Strontium ranelate

Identification

Name
Strontium ranelate
Accession Number
DB09267
Type
Small Molecule
Groups
Approved, Withdrawn
Description

Strontium ranelate, a strontium (II) salt of ranelic acid, is a medication for osteoporosis. 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) indicated for use in treatment of severe osteoporosis.

Furthermore, various clinical studies demonstrate the ability of strontium ranelate to improve and strengthen intrinsic bone tissue quality and microarchitecture in osteoporosis by way of a number of cellular and microstructural changes by which anti-fracture efficacy is enhanced.

Available for prescription use for a time in some parts of the world as Protelos (strontium ranelate) 2 g granules for oral suspension by Servier, it was ultimately discontinued in 2016-2017 owing to an increased adverse cardiac effects profile along with increased risk of venous thromboembolism (VTE) and various life threatening allergic reactions.

Structure
Thumb
Synonyms
Not Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OsseorGranule2 gOralLes Laboratoires Servier2004-09-21Not applicableEu
OsseorGranule2 gOralLes Laboratoires Servier2004-09-21Not applicableEu
OsseorGranule2 gOralLes Laboratoires Servier2004-09-21Not applicableEu
OsseorGranule2 gOralLes Laboratoires Servier2004-09-21Not applicableEu
OsseorGranule2 gOralLes Laboratoires Servier2004-09-21Not applicableEu
OsseorGranule2 gOralLes Laboratoires Servier2004-09-21Not applicableEu
ProtelosGranule2 gOralLes Laboratoires Servier2004-09-21Not applicableEu
ProtelosGranule2 gOralLes Laboratoires Servier2004-09-21Not applicableEu
ProtelosGranule2 gOralLes Laboratoires Servier2004-09-21Not applicableEu
ProtelosGranule2 gOralLes Laboratoires Servier2004-09-21Not applicableEu
Categories
UNII
04NQ160FRU
CAS number
135459-87-9
Weight
Average: 513.49
Monoisotopic: 513.795712
Chemical Formula
C12H6N2O8SSr2
InChI Key
XXUZFRDUEGQHOV-UHFFFAOYSA-J
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
IUPAC Name
distrontium(2+) ion 5-[bis(carboxylatomethyl)amino]-3-(carboxylatomethyl)-4-cyanothiophene-2-carboxylate
SMILES
[Sr++].[Sr++].[O-]C(=O)CN(CC([O-])=O)C1=C(C#N)C(CC([O-])=O)=C(S1)C([O-])=O

Pharmacology

Indication

Strontium ranelate is therapeutically indicated for the treatment of severe osteoperosis in: a) postmenopasual women, and b) adult men, who are at high risk of fractures, for whom treatment with other medical products approved for the treatment of osteoperosis is not possible due to, for example, contraindications or intolerance. [6]

In postmenopausal women, strontium ranelate can also reduce the risk of vertebral and hip fractures [6].

Associated Conditions
Pharmacodynamics

In general, it is believed that strontium ranelate is capable of affecting a rebalance in bone turnover in favour of bone formation by: (1) increasing osteoblast differentiation from progenitors, osteoblast activity and survival, as well as regulating osteoblast-induced osteoclastogenesis, and (2) decreasing osteoclast differentiation and activity, as well as increasing osteoclast apoptosis [1].

It has also been shown that strontium ranelate is capable of improving and strengthening various components of overall bone tissue quality like bone mineral density and bone microarchitecture [1, 2, 3].

Mechanism of action

The underlying pathogenesis of osteperosis involves an imbalance between bone resorption and bone formation. Osteoclasts are a kind of differentiated or specialized bone cell that breaks down bone tissue while osteoblasts are another set of differentiated bone cells that synthesize and rebuild bone tissue. When osteoclasts degrade bone tissue faster than the osteoblasts are capable of rebuilding the bone tissue, low or inadequate bone mass density and osteoperosis can resula One of the mechanisms with which strontium ranelate is thought to act is its functionality as an agonist of the extracellular calcium sensing receptors (CaSRs) [3] of osteoblasts and osteoclasts [2]. Ordinary interaction between calcium 2+ divalent cations with mature osteoclast CaSRs is known to induce osteoclast apoptosis. Subsequently, strontium 2+ divalent cations from strontium ranelate use can also bind CaSRs on osteoclasts to induce their apoptosis because of the strontium 2+ cation's close resemeblance to calcium 2+. Contact between extracelluar calcium 2+ and osteoclast CaSRs stimulates the phospholipase C (PLC) dependant breakdown of phosphatidylinositol 4,5-biphosphate (PIP2) into the two secondary messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Whereas the calcium-CaSRs interaction then performs IP3 Adependent translocation of nuclear factor NF-kB from the cytoplasm to the nucleus in mature osteoclasts, strontium-CaSRs interactions involves a DAG-PKC beta II (protein kinase C beta II) signalling pathway for translocating NF-kB from the cytoplasm to the nucleus in an IP3-independent manner. Although the calcium 2+ and strontium 2+ mediated signalling pathways are different, both CaSR interactions induce osteoclast apoptosis and are in fact capable of potentiating each other, leading to enhanced osteoclast apoptosis and decreased bone tissue degradation [4].

