- Strontium ranelate
- Accession Number
Strontium ranelate, a strontium (II) salt of ranelic acid, is a medication for osteoporosis. Some reports have shown that strontium ranelate can slow down the progression of osteoarthritis of the knee. This agent presents an atypical mechanism of action in which it increases deposition of new bone by osteoblasts and, simultaneously, 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.
- Small Molecule
- Approved, Withdrawn
- Average: 513.49
- Chemical Formula
- Not Available
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
- Contraindications & Blackbox Warnings
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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.
- 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.
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.
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
The effective half-life of strontium is approximately 60 hours 6.
The plasma dclearance is about 12 ml/min and its renal clearance is about 7 ml/min 6.
- Adverse Effects
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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
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Aluminum hydroxide The serum concentration of Strontium ranelate can be decreased when it is combined with Aluminum hydroxide. Calcium acetate The serum concentration of Strontium ranelate can be decreased when it is combined with Calcium acetate. Calcium carbonate The serum concentration of Strontium ranelate can be decreased when it is combined with Calcium carbonate. Calcium chloride The serum concentration of Strontium ranelate can be decreased when it is combined with Calcium chloride. Calcium citrate The serum concentration of Strontium ranelate can be decreased when it is combined with Calcium citrate. Calcium glucoheptonate The serum concentration of Strontium ranelate can be decreased when it is combined with Calcium glucoheptonate. Calcium gluconate The serum concentration of Strontium ranelate can be decreased when it is combined with Calcium gluconate. Calcium lactate The serum concentration of Strontium ranelate can be decreased when it is combined with Calcium lactate. Calcium Phosphate The serum concentration of Strontium ranelate can be decreased when it is combined with Calcium Phosphate. Calcium polycarbophil The serum concentration of Strontium ranelate can be decreased when it is combined with Calcium polycarbophil.Additional Data Available
- Extended DescriptionExtended DescriptionAvailable for Purchase
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- SeveritySeverityAvailable for Purchase
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- Food Interactions
- Avoid calcium supplements/calcium rich foods. Take strontium ranelate separated from calcium-containing food and supplements.
- Take on an empty stomach. Take strontium ranelate between meals and at least 2 hours after eating at bedtime for optimal bioavailability.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Osseor Granule 2 g Oral Les Laboratoires Servier 2016-09-07 2020-05-19 Osseor Granule 2 g Oral Les Laboratoires Servier 2016-09-07 2020-05-19 Osseor Granule 2 g Oral Les Laboratoires Servier 2016-09-07 2020-05-19 Osseor Granule 2 g Oral Les Laboratoires Servier 2016-09-07 2020-05-19 Osseor Granule 2 g Oral Les Laboratoires Servier 2016-09-07 2020-05-19 Osseor Granule 2 g Oral Les Laboratoires Servier 2016-09-07 2020-05-19 Protelos Granule 2 g Oral Les Laboratoires Servier 2004-09-21 Not applicable Protelos Granule 2 g Oral Les Laboratoires Servier 2004-09-21 Not applicable Protelos Granule 2 g Oral Les Laboratoires Servier 2004-09-21 Not applicable Protelos Granule 2 g Oral Les Laboratoires Servier 2004-09-21 Not applicableAdditional Data Available
- Application NumberApplication NumberAvailable for Purchase
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.Learn more
- Product CodeProduct CodeAvailable for Purchase
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.Learn more
- ATC Codes
- M05BX03 — Strontium ranelate
- M05BX — Other drugs affecting bone structure and mineralization
- M05B — DRUGS AFFECTING BONE STRUCTURE AND MINERALIZATION
- M05 — DRUGS FOR TREATMENT OF BONE DISEASES
- M — MUSCULO-SKELETAL SYSTEM
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- This compound belongs to the class of organic compounds known as tetracarboxylic acids and derivatives. These are carboxylic acids containing exactly four carboxyl groups.
- Organic compounds
- Super Class
- Organic acids and derivatives
- 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 / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds show 3 more
- 2-aminothiophene / 3,4,5-trisubstituted-2-aminothiophene / Alpha-amino acid or derivatives / Aromatic heteromonocyclic compound / Carbonitrile / Carbonyl group / Carboxylic acid / Carboxylic acid salt / Dialkylarylamine / Heteroaromatic compound / Hydrocarbon derivative / Nitrile / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organic salt / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Tetracarboxylic acid or derivatives / Thiophene / Thiophene carboxylic acid / Thiophene carboxylic acid or derivatives show 14 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- CAS number
- InChI Key
- IUPAC Name
- distrontium(2+) ion 5-[bis(carboxylatomethyl)amino]-3-(carboxylatomethyl)-4-cyanothiophene-2-carboxylate
- General References
- 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]
- 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]
- 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]
- 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]
- 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]
- Electronic Medicines Compedium Proteos (strontium ranelate) Monograph [Link]
- FDA label
- Download (345 KB)
- Download (36.7 KB)
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Treatment Compliance / Postmenopausal Osteoporosis 1 4 Completed Treatment Osteopenia / Osteoporosis / Primary Hyperparathyroidism 1 4 Completed Treatment Osteoporosis 1 4 Completed Treatment Postmenopausal Osteoporosis 1 Not Available Completed Treatment Osteoarthritis of the Knee 1
- Not Available
- Not Available
- Dosage Forms
Form Route Strength Tablet, effervescent 2 g Tablet, effervescent Oral 2 g Granule Oral 2 g Granule, for solution Oral 2 g Powder Oral 2 g Granule, for suspension Oral 2 g Tablet Oral 2 g Granule, for suspension Oral 2 gr
- Not Available
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 2.17 mg/mL ALOGPS logP 1.91 ALOGPS logP 0.27 ChemAxon logS -2.5 ALOGPS pKa (Strongest Acidic) 1.63 ChemAxon Physiological Charge -4 ChemAxon Hydrogen Acceptor Count 10 ChemAxon Hydrogen Donor Count 0 ChemAxon Polar Surface Area 187.55 Å2 ChemAxon Rotatable Bond Count 8 ChemAxon Refractivity 116.34 m3·mol-1 ChemAxon Polarizability 27.91 Å3 ChemAxon Number of Rings 1 ChemAxon Bioavailability 1 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon
- Predicted ADMET Features
- Not Available
- Mass Spec (NIST)
- Not Available
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available
Drug created on October 27, 2015 18:06 / Updated on June 12, 2020 10:52