Strontium ranelate

Strontium ranelate

Systematic (IUPAC) name
distrontium 5-[bis(2-oxido-2-oxoethyl)amino]-4-cyano- 3-(2-oxido-2-oxoethyl)thiophene-2-carboxylate
Clinical data
Pregnancy cat.	Only intended for use in postmenopausal women, no data on exposed pregnancies. If strontium ranelate is used inadvertently during pregnancy, treatment must be stopped.
Legal status	POM (UK)
Routes	Oral
Pharmacokinetic data
Bioavailability	25% (range 19–27%)
Protein binding	25% for plasma protein and high affinity for bone tissue
Metabolism	As a divalent cation, strontium is not metabolised. Does not inhibit cytochrome P450 enzymes
Half-life	60 hours
Excretion	Renal and gastrointestinal. Plasma clearance is about 12 ml/min (CV 22%) and renal clearance about 7 ml/min (CV 28%)
Identifiers
CAS number	135459-90-4 N
ATC code	M05BX03
PubChem	CID 6918182
ChemSpider	5293393 Y
Chemical data
Formula	C12H6N2O8SSr2
Mol. mass	513.491 g/mol
SMILES [Sr+2].[Sr+2].O=C([O-])CN(c1sc(c(c1C#N)CC([O-])=O)C([O-])=O)CC([O-])=O
InChI InChI=1S/C12H10N2O8S.2Sr/c13-2-6-5(1-7(15)16)10(12(21)22)23-11(6)14(3-8(17)18)4-9(19)20;;/h1,3-4H2,(H,15,16)(H,17,18)(H,19,20)(H,21,22);;/q;2*+2/p-4 Y Key:XXUZFRDUEGQHOV-UHFFFAOYSA-J Y
N (what is this?)  (verify)

Strontium ranelate, a strontium(II) salt of ranelic acid, is a medication for osteoporosis marketed as Protelos or Protos by Servier. On 13 May 2013, Servier released a Direct Healthcare Professional Communication which stated that important new restrictions for the use of Protelos are now in place, as randomised trials have shown an increased risk of myocardial infarction. Servier states that the use of Protelos is now restricted to treatment of severe osteoporosis in postmenopausal women at high risk for fracture.^[1] Studies indicate it can also slow the course of osteoarthritis of the knee. The drug is unusual in that it both increases deposition of new bone by osteoblasts and reduces the resorption of bone by osteoclasts. It is therefore promoted as a "dual action bone agent" (DABA).

Also European Pharmacovigilance Risk Assessment Committee (PRAC) recommends restriction in the use of strontium ranelate, based on a routine benefit-risk assessment of the medicine, which included data showing an increased risk of heart problems, including heart attacks.^[2] On January 10, 2014 PRAC has recommended that Protelos/Osseor should no longer be used to treat osteoporosis (PRAC recommends suspending use of Protelos/Osseor ).^[3]

Mode of action

Strontium, which has the atomic symbol Sr and the atomic number 38, belongs to the group II in the periodic table of the elements, just beneath calcium. Because its nucleus is very nearly the same size as that of calcium, the body easily takes up strontium and incorporates it into bones and tooth enamel in the place of calcium. Surprisingly, this is not a health problem and in fact, it can provide a health benefit. For example, in clinical trials, the drug strontium ranelate was found to aid bone growth, increase bone density, and lessen vertebral, peripheral, and hip fractures in women.

Strontium ranelate is an antiosteoporotic agent which both increases bone formation and reduces bone resorption, resulting in a rebalance of bone turnover in favor of bone formation. This is similar to the effects of choline stabilized orthosilicic acid.^[4][5]

Strontium ranelate stimulates the calcium sensing receptors and leads to the differentiation of pre-osteoblast to osteoblast which increases the bone formation. Strontium ranelate also stimulates osteoblasts to secrete osteoprotegerin in inhibiting osteoclasts formed from pre-osteoclasts in relation to the RANKL system, which leads to the decrease of bone resorption.

Indication

Strontium ranelate is registered as a prescription drug in more than 70 countries for the treatment of post-menopausal osteoporosis to reduce the risk of vertebral and hip fractures. In the United States, Strontium Ranelate is not approved by the FDA. In the United Kingdom, Strontium Ranelate is prescribed under the National Health Service as a medicine for the treatment of post menopausal osteoporosis.^[6]

2 major phase III clinical studies, SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment of Peripheral Osteoporosis), were started in 2000 to investigate the efficacy of strontium ranelate in reducing vertebral fractures and peripheral fractures, including hip fractures. In the 3 years results, reported in 2004, strontium ranelate showed significant reduction in vertebral fractures with 41% and hip fractures with 36% compared with patients treated with placebo.^[7]

The efficacy was sustained in 5 years data. The 5 years data confirmed that strontium ranelate can reduce the vertebral fractures significantly no matter the risk factors of the osteoporotic women have. These include their age (<70, 70-80 and >80), bone mineral density (osteoporotic and osteopenia), prevalent fractures (0 prevalent fracture, 1-2 prevalent fractures and >2 prevalent fractures), symptomatic fractures, body mass index and smoking.

Strontium ranelate shows antifracture efficacy in very old elderly and osteopenic patients. It is generally well tolerated.

Knee Osteoarthritis Study

A large international study, the "Strontium Ranelate Efficacy in Knee Osteoarthritis trial," or SEKOIA, reported in 2012 that the drug significantly slowed the course of knee OA compared to placebo in a double-blind ransomised controlled trial. The drug reduced knee OA pain symptoms, improved function, and reduced x-ray detectable cartilage loss, as shown by reductions in joint space narrowing over three years.^[8]

Contraindications

Strontium ranelate is contraindicated in hypersensitivity to the active substance or to any of the excipients. It is not recommended in patients with severe renal disease, i.e. creatinine clearance below 30 mL/min due to lack of data. Precaution is advised in patients at increased risk of venous thromboembolism (VTE), including patients with a history of VTE. Precaution is advised in patients with phenylketonuria, as strontium ranelate contains phenylalanine. Precaution as it interferes with colorimetric measurements of calcium in blood and urine.

Interactions

According to the manufacturer, strontium ranelate should be taken 2 hours apart from food, milk and derivative products, and medicinal products containing calcium. Should be taken 2 hours before antacids. Treatment should be suspended while taking oral tetracycline and quinolone antibiotics, as these chelate the strontium ion.

Side effects

The most common side effects include nausea, diarrhea, headache and eczema, but with only 2–4% increase compared with placebo group. However, most of the side effects resolved within 3 months. Occasional severe allergic reactions have been reported including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome)^[9]

References

External links

• PRAC recommends suspending use of Protelos/Osseor
• Protelos official site
• "First Head-To-Head Study Shows That Protelos(R) (Strontium Ranelate) Builds Better Bone Than Bisphosphonate". Medical News Today. 8 Dec 2008.