Osteoporose Heinrich Resch

Präsentation zum Thema: "Osteoporose Heinrich Resch"—  Präsentation transkript:

1 Osteoporose Heinrich Resch
II. Medizinische Abteilung mit Rheumatologie/Osteology & Gastroenterologie) KH Barmherzige Schwestern, 1060 Wien Akademisches Lehrkrankenhaus der Medizinischen Universität Wien

2 Hüftfrakturen Österreich
Alter > 50á) 14.000 12.000 10.000 8.000 6.000 4.000 2.000 Frauen Männer 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Quelle: Statistik Austria ; ICD-9, ICD-10 Dimai HP et al, 2009 unpublished data Korrekturfaktor Mehrfachregistrierung: ~0.97

3 Definition of Osteoporosis
A skeletal disorder characterized by… Normal • Excessive osteoclast-mediated bone resorption • Compromised bone strength • Increased risk of fracture at all skeletal sites Osteoporosis “Osteoporosis is one of the most common and debilitating chronic diseases, and a global healthcare problem.” International Osteoporosis Foundation “Osteoporosis has financial, physical, and psychosocial consequences, all of which significantly affect the individual, the family, and the community.” NIH Consensus Statement Boyle WJ, et al. Nature. 2003;423: NIH Consensus Development Panel. JAMA. 2001;285: Images:Y. Jiang. Osteoporosis & Arthritis Lab, University of Michigan.

4 Skeletal Form and Function
The skeleton is a dynamic organ comprised of over 200 discrete bones with mechanical, protective, and metabolic functions Composed of two types of bone: Cortical bone: Outer dense shell (~ 80% of total skeletal mass) Trabecular bone: Network of connecting plates inside the cortical shell (~ 20% of total skeletal mass) Dempster DW. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. 2006:7-11

5 Cortical Bone Dense outer shell of compact bone; defines bone shape
80% of skeletal mass Essential functions Provides biomechanical strength Attachment site for tendon and muscle Protection against excess trauma Turnover rate of 2–3% per year Dempster DW. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. 2006:7-11.

6 Trabecular Bone A sponge-like network of delicate plates of bone known as trabeculae 20% of skeletal mass Essential functions Mineral metabolism Strength and elasticity Higher turnover rate compared to cortical bone Dempster DW. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. 2006:7-11.

7 Standardisierte Laboruntersuchungen
großes internes Labor: Elektrolyte inkl. Ca, Ph Nierenparameter Leberparameter Alkalische Phosphatase Blutbild Knochenstoffwechselparameter im Serum PTH S-CTX P1NP S-OC 25(OH)Vit D ← Steuerhormon ← Abbaumarker - Osteoklasten ← Anbaumarker - Osteoblasten ← Anbaumarker - Osteoblasten ← Mineralisierung

8 Die Geschichte mit den schweren Knochen…….

9 Was wiegen die Knochen….
BMD g/cm2

10 Die Geschichte mit den schweren Knochen….

11 Falsche Messwerte Verkalkung der Aorta Skoliose Wirbelkörpereinbrüche
degenerative Veränderungen Adipositas Prothesen

12

13

14 The standardized risk ratio is a relative risk. I. e
The standardized risk ratio is a relative risk. I.e. the risk of one group compared to another. It is commonly used in medicine and BMD compares well in its ability to predict the relative risk of fracture compared to other common test in predicting the relative risks of other diseases.

15

16 Frakturschwelle unter Tscore -2.5

17 Klinische dichotomisierte Risikofaktoren [BMI = 25]
Fracture Risk Assessment II Klinische dichotomisierte Risikofaktoren [BMI = 25] Alter prävalente Fragilitätsfrakturen Positive Familienanamnese einer Hüft-FX Glucocorticoide Rheumatoide Arthritis andere Gründe sekundärer Osteoporose Tägliche Alkoholmenge ≥ 3 Einheiten/d (1 E ~ 8-10g) Kanis JA et al. Osteoporosis Int 2008;19(4):

18 Fracture Risk Assessment III
Kanis JA et al. Osteoporosis Int 2008;19(4):

19 FRAX Beispiel Kanis JA et al. Osteoporosis Int 2008;19(4):

20 FRAX Beispiel Kanis JA et al. Osteoporosis Int 2008;19(4):

21 1-ANTIRESORPTIV 2-KNOCHENANABOL
Die 4 Substanzgruppen 1-ANTIRESORPTIV KNOCHENANABOL BISPHOSPHONATE Etidronat Alendronat Risedronat Ibandronat Zoledronat RALOXIFEN CALCITONIN NaF MFP TERIPARATIDE 3-DUAL ACTING Sr RANELAT (DABA)

