Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial

Jean-Yves Reginster; Janusz Badurski; Nicholas Bellamy; William Bensen; Roland Chapurlat; Xavier Chevalier; Claus Christiansen; Harry Genant; Federico Navarro; Evgeny Nasonov; Philip N Sambrook; Timothy D Spector; Cyrus Cooper

doi:10.1136/annrheumdis-2012-202231

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Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial

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Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind randomized, placebo-controlled trial
Jean-Yves Reginster
Published on: 13 April 2016
Strontium and cardiovascular events
Mark J Bolland
Published on: 13 April 2016
Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial
Claire-Louise Murphy
Published on: 13 April 2016
Response to Dr Bolland's eLetter
Jean-Yves Reginster
Published on: 13 April 2016

Published on: 13 April 2016
Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind randomized, placebo-controlled trial
- Jean-Yves Reginster, Prof
Dear Editor,
We would like to reply to the recent letter by Murphy et al(1) regarding the possible influence of obesity and weight changes on the results of the SEKOIA trial of the efficacy and safety of strontium ranelate in knee osteoarthritis.2 Obesity and overweight are recognized risk factors for osteoarthritis,3 and so it is essential to include such patients in studies of potential treatments, since they are...
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Dear Editor,
We would like to reply to the recent letter by Murphy et al(1) regarding the possible influence of obesity and weight changes on the results of the SEKOIA trial of the efficacy and safety of strontium ranelate in knee osteoarthritis.2 Obesity and overweight are recognized risk factors for osteoarthritis,3 and so it is essential to include such patients in studies of potential treatments, since they are likely to constitute a substantial proportion of the patients who could hope to benefit from treatment. Almost half of the patients in SEKOIA were obese at baseline (44% had body mass index [BMI] ?30 kg/m2) with no relevant differences between the three treatment groups: 45% for the patients receiving strontium ranelate 1 g/day; 43% for strontium ranelate 2 g/day; and 44% for placebo. There was no significant variation in body weight over the 3 years of the trial in any of the treatment groups (mean changes were +0.20?4.42, +0.22?4.84, and -0.46?6.35 kg, respectively) and adjustment of the main study results for obesity did not produce substantial changes in the results on joint space narrowing (JSN) with strontium ranelate (treatment-placebo difference in JSN [mm] adjusted for obesity: E(SE) 0.10 (0.04), 95% CI 0.02-0.19, p=0.016 for 2 g/day; treatment-placebo difference in JSN [mm] not adjusted for obesity: E(SE) 0.10 (0.04), 95% CI 0.02-0.19, p=0.018 for 2 g/day).
Moreover, to ascertain the absence of a relationship between weight and JSW changes, JSN was evaluated according to quartiles of weight change, independently of treatment group, and the results did not show any obvious relationship (change in JSW in the lowest quartile [weight loss <2kg]: -0.33?0.68, change in JSW in the highest quartile [weight gain > 2.3 kg]: - 0.30?0.53 mm, respectively). No studies have been conducted to date to assess the efficacy of strontium ranelate combined with weight reduction; and there are no such data available in SEKOIA. However, we agree that weight control, and reduction when needed, and exercise are essential components of the management strategy of patients with knee osteoarthritis and could be associated with strontium ranelate treatment.
References
1. Murphy C-L, Murphy E, Duffy T et al. Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: results of a randomised double-blind, placebo-controlled trial. Ann Rheum Dis 2013;72:e13.
2. Reginster J-Y, Badurski J, Bellamy N et al. Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: results of a randomised double-blind, placebo-controlled trial. Ann Rheum Dis 2013;72:179-86.
3. Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet 2011;377:2115-26.
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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Published on: 13 April 2016
Strontium and cardiovascular events
- Mark J Bolland, Senior Research Fellow
- Other Contributors:
  Andrew Grey
Dear Editor,
In the report of their trial of strontium ranelate in knee osteoarthritis, Reginster and colleagues state that "Strontium ranelate was well tolerated" and that "The safety profile of strontium ranelate was satisfactory, in line with knowledge of this agent" (1). However, contemporaneously, the European Medicines Agency recommended that the use of strontium ranelate be restricted because it increased the r...
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Dear Editor,
In the report of their trial of strontium ranelate in knee osteoarthritis, Reginster and colleagues state that "Strontium ranelate was well tolerated" and that "The safety profile of strontium ranelate was satisfactory, in line with knowledge of this agent" (1). However, contemporaneously, the European Medicines Agency recommended that the use of strontium ranelate be restricted because it increased the risk of myocardial infarction in trials in osteoporosis (relative risk 1.6, 95% confidence interval 1.07 to 2.38), and there was an imbalance in adverse cardiac events with strontium in patients with osteoarthritis (2). The second statement presumably refers to the trial by Reginster and colleagues.
Can the authors clarify their statements regarding the safety of strontium? What was the risk of cardiovascular events with strontium in this trial, and how does this compare to the trials of strontium in osteoporosis the authors cited as demonstrating a satisfactory safety profile for strontium?
References
1. Reginster JY, Badurski J, Bellamy N, et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis 2013;72:179-86.
2. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/04/news_detail_001774.jsp&mid=WC0b01ac058004d5c1
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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Published on: 13 April 2016
Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial
- Claire-Louise Murphy, Rheumatology SpR
- Other Contributors:
