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.

[1]  J. Borer,et al.  Ischaemic cardiac events and use of strontium ranelate in postmenopausal osteoporosis: a nested case–control study in the CPRD , 2013, Osteoporosis International.

[2]  Balla Bernadett.  Strontium ranelate effect in postmenopausal women with different clinical levels of osteoarthritis , 2012 .

[3]  J. Pelletier,et al.  Strontium ranelate inhibits key factors affecting bone remodeling in human osteoarthritic subchondral bone osteoblasts. , 2011, Bone.

[4]  D. Hunter,et al.  Emerging drugs for osteoarthritis , 2011, Expert opinion on emerging drugs.

[5]  P. Ravaud,et al.  Influence of blinding sequence of radiographs on the reproducibility and sensitivity to change of joint space width measurement in knee osteoarthritis , 2010, Arthritis care & research.

[6]  P Tugwell,et al.  OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. , 2010, Osteoarthritis and cartilage.

[7]  Johanne Martel-Pelletier,et al.  Targeting subchondral bone for treating osteoarthritis: what is the evidence? , 2010, Best practice & research. Clinical rheumatology.

[8]  M. Sowers,et al.  Longitudinal changes of serum COMP and urinary CTX-II predict X-ray defined knee osteoarthritis severity and stiffness in women. , 2009, Osteoarthritis and Cartilage.

[9]  M-P. Hellio Le Graverand-Gastineau.  OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where we are headed? , 2009 .

[10]  M. Rybchyn,et al.  Osteoblasts play key roles in the mechanisms of action of strontium ranelate , 2009, British journal of pharmacology.

[11]  P. Delmas,et al.  Radiologic assessment of age-related knee joint space changes in women: a 4-year longitudinal study. , 2009, Arthritis and rheumatism.

[12]  M. Nevitt,et al.  Blinding images to sequence in osteoarthritis: evidence from other diseases. , 2009, Osteoarthritis and cartilage.

[13]  J. Reginster,et al.  Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. , 2009, Arthritis and rheumatism.

[14]  M. Hellio Le Graverand-Gastineau,et al.  OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where we are headed? , 2009, Osteoarthritis and cartilage.

[15]  P. Halbout,et al.  Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response , 2009, Osteoporosis International.

[16]  D. Reda,et al.  The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. , 2008, Arthritis and rheumatism.

[17]  E. Losina,et al.  Joint space narrowing and Kellgren-Lawrence progression in knee osteoarthritis: an analytic literature synthesis. , 2008, Osteoarthritis and cartilage.

[18]  J. Caverzasio.  Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms. , 2008, Bone.

[19]  K Henriksen,et al.  Should subchondral bone turnover be targeted when treating osteoarthritis? , 2008, Osteoarthritis and cartilage.

[20]  S. Gabriel,et al.  Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. , 2008, Arthritis and rheumatism.

[21]  T. Spector,et al.  Effects of strontium ranelate on spinal osteoarthritis progression , 2007, Annals of the rheumatic diseases.

[22]  Atlanta,et al.  Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. , 2008, Arthritis and rheumatism.

[23]  E. Brown,et al.  The calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation. , 2007, Biochemical pharmacology.

[24]  P. Marie.  Strontium ranelate: New insights into its dual mode of action , 2007 .

[25]  M. Karsdal,et al.  Strontium ranelate reduces the urinary level of cartilage degradation biomarker CTX-II in postmenopausal women. , 2007, Bone.

[26]  T. Spector,et al.  Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. , 2006, Arthritis and rheumatism.

[27]  Michael H Weisman,et al.  Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. , 2006, The New England journal of medicine.

[28]  F. Breedveld,et al.  Reading radiographs in pairs or in chronological order influences radiological progression in osteoarthritis. , 2005, Rheumatology.

[29]  L. Sharma,et al.  Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. , 2005, Arthritis and rheumatism.

[30]  J. Reginster,et al.  Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. , 2005, The Journal of clinical endocrinology and metabolism.

[31]  T. Spector,et al.  Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173] , 2005, Arthritis research & therapy.

[32]  J. Reginster,et al.  Total joint replacement of hip or knee as an outcome measure for structure modifying trials in osteoarthritis. , 2005, Osteoarthritis and cartilage.

[33]  C. Peterfy,et al.  Fixed-flexion radiography of the knee provides reproducible joint space width measurements in osteoarthritis , 2004, European Radiology.

[34]  A. Carr,et al.  Epidemiology of hip and knee pain and its impact on overall health status in older adults. , 2004, Rheumatology.

[35]  H. Genant,et al.  Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis. , 2004, Osteoarthritis and cartilage.

[36]  T. Spector,et al.  Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies , 2004, The New England journal of medicine.

[37]  M. Hochberg,et al.  Reliability of a quantification imaging system using magnetic resonance images to measure cartilage thickness and volume in human normal and osteoarthritic knees. , 2003, Osteoarthritis and cartilage.

[38]  E. Vignon,et al.  Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage , 2001, Annals of the rheumatic diseases.

[39]  J. Reginster,et al.  Strontium Ranelate Increases Cartilage Matrix Formation , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[40]  L. Komuves,et al.  Expression and signal transduction of calcium-sensing receptors in cartilage and bone. , 1999, Endocrinology.

[41]  M. Nevitt,et al.  Reliability of new indices of radiographic osteoarthritis of the hand and hip and lumbar disc degeneration. , 1993, The Journal of rheumatology.

[42]  C. Goldsmith,et al.  Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. , 1988, The Journal of rheumatology.

[43]  R. Moskowitz,et al.  Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. , 1986, Arthritis and rheumatism.