Trontium

Uses

Trontium is a non-hormonal medicine used to treat osteoporosis in postmenopausal women. Trontium reduces the risk of fracture at the spine and at the hip

About osteoporosis: Your body is constantly breaking down old bone and making new bone tissue. If you have osteoporosis, your body breaks down more bone than it forms so that gradually bone loss occurs and your bones become thinner and fragile. This is especially common in women after the menopause (change of life). Many people with osteoporosis have no symptoms and you may not even know that you have it. However, osteoporosis makes you more likely to have fractures (break bones), especially in your spine, hips and wrists.

Trontium is also used to associated treatment for these conditions: Severe Osteoporosis

How Trontium works

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 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 . 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.

Dosage

Trontium dosage

The recommended dose is one 2 gm sachet a day. Strontium should always be taken as per the advice of the doctor. Please check with your doctor in case of any confusion. Strontium is for oral use.

It is recommended that you take Strontium at bedtime. You may lie down immediately after taking Strontium if you wish. Take the granules contained in the sachets as a suspension in a glass of water (see instructions below). Strontium can interact with milk and milk products, so it is important that you mix Strontium only with water to be sure it works properly

Drink straight away. If for some reason you do not drink the medicine straight away, make sure you stir it again before drinking. You should not leave it more than 24 hours before you drink it. Your doctor may advise you to take calcium and vitamin D supplements in addition to Strontium. Do not take calcium supplements at bedtime, at the same time as Strontium. Your doctor will tell you how long you should continue to take Strontium. Osteoporosis therapy is usually required for a long period. It is important that you continue taking Strontium

If you forget to take Strontium: Do not take a double dose to make up for forgotten individual doses. Just carry on with the next dose at the normal time.

Side Effects

Like all medicines, Strontium can cause side effects, although not everybody gets them. The most common side effects are nausea, diarrhoea, headache and skin irritation. However,these effects were mild and short-lived and usually did not cause the patients to stop taking their treatment. Other events less commonly reported included blood clots, fainting fit, memory troubles and, in rare cases, seizures. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

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 . 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 .

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 .

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.

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

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 . Single administration of doses up to 11 g in healthy young male volunteers did not cause any particular symptoms .

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 .

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

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

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

Precaution

Before taking Trontium talk to your doctor:

• if you have severe kidney disease.
• if you are being treated or have been treated for blood clots.
• if you are confined to bed or if you are to undergo an operation. The risk of vein thrombosis (blood clots in the leg) may be increased in the event of lengthy immobilization.
• if you are allergic (hypersensitive) to strontium ranelate.

Trontium is not intended for use in children and adolescents. During treatment, if you experience an allergic reaction (such as swelling of the face, tongue or throat, difficulty in breathing or swallowing, skin rash), you must stop taking Trontium and seek medical advice immediately. If you have stopped treatment due to hypersensitivity reactions you should not re-start therapy with Trontium.

Interaction

Taking other medicines: Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. If you are taking medicines containing calcium, you should leave at least 2 hours before you take Trontium . If you take antacids (medicines to relieve heartburn) you should take them at least 2 hours after Trontium . If this is not possible, it is acceptable to take the two medicines at the same time. You should stop taking Trontium if you have to take oral tetracyclines or quinolones (two types of antibiotics). You can take Trontium again when you have finished taking these antibiotics. If you are unsure about this ask your doctor.

Taking Trontium with food and drink: Food, milk and milk products reduce the absorption of strontium ranelate. It is recommended that you take Trontium in-between meals, preferably at bedtime at least two hours after food, milk or milk products or calcium supplements.

Food Interaction

• 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.

Volume of Distribution

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

Elimination Route

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.

Half Life

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

Clearance

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

Elimination Route

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

Pregnancy & Breastfeeding use

Pregnancy: Trontium is meant for use only in postmenopausal women. Therefore, this should not be taken during pregnancy. If you take it by accident during pregnancy, stop taking it straight away and talk to your doctor.

Breast-feeding: Trontium is meant for use only in postmenopausal women. Therefore, breast-feeding women should not take this medicine. If you take it by accident during breast- feeding, stop taking it straight away and talk to your doctor.

Contraindication

Trontium is not intended for use in children and adolescents. During treatment, if you experience an allergic reaction (such as swelling of the face, tongue or throat, difficulty in breathing or swallowing, skin rash), you must stop taking Trontium and seek medical advice immediately. If you have stopped treatment due to hypersensitivity reactions you should not re-start therapy with Trontium

Acute Overdose

If you take too many sachets of Trontium, tell your doctor. They may advise you to drink milk or take antacids to reduce the absorption of the active ingredient.

Storage Condition

Keep out of the reach and sight of children. Store at a cool and dry place, away from light

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