At the same time, given the simiarity between the calcium 2+ and strontium 2+ cations [A3152], strontium 2+ cations from strontium ranelate are seemingly also able to act as an agonist and stimulate the CaSRs on osteoblasts, possibly in tandem with various local osteoblast stimulatory growth factors like transforming growth factor β (TGF β) and/or bone morphogenetic proteins (BMPs), to stimulate cyclic D genes and early oncogenes like c-fos and egr-1 that can mediate the mitogenesis and proliferation of new or more osteoblasts [5]. Moreover, although the involvement of the PLC mediated pathway may be a part of the signalling mechanism in osteoblasts following the stimulation of their CaSRs, this has not yet been fully elucidated [5].

Furthermore, strontium ranelate is also thought to be capable of stimulating osteoblasts to enhance the expression of osteoprotegerin while also concurrently reducing the expression of receptor activator of nuclear factor kappa-Β ligand (RANKL) in primary human osteoblastic cells. As osteoprotegerin can competitively bind to RANKL as a decoy receptor, which can prevent RANKL from binding to RANK, which is an activity that facilitates the signaling pathway for the differentiation and activaiton of osteoclasts. The subsequent net effect of these actions ultiamtely results in decreased osteoclastogenesis. [3]

Moreover, bone biopsies obtained from patients treated with stronatium ranelate in clinical study reveal improvements in intrinsic bone tissue quality and microarchitecutre in ostepoerosis as evidenced by increased trabecular number, decreased trabecular separation, lower structure model index, and increased cortical thickness associated with a shift in trabecular structure from rod to plate like configurations compared with control patients [3].

Additionally, strontium from administered strontium ranelate is absorbed onto the crystal surface of treated bones and only slightly substitiutes for calcium in the apatite crystal of newly formed bone. As a result, there is an increased X-ray absorption of strontium as compared to calcium, which can lead to an amplification of bone mineral density (BMD) measurement by dual-proton X-ray absorptiometry. In essence, although strontium ranelate use can increase BMD some of the observations may be overestimations due to skeletal accretion of strontium in strontium ranelate treated patients [3].

Having the ability to both generate more osetoblasts and decrease the number of osteoclasts gives strontium ranelate an apparent dual mechanism of action when used to treat osteoperosis.

Absorption

The absolute bioavailability of strontium is about 25% (within a range of 19-27%) after an oral dose of 2 g strontium ranelate. Maximum plasma concentrations are reached approximately 3-5 hours after a single dose of 2 g. Steady state is reached after 2 weeks of treatement. The intake of strontium ranelate with calcium or food reduces the bioavailablity of strontium ranelate by about 60-70%, compared with administration 3 hours after a meal [6].

Due to the relatively slow absorption of strontium, food and calcium intake should be avoided both before and after administration of strontium ranelate. Conversely, oral supplementation with vitamin D has no effect on strontium exposure whatsoever. [6]

Volume of distribution

Strontium has a volume of distribution of about 1 L/kg [6].

Protein binding

The binding of strontium to human plasma proteins is low (25%) and strontium has a high affinity for bone tissue [6].

Metabolism

As a divalent cation, strontium is not metabolized [6].

Route of elimination

The elimination of strontium is time and dose independent. Strontium excretion occurs via the kidneys and the gastrointetinal. [6]

Half life

The effective half-life of strontium is approximately 60 hours [6].

Clearance

The plasma dclearance is about 12 ml/min and its renal clearance is about 7 ml/min [6].

Toxicity

Strontium ranelate has been withdrawn worldwide owing to an increased adverse cardiac effects profile along with increased risk of venous thromboembolism (VTE) and various life threatening allergic reactions.

In pooled randomised placebo-controlled studies of post-menopausal osteoporotic patients, a significant increase in myocardial infarction has been observed in patients treated with strontium ranelate compared to placebo [6]. Patients with significant risk factors for cardiovascular events (ie. hypertension, hyperlipidemia, diabetes mellitus, smoking) would be susceptible to an even higher risk of cardiac ishaemic events like myocardial infarction [6].

In phase III placebo-controlled studies, strontium ranelate treatment was associated with an increase in the annual incidence of venous thromboembolism (VTE), including pulmonary embolism. This places substantial risk on patients at risk of VTE and elderly (over 80 years) patients at risk of VTE who may be more commonly associated with illnesses or conditions leading to immobilisation [6].

Life-threatening cutaneous reactions like Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported with the use of strontium ranelate. In particular, a higher incidence of such reactions has been reported in patients of Asian origin. [6]

In a pooled analysis of randomised placebo-controlled studies in post-menopausal osteoporotic patients, the most common adverse reactions consisted of nausea and diarrhea [6].

Nevertheless, good tolerance was shown in a clinical study investigating the repeated administration of 4 g strontium ranelate per day over 25 days in healthy postmenopausal women [Label]. Single administration of doses up to 11 g in healthy young male volunteers did not cause any particular symptoms [Label].

