Osteoporosis prevention, diagnosis and management in postmenopausal women and men over 50 years of age

Recommendations

Strontium ranelate

Evidence statement

Treatment of osteoporosis

A Cochrane systematic review (SR)1 reported on four RCTs (7093 participants) that compared the effectiveness of strontium ranelate daily to placebo for treating osteoporosis. Participants were postmenopausal women with prevalent vertebral fractures and/or a lumbar spine BMD T-score of ≤–2.5. All RCTs investigated a daily dose of strontium ranelate 0.5–2.0 g concurrently with calcium and vitamin D supplementation for 2–5 years. Women with osteoporosis who were treated with strontium ranelate 2 g per day showed a 37% reduction in vertebral fractures (two RCTs, n = 5082, relative risk [RR]: 0.63, 95% confidence interval [CI]: 0.56–0.71, number needed to treat [NNT]: 13) and a 14% reduction in non-vertebral fractures (two RCTs, n = 6572, RR: 0.86, 95% CI: 0.75–0.98, NNT: 10) over three years. Post hoc analyses suggested it was effective for hip fracture prevention in an older group with low hip BMD.

Safety

The same Cochrane SR1 reported safety data from four RCTs. There were no significant differences compared to placebo for rate of adverse events, rate of withdrawal related to an adverse event, or rate of serious adverse events. Participants treated with strontium ranelate showed an increase in diarrhoea (RR: 1.38, 95% CI: 1.02– 1.87). Data from two RCTs (n = 6669) showed an increased risk of vascular system disorders including venous thromboembolism (2.2% versus 1.5%, odds ratio [OR]: 1.5, 95% CI: 1.1–2.1) and pulmonary embolism (0.8% versus 0.5%, OR: 1.7, 95% CI: 1.0–3.1). Strontium ranelate was associated with an increased risk of headache (3.9% versus 2.9%), seizures (0.3% versus 0.1%), memory loss (2.4% versus 1.9%) and disturbance in consciousness (2.5% versus 2.0%).

Grade: A

Recommendation 23
Strontium ranelate at a dose of 2 g per day is an effective second-line option for reducing the risk of further osteoporotic fractures in postmenopausal women with prevalent fractures. Strontium ranelate should not be used in patients with previous or clinically active cardiovascular disease or uncontrolled hypertension and should only be used when other medications for the treatment of osteoporosis are unsuitable.

There is currently no evidence available for the effect of strontium ranelate in reducing fracture risk in men and early postmenopausal women. However, there is evidence to support the effectiveness of strontium ranelate 2 g per day for the prevention of bone mineral density (BMD) loss in early postmenopausal women, both Caucasian and Asian,1,2 and men.3 There is strong evidence to support the effectiveness of strontium ranelate 2 g per day for reducing the risk of further osteoporotic fractures in postmenopausal women with prevalent fractures.1 Based on indirect comparisons, strontium ranelate appears to have similar efficacy to other therapies for spinal fractures apart from denosumab, where it is inferior.4 The effect of strontium may be partially blunted by prior bisphosphonates.5 Strontium may also be beneficial for fracture healing.6 Research suggests that strontium ranelate has a relatively greater effect on bone resorption than bone formation.7

Strontium ranelate was listed on the Pharmaceutical Benefits Scheme until 31 July 2016 for the treatment of women and men following a minimal trauma fracture and for the prevention of the first fracture in women 70 years of age or older with a T-score of ≤–3.0. Strontium ranelate is now available only on private prescription.

Strontium ranelate has been associated with an increased risk of venous thromboembolism in some randomised controlled trials (RCTs).1 Recently, the European Medicines Agency (EMA) reviewed the risk benefit ratio based on the findings of an increase in the risk of cardiovascular (CV) disease in those with pre-existing CV disease and uncontrolled hypertension in the clinical trial program. While this effect has not been observed in observational studies,8,9 the EMA recommended suspension of strontium ranelate until more data become available.10 In Australia, a black box warning was added to the product information for strontium ranelate in 2014 after a review by the Therapeutic Goods Administration. Strontium ranelate should only be used when other options cannot be tolerated or are contraindicated, and where its use may be beneficial.11

  • Strontium ranelate is not recommended for patients with severe renal impairment.1
  • Do not use strontium ranelate in patients with current (or a history of) ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, venous thromboembolism or in patients with systolic blood pressure (BP) ≥160 mmHg or diastolic BP ≥90 mmHg.
  • Calcium reduces absorption of strontium – administration of each should be separated by at least two hours.12
  • Strontium ranelate may form poorly soluble chelates with tetracyclines, reducing their absorption and antiinfective activity, so administration of these medications should be separated by at least two hours.12
  • The effect of strontium retention in bone and increased X-ray absorption of strontium compared to calcium leads to an amplification of BMD measurement by dual energy X-ray absorptiometry (DXA) that should be considered when using DXA to monitor treatment response.13 However, the greater increase in measured BMD is associated with greater efficacy for fracture-risk reduction, possibly because it reflects both compliance and the greater change in BMD seen in patients taking strontium ranelate.
  1. O’Donnell S, Cranney A, Wells G, et al. Strontium ranelate for preventing and treating postmenopausal osteoporosis. Cochrane Database Syst Rev 2006;4:CD005326. doi: 10.1002/14651858.CD005326.pub3.
  2. Liu JM, Wai-Chee Kung A, et al. Efficacy and safety of 2 g/day of strontium ranelate in Asian women with postmenopausal osteoporosis. Bone 2009;45(3):460–65.
  3. 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(2):592–601.
  4. Freemantle N, Cooper C, Diez-Perez A, et al. Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: A meta-analysis. Osteoporos Int 2013;24(1):209–17.
  5. Middleton ET, Steel SA, Aye M, Doherty SM. The effect of prior bisphosphonate therapy on the subsequent therapeutic effects of strontium ranelate over 2 years. Osteoporos Int 2012;23(1):295–303.
  6. Goldhahn J, Féron JM, Kanis J, et al. Implications for fracture healing of current and new osteoporosis treatments: An ESCEO consensus paper. Calcif Tissue Int 2012;90(5):343–53.
  7. 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(5):459–68.
  8. Cooper C, Fox KM, Borer JS. Ischaemic cardiac events and use of strontium ranelate in postmenopausal osteoporosis: A nested case-control study in the CPRD. Osteoporos Int 2014; 25(2):737–45.
  9. Abrahamsen B, Grove EL, Vestergaard P. Nationwide registry-based analysis of cardiovascular risk factors and adverse outcomes in patients treated with strontium ranelate. Osteoporos Int 2014; 25(2):757–62.
  10. European Medicines Agency. PRAC recommends suspending use of Protelos/Osseor (strontium ranelate). London, UK: EMA, 2014 [Accessed 17 February 2017].
  11. Carvalho NN, Voss LA, Almeida MO, et al. Atypical femoral fractures during prolonged use of bisphosphonates: Short-term responses to strontium ranelate and teriparatide. J Clin Endocrinol Metab 2011;96(9):2675–80. [Accessed 17 February 2017].
  12. Rossi S, editor. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2006. [Accessed 17 February 2017].
  13. Ortolani S, Vai S. Strontium ranelate: An increased bone quality leading to vertebral antifracture efficacy at all stages. Bone 2006;38(2 Supp 1):19–22. [Accessed 17 February 2017].

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