22 Die 4 Substanzgruppen 1-ANTIRESORPTIV 2-KNOCHENANABOL NaF MFP
BISPHOSPHONATE Etidronat Alendronat Risedronat Ibandronat Zoledronat RALOXIFEN CALCITONIN NaF MFP TERIPARATIDE 3-DUAL ACTING BIOLOGIKA-AK Sr RANELAT (DABA) RANKL AK Denosumab KATHEPSIN K AG SCL AK

23 Nachweis der Wirksamkeit einer Osteoporosetherapie: Information lt
Nachweis der Wirksamkeit einer Osteoporosetherapie: Information lt. österr. Fachinformation Nachweis der Wirksamkeit einer Osteoporosetherapie: Information lt. österr. Fachinformation vertebrale non-vertebrale Hüft- Intervention Fraktur Fraktur Fraktur Alendronat1  -  Ibandronat2   - - Risedronat3   Zoledronat4    Calcitonin5  - - Raloxifen6  - - Strontiumranelat7   -  Teriparatid (1-34)8   - - rhPTH (1-84)9  - - 1 FI Fosamax einmal wöchentlich 70mg, Stand Juni FI Bonviva 3mg 3ml-Injektionslösung in einer Fertigspritze, Stand März FI Actonel einmal wöchentlich 35mg, Stand August FI Aclasta, Stand Oktober FI Calcitonin „Novartis“ 100 I.E.-Nasalspray, Stand September FI Evista 60mg-Filmtabletten, Stand März FI Protelos 2g-Granulat zur Herstellung einer Suspension zum Einnehmen, Stand Februar FI Forsteo 20 Mikrogramm/80 Mikroliter, Injektionslösung in einem vorgefüllten Injektor, Stand September FI Preotact 100 Mikrogramm-Pulver und Injektionslösung zur Herstellung einer Injektionslösung, Stand April 2006.

24 Therapiekomfort Täglich Wöchentlich 3-monatlich 1xjährlich Tablette Pulver i.v.Injektion

25 Metaanalyse zum Hüftfrakturrisiko mit unterschiedlichen Vitamin D Dosen

26 Therapie der Wahl – SERMs?
Cave Thrombose KLINIK: Unspez Kreuzschmerz Keine Frakturen Gesund/ genetisches Risiko DEXA lumbal T-score: hip -1.48

27 Gewebsspezifische Wirkung
O N Basische Seitenkette O Benzothiophen OH S HO ER Antagonistische Effekte (Uterus, Brust) Tissue Dependent Action Agonistische Effekte (Knochen, Fettstoffwechsel) Erhöhung der BMD (Bone Mineral Density), somit Risikoreduktion von vertebralen Frakturen Senkt Gesamt- und LDL-Cholesterin ER = Östrogen Rezeptor

28 Invasives Mammacarcinom (Rezeptorstatus)
Fahrleitner-Pammer A Journal für Mineralstoffwechsel 2007; 14 (1): 39-44

29 M.B. 73a PMO – Bisphosphonate - Cave Verträglichkeit
KLINIK: Akuter Kreuzschmerz Periphere Frakturen St.p.Totalexst./ genetisches Risiko DXA: Niedrige Knochendichte Reflux?

30 Welches Bisphosphonat?/ Wie lange?
Oral Originalsubstanz/Generika Unverträglichkeit- mangelnde Wirkung Parenteral Ibandronat 3 Monate Zoledronat 12 Monate Dauer Jahre Folgetherapie – Drug Holiday

31 Ibandronate: Nonvertebral fracture for higher
versus lower ibandronate doses Fig. 1 Kaplan-Meier plot of time to nonvertebral fracture for higher versus lower ibandronate doses OI 2008

