Effect of Denosumab on Time to First Hip Fracture Through 36 Months Phase 3: The FREEDOM Trial Cumulative Incidence (%) Placebo Denosumab 60 mg Q6M 1.2 0.8 0.7% 0.4 0.0 0 6 12 18 Month 24 30 36 3,906 3,799 3,672 3,538 3,430 3,311 3,221 Denosumab, n 3,902 3,796 3,676 3,566 3,477 3,397 3,311 40% Number of patients at risk Placebo, n 1.2% Hip fractures were reduced by 40% (95% CI: 0.37, 0.97) P = 0.04 Cummings SR, et al. N Engl J Med. 2009;361:756-765. Copyright 2009 Massachusetts Medical Society. All rights reserved. 2010 Amgen. All rights reserved.
The Effect of Denosumab on Time to First Nonvertebral Fracture Through 36 Months Phase 3: The FREEDOM Trial Cumulative Incidence (%) Placebo 8 6.5% 6 4 2 0 0 6 12 18 24 30 36 Month Number of patients at risk Placebo, n 8.0% Denosumab 60 mg Q6M 3,906 3,750 3,578 3,410 3,264 3,121 3,009 Denosumab, n 3,902 3,759 3,594 3,453 3,337 3,228 3,130 Nonvertebral fractures were reduced by 20% (95% CI: 0.67, 0.95) P = 0.01 Cummings SR, et al. N Engl J Med. 2009;361:756-765. Copyright 2009 Massachusetts Medical Society. All rights reserved. 2010 Amgen. All rights reserved. 20%
Percent Change in Lumbar Spine BMD Percent Change Lumbar Spine BMD mean (95%CI) 14 12 8 6 4 2 13.7% LS BMD increase vs. Freedom baseline 10 0 BL 1 2 3 Exposure (Years) p < 0.002 from placebo and baseline 4 5 Denosumab long-term (N=2208) Placebo (N=2088) BMD continued to significantly increase in years 4 and 5 with long-term denosumab treatment Papapoulos S, et al. Osteoporos Intl 2011(suppl 1) OC25 Do not copy. Do not distribute. March 2011
Percent Change in Total Hip BMD Percent Change Total Hip BMD mean (95% CI) 8 6 4 7.0% Hip BMD increase vs. Freedom baseline 2 0-2 BL 1 2 3 Exposure (Years) p < 0.002 from placebo and baseline 4 5 Denosumab long-term (N=2208) Placebo (N=2088) BMD continued to significantly increase in years 4 and 5 with long-term denosumab treatment Papapoulos S, et al. Osteoporos Intl 2011(suppl 1) OC25 Do not copy. Do not distribute. March 2011
Yearly Incidence of New Vertebral Fractures Placebo Denosumab EXTENSION Study FREEDOM Study 4.0 Yearly Incidence of New Vertebral Fracture (%) 3.5 3.1% 3.1% 3.0 2.2% 2.5 2.0 1.4% 1.5 1.1% 0.9% 1.0 0.7% 0.5 0.0 N Years of 4/5 Exposure 3691 3702 1 3400 3453 2 Papapoulos S, et al. Osteoporos Intl 2011(suppl 1) OC25 3186 3247 2100 3 Annualized rate Do not copy. Do not distribute. March 2011
Yearly Incidence of Nonvertebral Fractures Placebo Denosumab EXTENSION Study FREEDOM Study 3.5 Yearly Incidence of Nonvertebral Fractures (%) 3.1% 3.0 2.6% 2.7% 2.5 2.3% 2.0% 2.0 1.9% 1.5 1.2% 1.1% 1.0 0.5 0.0 Years of Exposure 1 2 Papapoulos S, et al. Osteoporos Intl 2011(suppl 1) OC25 3 4 5 Do not copy. Do not distribute. March 2011
Teriparatide, zoledronic acid and denosumab have the highest probabilities of being most efficacious for non-vertebral and vertebral fractures, and having the greatest effect sizes. The estimates from indirect comparisons were robust to differences in methodology
Αντικαταγματική δράση Σπονδυλικά ΜηΣπονδυλικά Ισχίου Οιστρογόνα Καλσιτονίνη Ραλοξιφαίνη () Αλενδρονάτη Ρισεδρονάτη Ζολεδρονικό Ιμπανδρονάτη Τεριπαρατίδη Ρανελικό Στρόντιο () Denosumab