Buy Bivalos powder for oral suspension 2g No. 28 in pharmacies

Pharmacological properties of the drug Bivalos

Strontium ranelate (5-[bis(carboxymethyl) amino] 2-carboxy-4-cyano-3-thiophenacetic acid, distrontium salt) has a dual mechanism of action and is indicated for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and femoral fractures. In vitro studies have found that strontium ranelate increases bone formation in bone tissue culture, as well as the proliferation of osteoblast precursors and collagen synthesis in bone cell culture; reduces bone resorption by reducing the differentiation of osteoclasts and reducing their resorptive activity. The dual mechanism of action leads to a rebalancing of metabolic processes in bone tissue in favor of osteogenesis. In experimental studies, strontium ranelate increased trabecular bone mass, trabecular number, and trabecular thickness. This led to increased bone strength. Clinical and experimental studies have demonstrated that strontium in bone tissue is mainly adsorbed on the surface of apatite crystals and only in small amounts replaces calcium in apatite crystals in newly formed bone tissue. Strontium ranelate does not alter the characteristics of bone crystals. In a study of iliac crest bone biopsies obtained up to 60 months after initiation of strontium ranelate therapy at a dose of 2 g/day, no adverse effects on bone quality or mineralization were noted. The average bone mineral density (BMD) during treatment with strontium ranelate increases compared to the baseline level by approximately 4% per year in the lumbar spine and by 2% per year in the femoral neck, reaching after 3 years (according to various studies) increases on average by 13–15% and 5–6%, respectively. When using strontium ranelate compared with placebo, starting from the 3rd month of treatment and throughout 3 years of therapy, an increase in the level of biochemical markers of bone formation (bone-specific ALP and C-terminal propeptide of procollagen type I) and a decrease in the level of biochemical markers of resorption are noted bone (serum C-telopeptide and cross-linked N-telopeptide in urine). In addition, a slight decrease in the concentration of calcium and parathyroid hormone (PTH) in the blood serum, an increase in the concentration of phosphorus in the blood and the total activity of alkaline phosphatase without any clinical manifestations were noted. Strontium ranelate consists of two stable strontium atoms and a ranelic acid molecule. The organic part of the compound provides better characteristics of the molecular weight, pharmacokinetics and tolerability of the drug. Due to the high polarity of the compound, a low degree of absorption, tissue distribution and binding of ranelic acid to blood plasma proteins is noted. Ranelic acid does not accumulate in the body; there is also no data indicating its metabolic transformations in the body of animals and humans. After absorption, ranelic acid is quickly excreted unchanged in the urine. The absolute bioavailability of strontium after oral administration of 2 g of strontium ranelate is approximately 25% (range 19–27%). The maximum concentration in blood plasma is achieved 3–5 hours after a single dose of 2 g. Equilibrium concentration is achieved 2 weeks after the start of treatment. Simultaneous administration of strontium ranelate with food or calcium salts reduces the bioavailability of strontium by approximately 60–70% compared to taking the drug 3 hours after a meal. Due to the relatively slow absorption of strontium, it is necessary to avoid food and calcium supplements both before and after taking strontium ranelate. Oral vitamin D supplements do not affect strontium concentrations. The volume of distribution of strontium is about 1 l/kg. The binding of strontium to human plasma proteins is low (25%), strontium has a high affinity for bone tissue. When determining the concentration of strontium in biopsy samples of the iliac crest of patients who were treated with strontium ranelate at a dose of 2 g/day up to 60 months inclusive, it was found that the value of strontium concentration in bone tissue can reach a plateau 3 years after the start of treatment. There are no data on the kinetics of strontium excretion from bone tissue after the end of therapy. As a divalent cation, strontium is not metabolized in the body. Strontium ranelate does not inhibit enzymes of the cytochrome P450 system. Strontium excretion depends on dose and time. The effective half-life of strontium is about 60 hours. Strontium is eliminated from the body in urine and feces. Its clearance from blood plasma is about 12 ml/min (coefficient of variation is 22%), and renal clearance is about 7 ml/min (coefficient of variation is 28%). Population pharmacokinetic data indicate that there is no relationship between age and the rate of strontium excretion in the target group of patients. Data on pharmacokinetics in patients with impaired liver function are not available, however, given the pharmacokinetic properties of strontium, no characteristic effect can be expected. The research program for the drug's effectiveness in preventing bone fractures consisted of two placebo-controlled studies: the SOTI study and the TROPOS study. The SOTI study included 1649 postmenopausal women with an established diagnosis of osteoporosis (with low BMD of the lumbar spine and a history of fractures in more than half of the women); the average age of the study participants was 70 years. The TROPOS study included 5091 postmenopausal women with an established diagnosis of osteoporosis (low BMD at the femoral neck and a history of fractures in more than half of the women); the average age of the study participants was 77 years. Both studies included 1556 patients aged over 80 years at the time of enrollment (accounting for 23.1% of the entire study population). In addition to strontium ranelate 2 g/day or placebo, patients took calcium and vitamin D supplements throughout the study period. Bivalos reduced the relative risk of developing new vertebral fractures over 3 years by 41% (SOTI study, Table 1 ). The effect was statistically significant starting from the 1st year of the study. Similar benefits were demonstrated in women with multiple fractures before the start of the study. The relative risk of symptomatic vertebral fractures (defined as fractures accompanied by back pain and/or a decrease in height of at least 1 cm) decreased by 38%. The use of Bivalos compared to placebo was also accompanied by a decrease in the number of cases of height loss of at least 1 cm. The results of studying the quality of life using an assessment using a special QUALIOST scale, as well as a scoring scale of general well-being based on the general scale of the SF-36 questionnaire, demonstrated the advantages of the drug compared with placebo. The effectiveness of the drug in reducing the risk of developing new cases of vertebral fractures was confirmed in the TROPOS study, including in patients with osteoporosis who did not have fractures before treatment. Table 1 Number of patients with vertebral fractures and a decrease in the relative risk of their development

Analysis of pooled data from the SOTI and TROPOS studies showed that in patients (over 80 years of age at study entry), Bivalos reduced the relative risk of developing new vertebral fractures by 32% over the 3-year study period (fracture rate with placebo was 26.5%). , and when taking strontium ranelate - 19.1%). Among patients without a history of fractures, but with at least one additional risk factor for fractures (n = 176), in whom pre-treatment BMD values ​​of the lumbar spine and/or femoral neck were in the range characteristic of osteopenia, use of the drug Bivalos for 3 years of treatment reduced the risk of developing a first vertebral fracture by 72% (the incidence of vertebral fracture with strontium ranelate was 3.6%, and with placebo - 12.0%). Following the TROPOS study, data were analyzed in the subgroup of patients over 74 years of age at high risk of fracture—femoral neck BMD T-score ≤ –3 SD (the range used in the study was –2.4 SD according to NHANES III). In this group (n=1977, i.e. 40% of patients who took part in the TROPOS study), Bivalos reduced the risk of hip fractures by 36% over 3 years of treatment compared with placebo (Table 2). Table 2 Proportion of patients with femoral fractures and reduced relative risk among patients with BMD ≤–2.4 SD (NHANES III) aged ≥74 years

Buy Bivalos powder for oral suspension 2g No. 28 in pharmacies

Bivalos Buy Bivalos in pharmacies DOSAGE FORMS powder for oral suspension 2g

MANUFACTURERS Servier Laboratories (France)

GROUP Drugs for the treatment of osteoporosis

COMPOSITION The active substance is strontium ranelate. 1 sachet contains 2 g of the active substance. Excipients: aspartame (E951), maltodextrin, mannitol.

