Singapore Drugs Database

Indication

Strontium ranelate is therapeutically indicated for the treatement 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. [L1127] In postmenopausal women, strontium ranelate can also reduce the risk of vertebral and hip fractures [L1127].

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) [A31553] of osteoblasts and osteoclasts [A31542]. 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 [A31565]. 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 [A31580]. 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 [A31580]. 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. [A31553] 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 [A31553]. 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 [A31553]. 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.

Pharmacokinetics

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 [L1127]. 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. [L1127]

Distribution

Strontium has a volume of distribution of about 1 L/kg [L1127].

Metabolism

As a divalent cation, strontium is not metabolized [L1127].

Elimination

Clearance

The plasma dclearance is about 12 ml/min and its renal clearance is about 7 ml/min [L1127].

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 [L1127]. 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 [L1127]. 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 [L1127]. 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. [L1127] In a pooled analysis of randomised placebo-controlled studies in post-menopausal osteoporotic patients, the most common adverse reactions consisted of nausea and diarrhea [L1127]. 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 [FDA Label]. Single administration of doses up to 11 g in healthy young male volunteers did not cause any particular symptoms [FDA 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 [L1127]. There are no data from the use of strontium ranelate in pregnant women [L1127]. Physico-chemical data suggests strontium ranelate can be excreted into human milk. Strontium ranelate should not be used during breastfeeding [L1127]. No effects were observed on male and female fertility in animal studies [L1127].

Active Ingredient/Synonyms

Strontium ranelate | Strontium ranelate |