About the use of the drug Xidifon for calcium metabolism disorders

About the use of the drug Xidifon for calcium metabolism disorders

Currently, the need for the use of Xydifon has been proven in the complex treatment of diseases such as calcium nephrolithiasis and other kidney diseases with impaired calcium metabolism (dysmetabolic nephropathy, interstitial nephritis), hypervitaminosis D, hyperparathyroidism, as a means of preventing osteoporosis, immobilization, epilepsy, Recklinghausen's disease , Fahr's disease, dermatomyositis, progressive myositis ossificans and other myositis, with myofascial calcium deposits and atopic bronchial asthma. In addition, Xidifon has proven itself to be an accelerator of the elimination of heavy metal salts from the body in children [5]. The pharmacological properties of Xidifon have been studied in various pathological processes (including hypervitaminosis D and hyperparathyroidism) in humans and in animal experiments. The drug is eliminated from the body in the first 5–6 hours after a single oral dose. Over the next 6 hours, there is a gradual decrease in its excretion. A study of the pharmacokinetics of Xidifon revealed differences depending on the motor activity of patients, their age and the method of drug administration. It has been established that when Xydifon is taken orally, its concentration in the blood and urine increases sharply for a short time (within 1-2 hours), then gradually decreases and after 10-12 hours the drug is not detected in the urine. Absorption from the stomach averages 1–2% of the orally administered dose. Accordingly, a decrease in the concentration of the drug in the urine indicates its therapeutic effect. Xidifon reduces the concentration of ionized calcium and normalizes the level of total calcium in the blood [6]. From a clinical point of view, an extremely important property of Xydifon is its ability to stabilize cell membranes, the so-called membrane-protective properties with normalization of calcium homeostasis at the cellular level. It has been shown that Xidifon, like other diphosphonates, is fixed on the surface of cell membranes and is included in their structure, providing stability and resistance to spontaneous and enzymatic (phospholipase) hydrolysis of the phospholipid component of the membranes. It is the stabilization of membrane structures that is one of the main mechanisms for normalizing calcium homeostasis in cells [7,8]. In the process of searching for means of protection against mitochondrial pathology, an experiment was also conducted confirming the effect of Xydifon on smooth muscle mitochondria (bladder) and on their contractile ability. It has been shown that Xidifon potentiates the energy-dependent accumulation of calcium in mitochondrial fractions, which indicates its positive effect on calcium metabolism in mitochondria and on the contractile activity of smooth muscles [9,10]. As mentioned earlier, Xidifon has a wide range of applications in clinical practice. Let us take a closer look at some diseases in the pathophysiological treatment of which this drug is successfully used. Hyperparathyroidism is an endocrine disease characterized by increased production of the polypeptide hormone parathyrin or parathyroid hormone in the parathyroid glands. Parathyroid hormone is the main mediator of maintaining calcium homeostasis in the body. The secretion of parathyroid hormone is regulated directly by the plasma concentration of ionized calcium, and its action is aimed at increasing the concentration of plasma calcium. In developed countries, primary hyperparathyroidism is considered one of the main endocrinological problems along with diabetes mellitus and thyroid diseases. Since the early 70s of the 20th century, this pathology has ceased to be considered rare thanks to the introduction of systematic laboratory screening and the use of automatic analyzers for calcium levels in the blood [11]. Diffuse hyperplasia of all four glands occurs in 15–20% of patients, and in approximately half of them, as part of hereditary syndromes (in particular, multiple endocrine neoplasia syndrome type I or IIa). Typically, the disease is detected incidentally when hypercalcemia is detected in a patient in the absence of any symptoms [12]. Primary hyperparathyroidism is the most common cause of hypercalcemia. The disease occurs 2–4 times more often in women and affects 0.05–0.1% of the population, reaching 0.2% among hospitalized patients. Among women over 50 years of age, primary hyperparathyroidism is diagnosed in almost every second woman. The prevalence of primary hyperparathyroidism increases with age, but the disease can affect people of all ages, including children. In addition to primary, secondary and tertiary hyperparathyroidism are distinguished. Primary hyperparathyroidism is a disease initially caused by a tumor or hyperplastic change in one or more parathyroid glands, which leads to unregulated hypersecretion of parathyroid hormone and disruption of calcium homeostasis in the body. Secondary hyperparathyroidism is secondary hyperfunction and hyperplasia of the parathyroid glands, occurs with prolonged hypocalcemia (more often with chronic renal failure). Tertiary hyperparathyroidism is the occurrence of an autonomously functioning adenoma of the parathyroid glands against the background of long-existing secondary hyperparathyroidism. The