Calcium channel ( IC50 = 0.5 mM )

Strontium Ranelate enhanced bone mass in the vertebrae of intact adult mice is the consequence of increased bone formation and decreased bone resorption[2]. The histological evaluation of the trabecular bone volume in the tibial metaphysis confirms that strontium ranelate also increases bone mass in intact adult rats, as determined by dual-energy X-ray absorptiometry in the lumbar vertebra and femur[2]. It has been discovered that strontium ranelate increases bone formation in alveolar bone and decreases bone resorption in normal adult Macaca fascicularis monkeys, which exhibit extensive bone remodeling[2]. As evidenced by bone ash, bone mineral content, and histomorphometric analysis in the tibial metaphysis, short-term (3 months) treatment with strontium ranelate in ovariectomized rats prevents trabecular bone loss induced by oestrogen deficiency. This is the outcome of reduced bone resorption and preserved bone formation. Long-term studies confirm that strontium ranelate has positive effects on bone mass and microarchitecture in ovariectomized rats. Strontium ranelate was found to have a positive effect on bone resistance in this two-year study due to its ability to increase bone mass and microarchitecture, which in turn led to a notable improvement in bone strength [2].

In murine marrow stromal cells, strontium ranelate has been shown to elevate prostaglandin E2 production and alkaline phosphatase activity in a manner that is dependent on COX-2.

Absorption, Distribution and Excretion
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. 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.
The elimination of strontium is time and dose independent. Strontium excretion occurs via the kidneys and the gastrointetinal.
Strontium has a volume of distribution of about 1 L/kg.
The plasma dclearance is about 12 ml/min and its renal clearance is about 7 ml/min.

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Metabolism / Metabolites
As a divalent cation, strontium is not metabolized.

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Biological Half-Life
The effective half-life of strontium is approximately 60 hours.

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

[1]. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone. 2008 Jan;42(1):129-38. Epub 2007 Sep 12.

[2]. Strontium ranelate: a dual mode of action rebalancing bone turnover in favour of bone formation. Curr Opin Rheumatol. 2006 Jun;18 Suppl 1:S11-5.

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.

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Drug 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. In postmenopausal women, strontium ranelate can also reduce the risk of vertebral and hip fractures.
FDA Label
Treatment of severe osteoporosis in postmenopausal women at high risk for fracture to reduce the risk of vertebral and hip fractures. Treatment of severe osteoporosis in adult men at increased risk of fracture. The decision to prescribe strontium ranelate should be based on an assessment of the individual patient's overall risks.
Treatment of severe osteoporosis in postmenopausal women at high risk for fracture to reduce the risk of vertebral and hip fractures. , , Treatment of severe osteoporosis in adult men at increased risk of fracture. , , The decision to prescribe strontium ranelate should be based on an assessment of the individual patient's overall risks. ,
Osteoporosis
Osteoporosis

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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) of osteoblasts and osteoclasts. 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. At the same time, given the similarity between the calcium 2+ and strontium 2+ cations, 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. 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. 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. 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. 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. 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.

C12H6N2O8SSR2

513.49

513.8

C, 28.07; H, 1.18; N, 5.46; O, 24.93; S, 6.24; Sr, 34.13

135459-87-9

6918182

Light yellow to yellow solid powder

1.8±0.1 g/cm3

778.8±60.0 °C at 760 mmHg

>310°C (dec.)

424.8±32.9 °C

0.0±2.8 mmHg at 25°C

1.695

-0.9

0

11

4

25

533

0

[Sr+2].S1C(C(=O)O[H])=C(C([H])([H])C(=O)[O-])C(C#N)=C1N(C([H])([H])C(=O)O[H])C([H])([H])C(=O)O[H].S1C(C(=O)O[H])=C(C([H])([H])C(=O)[O-])C(C#N)=C1N(C([H])([H])C(=O)O[H])C([H])([H])C(=O)O[H]

XXUZFRDUEGQHOV-UHFFFAOYSA-J

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

distrontium;5-[bis(carboxylatomethyl)amino]-3-(carboxylatomethyl)-4-cyanothiophene-2-carboxylate

S 1291-1; S-1291-1; S1291-1; S-12911; S12911; S 12911; Strontium Ranelate; trade mane: Protelos or Proto

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product is not stable in solution, please use freshly prepared working solution for optimal results.  (2). Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)