Category Archives: Strontium

Strontium Ranelate Associated with Unfavorable Cardiac Risk


Nationwide registry-based analysis of cardiovascular risk factors and adverse outcomes in patients treated with strontium ranelate.

National registers showed that a large proportion of patients treated with strontium ranelate have conditions that may now contraindicate use. The risk of death in strontium ranelate-treated patients was significantly higher than that seen in users of other osteoporosis drugs even after adjusting for cardiovascular risk factor profile.
The European Medicines Agency (EMA) recently warned that strontium ranelate should be avoided in patients with ischaemic heart disease (IHD), peripheral vascular disease (PVD) or cerebrovascular disease (CVD), and in patients with uncontrolled hypertension. We investigated to what extent patients beginning strontium ranelate had cardiovascular conditions and determined the rates of MI, stroke and death.
Using the Danish National Prescription Database, we identified all 3,252 patients aged 50+ who began strontium ranelate in 2005-2007 and 35,606 users of other osteoporosis drugs as controls. Hospital contacts and causes of death were retrieved from national registers.
Patients starting strontium were older than patients treated with other osteoporosis drugs and more likely to suffer from IHD, PVD or CVD (combined prevalence 19.2 % in female users and 29.5 % in male users). The adjusted risk of MI was not significantly increased (women: HR 1.05 [95 % CI 0.79-1.41, p = 0.73]; men: 1.28 [0.74-2.20, p = 0.38]). For stroke, the adjusted HR was 1.23 (0.98-1.55, p = 0.07) in women and 1.64 (0.99-2.70, p = 0.05) in men. All-cause mortality was higher in strontium users (women: adjusted HR 1.20 [1.10-1.30, p < 0.001]; men: adjusted HR 1.22 [1.03-1.45, p < 0.05]).
Patients treated with strontium ranelate have an unfavourable cardiovascular risk profile compared with users of other osteoporosis drugs. However, only the risk of death differed significantly from the rates observed in users of other osteoporosis drugs adjusted for risk factor profile. A large proportion of patients currently treated with strontium ranelate have conditions that would now be considered contraindications according to EMA.

Abrahamsen B, Grove EL, Vestergaard P
Osteoporos Int Feb 2014
PMID: 24322475

Strontium Ranelate Not Associated with Heart Attacks or Other Cardiac Events


Ischaemic cardiac events and use of strontium ranelate in postmenopausal osteoporosis: a nested case-control study in the CPRD.

We explored the cardiac safety of the osteoporosis treatment strontium ranelate in the UK Clinical Practice Research Datalink. While known cardiovascular risk factors like obesity and smoking were associated with increased cardiac risk, use of strontium ranelate was not associated with any increase in myocardial infarction or cardiovascular death.
It has been suggested that strontium ranelate may increase risk for cardiac events in postmenopausal osteoporosis. We set out to explore the cardiac safety of strontium ranelate in the Clinical Practice Research Datalink (CPRD) and linked datasets.
We performed a nested case-control study. Primary outcomes were first definite myocardial infarction, hospitalisation with myocardial infarction, and cardiovascular death. Cases and matched controls were nested in a cohort of women treated for osteoporosis. The association with exposure to strontium ranelate was analysed by multivariate conditional logistic regression.
Of the 112,445 women with treated postmenopausal osteoporosis, 6,487 received strontium ranelate. Annual incidence rates for first definite myocardial infarction (1,352 cases), myocardial infarction with hospitalisation (1,465 cases), and cardiovascular death (3,619 cases) were 3.24, 6.13, and 14.66 per 1,000 patient-years, respectively. Obesity, smoking, and cardiovascular treatments were associated with significant increases in risk for cardiac events. Current or past use of strontium ranelate was not associated with increased risk for first definite myocardial infarction (odds ratio [OR] 1.05, 95 % confidence interval [CI] 0.68-1.61 and OR 1.12, 95 % CI 0.79-1.58, respectively), hospitalisation with myocardial infarction (OR 0.84, 95 % CI 0.54-1.30 and OR 1.17, 95 % CI 0.83-1.66), or cardiovascular death (OR 0.96, 95 % CI 0.76-1.21 and OR 1.16, 95 % CI 0.94-1.43) versus patients who had never used strontium ranelate.
Analysis in the CPRD did not find evidence for a higher risk for cardiac events associated with the use of strontium ranelate in postmenopausal osteoporosis.

