Osteo-artrose, zijn er nieuwe behandelingsmogelijkheden?

•  Prof Dr Willem F Lems, VUmc en Reade •  IWO, 3 october 2012

Osteo-arthrose (OA)

•  Inleiding Felson: in VS 20 miljoen patienten met OA, in 2020 naar verwachting 40 miljoen!

•  Hoe is dat in Nederland?

Cooper et al, BMJ 2011

Standardised Mortality: 1.55, (95% c.i. 1.41-1.70)

Metabolic Bone Changes in Rheumatic Diseases

Lories, Cytokine Growth Factor Rev. 2005

Clinical update: treating osteoarthritis.

Lohmander S, Lancet 2007

Lancet 2011

Lancet 2011

Hoekstenen behandeling osteo-artrose

•  Voorlichting, leefregels ; •  Fysiotherapie; •  Paracetamol; •  NSAIDs/Coxibs, cave side effects; •  Locale injecties met Glucocorticoiden; •  Chrirurgische Interventies; •  Experimentele therapie (anti Nerve Growth

factor, kraakbeentransplantatie; anti/osteoporose drugs)

Finish!

Controverse 1: Glucosaminen effectief?

•  Glucosamine: Studies using a non-Rotta preparation failed to show a benefit in pain, while those with Rotta….show that glucosamine was superior to placebo” (Towheed, Cochrane 2005)

Joint Space Narrowing: -0,031 mm (placebo) versus -0,06 mm (verum): 0,24 mm (p=0,043)

Rates of a Primary Response in the Five Groups at 4 and 24 Weeks

Clegg, D. et al. N Engl J Med 2006;354:795-808

Maar,

•  Glucosamine-hydrochloride ipv glucosamine sulfaat; •  Forse placebo-response; •  Niet-optimale patienten-groep?

•  Conclusie: wat betreft de primaire uitkomstmaat zijn de resultaten van de GAIT-trial negatief;

•  Een korte proefbehandeling van 3 maanden kan zinvol zijn.

Lems en Bijlsma Ned Tijdschr Geneeskunde mei 2006

Ann Int Med 2008; 268-277

Controverse II: Chondrotoine, Not Recommended by NICE

•  Chondrotoine (meta-analysis): Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondrotoin is minimal or non-existent” (Reichenbach, Ann Int Med 2007);

Ann Int Med 2012

Controverse III: zijn alle voedingssupplementen veilig?

• 

Seminar Arthritis Rheum 2009

“”NGF is overexpressed in may inflammatory and degenerative rheumatic diseases”

EULAR 2010: tanezumab reduces OA-knee pain (WOMAC).

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10

baseline 32 weeks

placebo2,5 mg5 mg10 mg

Brown et al, EULAR OP 157

* * **

*: p<0.05; **: p<0.01

GEN news highlights: June 24, 2010 Trials Halted as Pfizer's Tanezumab Shown to Worsen Osteoarthritis

•  “”The clinical hold requested by FDA follows what Pfizer describes as a small number of reports that osteoarthritis patients receiving the mAb candidate experienced worsening of their disease and needed joint replacements””

•  “As a result of the clinical hold all patients in the ongoing Phase III osteoarthritis program for tanezumab will have their treatment with the active drug stopped, and no new patients will be enrolled.

What about anti-osteoporotic drugs?

Strontium ranelate – Rationale in OA in vitro results

*  Henro(n  et  al.  JBMR  2001;16:  299-­‐308  

Proteoglycan  produc0on  (RIA)  

Ü  p  <  0.001  

•  In normal and OA human chondrocytes cultures, Strontium ranelate (10-3 M) demonstrated a potential structure modifying effect: –  Increases type II collagen synthesis –  Increases high molecular weight proteoglycan synthesis

–  Enhance IGF1-stimulated proteoglycan synthesis

Stron(um  ranelate  

Normal     OA  0  

400  

800  

1200  

ng/µg  DN

A  

Ü  p  =  0.02  

Control  

12  weeks  

A  16-­‐week  osteoarthri(s  interven(on  study  in  the  dog  ACL  model  

4  weeks  

Anterior  Cruciate  Ligament    sec(on  (right  knee)  

Treatment  ini0a0on  

These  effects  are  associated  with  a  decrease  in  subchondral  bone  sclerosis.  

N=40  dogs:  25,  50,  75  mg/kg/day    of  SrRan  orally  versus  placebo.  

*  Osteoporosis  Interna3onal  2012.  Jean-­‐Pierre  Pelle(er  et  al.    

Strontium ranelate – Rationale in OA In vivo results

•  Positive effect of Strontium Ranelate on: –  Macroscopic lesions of femoral condyles and tibial plateaus

–  Subchondral bone thickness –  COLLAGEN

Reduction of urinary CTX II in post menopausal women

*  Alexandersen  et  al.  Bone  2007  (40:219-­‐222)  

•  Postmenopausal women phase I study –  After 6 and 12 weeks of treatment with strontium ranelate 2 g/day a significant

decrease (around 40%) on the urinary CTX II levels compared to baseline was observed in 36 healthy volunteers.

•  TROPOS phase III study –  In 2,617 patients treated for 3 years with strontium ranelate 2 g/d or placebo*

a 15-20% urinary CTX II decrease was observed in the strontium ranelate group compared with placebo.

24   36   Months  

U-­‐CTX  II  

(%  /  mmol  creat.)  