INTERNATIONAL NON-PROPENTED NAME Strontium ranelate

PHARMACOLOGICAL ACTION Bivalos is a non-hormonal drug for the treatment of osteoporosis in postmenopausal women. Stimulates the formation and inhibits bone resorption, which leads to normalization of bone structure and, as a result, reducing the risk of vertebral and femoral neck fractures. Strontium ranelate does not change the crystallization characteristics of bone tissue. The combined effects of strontium distribution in bone tissue and increased radiographic absorption of strontium relative to calcium lead to increased bone mineral density (BMD). The medicinal formula of strontium ranelate contains two atoms of stable strontium and one molecule of ranelic acid, as well as an organic part, due to which the required molecular weight values ​​are achieved, favorable pharmacokinetic properties and good tolerability of the drug are ensured. Absorption, distribution and binding of ranelic acid to plasma proteins are quite low, due to the high polarity of the molecule. Ranelic acid does not accumulate and does not exhibit metabolic activity in animals and humans. Absorbed ranelic acid is quickly and unchanged excreted from the human body through the kidneys. The absolute bioavailability of strontium after oral administration of 2 g of strontium ranelate is 25%. Maximum plasma concentrations are achieved 3-5 hours after a single dose of 2 g of the drug. A steady state is achieved after 2 weeks of therapy. Being a divalent cation, strontium is not metabolized in the human body. Strontium ranelate does not inhibit enzymes of the cytochrome P450 system. The effective half-life of strontium is approximately 60 hours. Strontium is excreted through the kidneys, gastrointestinal tract and breast milk.

INDICATIONS FOR USE Treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and femoral neck fractures.

CONTRAINDICATIONS Hypersensitivity to strontium ranelate or any other component of the drug. Pregnancy and breastfeeding: the drug is intended only for the treatment of postmenopausal women. Strontium ranelate should not be prescribed during pregnancy and lactation. Use in children and adolescents, patients in this age group is not recommended.

SIDE EFFECTS General: nausea, diarrhea, headache and skin irritation. These effects are mild, short-term in nature and do not require discontinuation of the drug.

INTERACTIONS Milk and dairy products, as well as medications containing calcium, may reduce the bioavailability of strontium ranelate by approximately 60-70%. The simultaneous use of antacid drugs and the drug Bivalos is allowed. When prescribing antibiotics from the group of tetracyclines or quinolones, treatment with Bivalos should be suspended. When combined with vitamin D, no interactions were found. When combining Bivalos with non-steroidal anti-inflammatory drugs (including acetylsalicylic acid), anilides (such as paracetamol), H2 blockers, proton pump inhibitors, diuretics, digoxin and cardiac glycosides, organic nitrates and other vasodilators used for heart disease, calcium channel blockers, beta-blockers, ACE inhibitors, angiotensin receptor antagonists, selective beta2-agonists, oral anticoagulants, platelet aggregation inhibitors, statins, fibrates and benzodiazepine derivatives, no interaction was established.

METHOD OF APPLICATION AND DOSAGE The drug should be taken orally only in the form of a suspension obtained after stirring the powder in a glass of water. The recommended dose is 2 g (contents of one sachet) per day. Due to the chronic nature of the disease, Bivalos is intended to be taken for a long time. Due to the fact that milk and dairy products can reduce the absorption of strontium ranelate, it is necessary to take the drug between meals, preferably before bedtime, at least 2 hours after eating milk, dairy products and/or dietary supplements or calcium supplements . The prepared suspension should be consumed orally immediately after preparation. If the dietary intake of calcium and vitamin D is insufficient, patients taking Bivalos must additionally be prescribed these substances in the form of nutritional supplements. In elderly patients, no dose adjustment is required. In patients with mild or moderate renal failure, no dose adjustment is required. Since strontium ranelate is not metabolized in the body, no dose changes are required in patients with liver failure.

SPECIAL INSTRUCTIONS Due to the lack of data on the safety of the use of strontium ranelate in patients with severe renal failure, the drug is not recommended for use in patients with creatinine clearance less than 30 ml/min. Bivalos should be used with caution in patients at high risk of thromboembolism (VTE), including patients with a history of episodes of VTE. The presence of the excipient aspartame in Bivalos may cause an undesirable reaction in patients with phenylketonuria. Strontium ranelate affects the results of colorimetric methods for assessing calcium levels in blood and urine. Bivalos does not affect the ability to drive vehicles or perform work that requires an increased speed of psychophysical reactions.

STORAGE CONDITIONS List B. Keep out of the reach of children.

Use of the drug Bivalos

For oral use. The recommended daily dose is 2 g of strontium ranelate (contents of 1 single-dose package) per day; before use, the contents of the package are dissolved in a glass of water. Bivalos should be taken between meals. It is recommended to take Bivalos before bed, preferably no earlier than 2 hours after eating. The contents of one sachet should be poured into a glass, add water and stir the granules in the water until a suspension is formed (uniform distribution of the granules in the water). The suspension must be drunk immediately after preparation. The shelf life of the prepared suspension is 24 hours. If the suspension cannot be drunk immediately after preparation, it should be stirred before taking. Bivalos is intended for long-term use.

