Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial

Abstract

Objective:

The osteoporosis drug strontium ranelate dissociates bone remodelling processes. It also inhibits subchondral bone resorption and stimulates cartilage matrix formation in vitro. Exploratory studies in the osteoporosis trials report that strontium ranelate reduces biomarkers of cartilage degradation, and attenuates the progression and clinical symptoms of spinal osteoarthritis, suggesting symptom- and structure-modifying activity in osteoarthritis. We describe the rationale and design of a randomised trial evaluating the efficacy and safety of strontium ranelate in knee osteoarthritis.

Research design, methods, and results:

This double-blind, placebo-controlled trial (98 centres, 18 countries) includes ambulatory Caucasian men and women aged ≥50 years with primary knee osteoarthritis of the medial tibiofemoral compartment (Kellgren and Lawrence grade 2 or 3), joint space width (JSW) 2.5 to 5 mm, and knee pain on most days in the previous month (intensity ≥40 mm on a visual analogue scale). Patients are randomly allocated to three groups (strontium ranelate 1 or 2 g/day, or placebo). Follow-up is expected to last 3 years. The primary endpoint is radiographic change in JSW from baseline in each group versus placebo. The main clinical secondary endpoint is WOMAC score at the knee. Safety is assessed at every visit. It is estimated that 1600 patients are required to establish statistical significance with power >90% (0.2 mm ± 10% between-group difference in change in JSW over 3 years). Recruitment started in April 2006. The results are expected in spring 2012.

Clinical trial registration:

The trial is registered on www.controlled-trials.com (number ISRCTN41323372).

Conclusions:

This randomised, double blind, placebo-controlled study will establish the potential of strontium ranelate in improving structure and symptoms in patients with knee osteoarthritis.

Keywords::

• DMOAD
• Joint space width
• Knee osteoarthritis
• Knee radiograph
• Randomized clinical trial
• Strontium ranelate
• Structure-modifying treatment

Transparency

Declaration of funding

The study is funded by Servier, France. The sponsor supports the work of the Executive Committee, but does not make any scientific or research decisions independent of this Committee, which was responsible for the decision to submit the final version of the manuscript for publication.

Declaration of financial/other relationships

All authors were involved in the conception and design of the study and the preparation of the manuscript. The final version was approved by all authors.

C.Co. has received consulting fees from Amgen, ABBH, Novartis, Pfizer, Merck Sharp and Dohme, Eli Lilly and Servier. J.-Y.R. has received consulting fees or paid advisory boards from Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex and UCB, lecture fees from Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed and Novo-Nordisk, and grant support from Bristol Myers Squibb, Merck Sharp and Dohme, Rottapharm, Teva, Lilly, Novartis, Roche, GlaxoSmithKline, Amgen and Servier. R.C. has received research funding and/or honoraria from Merck, Amgen, Servier, Lilly, Roche and Novartis. C.Ch. is Chairman of Nordic Bioscience A/S and Chairman of CCBR/Synarc. He has received consulting fees from Roche, Eli Lilly, Novartis, Novo Nordisk, Proctor and Gamble, Groupe Fournier, Besins EscoVesco, Merck Sharp and Dohme, Chiesi, Boehringer Mannheim, Pfizer, GlaxoSmithKline and Amgen. H.G. has received consulting fees from Servier, Novartis, Pfizer, GSK, Roche, Genentech, Lilly, Amgen, Merck, ONO and Bristol Myers Squibb, and has stock ownership in Synarc. N.B. has received consulting fees from Servier and is registered copyright and trademark holder of the WOMAC Index. W.B. has received research funding, consulting fees and/or honoraria from Abbott, Amgen, Bristol Myers Squibb, Janssen, Merck-Schering, Lilly, Novartis, Pfizer, Wyeth, Proctor and Gamble, Roche, Sanofi, Servier, Aventis, UCB and Warner Chilcott. F.N. has received National coordinator fees from Servier. J.B. has received lecture fees from Servier and Amgen. E.N. has received consulting fees, and has been paid for advisory boards participation or lecture fees from Merck Sharp and Dohme, and Rocher. X.C. has received consulting fees or has been paid for advisory board participation by Expanscience, Negma, Genevriers, Merck Sharp and Dohme, Rottapharm, Fidia, Servier, Pierre Fabre and Smith Nephews, lecture fees from Merck Sharp and Dohme, Servier, Expanscience, Ibsa and Genzyme, and grant support from Roche for the department association. P.N.S. has received national coordinator fees from Servier.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgements

Presented as a poster at the Regional IOF congress in Dubai (19–22 October, 2011): Reginster JY, Chapurlat R, Christiansen C et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: a randomized, double-blind, placebo-controlled international trial. Osteoporos Int 2011;22(Suppl 5):S742. P189 (abstract).