Ü  

Ü  

Ü  Ü  Ü  

0   3   6   12  

90  

100  

110   Placebo  

Stron(um  ranelate  2  g  

*  p<0.001  

Canada  (259)  

Australia  (66)  

Russia  (94)  UK  (169)  

France  (73)  Portugal  (14)  

Spain  (185)   Italy  (103)  

Belgium  (115)  

Germany  (40)  

Denmark  (241)   Poland  (142)  

Austria  (57)  

Estonia  (29)  Lithuania  (9)  

Romania  (27)  

Czech  republic  (44)  

NETHERLANDS  (16)  

First  Visit  First  Pa(ent:  April  2006  Last  Visit  Last  Pa(ent:  February  2011  Study  dura(on:  3  years    

Worldwide study 98 centres, 18 countries - 1,683 patients included

Objec0ve:  Efficacy  and  safety  of  two  doses  of  stron(um  ranelate  (1  g  and  2  g  per  day)  versus  placebo  in  reducing  radiological  progression  of  knee  osteoarthri(s  over  3  years  

M12   M18   M24  Visits  (months)   M0   M6   M30   M36  

Design:  Interna(onal  (18  countries,  98  centres),  double-­‐blind,  placebo-­‐controlled,  randomised  3-­‐year  study  

Placebo  

Stron0um  ranelate  2  g/day  

Randomisa(on  

Selec0on  

N=558  

N=566  

N=559  

Double  blind  treatment  period    

Stron0um  ranelate  1  g/day  

N=1683  

SEKOIA study Design

Cooper  et  al.  CMRO  2012  (28:231-­‐239)  

Main inclusion criteria

 Caucasian  males  or  females    

 Aged  50  years  or  over     Ambulatory  (able  to  walk  unassisted)  

 Primary  knee  osteoarthri(s  based  on  Clinical  criteria  of  the  American  College  of  Rheumatology  (Altman  et  al,  1986)    

•  Knee  pain  on  most  days  of  the  previous  month  (1/2  days)  

•  Intensity  of  at  least  40  mm  on  a  VAS    

•  At  least  3  of  the  followings:  age  >50  years,  s(ffness  <30  minutes,  crepitus,  bony  tenderness,  bony  enlargement,  no  palpable  warmth.  

Cooper  et  al.  CMRO  2012  (28:231-­‐239)  

Placebo  

Stron(um  ranelate  1  g  

Stron(um  ranelate  2  g  

Stron(um  ranelate  1  g  -­‐  placebo  =  0,14  (0.04)    -­‐    95%CI  [0.05;  0.23]  Stron(um  ranelate  2  g  -­‐  placebo  =  0,10  (0.04)    -­‐    95%CI  [0.02;  0.19]  

-­‐0.45  

-­‐0.40  

-­‐0.35  

-­‐0.30  

-­‐0.25  

-­‐0.20  

-­‐0.15  

-­‐0.10  

-­‐0.05  

0  

p=0.018  

p<0.001  

NS  

(mm)  

-­‐0.37  

-­‐0.23  -­‐0.27  

Significantly lower JSN in both strontium ranelate groups compared with placebo

ITT  =  1371  Reginster  et  al.  Osteoporos  Int  (2012)  23  (Suppl  2):S57–S84,  OC3  

ITT  N=1371  

Stron0um  ranelate  1  g  -­‐  placebo  =  -­‐1,3  (4.0)  mm  Stron0um  ranelate  2  g  -­‐  placebo  =  -­‐8.0  (4.0)  mm  

-­‐41  

-­‐52  

-­‐65  

-­‐55  

-­‐45  

-­‐35  

p=0.045  

NS  

Placebo  Stron0um    ranelate  2  g  

(mm)  

Improvement of total WOMAC for strontium ranelate compared with placebo

-­‐42  

NS  

Stron0um    ranelate  1  g  

Reginster  et  al.  Osteoporos  Int  (2012)  23  (Suppl  2):S57–S84,  OC3  

Osteo-artrose

•  Epidemiologie: grote patienten-aantallen; •  Diagnostiek: discrepantie radiologie en

klachten; •  Therapie: vooral symptomatisch;

•  Onderzoek naar osteo-artrose is een noodzaak en een uitdaging!

Dank voor uw aandacht!

Radiological inclusion criteria

Kellgren and Lawrence grade II or III

Predominant osteoarthritis of the medial compartment of the knee

Joint space width between 2.5 mm and 5 mm

Main exclusion criteria •  Predominant osteoarthritis of the lateral compartment of the knee

•  Knee prosthesis (or planned within 1 year)

•  Previous surgical operation of the knee

•  Secondary osteoarthritis of the knee

•  Medical history of venous thrombolic events (VTE) or patients at high risk of VTE

•  Progressive major illnesses

•  Previous treatments likely to have an action on cartilage and bone metabolism –  BPs <1 year prior to selection –  Diacerein, chondroitin sulfate, glucosamine (all forms, ≥1500 mg/day),

avocado/soybean <3 months prior to selection –  Treatment with anti MMPs inhibitory properties –  Glucocorticoids (oral, inhaled >1500 µg/day; or intra-articular <3 months prior

to selection) Cooper  et  al.  CMRO  2012  (28:231-­‐239)  

BMJ 2001

*  Gensburger  D,  Arlot  M,  Sornay-­‐Rendu  E,  Roux  JP,  Delmas  P.,  Arthri3s  Rheum  2009;  61(3):336-­‐343  

15  mm  

10  mm  

Automated  lines  

Primary endpoint for structure modifying treatment

•  Radiological Joint Space Narrowing (JSN) of the medial tibio-femoral compartment of the target joint

•  Central reading in Pr. R. Chapurlat center (Lyon, France) •  Semi-automated validated method* •  Second independent reading Pr. JY Reginster (Liège, Belgium, same method)

The key-question:

•  RNG 475 (Servier): phase 2 •  ANG-antibody (Amgen): phase 1 •  PG 110 (Abbott): phase 1 •  … Astra Zeneca