32 % Patienten mit neuer vertebraler Fraktur
Zoledronsäure reduziert das 3-Jahres-Risiko morphometrischer vertebraler Frakturen (Stratum I) um 70% ZOL 5 mg Plazebo 15 70%* (62%, 76%) 71%* (62%, 78%) 10.9% (310/2853) 10 7.7% (220/2853) 60%* (43%, 72%) % Patienten mit neuer vertebraler Fraktur 3.7% (106/2853) 3.3% (92/2822) 5 2.2% (63/2822) Zoledronic Acid Reduced 3-Year Risk of New Morphometric Vertebral Fractures (Stratum I) by 70% This slide presents data for the co-primary end point assessing relative risk reduction in morphometric vertebral fracture with ZOL 5 mg vs placebo over 3 years. Data shown here are the percentage of patients with new vertebral fracture at 1, 2, and 3 years in both treatment groups. Incident morphometric vertebral fracture (height reduction from baseline of ≥20% and 4 mm) was evaluated in patients without concomitant osteoporosis therapy (Stratum I). Among Stratum I patients, ZOL 5 mg reduced the risk of new vertebral fractures by 60% compared with placebo in the first year of the trial, by 71% in year 2, and by 70% in year 3 (P < for each time point). At 3 years, 3.3% of zoledronic acid patients in Stratum I exhibited new fractures, compared with 10.9% of placebo patients in Stratum I. This reflects a statistically significant relative risk reduction of 70% (P < .0001) versus placebo over 3 years. Patients included in this analysis (n = 5675) include the total number with a baseline and at least 1 follow-up radiograph. Any missing data for earlier visits have been imputed from later visits. The total follow-up radiographs at each follow-up visit were 5630 at year 1, 5196 at year 2, and 4910 at year 3. Reference Black DM, Delmas PD, Eastell R, et al, for the HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356: 1.5% (42/2822) 0–1 0–2 0–3 Jahre *P < .0001, relative Risikoreduktion vs. Plazebo (95% Konfidenzintervall) Black DM, et al. N Engl J Med. 2007;356:

33 Zoledronsäure reduziert das kumulative 3-Jahres-Risiko klinischer
Frakturen (Hüfte, klinische Vertebralfx, non-vertebrale Fx) ZOL 5 mg Placebo 25%‡ (13%, 36%) 15 10,7% (388/3861) 10 41%* (17%, 58%) 77%† (63%, 86%) 8,0% (292/3875) kumulative Häufigkeit (%) neuer klinischer Frakturen über 3 Jahre 5 2,5% (88/3861) 2,6% (84/3861) 1,4% (52/3875) 0,5% (19/3875) Hüftfrakturen klinische Vertebralfrakturen non-vertebrale Frakturen Werte über den Balken sind kumulierte Ereignisraten über 3 Jahre gemäß Kaplan-Meier-Schätzung. *P = 0,0024; †P < 0,0001; ‡P = 0,0002; relative Risikoreduktion gegenüber Placebo §Hüftfrakturen wurden aus der Analyse der non-vertebralen Frakturen nicht ausgeschlossen. Black DM, et al. N Engl J Med. 2007;356:

34 Chronischer Kreuzschmerz Periphere Frakturen
A.P.78a BP Langzeit Therapie unabhängige Logistik cave Darm, Thrombose KLINIK: Chronischer Kreuzschmerz Periphere Frakturen Obstpation/ genetisches Risiko Venensituation DXA: Niedrige Knochendichte

35 Long-term Treatment Effect of Strontium Ranelate (SOTI and TROPOS, follow-up 5 years)
Reginster et al., Calcif Tissue Int 2007, 80: S47

36 PTH (TPTD,rhPTH) Intermittierend appliziert
Proliferation der Präosteoblasten Anregung der Osteoblastenaktivität Hemmung des Osteoblastenabbaus Insgesamt Steigerung des Knochenumbaus (auch Osteoklasten werden, wenn auch etwas verzögert, angeregt)  mehr Osteoblasten = osteoanabole (knochenaufbauende) Wirkung

37 Vergleich TPTD mit rhPTH(1-84)

38 TPTD20 Followed with Antiresorptive Treatment Lumbar Spine BMD
Source: RMP.B3DSBJV3.SASPGM(BDSALLL8) Review: Anwar Hossain 6/17/02’ Hossain 2 4 6 8 10 12 14 16 18 No OP drug use (n=144) AR < 6 months and at least 2yrs (n = 65) AR > 6 mos and at least 18 mos (n = 34) Reviewer Memo: revised legend language for duration G. Pohl approved thru disclosure Percent change in BMD Das war dasunmittelbare Studienkollektiv aus der Zulassungsstudie Endpoint Visit 1 Visit 2 Visit 3 (+6 months) (+18 months) (+30 months) AKS07 Lindsay, Scheele et al. Endo Soc Eli Lilly and Company Slide Modified: on: 6/14/2002 2:38:51 PM SL9 Rev: 425 on: 6/17/2002 4:57:03 PM SL9 Rev: 435 on: 10/29/ :13:29 AM SL9 Rev: 466 on: 10/30/2002 9:25:43 AM SL9 Rev: 471 on: 11/20/2002 9:19:40 AM SL9 Rev: 483 Memo: Hossain checked data on 6/17/02; added “fracture prevention trial baseline through follow-up study” added reference to meeting presentation (Endo Soc 2002) - perron G. Pohl reviewed and made format and word changes to slideset

