Background/Purpose:
Treatments for osteoarthritis focus on improving symptoms through non-pharmacological and pharmacological approaches. Strontium ranelate (SrRan), a treatment for osteoporosis, was shown to stimulate cartilage matrix formation in vitro, and to reduce radiographic spinal OA progression in osteoporotic women with spinal OA.
The objective of SEKOIA phase III study was to compare the efficacy of SrRan with placebo for reducing radiological progression of knee OA.
Methods:
SEKOIA is a double-blind, placebo-controlled, randomized, 3-year study involving 1683 patients with symptomatic primary knee OA (Kellgren and Lawrence [KL] grade 2 or 3, joint space width [JSW] 2.5–5 mm) randomly allocated to SrRan 1 or 2g/day, or placebo. Primary endpoint was radiographic change in JSW of the medial tibiofemoral compartment from baseline to LOCF. Group comparisons were performed in the ITT using a general linear model with Dunnett’s multiple comparison procedure with baseline JSW, center and sex as covariates. JSW was measured yearly using a validated computer-assisted centralised reading method. Secondary endpoints included radiological progression (JSN≥0.5mm)1, radio-clinical progression (JSN≥0.5mm and WOMAC improvement≤20%)2, WOMAC scores, knee pain, and adverse events.
Results:
The ITT set included 1371 (82%) patients. Age was 63±7 years, BMI was 30±5 kg/m2, JSW was 3.5±0.8 mm. 61% were KL II. 69% were female. SrRan was associated with less progression of cartilage degradation, decrease in JSW was –0.23±0.56 mm with 1g/day;–0.27±0.63 mm with 2g/day and –0.37±0.59 mm with placebo; estimated differences (SE) were 0.14(0.04),p<0.001 for 1g/day and 0.10(0.04),p=0.018 for 2g/day with no difference between doses. Results were confirmed in the Randomised Set and sensitivity analyses demonstrated minimal impact of missing post-baseline data.
There were less radiological and radioclinical progressors with SrRan 1 and 2 g/day:
|
Secondary criteria |
Strontium ranelate 1 g/day (n=445) |
|
Strontium ranelate 2 g/day (n=454) |
|
Placebo value (n=472) |
||||
|
|
n % |
E (SE)* |
p value |
|
n % |
E (SE)* |
p value |
|
|
|
Radiological progression |
99 (22%) |
–10.80 (2.9) (–16.54;–5.06) |
<0.001 |
|
116 (26%) |
–7.50 (3.0) (–13.34;–1.66) |
0.012 |
|
156 (33%) |
|
Radioclinical progression |
32 (8%) |
–3.94 (1.98) (–7.83; –0.05) |
0.049 |
|
28 (7%) |
–5.12 (1.91) (–8.86;–1.37) |
0.008 |
|
53 (12%) |
*Estimated difference versus placebo
Greater reductions in total WOMAC score (p=0.045), pain (p=0.028) and physical function subscore (p=0.099), and knee pain (p=0.065) were observed with SrRan 2 g/day. SrRan was well tolerated: 86%, 88% and 87% reported an emergent adverse event (EAE) in the SrRan 1g, 2g and placebo group respectively, 17% of the patients in each group reported a serious EAE. 1 EAE in each SrRAn group, 3 in the placebo group led to death.
Conclusion:
SrRan 1 and 2g/day delayed radiographic progression of knee OA, evidencing a structure-modifying effect. This structural effect is translated clinically into a lower number of patients having a radiological progression over thresholds known to be predictive of OA-related surgery suggesting that SrRan could reduce the number of patients needing knee surgery in the long-term. The structural effect was accompanied by symptom improvement at the dose of 2g/day.
References
1 Bruyere et al, ARD 2005-64:1727-1730
2 Altman et al, Ost Cart 2005-13,13-19
Disclosure:
J. Y. Reginster,
Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex, UCB,
5,
Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed, Novo-Nordisk,
,
Bristol Myers Squibb, Merck Sharp and Dohme, Rottapharm, Teva, Lilly, Novartis, Roche, GlaxoSmithKline, Amgen, Servier,
2;
R. Chapurlat,
Merck, Amgen, Servier, Lilly, Roche, Novartis,
2;
C. Christiansen,
Nordic, Bioscience A/S, CCBR/Synarc,
9,
Roche, Eli Lilly, Novartis, Novo Nordisk, Proctor and Gamble, Groupe Fournier, Besins EscoVesco, Merck Sharp and Dohme, Chiesi, Boehringer Mannheim, Pfizer, GlaxoSmithKline, Amgen.,
5;
H. Genant,
Servier, Novartis, Pfizer, GSK, Roche, Genentech, Lilly, Amgen, Merck, ONO, Bristol Myers Squibb,
5,
Synarc, Inc.,
1;
N. Bellamy,
Servier,
5;
W. Bensen,
Abbott, Amgen, Bristol Myers Squibb, Janssen, Merck-Schering, Lilly, Novartis, Pfizer, Wyeth, Proctor and Gamble, Roche, Sanofi, Servier, Aventis, UCB, Warner Chilcott,
5;
F. Navarro,
Servier,
5;
J. Badurski,
Servier, Amgen,
5;
E. Nasonov,
Merck Sharp and Dohme, Rocher,
5;
X. Chevalier,
Expanscience, Negma, Genevriers, Merck Sharp and Dohme, Rottapharm, Fidia, Servier, Pierre Fabre, Smith Nephews,Ibsa, Genzyme,
5,
Roche for the department association,
2;
P. Sambrook,
Servier ,
5;
T. Spector,
Servier,
5,
Pfizer Inc,
2,
Expanscience, Ono Pharma,
5;
C. Cooper,
Amgen, ABBH, Novartis, Pfizer, Merck Sharp and Dohme, Eli Lilly, Servier,
5.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/strontium-ranelate-in-knee-osteoarthritis-trial-sekoia-a-structural-and-symptomatic-efficacy/