Cooper C, Fox KM, Borer JS
Osteoporos Int Feb 2014
PMID: 24322476 | Free Full Text

European Medicines Agency Recommends Restricting the use of Strontium Ranelate

In January 2014, the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) recommended that Protelos/Osseor (Strontium Ranelate) should no longer be used to treat osteoporosis. Then, in February 2014,  it concluded its review of Protelos/Osseor and recommended further restricting the use of the medicine to patients who cannot be treated with other medicines approved for osteoporosis.

The following is from their press release:

In addition these patients should continue to be evaluated regularly by their doctor and treatment should be stopped if patients develop heart or circulatory problems, such as uncontrolled high blood pressure or angina. As recommended in a previous review, patients who have a history of certain heart or circulatory problems, such as stroke and heart attack, must not use the medicine.

These final recommendations from the Agency’s Committee for Medicinal Products for Human Use (CHMP) come after initial advice from the Pharmacovigilance Risk Assessment Committee (PRAC) to suspend the medicine due to its cardiovascular risk.

‘The CHMP agreed with the PRAC’s overall assessment of the risks of Protelos/Osseor. Both committees worked in close collaboration and the PRAC’s recommendation was instrumental for us to fully assess the benefit-risk profile of the medicine’, said Tomas Salmonson, chair of the CHMP. ‘However, the CHMP considered that, for patients who have no alternative treatment, regular screening and monitoring to exclude cardiovascular disease will sufficiently reduce the risk identified by the PRAC so that these patients can continue to have access to the medicine.’

In arriving at its conclusions, the CHMP noted that study data showed a beneficial effect in preventing fractures, including in patients at high risk of fracture. In addition, available data do not show evidence of an increased cardiovascular risk with Protelos/Osseor in patients who did not have a history of heart or circulatory problems.

The CHMP considered that the cardiovascular risk in patients taking Protelos/Osseor can be managed by restricting its use to patients with no history of heart and circulatory problems and limiting its use to those who cannot take other medicines approved for the treatment of osteoporosis. In addition, patients treated with Protelos/Osseor should be screened and monitored regularly, every 6 to 12 months.

Additional risk minimisation measures include providing educational material to prescribers to ensure that only the appropriate patients are treated with the medicine. Importantly, the company is required to conduct further research to demonstrate the effectiveness of the new measures. The Committee concluded that given the benefits seen in preventing fractures in patients at high risk, Protelos/Osseor should remain an option for patients with no history of cardiovascular disease who cannot take other medicines.

In deciding on how Protelos/Osseor should be used, the CHMP took into account thePRAC’s analysis of its benefits and risks as well as advice from osteoporosis experts that there is a group of patients who could benefit from the medicine.

‘The PRAC has worked closely with the CHMP throughout the procedure and while we acknowledge that the recommendations of the two committees differed, our understanding of the medicine’s benefit-risk profile is closely aligned and we share a common view of the importance of effective monitoring of cardiovascular risk’, said June Raine, chair of the PRAC. ‘The PRAC will continue to monitor the safety of Protelos /Osseor and the effectiveness of risk minimisation in long term use.’

The CHMP’s recommendation will now be sent to the European Commission, which will then issue a final decision.

 Information to patients

  • Protelos/Osseor will only be prescribed for preventing fractures in post-menopausal women and men with severe osteoporosis who have a high risk of fracture and cannot be treated with other medicines approved for osteoporosis.
  • Before starting treatment, your doctor will assess your risk of heart disease and high blood pressure and continue to check your risk at regular intervals during treatment.
  • You should not take Protelos/Osseor if you have or have had heart or circulatory problems such as stroke, heart attack, or obstruction of the blood flow in the arteries.
  • Your treatment with Protelos/Osseor will be stopped if you develop heart or circulatory problems during treatment.
  • If you have any questions, speak to your doctor or pharmacist.

