Strontium ranelate — new safety warnings
Published in Health News and Evidence
Date published: About this date
Practice points | Increased risk of cardiac events | Product information updated | New international recommendations | Increased risk of MI not previously identified in key trials | How health professionals can help | References
The product information for strontium ranelate (Protos) has been updated following European Medicines Agency reports that it may increase the risk of serious heart problems, including myocardial infarction.
These findings came from an analysis by the EMA of pooled data from randomised, placebo-controlled clinical studies, performed as part of a routine safety assessment.
The TGA-approved indication is now for treatment of severe (established) osteoporosis in men at increased risk of fracture and for treatment of severe (established) osteoporosis in postmenopausal women who are at high risk of fracture.
New contraindications have also been added to include people with a history of, or currently experiencing, a range of heart or circulatory problems.
- Only use strontium ranelate for the treatment of severe (established) osteoporosis in postmenopausal women at high risk of fracture, to reduce fracture risk, and to treat severe (established) osteoporosis in men at increased fracture risk.1
- Prescribe strontium ranelate based on an assessment of the individual patient’s risks; evaluate the patient’s risk of developing cardiovascular disease before and routinely during treatment.1–3
- Do not use strontium ranelate in patients with current, or a history of, ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, or in patients with
systolic BP ≥ 160 mmHg, or diastolic BP ≥ 90 mmHg.1,2 Stop treatment if these conditions or symptoms develop.1,2
- Careful consideration is advised before prescribing strontium ranelate for patients with significant risk factors for cardiovascular events (eg. hypertension, hyperlipidaemia, diabetes mellitus, smoking).1,3
The product information for the osteoporosis medicine strontium ranelate (Protos) has been updated after the EMA found that use of the medicine increases the risk of serious heart problems.1,2,4
The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) found that strontium ranelate increases the risk of MI in postmenopausal women.2,4,5
Analysis of pooled data from randomised, placebo-controlled clinical studies in around 7500 postmenopausal women showed that women using strontium ranelate were at increased risk of MI compared with those given placebo (1.7% vs 1.1%, relative risk 1.6, 95% confidence interval 1.07 to 2.38),2 but mortality was not increased.2,4
The analysis also found an ‘imbalance in the number of serious heart events seen with the medicine’ in one study of men with osteoporosis and another study of patients with osteoarthritis.2
This analysis was performed as part of a routine Periodic Safety Update Report assessment.4
These new findings were of particular concern in view of previous findings of increased incidence of venous thromboembolism in people taking strontium ranelate.1,2,4,6,7 Strontium ranelate is also contraindicated in people with current or previous VTE events or during periods of prolonged (temporary or permanent) immobilisation.1,8
The TGA-approved indications and contraindications for strontium ranelate have been revised as follows.
- treatment of severe (established) osteoporosis in postmenopausal women at high risk of fracture, to reduce the risk of fracture
- treatment of severe (established) osteoporosis in men at increased risk of fracture.1
- history of ischaemic heart disease, peripheral arterial disease or cerebrovascular disease
- systolic BP ≥ 160 mmHg or diastolic BP ≥ 90 mmHg.1
Prescribers are also advised that:
- treatment should only be initiated by a doctor with experience of treating osteoporosis
- the decision to prescribe strontium ranelate should be based on an assessment of the individual patient’s overall risks
- patients should be evaluated for cardiovascular risk before starting treatment and during treatment
- patients with significant risk factors for cardiovascular events should only be treated with strontium ranelate after careful consideration
- treatment should be stopped if:1
- the patient develops ischaemic heart disease, peripheral arterial disease or cerebrovascular disease
- systolic BP is ≥ 160 mmHg
- diastolic BP is ≥ 90 mmHg.
The revisions to the Australian product information reflect a series of recommendations and restrictions made by the EMA’s PRAC and Committee for Medicinal Products for Human Use, and the UK’s Medicines and Healthcare Products Regulatory Agency.2,3
The new restrictions were considered necessary by the EMA to keep the benefit–risk balance favourable for strontium ranelate use and have been sent to health professionals in the European Union.2 The recommendations have also been sent to the European Commission for a legally binding decision.2
A further in-depth review of the benefits and risks of strontium ranelate by the EMA is also planned.2
Whereas the pooling of data from trials has led to the identification by the EMA of an increase in the risk of cardiac problems, this was not previously identified in the individual key randomised controlled trials or extension studies of strontium ranelate.9–12 However, such studies are rarely designed and powered to show differences in rates of adverse events.
A recent randomised placebo-controlled trial in men did show an ‘imbalance of the incidence of coronary artery disorders (angina pectoris and coronary artery disease) between strontium and placebo treated men’ (8.7% vs 4.6%)’.13 However, the investigators reported a similar imbalance in the relevant medical histories between the strontium-treated and placebo-treated groups (21% vs 16%), in particular for myocardial ischaemia (10.3% vs 3.4%).13
Many of the people who need to be treated for severe established osteoporosis will be older people who may have cardiac risk factors. Consider individual patient risk factors and patient suitability when deciding whether to initiate or continue treatment with strontium ranelate.
For further information on strontium ranelate see the NPS RADAR review Strontium ranelate (Protos) for postmenopausal osteoporosis.
- Servier laboratories (Australia) Pty Ltd. Protos (strontium ranelate) product information 2012 Updated 30 May 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-02840-3
- European Medicines Agency. Recommendation to restrict the use of Protelos / Osseor (strontium ranelate). 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/04/news_detail_001774.jsp&mid=WC0b01ac058004d5c1 (accessed 3 June 2013).
- Medicines and Healthcare Products Regulatory Agency. Strontium ranelate (Protelos): risk of serious cardiac disorders—restricted indications, new contraindications, and warnings. 2013. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON266148 (accessed 3 June 2013).
- European Medicines Agency. PRAC recommends restriction in the use of Protelos/Osseor. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/human/000560/WC500142021.pdf (accessed 3 June 2013).
- European Medicines Agency. Meeting highlights from the Pharmacological Risk Asessment Committee (PRAC) 8-11 April 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/04/news_detail_001759.jsp&mid=WC0b01ac058004d5c1 (accessed 3 June 2013).
- O'Donnell S, Cranney A, Wells GA, et al. Strontium ranelate for preventing and treating postmenopausal osteoporosis. Cochrane Database Syst Rev 2006:CD005326. [PubMed]
- European Medicines Agency. Questions and answers on the review of Protelos and Osseor (strontium ranelate) Outcome of procedures under Article 20 of Regulation (EC) No 726/2004. 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2012/03/WC500124208.pdf (accessed 3 June 2013).
- Rossi S e. Australian Medicines Handbook, 2013. Adelaide.
- Reginster JY, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: Results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum 2008;58:1687–95. [PubMed]
- Reginster JY, Kaufman JM, Goemaere S, et al. Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis. Osteoporos Int 2012;23:1115–22. [PubMed]
- Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005;90:2816–22. [PubMed]
- Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459–68. [PubMed]
- Kaufman JM, Audran M, Bianchi G, et al. Efficacy and safety of strontium ranelate in the treatment of osteoporosis in men. J Clin Endocrinol Metab 2013;98:592–601. [PubMed]