Side effects of the drug Bivalos

The drug Bivalos was studied in clinical studies that involved about 8,000 patients. Long-term safety of the drug was assessed in postmenopausal women with osteoporosis receiving strontium ranelate 2 g/day for 60 months (n=3352) or placebo (n=3317) during clinical trials. The average age at enrollment was 75 years, and 23% of patients included in the study were aged 80–100 years. The overall incidence of side effects with strontium ranelate did not differ from that with placebo, and side effects were generally mild and reversible. The most commonly reported side effects were nausea and diarrhea, usually at the beginning of treatment, after which no significant differences were noted between the compared groups. Discontinuation of therapy was mainly due to nausea (1.3 and 2.2% in the placebo and strontium ranelate groups, respectively). The following are side effects that could be associated with the use of strontium ranelate according to the frequency of their development: very often (1/10); often (1/100, but ≤1/10); uncommon (1/1000 and ≤1/100); rare (1/10,000 and ≤1/1000); very rare (≤1/10,000). From the nervous system : often: headache, impaired consciousness, memory. Uncommon: convulsions. From the gastrointestinal tract Often: nausea, diarrhea, loose stools. Frequency not known: vomiting, abdominal pain, irritation of the oral mucosa, including stomatitis and/or ulcerative lesions of the oral mucosa. From the musculoskeletal system Frequency not known: musculoskeletal pain, including muscle spasm, myalgia, bone pain, arthralgia and pain in the extremities. From the skin and subcutaneous tissue Frequency is not known: manifestations of hypersensitivity reactions from the skin, including rash, itching, urticaria, angioedema, Stevens-Johnson syndrome; cases of severe hypersensitivity reactions - drug rash accompanied by eosinophilia and systemic symptoms (DRESS syndrome) (see section SPECIAL INSTRUCTIONS). Common: dermatitis, eczema. If serious allergic reactions develop, treatment with Bivalos should be discontinued. Uncommon: venous thromboembolism. Clinical studies lasting more than 4 years showed that the annual incidence of venous thromboembolism with strontium ranelate compared with placebo was about 0.7% with a relative risk of 1.42 (confidence interval 1.02, 1.98, p = 0.036 ). Laboratory data There was a reversible increase in activity (3 times the upper limit of normal) of creatine kinase (its musculoskeletal fraction) in the group of individuals who took strontium ranelate (1.4%) compared with placebo (0.6%). In most cases, these indicators spontaneously normalized without changing the treatment regimen.

A new approach to the treatment of postmenopausal osteoporosis from the standpoint of preserving “living” bone tissue

Bone is a unique living tissue that has the property of constant renewal and regeneration during a person’s life. The appearance of an imbalance in the processes of bone remodeling (resorption and bone formation), which occurs in old age or for other reasons, can cause a disruption in the ability of bone tissue to self-renew, an active decrease in bone mass and the development of osteoporosis (OP).

AP is a systemic skeletal disease characterized by a decrease in bone mass and strength and an increased risk of fractures. According to epidemiologists, in Russia, on average, every third woman and every fifth man over the age of 50 suffers from this disease, which is more than 10 million people. The medical, social and economic significance of AP is determined by the high frequency and severity of its complications—fractures, of which the femoral neck fracture is considered the most dangerous. In our country, patients with a hip fracture occupy 20% of trauma beds, 31–35% of patients die within the first year after the fracture, and 78% of survivors require outside care for a long time, i.e., they actually become disabled.

Postmenopausal AP is considered the most common type of the disease, accounting for about 80% of all cases of diagnosed AP. In most cases, AP develops asymptomatically and its first manifestation may be a fracture that occurs with minimal or even no trauma. A fracture is the cause of pain, bone deformities, limited range of motion, the need for constant medical care, psychological and other problems that lead to a significant decrease in the quality of life. 10% of elderly women have severe osteoporotic fractures of the vertebral bodies and another 50% have moderate compression deformities. Such patients complain of constant back pain, a significant decrease in height, hunching, decreased mood, depression and other psycho-emotional disorders. If the presence of compression fractures of the vertebral bodies is confirmed on an x-ray of the spine, the question of prescribing therapy for a postmenopausal woman can be resolved even without bone densitometry. In the absence of a history of fractures, diagnosis and treatment tactics can be determined only on the basis of a densitometric examination of the spine and femoral neck and analysis of specific risk factors for AP.

The most significant parameters that should be assessed in a postmenopausal woman when determining the risk of AP and fractures are age, body weight, presence of fractures over the age of 50 years, family history of AP and hip fracture, use of oral glucocorticoids and other drugs iatrogenic against AP, smoking, alcohol abuse, the presence of chronic diseases complicated by the development of secondary AP. Considering the increased susceptibility to fractures in old age in general, in women over 65 years of age in the presence of the above risk factors, the question of prescribing treatment for AP can be decided independently of bone mineral density (BMD) determined using bone densitometry. In earlier periods of menopause, treatment recommendations can be given only after a densitometric examination.

Modern approaches to the treatment of AP involve influencing bone metabolism from the perspective of “living” bone tissue, i.e. maintaining normal balance in the processes of bone remodeling, necessary to maintain optimal quantitative and qualitative characteristics of bone tissue in old age. The only drug for the treatment of AP that has a dual, multidirectional effect on bone metabolism (stimulating effect on bone formation and reducing resorption activity) is strontium ranelate.

Strontium ranelate (Bivalos) is a fundamentally new drug for the treatment of postmenopausal AP. Over the past two decades, numerous experimental and clinical studies have demonstrated the unique ability of strontium ranelate to simultaneously stimulate the formation and slow down bone resorption, and have also shown the high effectiveness of the drug in restoring bone mass and reducing the risk of fractures in patients with postmenopausal AP.

Mechanism of action of strontium ranelate in AP

Strontium, like calcium, is an element of the fourth group of the periodic table of elements. Its physicochemical properties are similar to calcium, it has a high affinity for bone tissue and selectively accumulates in the skeleton: 99% of strontium present in the body is concentrated in the bones. Strontium ranelate contains two stable strontium atoms bound to organic (ranelic) acid - this formula ensures optimal bioavailability and tolerability of the drug.

Strontium ranelate is the only drug whose positive effect on both processes of bone remodeling has been reliably proven in both fundamental and clinical studies. In particular, experimental studies have shown a stimulating effect on the process of bone formation. In a culture of cells from the calvaria of newborn rats, after 24 hours of exposure of the drug in a solution of strontium ranelate, an increase in the replication of preosteoblasts into mature osteoblasts, an increase in the activity of functioning osteoblasts and a significant increase in the process of bone formation by 30–35% were observed. An increase in the replication and differentiation of osteoblasts in human bone tissue has also been shown, probably due to the effect on calcium-sensitive receptors of preosteoblasts. There is also evidence of increased differentiation and increased life expectancy of osteocytes—cells that perform trophic and structural functions in bone tissue and, thus, affect bone quality.

Simultaneously with the stimulation of bone formation, strontium ranelate reduces the rate of bone resorption, slowing down the differentiation of progenitor cells into mature osteoclasts due to its effect on the “RANK-RANKL-osteoprotegerin” system regulating bone remodeling. Strontium ranelate enhances the production of osteoprotegerin protein by osteoblasts, which blocks the interaction of RANK and RANKL on preosteoclasts, thereby inhibiting the maturation of osteoclasts and reducing bone resorption activity. The production of osteoprotegerin decreases significantly with age, in particular in postmenopause due to estrogen deficiency; This is partly associated with increased bone resorption and the development of OP in postmenopausal women. Thus, strontium ranelate affects physiological regulatory mechanisms without interfering with the functioning and viability of bone cells.