In patients with mild to moderate renal impairment (30-70 ml/min creatine clearance), strontium clearance decreases as creatinine clearance decreases (approximately 30% decrease over the creatinine clearance range 30 to 70 ml/min) and thereby induces an increase in strontium plasma levels. However, no dosage adjustment is required for patients with miod to moderate renal impairment - although no pharmacokinetic data exists for patients with severe renal impairment associated with creatinine clearance below 30 ml/min [6].

There are no data from the use of strontium ranelate in pregnant women [6].

Physico-chemical data suggests strontium ranelate can be excreted into human milk. Strontium ranelate should not be used during breastfeeding [6].

No effects were observed on male and female fertility in animal studies [6].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
Aluminum hydroxideThe serum concentration of Strontium ranelate can be decreased when it is combined with Aluminum hydroxide.
CalciumThe serum concentration of Strontium ranelate can be decreased when it is combined with Calcium.
Calcium acetateThe serum concentration of Strontium ranelate can be decreased when it is combined with Calcium Acetate.
Calcium CarbonateThe serum concentration of Strontium ranelate can be decreased when it is combined with Calcium Carbonate.
Calcium cationThe serum concentration of Strontium ranelate can be decreased when it is combined with Calcium cation.
Calcium ChlorideThe serum concentration of Strontium ranelate can be decreased when it is combined with Calcium Chloride.
Calcium CitrateThe serum concentration of Strontium ranelate can be decreased when it is combined with Calcium Citrate.
Calcium glubionateThe serum concentration of Strontium ranelate can be decreased when it is combined with Calcium glubionate.
Calcium GluceptateThe serum concentration of Strontium ranelate can be decreased when it is combined with Calcium Gluceptate.
Calcium gluconateThe serum concentration of Strontium ranelate can be decreased when it is combined with Calcium gluconate.
Food Interactions
Not Available

References

General References
  1. Fonseca JE, Brandi ML: Mechanism of action of strontium ranelate: what are the facts? Clin Cases Miner Bone Metab. 2010 Jan;7(1):17-8. [PubMed:22461285]
  2. Stepan JJ: Strontium ranelate: in search for the mechanism of action. J Bone Miner Metab. 2013 Nov;31(6):606-12. doi: 10.1007/s00774-013-0494-1. Epub 2013 Aug 9. [PubMed:23925392]
  3. Hamdy NA: Strontium ranelate improves bone microarchitecture in osteoporosis. Rheumatology (Oxford). 2009 Oct;48 Suppl 4:iv9-13. doi: 10.1093/rheumatology/kep274. [PubMed:19783592]
  4. Hurtel-Lemaire AS, Mentaverri R, Caudrillier A, Cournarie F, Wattel A, Kamel S, Terwilliger EF, Brown EM, Brazier M: The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis. New insights into the associated signaling pathways. J Biol Chem. 2009 Jan 2;284(1):575-84. doi: 10.1074/jbc.M801668200. Epub 2008 Oct 16. [PubMed:18927086]
  5. Sharan K, Siddiqui JA, Swarnkar G, Chattopadhyay N: Role of calcium-sensing receptor in bone biology. Indian J Med Res. 2008 Mar;127(3):274-86. [PubMed:18497443]
  6. Electronic Medicines Compedium Proteos (strontium ranelate) Monograph [Link]
External Links
PubChem Compound
6918182
PubChem Substance
310265162
ChemSpider
5293393
ChEMBL
CHEMBL3707306
Wikipedia
Strontium_ranelate
ATC Codes
M05BX03 — Strontium ranelateM05BX53 — Strontium ranelate and colecalciferol
FDA label
Download (345 KB)
MSDS
Download (36.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentCompliance / Postmenopausal Osteoporosis (PMO)1
4CompletedTreatmentBone destruction / Osteopenia / Primary Hyperparathyroidism1
4CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
4CompletedTreatmentBone destruction1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
GranuleOral2 g
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.17 mg/mLALOGPS
logP1.91ALOGPS
logP0.27ChemAxon
logS-2.5ALOGPS
pKa (Strongest Acidic)1.63ChemAxon
Physiological Charge-4ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area187.55 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity116.34 m3·mol-1ChemAxon
Polarizability27.91 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as tetracarboxylic acids and derivatives. These are carboxylic acids containing exactly four carboxyl groups.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Tetracarboxylic acids and derivatives
Direct Parent
Tetracarboxylic acids and derivatives
Alternative Parents
Alpha amino acids and derivatives / 3,4,5-trisubstituted-2-aminothiophenes / Thiophene carboxylic acids / Dialkylarylamines / Heteroaromatic compounds / Carboxylic acid salts / Nitriles / Carboxylic acids / Organopnictogen compounds / Organic salts
show 3 more
Substituents
Tetracarboxylic acid or derivatives / Alpha-amino acid or derivatives / 3,4,5-trisubstituted-2-aminothiophene / Thiophene carboxylic acid / Thiophene carboxylic acid or derivatives / Dialkylarylamine / 2-aminothiophene / Thiophene / Heteroaromatic compound / Carboxylic acid salt
show 14 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Drug created on October 27, 2015 18:06 / Updated on November 02, 2018 07:00