Information to healthcare professionals

Healthcare professionals in the EU Member States will receive a letter informing them of the updated recommendations on the use of Protelos/Osseor. The letter will advise them of the following:

  • Protelos/Osseor should only be used to treat severe osteoporosis in postmenopausal women and men at high risk of fracture, for whom treatment with other medicinal products approved for the treatment of osteoporosis is not possible due to, for example, contraindications or intolerance;
  • Protelos/Osseor must not be used in patients with established, current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease, or those with uncontrolled hypertension;
  • Doctors should continue to base their decision to prescribe Protelos/Osseor on an assessment of the individual patient’s risks. The patient’s risk of developing cardiovascular disease should be evaluated before starting treatment and on a regular basis thereafter, generally every 6 to 12 months;
  • Protelos/Osseor should be stopped if the patient develops ischaemic heart disease, peripheral arterial disease or cerebrovascular disease, or if hypertension is uncontrolled;
  • Doctors should review their patients currently on Protelos/Osseor as necessary.

This final EMA recommendation on the use of Protelos/Osseor was based on an analysis of pooled data from randomised studies in around 7,500 post-menopausal women with osteoporosis. The results showed an increased risk of myocardial infarction with Protelos/Osseor as compared with placebo (1.7% versus 1.1 %), with a relative risk of 1.6 (95% CI, 1.07 to 2.38), and an increased risk of venous thrombotic and embolic events — 1.9% versus 1.3 % with a relative risk of 1.5 (95% CI, 1.04 to 2.19).

Available data do not show evidence of an increased cardiovascular risk in patients without established, current or past history of ischaemic heart disease, peripheral arterial disease or cerebrovascular disease, or in those without uncontrolled hypertension.

Regarding the benefits, the efficacy data showed an effect in preventing fractures, including in patients at high risk of fracture.

More about the medicine

Protelos/Osseor (strontium ranelate) is authorised in the EU to treat severe osteoporosis (a disease that makes bones fragile) in women who have been through the menopause and who are at high risk of fracture (broken bones) to reduce the risk of fractures of the spine and the hip. It is also used to treat severe osteoporosis in men who are at high risk of fracture.

The current recommendations add to EMA recommendations made in April 2013 not to use Protelos/Osseor in patients with known circulatory problems.

More about the procedure

The review of Protelos/Osseor was initiated in May 2013 at the request of European Commission under Article 20 of Regulation (EC) No 726/2004.

The first stage of this review was conducted by the Pharmacovigilance Risk Assessment Committee (PRAC), the committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. The PRAC’s recommendations were then sent to the Committee for Medicinal Products for Human Use (CHMP) responsible for all questions concerning medicines for human use, which adopted the Agency’s final opinion.

Further information on the PRAC recommendation and the background to this review can be found on Agency’s website. The CHMP opinion will now be forwarded to the European Commission, which will issue a final decision in due course.

Strontium Increases Bone Density Measurement by Increased Attenuation of X-rays


The correction of BMD measurements for bone strontium content.

Strontium ranelate (SR) is a new oral treatment for osteoporosis associated with large increases in bone mineral density (BMD) compared with alternative therapies such as bisphosphonates. Much of the BMD increase during SR treatment is a physical effect caused by the increased attenuation of X-rays due to the accumulation of strontium in bone tissue. The aim of this study was to assess the contribution made by bone strontium content (BSC) to the overall BMD increase by evaluating the percentage F of the BMD change explained by the physical presence of strontium in bone. A value of F less than 100% would provide evidence of the anabolic effect of SR as an additional factor contributing to the overall BMD increase. Studies of mixtures of strontium hydroxyapatite (SrHA) and calcium hydroxyapatite (CaHA) scanned on a variety of dual-energy X-ray absorptiometry (DXA) systems show that a 1% molar ratio of SrHA/(CaHA+SrHA) causes a 10% overestimation of BMD. The correction of spine BMD measurements for the physical effects of strontium depends on knowledge of 2 further factors: (1) bone biopsy measurements of iliac crest BSC and (2) the ratio R of BSC at the DXA site to BSC at the iliac crest measured in animal studies. We used clinical trial data and values of R(spine) measured in studies of monkeys and beagle dogs to determine values of F(spine) for 1, 2, and 3 yr treatment with SR. Based on the average value of R(spine) approximately 0.7 for male and female monkeys, we found values for F(spine) approximately 75-80% for 1, 2, and 3 yr of treatment. Using the value of R(spine) approximately 1.0 from the beagle study gave values of F(spine) approximately 100%. Although values of F(spine) as low as 40% are possible, we conclude that the most likely figure is 75% or greater. However, it is apparent that there are large uncertainties in the correction of BMD results for the effect of bone strontium and that the most important of these is the inference of BSC values at DXA scan sites from measurements of iliac crest bone biopsy specimens.