The dual effect of the drug on bone remodeling processes has been confirmed in clinical studies. In the SOTI (Spinal Osteoporosis Therapeutic Intervention) study, which randomized 1649 women with confirmed postmenopausal AP, after 3 months of treatment with strontium ranelate, a significant increase in bone-specific alkaline phosphatase (CS-ALP) was noted, indicating stimulation of bone formation, and a parallel decrease level of type I collagen C-telopeptide (CTx), a marker of resorption activity. Similarly, in the TROPOS (TReatment Of Peripheral OSteoporosis) study, which included 5091 women over the age of 70 years, during the entire period of treatment with strontium ranelate, the level of CS-ALP was significantly higher, and the resorption marker N-telopeptide collagen type I (NTx) - lower than in patients in the placebo group. Data from histomorphometric analysis of biopsy material after 5 years of treatment with strontium ranelate reliably confirm its stimulating effect on bone formation (an increase in osteoblastic surfaces by 38% and an increase in the rate of mineralization in trabecular and cortical bone by 8% and 11%, respectively, compared with placebo) and an inhibitory effect on resorption (reduction in the number of endosteal eroded surfaces, trabecular osteoclastic surfaces and the total number of osteoclasts).

Thus, strontium ranelate has the unique property of a double, multidirectional effect on the processes of bone remodeling, in contrast to drugs from other pharmacological groups, which is important from the standpoint of the physiological effect on “living” bone tissue in the treatment of AP. By improving the balance between resorption and bone formation, strontium ranelate increases the degree of bone mineralization and increases the thickness of mineralized sites in new bone tissue. The newly formed bone is characterized by high quality - according to biopsies carried out as part of various clinical studies, during therapy with strontium ranelate, no signs of osteomalacia or mineralization defects were detected in the bone tissue, in particular, no signs of increased osteoid thickness, hypermineralization or delayed primary mineralization were found .

Clinical efficacy of strontium ranelate in postmenopausal AP

Treatment of postmenopausal AP is aimed at reducing the risk of bone fractures, increasing BMD and bone strength. In addition, an important goal of drug therapy is to reduce back pain, increase physical activity and improve the quality of life of patients. The main criterion for the effectiveness of any drug used in the treatment of AP is the reduction in the risk of new fractures, proven in double-blind controlled studies with a duration of therapy of at least 3 years. The clinical efficacy and safety of strontium ranelate have been convincingly demonstrated in several large-scale clinical trials conducted at 75 clinical sites in 12 countries, involving 9196 postmenopausal women treated with strontium ranelate for up to 8 years inclusive.

Strontium ranelate has shown good data on the prevention of fractures of any location. In the SOTI study in patients with postmenopausal AP, a significant reduction in the likelihood of vertebral fractures after 1 year of taking the drug was 49% (p<0.001), and after 3 years - 41% (p<0.001) (Fig. 1).

Another large study, TROPOS, confirmed the effectiveness of strontium ranelate in the prevention of vertebral fractures, and also demonstrated its effectiveness in reducing the risk of peripheral fractures in postmenopausal women. In particular, after 3 years, a significant reduction in the risk of all non-vertebral fractures by 16% was found compared to placebo, and in the group of patients with a high risk of hip fracture (femoral neck BMD according to T-criterion ≤–3.0) - a decrease in the number of patients who had a fracture of this localization, by 36% (p <0.05) (Fig. 2).

Resistance does not develop to strontium ranelate, and its antifracture effectiveness does not weaken even with long-term therapy—up to 5–8 years. Analysis of the results of long-term treatment with strontium ranelate in women suffering from postmenopausal AP showed that after 5 years the risk of developing vertebral fractures was significantly reduced by 24% (p <0.001), non-vertebral fractures by 15% (p = 0.03), and cervical fractures. hips in patients aged 74 years and older—by 43% (p=0.036). When observing patients who took strontium ranelate for up to 8 years, a consistently high adherence to therapy (87.9%) and preservation of antifracture activity were noted. It is important that the effectiveness of strontium ranelate does not depend on the severity of AP, the presence of a history of vertebral fractures, body weight, the ratio of risk factors and the initial activity of bone remodeling. In the latest European clinical guidelines for the diagnosis and treatment of postmenopausal AP (2008), strontium ranelate is presented as one of the drugs with the widest and most proven effectiveness in reducing the risk of fractures in various locations.

Strontium ranelate promotes a pronounced increase in BMD in both the axial and peripheral skeleton. A significant increase in BMD compared to placebo is observed after 6 months of treatment, and after 3 years the increase in bone mineral saturation is 14.4% in the lumbar vertebrae, 8.3% in the femoral neck and 9.8% in the hip as a whole compared with placebo (p<0.001) (Fig. 2)]. On average, when treated with strontium ranelate, one can expect an annual increase in BMD in the spine by 4% and in the femoral neck by 2%. At the same time, a clear correlation was noted between the increase in BMD during treatment with strontium ranelate and its effectiveness in preventing fractures. Thus, for every 1% increase in BMD of the femoral neck, the risk of a new vertebral fracture within 3 years decreases by 3%. Thus, an increase in BMD during strontium ranelate therapy can serve as a marker of the clinical effectiveness of treatment.

Improving the subjective well-being and quality of life of patients is one of the most important goals of therapy for AP. Strontium ranelate is the first drug whose effect on all aspects of the quality of life of patients with AP has been specifically studied. The drug significantly reduces the risk of developing clinical vertebral fractures accompanied by pathological symptoms (back pain, decreased height, limited physical activity) after a year of treatment by 52% (p=0.003), after 3 years - by 38% (p<0.001). During therapy, the number of patients experiencing back pain decreases (after 12 months - by 29%, p = 0.03, after 3 years - by 32%, p = 0.006), as well as the number of patients with a decrease in height. In general, the drug has a positive effect on both physical and psycho-emotional aspects of quality of life, significantly improving the overall well-being of treated patients with AP compared to the placebo group (p <0.05).

Experience of using Bivalos (strontium ranelate) in Russia

Strontium ranelate was registered in the Russian Federation in 2005 under the commercial name “Bivalos”. The widespread use of Bivalos in domestic clinical practice for 3 years confirmed the high effectiveness, good tolerability and ease of use of the drug in women suffering from postmenopausal AP.