  Eithne Murphy, Trevor Duffy, Miriam O'Sullivan, Maurice Barry
Dear Editor,
We read with interest the paper regarding Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo- controlled trial. We note the exclusion criteria included secondary knee osteoarthritis. On review of the results section it appears that many of the patients both the randomised and the intention to treat groups e.g. the stronti...
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Dear Editor,
We read with interest the paper regarding Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo- controlled trial. We note the exclusion criteria included secondary knee osteoarthritis. On review of the results section it appears that many of the patients both the randomised and the intention to treat groups e.g. the strontium 1gm/day group, strontium 2gm/day group and placebo group were either overweight or obese having a raised BMI between 29kg/m2 and 30kg/m2. It is well documented in the literature that patients who are obese are more likely to have knee osteoarthritis (2). It is also included in the ACR criteria as one of the most common causes of secondary osteoarthritis. Our question is whether those with a raised BMI should have been excluded from the study. Also, we do not know from the study what the patients mean BMI was at the start and end of the study, therefore we can not extrapolate as to whether a change in BMI may have influenced the results. Also although strontium ranelate does appear to have structure-modifying activity with smaller degradations in joint space width, we note that these effects were minimal. The study suggests that 14 patients (95% CI 9 to 57) would need to be treated with 2gm strontium ranelate over the study duration to prevent one case of radiological progression ? 0.5mm, a threshold known to predict osteoarthritis related surgery. Therefore although this study shows that strontium ranelate has a beneficial effect in patients with osteoarthritis, it would be interesting to see if investing in weight loss and exercise regimes would be as or more effective. It has been shown that if all overweight and obese people reduced their weight by 5 kg or until their BMI was within the recommended normal range, 24% of surgical cases of knee osteoarthritis might be avoided. (95% CI 19-27%) (3). A study looking at radiological joint space width in patients with a raised BMI post weight loss and exercise regime would be of great interest.
References
1. Jean-Yves Reginster, Janusz Badurski, Nicholas Bellamy, et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis 2013 72:179-186.
2. C Cooper, S Snow, TE McAlindon, et al. Risk factors for the incidence and progression of radiographic knee osteoarthritis. Arthritis Rheum 2000;43:995-1000.
3. Coggon D, Reading I, Croft P et al. International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity 2001;25(5):622-627.
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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Published on: 13 April 2016
Response to Dr Bolland's eLetter
- Jean-Yves Reginster, Professor
Dear Editor,
The work carried out by the authors on calcium and the cardiovascular risk is of primary importance. We thank the authors for questions and comments on the SEKOIA study, safety being a primary concern for us.
The number of emergent adverse events reported in SEKOIA study was similar in the 3 treatments groups: 85.8%, 87.9% and 86.5% in the SrRan 1g, SrRan 2g and placebo groups as well as the number...
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Dear Editor,
The work carried out by the authors on calcium and the cardiovascular risk is of primary importance. We thank the authors for questions and comments on the SEKOIA study, safety being a primary concern for us.
The number of emergent adverse events reported in SEKOIA study was similar in the 3 treatments groups: 85.8%, 87.9% and 86.5% in the SrRan 1g, SrRan 2g and placebo groups as well as the number of serious emergent adverse events: 17.0%, 16.5% and 17.4%, respectively. The adverse reactions considered by the investigators as related to the study drug were similar to those reported in osteoporotic patients: diarrhea (3.3%, 6.6% and 2.7%, respectively), nausea (2.0%, 2.7% and 1.8% respectively), and headache (1.6 in each SrRAn group and 0.7% in the placebo group). Regarding cutaneous safety, 16.3% of the patients reported a skin disorders in the SrRan 2g group compared to 12.4% and 12.2% in the SrRan 1g group and in the placebo group, respectively which is in line with the incidence of skin reaction in osteoporotic patients. No cases of DRESS, SJS or TEN were reported.
When specifically focusing on cardiac safety, a similar incidence of cardiac events was reported in the 3 treatment groups: 5.5%, 5.7% and 5.8%, respectively. Five cases of serious myocardial infarction were reported in the 2g group while 1 case was reported in the SrRan 1g group and in the placebo group. All events occurred in patients with major cardiovascular risk factors or comorbidities. All patients were suffering from hypertension from several years and all but one were overweight or obese. Among the strontium-ranelate treated patients, all presented additional risks factors such as hypercholesterolemia, diabetes, or previous or family myocardial ischaemia. Based on this small number of events and on the presence of numerous comorbidities, it seemed difficult at the time of the results to formally conclude to a higher risk of MI with SrRan. These results were then submitted to the European agency and were part of the routine benefit-risk assessment of the strontium ranelate. When applying at posteriori, the newly contraindication of the European agency to the SEKOIA population (i.e. when excluding patients with pathology at baseline corresponding to the newly defined contraindications: uncontrolled hypertension, thromboembolic events including deep vein thrombosis and pulmonary embolism, ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease), the number of MI become comparable between the 3 treatment groups: 1 event in the SrRan 1g group, 2 in the SrRan 2g group and 1 in the placebo group, demonstrating that the contraindications are effective to minimize the cardiac risk in this population of OA patients.
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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