Blake GM, Fogelman I
J Clin Densitom
PMID: 17543560

Review: Strontium Increases Bone Formation and Reduces Resorption, but may Increase Risk of Venous Thromboembolism


Strontium ranelate: a review of its use in the treatment of postmenopausal osteoporosis.

This is a review of the pharmacology of strontium ranelate (Protelos, Protos, Protaxos, Bivalos, Osseor), and its efficacy and tolerability in the treatment of patients with postmenopausal osteoporosis. Strontium ranelate is a divalent strontium salt of ranelic acid that is capable of increasing bone formation and reducing bone resorption, thereby uncoupling and rebalancing bone turnover in favour of bone formation. The drug is effective in reducing the risk of fractures, including both vertebral and nonvertebral fractures, in patients with postmenopausal osteoporosis, according to data from two large, double-blind, placebo-controlled, multicentre trials of 5 years’ duration, and reduced the risk of hip fracture in high-risk patients in a post hoc analysis of one trial. Moreover, data from patients who continued to receive the drug during the 3-year extension phases of these trials indicate that strontium ranelate continues to provide protection against new vertebral fractures and nonvertebral fractures for up to 8 years of therapy. It also improves bone mineral density at numerous sites and both increases markers of bone formation and decreases markers of bone resorption. Strontium ranelate is administered orally as a suspension and is generally well tolerated. The nature of adverse events was generally similar regardless of treatment duration in clinical trials, with the most commonly reported being nausea and diarrhoea over 5 years of treatment, and memory loss and diarrhoea during longer-term treatment. Although an increased risk of venous thromboembolism was associated with strontium ranelate relative to placebo over 5 years of treatment in a pooled analysis of clinical trials, postmarketing data have not confirmed this finding. Overall, the clinical data available suggest that strontium ranelate is an effective and generally well tolerated option for the first-line treatment of postmenopausal osteoporosis.

Deeks ED, Dhillon S
Drugs Apr 2010
PMID: 20394457

Strontium Safe and Reduces Fracture Risk Over 10 Years in Postmenopausal Women


Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis.

In an open-label extension study, BMD increased continuously with strontium ranelate over 10 years in osteoporotic women (P < 0.01). Vertebral and nonvertebral fracture incidence was lower between 5 and 10 years than in a matched placebo group over 5 years (P < 0.05). Strontium ranelate’s antifracture efficacy appears to be maintained long term.
Strontium ranelate has proven efficacy against vertebral and nonvertebral fractures, including hip, over 5 years in postmenopausal osteoporosis. We explored long-term efficacy and safety of strontium ranelate over 10 years.
Postmenopausal osteoporotic women participating in the double-blind, placebo-controlled phase 3 studies SOTI and TROPOS to 5 years were invited to enter a 5-year open-label extension, during which they received strontium ranelate 2 g/day (n = 237, 10-year population). Bone mineral density (BMD) and fracture incidence were recorded, and FRAX® scores were calculated. The effect of strontium ranelate on fracture incidence was evaluated by comparison with a FRAX®-matched placebo group identified in the TROPOS placebo arm.
The patients in the 10-year population had baseline characteristics comparable to those of the total SOTI/TROPOS population. Over 10 years, lumbar BMD increased continuously and significantly (P < 0.01 versus previous year) with 34.5 ± 20.2% relative change from baseline to 10 years. The incidence of vertebral and nonvertebral fracture with strontium ranelate in the 10-year population in years 6 to 10 was comparable to the incidence between years 0 and 5, but was significantly lower than the incidence observed in the FRAX®-matched placebo group over 5 years (P < 0.05); relative risk reductions for vertebral and nonvertebral fractures were 35% and 38%, respectively. Strontium ranelate was safe and well tolerated over 10 years.
Long-term treatment with strontium ranelate is associated with sustained increases in BMD over 10 years, with a good safety profile. Our results also support the maintenance of antifracture efficacy over 10 years with strontium ranelate.

Reginster JY, Kaufman JM, Goemaere S, Devogelaer JP…
Osteoporos Int Mar 2012
PMID: 22124575 | Free Full Text

Strontium Prevents Inhibitory Effect of AGEs on Osteoblasts


Strontium ranelate prevents the deleterious action of advanced glycation endproducts on osteoblastic cells via calcium channel activation.