A Russian multicenter, one-year study examined the effectiveness of Bivalos in 60 postmenopausal women with confirmed systemic AP. The results of the work convincingly demonstrated the positive effect of the drug on the increase in BMD in various parts of the skeleton: on average by 4.7% in the spine (p<0.000001), by 2.0% in the femoral neck (p<0.0001) and 3 .1% in the proximal femur overall (p<0.000001). Data were also obtained, correlated with the results of international studies, on significant multidirectional changes in the level of markers of bone formation (CS-ALP) and resorption (CTx) and an improvement in the quality of life of patients. More than 70% of doctors and patients rated Bivalos therapy as good and more than 90% highly rated the drug’s tolerability.

The rapid onset of clinical effectiveness and improvement in the general well-being of patients when prescribing therapy for AP is an important factor for motivating patients with AP for long-term treatment. Experience of using Bivalos at MONIKI named after. M.F. Vladimirsky with the inclusion of 40 women with established postmenopausal AP showed that a significant increase in BMD can be expected already 6 months after the start of treatment: on average by 4.4% in the spine (p<0.001) and by 2.4% in femoral neck (p<0.05). Bivalos helps reduce the level of CTx and increase the concentration of osteocalcin during the first months of treatment, which confirms the data on the dual mechanism of action of the drug on bone remodeling. When surveying patients using the QUALEFFO-41 questionnaire, after 3 months, women noted a significant decrease in back pain (p<0.001), mobility (p=0.01) and the total indicator of quality of life (p<0.05), and after 6 months—indicated an increase in social activity (p<0.05) and an increase in the overall assessment of one’s own health (p<0.05).

Thus, the experience of using Bivalos in Russia has confirmed the high effectiveness of the drug in affecting bone mass, influencing the processes of bone metabolism and the quality of life of patients. Ease of use combined with high efficiency ensures high adherence to treatment in long-term treatment of postmenopausal AP. From the standpoint of pharmacoeconomics, strontium ranelate is characterized by a favorable efficiency/cost ratio in European countries, therefore the clinical and economic feasibility of using Bivalos for the treatment of women with postmenopausal AP in Russia can be considered quite justified.

Recommendations for taking strontium ranelate

The drug has no significant contraindications for use and is well tolerated. In the SOTI and TROPOS studies, over 3 years of follow-up, there was no significant difference in the incidence of adverse reactions between the groups of patients taking strontium ranelate and placebo. The most common side effects with strontium ranelate were nausea (6.6% vs. 4.3% in the placebo group), diarrhea (6.1% vs. 3.6%, respectively), and headache (3.0 vs. 2.4%). respectively). These side effects, as a rule, do not require cessation of therapy and go away on their own within the first 3 months. There is evidence that in rare cases, venous thrombosis and thromboembolism can be observed - 0.9% versus 0.6% in the placebo group, however, the likelihood of developing thrombosis during treatment with strontium ranelate does not exceed the average population data (in women aged 70–79 years it is 0.82%, and in the general population after 75 years - 1.2%). The drug does not increase the risk of developing serious complications from the upper gastrointestinal tract (ulcers, erosive gastritis and esophagitis, etc.). Due to the lack of experience with use, the drug should not be prescribed to women of childbearing age and patients with creatinine clearance less than 30 ml/min.

The recommended regimen for taking strontium ranelate is daily at a dosage of 2 g (1 sachet) 2 hours after dinner. Strontium ranelate can be combined (but not taken simultaneously) with calcium (1000 mg/day) and vitamin D (400–800 IU/day) supplements. In elderly women and patients with moderate impairment of liver and kidney function, no dose adjustment is required.

Conclusion

From the modern point of view of the treatment of postmenopausal AP, strontium ranelate (Bivalos) is an innovative drug that physiologically regulates the function of bone cells and the activity of bone remodeling processes - resorption and bone formation. While maintaining the properties of “living bone tissue,” in postmenopausal patients with AP, Bivalos significantly reduces the risk of developing vertebral and peripheral fractures, including femoral neck fractures, significantly increases BMD and increases bone strength. The drug demonstrates good effectiveness, tolerability and ease of use even with long treatment periods—8 years or more.

Currently, strontium ranelate is positioned as a first-line drug for the treatment of postmenopausal AP in the European Union and Eastern Europe, Australia, Hong Kong, Singapore, etc. Strontium ranelate is included in the American, European and Russian clinical guidelines for the diagnosis and treatment of osteoporosis.

L. A. Marchenkova , Candidate of Medical Sciences, State University of Monica named after. M. F. Vladimirsky, Moscow

Special instructions for the use of the drug Bivalos

Patients receiving treatment with strontium ranelate are advised to take vitamin D and calcium supplements if dietary intake is insufficient. Consumption of food, including milk and dairy products, and medications containing calcium, may reduce the absorption and bioavailability of strontium ranelate by approximately 60–70%. Therefore, the interval between taking Bivalos and these substances should be at least 2 hours. Given the slow absorption of strontium ranelate, it is recommended to take Bivalos before bed, preferably no earlier than 2 hours after meals. The effectiveness and safety of strontium ranelate have been established in women of different age categories (up to the age of 100 years at the time of inclusion in the study) in the postmenopausal period with osteoporosis. There is no need for dose adjustment depending on age. Patients with mild to moderate renal failure (creatinine clearance 30–70 ml/min) do not require dose adjustment. Strontium ranelate is not recommended for use in patients with severe renal impairment (creatinine clearance ≤30 ml/min) due to lack of data. In patients with chronic renal failure, periodic assessment of renal function is recommended. The question of continuing therapy with Bivalos in patients with severe renal failure is decided individually. Strontium ranelate is not metabolized, so patients with impaired liver function do not need dose adjustment. The effectiveness and safety of strontium ranelate in children and adolescents has not been established, therefore its use in these age groups is not recommended. Clinical studies have shown that strontium ranelate therapy was associated with an increased annual incidence of venous thromboembolism, including pulmonary embolism. The reason for this has not been established. Bivalos should be used with caution in patients with an increased risk of developing venous thromboembolism, including patients with a history of this pathology. When treating patients at risk, special attention should be paid to identifying possible signs and symptoms of venous thromboembolism and appropriate prevention. Strontium can affect the results of determining the concentration of calcium in the blood and urine using the colorimetric method. Therefore, to accurately assess the concentration of calcium in the blood and urine in clinical practice, it is recommended to use the inductively coupled plasma atomic emission spectrometry method or the atomic absorption spectrometry method. Bivalos contains aspartame, which is a source of phenylalanine, which is contraindicated in patients with phenylketonuria. During use of the drug, it is possible to develop a severe hypersensitivity reaction - a drug rash, which is accompanied by eosinophilia and systemic symptoms (DRESS syndrome). (See SIDE EFFECTS section). DRESS syndrome is characterized by rash, fever, eosinophilia, and systemic symptoms (adenopathy, hepatitis, interstitial nephropathy, and interstitial lung disease). Most often, DRESS syndrome develops 3–6 weeks after starting the drug. After stopping the drug and starting GCS therapy, the prognosis is favorable. Recovery may be gradual. After discontinuation of GCS therapy, symptoms may resume. Patients should be warned about the need to immediately stop taking the drug and consult a doctor if a rash occurs while taking Bivalos. Patients who have stopped treatment with the drug due to hypersensitivity reactions should in no case resume taking it in the future. The drug Bivalos is intended only for use in postmenopausal women. There are no clinical data on the use of strontium ranelate during pregnancy. Experimental studies have shown that in high doses it can cause reversible changes in bone tissue in the offspring of rats and rabbits that were given the drug during pregnancy. If pregnancy occurs, Bivalos should be discontinued. Strontium is excreted in breast milk, so it is not recommended to administer strontium ranelate during breastfeeding. Strontium ranelate does not affect the ability to drive vehicles or operate machinery. If signs of side effects appear, caution must be exercised.

