Strontium ranelate for osteoporosis

• osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption
• strontium was originally identified in the lead mines near Strontium in Scotland in the late 1700s - strontium ranelate increases bone formation and decreases bone resorption
  • strontium ranelate is composed of two atoms of stable strontium combined with a carrier molecule, ranelic acid. No mechanism of action has been clearly established for the drug in osteoporosis. However, in the short term, strontium is absorbed on to the surface of hydroxyapatite crystals and, in the longer term, there is limited replacement of calcium by strontium in the bone (1)
• an evaluation of the efficacy of strontium ranelate in preventing vertebral fractures was examined in a phase 3 trial (2)
  • randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years
    • calcium and vitamin D supplements were given to both groups before and during the study
    • vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months
  • the study revealed that:
    • new vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73)
    • strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons)
    • there were no significant differences between the groups in the incidence of serious adverse events
  • the study authors concluded that the teatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures
• a systematic review concluded that (3):
  • there is evidence to support the efficacy of strontium ranelate for the reduction of vertebral fractures (and to a lesser extent non-vertebral fractures) in postmenopausal osteoporotic women and an increase in BMD (all sites) in postmenopausal women with and without osteoporosis
  • diarrhoea may occur however, adverse events leading to study withdrawal were not significantly increased in the strontium ranelate group
  • potential risks revealed in the systematic analysis were related to vascular and neurological systems
    • the risk of vascular system disorders including venous thromboembolism (two trials, n = 6669, 2.2% versus 1.5%, OR 1.5, 95% CI 1.1 to 2.1) and pulmonary embolism (two trials, n = 6669, 0.8% versus 0.4%, OR 1.7, 95% CI 1.0 to 3.1) as well as nervous system disorders such as headaches (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%) was slightly increased with taking 2 g of strontium ranelate daily over a 3 to 4 year period

A review of available safety data for strontium ranelate (Protelos) has raised concern about its cardiovascular safety beyond the already recognised risk of venous thromboembolism. An analysis of randomised controlled trial data has identified an increased risk of serious cardiac disorders, including myocardial infarction (relative risk compared with placebo was 1.6 [95% CI 1.07-2.38]) (4)

• Advice for healthcare professionals (4):
  • Use of strontium ranelate is now restricted to treatment of severe osteoporosis
    • in postmenopausal women at high risk of fracture
    • in men at increased risk of fracture
  • Treatment should only be initiated by a physician with experience in the treatment of osteoporosis, and the decision to prescribe strontium ranelate should be based on an assessment of the individual patient's overall risks
  • Strontium ranelate should not be used in patients with: ischaemic heart disease, peripheral arterial disease; cerebrovascular disease; a history of these conditions; or in patients with uncontrolled hypertension
  • Prescribers are advised to assess the patient's risk of developing cardiovascular disease before starting treatment and thereafter at regular intervals
  • Patients with significant risk factors for cardiovascular events (eg, hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with strontium ranelate after careful consideration
  • Treatment should be stopped if the patient develops ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, or if hypertension is uncontrolled
  • Healthcare professionals should review patients at a routine appointment and consider whether or not to continue treatment

Notes (1):

• side effects with strontium ranelate
  • in published clinical trials, strontium ranelate did not differ from placebo in the overall incidence of unwanted effects or treatment withdrawal due to unwanted effects
    • rate of reported gastrointestinal disorders was higher with strontium ranelate than with placebo (especially nausea (6.6% vs. 4.3%) and diarrhoea (6.5% vs. 4.6%)- these effects appear to wane with continued treatment, they accounted for most of the treatment discontinuations in clinical trials with strontium ranelate
    • headaches, dermatitis and eczema were also commonly reported
    • increased incidence of thrombosis - treatment with strontium ranelate was associated with increased incidence of thrombosis (3.3% vs. 2.2% with placebo)
    • there are rare reports of the hypersensitivity syndrome known as DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome occurring associated with use of strontium ranelate (5)
• affects laboratory measurement of calcium
  • if requesting routine assays of blood or urinary calcium concentrations then should detail the fact that a patient is taking strontium ranelate. This is because strontium interferes with colorimetric methods, resulting in false high readings and the potential for unnecessary further investigation
• concomitant administration of other foods and medicines
  • food, milk and calcium-containing products may reduce the bioavailability of strontium by 60-70%
  • antacids containing aluminium or magnesium - these may also reduce absorption of strontium by 20-25% if taken within 2 hours
  • tetracycline or quinolone
    • if treatment with either of these medications as oral preparations then stop treatment with strontium ranelate since strontium can form complexes with these antibacterials and thereby reduce their absorption
• phenyletonuria patients
  • strontium ranelate granules contain aspartame, a source of phenylalanine, which may be harmful for patients with phenylketonuria

Reference:

• (1) Drug and Therapeutics Bulletin 2006;44(4):29-32.
• (2) Meunier PJ et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Eng J Med 2004;350: 459-68.
• (3) O'Donnel S et al. Strontium ranelate for preventing and treating postmenopausal osteoporosis. Cochrane Database Syst Rev. 2006 Jul 19;3:CD005326.
• (4) MHRA (April 2013). Strontium ranelate (Protelos): risk of serious cardiac disorders - restricted indications, new contraindications, and warnings
• (5) Servier Laboratories (November 2007). Direct Healthcare Professional Communication on cases of hypersensitivity syndromes in post menopausal women treated with strontium ranelate.