Accumulation of advanced glycation endproducts (AGEs) in bone tissue occurs in ageing and in Diabetes mellitus, and is partly responsible for the increased risk of low-stress bone fractures observed in these conditions. In this study we evaluated whether the anti-osteoporotic agent strontium ranelate can prevent the deleterious effects of AGEs on bone cells, and possible mechanisms of action involved. Using mouse MC3T3E1 osteoblastic cells in culture we evaluated the effects of 0.1mM strontium ranelate and/or 100 μg/ml AGEs-modified bovine serum albumin (AGEs-BSA) on cell proliferation, osteogenic differentiation and pro-inflammatory cytokine production. We found that AGEs-BSA alone decreased osteoblastic proliferation and differentiation (P<0.01) while increasing IL-1β and TNFα production (P<0.01). On its own, strontium ranelate induced opposite effects: an increase in osteoblast proliferation and differentiation (P<0.01) and a decrease in cytokine secretion (P<0.01). Additionally, strontium ranelate prevented the inhibitory and pro-inflammatory actions of AGEs-BSA on osteoblastic cells (P<0.01). These effects of strontium ranelate were blocked by co-incubation with either the MAPK inhibitor PD98059, or the calcium channel blocker nifedipine. We also evaluated by Western blotting the activation status of ERK (a MAPK) and b-catenin. Activation of both signaling pathways was decreased by AGEs treatment, and this inhibitory effect was prevented if AGEs were co-incubated with strontium ranelate (P<0.01). On its own, strontium ranelate increased both pERK and activated b-catenin levels. In conclusion, this study demonstrates that strontium ranelate can prevent the deleterious in vitro actions of AGEs on osteoblastic cells in culture by mechanisms that involve calcium channel, MAPK and b-catenin activation.

Fernández JM, Molinuevo MS, Sedlinsky C, Schurman L…
Eur. J. Pharmacol. Apr 2013
PMID: 23499695

Review: Nutrients for Bone Health


Essential Nutrients for Bone Health and a Review of their Availability in the Average North American Diet.

Osteoporosis and low bone mineral density affect millions of Americans. The majority of adults in North America have insufficient intake of vitamin D and calcium along with inadequate exercise. Physicians are aware that vitamin D, calcium and exercise are essential for maintenance of bone health. Physicians are less likely to be aware that dietary insufficiencies of magnesium, silicon, Vitamin K, and boron are also widely prevalent, and each of these essential nutrients is an important contributor to bone health. In addition, specific nutritional factors may improve calcium metabolism and bone formation. It is the authors’ opinion that nutritional supplements should attempt to provide ample, but not excessive, amounts of factors that are frequently insufficient in the typical American diet. In contrast to dietary insufficiencies, several nutrients that support bone health are readily available in the average American diet. These include zinc, manganese, and copper which may have adverse effects at higher levels of intake. Some multivitamins and bone support products provide additional quantities of nutrients that may be unnecessary or potentially harmful. The purpose of this paper is to identify specific nutritional components of bone health, the effects on bone, the level of availability in the average American diet, and the implications of supplementation for each nutritional component. A summary of recommended dietary supplementation is included.

Price CT, Langford JR, Liporace FA
Open Orthop J 2012
PMID: 22523525 | Free Full Text

Oral intake of 2 gm/day of strontium ranelate have improved bone strength and reduced fracture rates in women with osteoporosis, but there are reports of increased risks of venous blood clots and memory loss [82, 87].

Review: Nutrients Involved in Maintaining Healthy Bone


Update on nutrients involved in maintaining healthy bone.

Osteoporosis is a leading cause of morbidity and mortality in the elderly and influences quality of life, as well as life expectancy. Currently, there is a growing interest among the medical scientists in search of specific nutrients and/or bioactive compounds of natural origin for the prevention of disease and maintenance of bone health. Although calcium and vitamin D have been the primary focus of nutritional prevention of osteoporosis, a recent research has clarified the importance of several additional nutrients and food constituents. Based on this review of the literature, supplementation with vitamins B, C, K, and silicon could be recommended for proper maintenance of bone health, although further clinical studies are needed. The results of studies on long-chain polyunsaturated fatty acids, potassium, magnesium, copper, selenium, and strontium are not conclusive, although studies in vitro and in animal models are interesting and promising.

Rondanelli M, Opizzi A, Perna S, Faliva MA
Endocrinol Nutr Apr 2013
PMID: 23273614