Bone fragility, which characterizes postmenopausal osteoporosis, develops as a result of both an imbalance of bone remodeling at the cellular level, which leads to the predominance of bone resorption over bone formation, and an increase in the rate of remodeling at the tissue level. Most drugs for the treatment of osteoporosis (OP) with proven antifracture activity are substances that suppress bone resorption (bisphosphonates, estrogens, selective estrogen receptor modulators, calcitonins). Existing antiresorptive therapy for OP is implemented through suppression of osteoclast activity, which causes a decrease in bone metabolism and reduces the depth of resorptive cavities. This helps improve mechanical strength and increases bone mineralization.

However, bone remodeling is a two-way process, i.e., a decrease in osteoclast activity due to antiresorptive treatment is accompanied by a decrease in osteoblast activity. There is no doubt that antiresorptive therapy stops the progression of AP. This is evidenced by an increase in bone mineral density due to the filling of remodeling spaces and increased matrix mineralization. However, antiresorptive therapy only preserves, but does not restore, the destroyed microarchitecture. In severe cases of AP, stopping bone loss alone may not be enough to eliminate the risk of future fractures. In these cases, treatment that stimulates bone formation and restores bone loss can prevent fractures.

Among costimulating drugs, parathyroid hormone (teriparatide) significantly reduces the risk of fractures, which in small doses and intermittent administration has an anabolic effect on bone tissue, accelerating bone turnover (bone formation and bone resorption), but bone formation to a greater extent. Until recently, there were no drugs that had been convincingly demonstrated to both stimulate bone formation and reduce the rate of resorption in combination with a proven effect in reducing the risk of fractures. Since the 1990s Numerous experimental and then clinical studies (CTs) appeared, showing that strontium salts, considered as a costimulating agent, also have an antiresorptive effect, and strontium ranelate (SR), a medical preparation based on strontium and ranelic acid, can reduce the risk fractures in postmenopausal AP. In September 2004, a drug called “Protelos” was registered in Europe; on March 30, 2005, SR was registered in Russia under the commercial name Bivalos.

Pharmacokinetics

Strontium (Sr) is a divalent cation with a molecular weight of 87.62 Da and ranks 15th in frequency of occurrence in the earth's crust. Like calcium, strontium is an element of the fourth group of the periodic table of elements, but is in the next period and has a larger atomic radius.

Free, i.e. not bound to protein, strontium is excreted by the kidneys, to a lesser extent through the gastrointestinal tract (GIT) and with sweat, although some of it remains in the bones and very little in soft tissues. Intestinal absorption of strontium taken on an empty stomach is 25–30%, but the presence of calcium reduces strontium absorption by more than half. The absorption of the latter is due to both passive diffusion and active transport, and the same transporters are used as for calcium. In this regard, the absorption of strontium depends on vitamin D and decreases with age, as well as when the diet contains chelating agents, calcium and phosphorus.

The normal concentration of strontium in blood plasma is 0.11–0.31 µmol/l. Since strontium is close in physical and chemical properties to calcium, it predominantly accumulates in the skeleton, so that its share in bone tissue exceeds 99% of the total amount in the body. Strontium entering the body as part of drugs accumulates in the skeleton in direct proportion to the level in plasma. Its accumulation also depends on the duration of use and gender, and it predominantly accumulates in trabecular, rapidly renewing bone. Like calcium, strontium is excreted primarily by the kidneys, partially reabsorbed in the renal tubules. However, its reabsorption occurs to a much lesser extent than calcium, and, accordingly, it is excreted more quickly in the urine. The half-life of strontium in blood plasma is 62 hours, the maximum concentration is reached after 15 days, and the degree of its increase in blood plasma is dose-dependent. After discontinuation of strontium-containing drugs, its plasma level decreases rapidly.

A theoretical calculation of the elimination of strontium from bone tissue showed that the first fast elimination phase (half-life of 41 days) is followed by a slow elimination phase with a half-life of 3 years. The presence of the second phase may be a consequence of the slow removal of strontium included in old crystals. In the second phase, strontium excretion is stimulated by vitamin D and suppressed by bisphosphonates. In a study on monkeys, as early as 6 weeks after discontinuation of strontium ranelate at doses up to 750 mg/kg/day for 13 weeks, strontium content in bone tissue decreased by more than half.

Strontium ranelate, used for medical purposes, contains two stable strontium atoms bound to organic (ranelic) acid. This structure ensures an optimal ratio between strontium and the organic part of the molecule, good bioavailability of strontium and good gastrointestinal tolerability of the drug.

Evidence for a dual mechanism of action for Bivalos (strontium ranelate)

It is assumed that CP has a direct stimulating effect on osteoblasts, independent of the synthesis of local growth factors, since studies on calvarial cells did not reveal a connection between the addition of CP and the synthesis of messenger RNA (mRNA), such growth factors as insulin-like growth factor-1 (IGF-1) and IGF-2, platelet-derived growth factors A and B, transforming growth factor-beta1 and fibroblast growth factor.

Cell culture from the calvaria of newborn rats demonstrated an increase in the rate of bone formation by 30–35% (p

Brennan T. et al. (2006) demonstrated in cultured human osteoblasts by measuring alkaline phosphatase activity and labeled thymidine binding that CP increased the replication and differentiation of human osteoblasts. In a study by Choudhary S. et al. (2007) showed that CP also affects osteoblastic differentiation through enhancing prostaglandin E2-dependent growth factor production.