39 BMD unter Teriparatide vs Alendronate bei GIO
Saag et al, NEJM (2007) 357:

40 Effects of Prior Antiresorptive Therapy on the Bone Mineral Density Response to Teriparatide Treatment S. Boonen et al. J Clin. Endocrinol Metab. 2007; epub

41 Wachstumsfaktoren Hormone, Zytokine
Regulation des Knochenstoffwechsels durch Steuerpeptide OPG/Denosumab Stammzelle RANKL RANK Pre-Fusion OC Wachstumsfaktoren Hormone, Zytokine X vielkerniger OC RANKL X aktivierter OC Osteoblast

42 Fully human monoclonal antibody IgG2 immunoglobulin isotype
Properties of Denosumab Fully human monoclonal antibody IgG2 immunoglobulin isotype High specificity for RANK Ligand No detectable binding to TNFα, TNFβ, TRAIL, or CD40L No neutralizing antibodies detected in clinical trials to date Effects on bone resorption appear reversible High affinity for human RANK Ligand r factor kappa B) ligand, an essential mediator of osteoclast activity.1-3 No neutralizing antibodies have been detected in clinical trials to date.1,3 Binding of denosumab to RANK Ligand was investigated in an in-vitro study using flow cytometry and ELISA. Binding affinity was measured using BIAcore and a kinetic exclusion assay. Denosumab bound both soluble and membrane-bound forms of human RANK Ligand. This binding was inhibited by excess human RANK Ligand, but not by TNF-, TNF-, TRAIL or CD40 Ligand. The dissociation constants of denosumab were calculated to be 9.5 x 10-11M and x 10-12M using the BIAcore and kinetic exclusion assay, respectively.2 No neutralizing antibodies have been detected in clinical trials to date: In a phase 1, double-blind study, 49 healthy postmenopausal women were randomized to receive a single dose of denosumab 0.01, 0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg or placebo. No anti-denosumab antibodies were detected in subjects enrolled in this study.1 In a phase 2 study, 412 postmenopausal women with low bone mineral density (BMD) were randomized to receive denosumab SC either every three months (6, 14, or 30 mg) or every six months (14, 60, 100, or 210 mg), open-label alendronate (70mg orally once weekly), or placebo. Denosumab-binding antibodies were observed in two subjects—one at 1 month and the other at 12 months. These antibodies were not neutralizing and were not detected in subsequent samples in either subject.3 The effects of denosumab on bone resorption appear reversible.3 Note: The graphic in the slide is a ribbon depiction of denosumab. Bekker PJ, et al. J Bone Miner Res. 2004;19: Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med. 2006;354: TNF = tumor necrosis factor; TRAIL = TNFα-related apoptosis-inducing Ligand. Bekker PJ, et al. J Bone Miner Res. 2004;19: Data on file, Amgen. Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med. 2006;354: 42

43 The FREEDOM Trial Österreichische Zentren: 7808/100 Patienten
Fracture Efficacy Evaluation in Patients with Osteoporosis with Densosumab Over 6 Months Österreichische Zentren: 7808/100 Patienten Universitätsklinik Graz KH Hietzing KH Barmherzige Brüder Menox Klimax KH Speising KH Barmherzige Schwestern, Wien

44 Jährliche Reduktion des vertebralen Fraktur Risikos
78% p < 0,0001 Placebo Denosumab 65% p < 0,0001 3,1% 3,1% 61% p < 0,0001 2,2% Crude incidence (%) 1,1% 0,9% 0,7%

45 40% p = 0,036 Hüftfrakturen Placebo Denosumab Cumulative Incidence (%)
1,2% 40% p = 0,036 95% CI (3 to 63%) Cumulative Incidence (%) 0,7% 6 12 18 24 30 36 Study Month