Strontium ranelate at a concentration of 0.1–1 mmol/l primarily has an effect on bone resorption, suppressing the activity of osteoclasts and without affecting their viability and adhesive properties. In a study on chicken bone marrow cell culture, stimulation of osteoclast differentiation with 1,25-dihydroxyvitamin D3 was used. Strontium ranelate at a concentration of 1 mmol/l reduced the number of osteoclasts expressing markers of functioning (carbohydrate anhydrase II and vitronectin receptor).

Currently, in the pathogenesis of postmenopausal AP, a significant role is played by imbalances in the osteoprotegerin / RANK (receptor activator of nuclear factor kB) / RANKL (receptor activator of nuclear factor kB ligand) system, which is of key importance in the regulation of bone metabolism. RANK is expressed on osteoclasts and RANKL is produced on the surface of osteoblasts. The interaction between RANK and RANKL leads to the differentiation and activation of osteoclasts, which enhances bone resorption. Osteoprotegerin is a protein secreted by osteoblasts that blocks the RANK/RANKL interaction, thereby reducing bone resorption. In the mechanism of development of postmenopausal AP, accelerated bone resorption plays a significant role, to some extent linking this with an age-related decrease in the production of osteoprotegerin. Recent studies have shown that SR enhances the production of osteoprotegerin by osteoblasts and thus suppresses accelerated bone resorption.

Thus, data from in vitro experiments indicate that SR suppresses the activity of osteoclasts without exerting a toxic effect on them, while at the same time stimulating maturation and enhancing the activity of osteoblasts. Thus, CP increases bone formation and the survival of bone-forming cells, enhances the expression of osteoprotegerin, which is included in the dual effect of CP on bone turnover, helping to reduce bone resorption.

Results of a study of the effectiveness of Bivalos in postmenopausal AP

Over the past 10 years, four large clinical trials have been conducted that examined the effect of Bivalos on bone markers, bone mineral density (BMD); vertebral and non-vertebral fractures, and the safety of its long-term use in postmenopausal AP was assessed. The main criterion for the clinical effectiveness of Bivalos was to study its effect on reducing the risk of new fractures both in the entire group of patients included in the study and in different subgroups depending on the age of the participants, risk factors, and the presence of previous fractures, since it is well known that that the risk of new fractures increases significantly in the first year after the fracture occurs.

The phase II studies PREVOS (Prevention of Early Postmenopausal bone loss by Strontium ranelat) and STRATOS (Strontium Ranelate for Treatment of Osteoporosis) involving 160 and 353 women, respectively, showed that the effective dose of Bivalos was 2.0 g when taken daily. Both studies demonstrated a significant dose-dependent increase in BMD in the vertebrae and femur.

When assessing the dynamics of bone markers, an increase in the levels of bone formation markers (PREVOS and STRATOS) and a decrease in bone resorption rates (STRATOS) were revealed. The STRATOS study found a reduction in the risk of vertebral fractures of 49% (0.5 g group) and 44% (2.0 g group) compared with placebo.

These encouraging results stimulated the large-scale SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (TReatment Of Peripheral OSteoporosis) studies. The main statistical analyzes for these two studies were performed after 3 years. By now finished

5-year trial of SR for the treatment of postmenopausal AP, statistical analysis performed. The drug testing program involved 75 centers from 12 countries.

SOTI included 1649 postmenopausal women with established AP (mean age 69.3 years), TROPOS included 5091 late postmenopausal women (mean age 76.7 years). Before inclusion of patients in these studies, a pilot study (FIRST) was undertaken, the goals of which were to normalize calcium and vitamin D levels in patients with AP, as well as to select patients for two main clinical trials. A total of 9196 women (mean age 74 years) were included in the study. In all patients, blood levels of vitamin D and calcium were determined and calcium intake from food was assessed using a standardized questionnaire in order to prescribe the necessary calcium and vitamin D supplements (500 or 1000 mg calcium and 400 or 800 IU vitamin D) according to the results. . This therapy was continued throughout subsequent studies.

In the SOTI study, the use of Bivalos demonstrated a statistically significant increase in bone formation in terms of bone alkaline phosphatase (ALP) and a decrease in bone resorption in terms of C-terminal telopeptide (CTx) compared to placebo (Fig. 1). When compared with the initial level, only ALP changed significantly, and CTx changed in two phases (decrease after three to six months and increase by 5% from the initial level by the third year of treatment), which may indicate the predominant effect of Bivalos on enhancing osteosynthesis. In patients receiving Bivalos, the level of CTx by the third year of treatment was statistically significantly lower than in the placebo group. The increase in BMD was 12.7% in the lumbar vertebrae, 7.2% in the femoral neck and 8.6% in the total hip, which was 14.4, 8.3 and 9.8% higher, respectively, compared to placebo ( p Fig. 2). Adjusted for greater x-ray absorption by strontium, vertebral BMD increased by 6.8% compared with baseline, which is comparable to the results of three years of bisphosphonate treatment for postmenopausal AP. The SOTI study revealed a significant reduction in the risk of morphometric and clinical fractures of the vertebral bodies by 50% after a year of treatment and by 41% after 3 years (p

Throughout the entire TROPOS study, starting from three months, in the Bivalos group the content of ALP was higher, and the resorption marker N-telopeptide (NTx) was significantly lower than in patients in the placebo group.

Thus, in all CIs, a small but significant increase in ALP was observed, which indicated stimulation of bone formation during Bivalos therapy and a simultaneous decrease in the levels of CTx and NTx, indicating a decrease in bone resorption, which confirms the unique multidirectional effect of Bivalos on bone remodeling. It is known that most antiresorptive drugs prevent bone destruction by reducing the rate of bone remodeling, which is manifested by a decrease in the content of markers of bone resorption (more than 50% for bisphosphonates and about 30% for raloxifene) and markers of bone formation (about 50% for bisphosphonates and 20% for raloxifene) . The use of parathyroid hormone significantly increases the level of markers of both bone resorption and bone formation. The mechanism of action of Bivalos is clearly different from the drugs mentioned, since along with a decrease in the levels of bone resorption markers, there is an increase in those of bone formation.

Recently, the results of histomorphometric analysis of 136 bone biopsies from 5 years of treatment of patients from the three aforementioned studies (STRATOS, SOTI and TROPOS) were published: 49 from the treatment groups and 89 from the placebo groups. The stimulating effect of Bivalos on bone formation was confirmed: an increase in osteoblastic surfaces by 38% during treatment with the latter compared with placebo (p = 0.047), a greater rate of mineralization in both trabecular (by 8%; p = 0.008) and cortical bone (11%). ; p = 0.033). The effect on bone resorption was a trend toward reductions in endosteal eroded surfaces, trabecular osteoclastic surfaces, and osteoclast counts (-14%, -9%, -9%, respectively). These results are consistent with those of the above studies on biochemical markers of bone metabolism.

In the TROPOS study, the dynamics of BMD corresponded to those in the SOTI study: in all measured areas, a significant and reliable increase was noted. After three years of treatment, a significant reduction in the risk of all non-vertebral fractures by 16% was found compared to placebo. In the group of patients with initial BMD at the femoral neck according to the T-criterion of 3.0 and below, a significant reduction in the risk of hip fractures by 36% was noted.

An analysis of the results of both studies after three years of treatment, conducted by Roux C. et al., showed that the antifracture effectiveness of Bivalos does not depend on the age of the patients, initial BMD, or the presence or absence of previous vertebral fractures.

The TROPOS study found that over five years of taking Bivalos, the risk of all non-vertebral fractures decreased by 15% (p = 0.03), fractures of large non-vertebral bones (femur, humerus, ribs, clavicle, pelvis) - by 16% (p = 0.04) and all vertebral fractures – by 24% (p Fig. 3).

Safety and tolerability of Bivalos

In the SOTI and TROPOS studies, Bivalos was well tolerated by patients; there was no significant difference compared with the placebo group in the frequency of all side effects recorded over three years of observation. Increased attention was paid to gastrointestinal side effects (see table).

As can be seen from the table, only diarrhea occurred significantly more often when taking Bivalos, but the difference in the incidence of this side effect disappeared after 3–6 months of treatment. The overall incidence of individual symptoms during treatment with Bivalos or placebo was assessed by analyzing pooled data from the SOTI and TROPOS studies. The most common side effects were nausea (6.6 vs. 4.3% in the placebo group) and headache (3.0 vs. 2.4%, respectively). These side effects were generally characteristic of the initial stage of treatment with the drug and subsequently disappeared, with no significant differences between the groups. In the first three months of treatment, a transient increase in phosphorus levels and a decrease in calcium in the blood plasma were also noted. The incidence of complications such as venous thrombosis and thromboembolism was 0.9 in the Bivalos group and 0.6% in the placebo group with an RR of 1.42 (confidence interval (CI) - 1.02-1.98; p = 0. 03) compared to placebo. However, if we look at population data, the frequency of thrombosis in women aged 60–74 years is 0.45, 70–79 years – 0.82, and in general after 75 years – 1.2%.

Thus, contraindications to treatment with Bivalos may include gastrointestinal diseases accompanied by diarrhea; chronic renal failure with creatinine clearance less than 30 ml/min; high risk of thrombosis and thromboembolism, as well as indications of these diseases in the anamnesis.

It was assumed that in elderly patients who experience a natural decline in renal function, the accumulation of CP in the bones and blood plasma when taking a dose of up to 4 g / day may become comparable to what causes osteomalacia in experimental laboratory animals and patients with chronic renal failure . However, a subanalysis of data from patients over 80 years of age did not reveal signs of osteomalacia, and the effectiveness of treatment for postmenopausal AP was no worse, and in a number of respects better than in younger patients.

It was very important for a drug that accumulates in bone tissue and is used for a long time to treat AP, to study its effect on bone tissue mineralization. Histomorphometric studies of bone biopsies from the iliac wing, carried out in different clinical trials, did not reveal signs of osteomalacia or any mineralization defects. In particular, no increase in osteoid thickness or delay in primary mineralization was detected.

conclusions

Based on an analysis of experimental work and clinical trials, it can be argued that Bivalos (strontium ranelate) is an effective drug for the treatment of postmenopausal AP and the prevention of the risk of both vertebral and non-vertebral fractures. It significantly increases BMD, has a dual effect on bone remodeling, stimulating the formation of new bone and reducing the rate of bone resorption, and increases bone strength. Bivalos is safe for long-term use, does not disrupt bone mineralization and the structure of the crystal lattice, is well tolerated by patients, is easy to use, ensuring a high level of patient adherence to treatment.

Bivalos has taken its rightful place among drugs for the treatment of postmenopausal AP. It is positioned as a first-line treatment for postmenopausal AP in clinical guidelines in Australia, Austria, Belgium, Bulgaria, Hungary, Germany, Hong Kong, Italy, Spain, Latvia, Singapore, Slovenia and France.

Strontium ranelate is included in the American Clinical Guidelines (ICSI Health Care Guidelines for Diagnosis and Treatment of Osteoporosis, www.icsi.org), which states that it is a dual-action drug on bone tissue with a pronounced antifracture effect on the vertebrae.

Interactions of the drug Bivalos

Taking medications containing calcium may reduce the bioavailability of strontium ranelate by approximately 60–70%. Therefore, an interval of at least 2 hours must be maintained between taking Bivalos and the above-mentioned medications. The use of aluminum and magnesium hydroxide simultaneously or less than 2 hours before taking strontium ranelate leads to a slight decrease in the absorption of strontium ranelate (20–25% reduction in AUC). The use of antacids 2 hours after taking strontium ranelate has virtually no effect on the absorption of strontium ranelate, therefore antacids containing aluminum and magnesium hydroxide are recommended to be taken at least 2 hours after taking Bivalos. However, if it is not possible to adhere to taking antacid medications at least 2 hours after taking Bivalos due to the recommended use of Bivalos before bedtime, then simultaneous use of Bivalos and antacid medications is allowed. Divalent cations of strontium ranelate can form complexes in the gastrointestinal tract with oral tetracycline and oral quinolone antibacterial drugs and reduce their absorption. Concomitant use of strontium ranelate with these medications is not recommended. During the use of tetracyclines or quinolones for oral use, treatment with Bivalos should be temporarily discontinued. No interactions have been observed with oral vitamin D preparations. Clinical studies have not revealed any interaction or increase in the level of strontium in the blood when used with drugs commonly used in this group of patients simultaneously with the drug Bivalos. These drugs include: NSAIDs (including acetylsalicylic acid), anilides (for example paracetamol), H2 receptor antagonists and proton pump inhibitors, diuretics, digoxin and cardiac glycosides, organic nitrates, calcium channel blockers, β-adrenergic blockers, ACE inhibitors, antagonists angiotensin II, selective β2-adrenergic receptor agonists, oral anticoagulants, antiplatelet agents, statins, fibrates and benzodiazepine derivatives.

Overdose of the drug Bivalos

In a clinical study examining the effect of repeated administration of strontium ranelate to healthy postmenopausal women at a dose of 4 g/day for more than 25 days, the drug was well tolerated. A single use of strontium ranelate in a dose of up to 11 g in volunteers (healthy young men) did not cause the development of any clinically significant side effects. After overdose episodes during clinical studies (up to 4 g/day, with a maximum treatment duration of 147 days), no clinically significant side effects were observed. In order to reduce the absorption of the active substance, it is advisable to take milk or antacids. In case of significant overdose, gastric lavage is recommended.