etiology of the disease is unknown in most cases. The pathogenesis of clinical manifestations is multifaceted. It is based on the autonomization of parathyroid hormone production and the lack of feedback control in response to hypercalcemia [12]. The main targets of parathyroid hormone are bones and kidneys. The classic bone lesion observed in this pathology, osteitis fibrosa cystica, is now becoming less common. The most sensitive radiological sign of bone tissue damage is subperiosteal resorption of the middle phalanges of the fingers. An increased level of parathyroid hormone leads to constant resorption of calcium from the bones, which, in turn, can lead to osteopenia. Increased urinary calcium excretion also predisposes to the formation of nephrolithiasis. Other symptoms of hyperparathyroidism are associated with hypercalcemia itself and are not directly related to hyperparathyroidism. They may include muscle weakness, fatigue, hypovolemia, nausea, vomiting and, in extreme cases, lead to hyperosmolar hypercalcemic coma and death. Neuropsychiatric manifestations are the most common and may include depression, anxiety, memory impairment or very subtle disorders that often cannot be accurately characterized by patients. In severe cases, with calcemia exceeding 3 mmol/l, stuporous states and even coma are possible. Elevated calcium concentrations in the blood can increase gastric acid secretion, gastrin production, and contribute to the development of peptic ulcers. The development of gallstones and pancreatitis has also been associated with hyperparathyroidism in some patients. As a laboratory diagnosis, an increased level of intact parathyroid hormone is determined simultaneously with an increased concentration of ionized or total serum calcium, which confirms the diagnosis of hyperparathyroidism [11]. Determination of vitamin D and its metabolites is justified only if hyper- or hypovitaminosis is suspected. Drug therapy involves treating the hypercalcemia itself. The primary goal is to rehydrate patients, which can be achieved by drinking plenty of fluids in uncomplicated cases. In emergency situations, intravenous replenishment of the circulating plasma volume with sodium chloride and the administration of diuretics such as furosemide are used. For the purpose of pathophysiological treatment, the administration of diphosphonates (Xidifon) is used. Usually the effect occurs 4–5 days after the start of therapy. In the group of patients where a more rapid reduction in the level of calcemia is necessary, a synthetic salmon calcitonin preparation can be used. The effect occurs quickly, but after a few days complete refractoriness to this type of therapy develops. Glucocorticoids are also used as first-line drugs, especially in the case of paraneoplastic hypercalcemia, hypervitaminosis A and D. Experience with calcimimetics (a group of drugs that block calcium receptors on parathyroid cells) is promising, although it is not yet sufficient. The radical treatment for hyperparathyroidism is surgery [11]. Another, less common pathology, for the treatment of which Xydifon is successfully used, is hypervitaminosis D. This is a condition that occurs with an overdose of vitamin D or increased individual sensitivity, which is accompanied by the development of the symptom complex D–vitamin intoxication. Among the causes of this pathology are the use of large doses of vitamin D for treatment or prevention; usually the total dose is above 1 million IU. Sometimes hypervitaminosis is caused by small doses, which is explained by increased sensitivity to vitamin D. The pathogenesis is based on the toxic effect of vitamin D on cell membranes, metabolic disorders with the development of hypercalcemia and hypercalciuria, hyperphosphaturia, acidosis, calcification of tissues and internal organs. The clinical picture is characterized by lack of appetite, vomiting, combined with constipation, delayed physical development in children, thirst, and polyuria. The patient is excited, then becomes lethargic, convulsions, increased blood pressure, and slowed pulse may be observed. The leading biochemical signs are hypercalcemia, hypercalciuria. Differential diagnosis must be made with hyperparathyroidism and idiopathic calcinosis. The main treatment measure is to stop taking vitamin D, which leads to an improvement in the condition. In severe cases, especially in children in the first months of life, parenteral administration of an isotonic solution of sodium chloride and glucose, cardiovascular drugs, ascorbic acid and vitamins A, B is indicated; Prednisolone 1 mg/kg is also used for 5–7 days. It is necessary to carry out measures aimed at detoxification, restoration of impaired functions of internal organs, normalization of mineral metabolism and removal of calcium salts from the body. As mentioned above, the pathogenesis of hypervitaminosis D is based on the toxic effect of vitamin D on cell membranes, and therefore the use of the drug Xidifon leads to significant clinical improvement. The prognosis for this pathology depends on the degree of damage to internal organs. In case of intoxication with vitamin D and parathyroid hormone, morphological studies have shown that Xidifon helps accelerate the regeneration processes of damaged kidney tissue [13–15]. Not only the positive effect of the drug was noted, but also a general membrane-stabilizing and anti-inflammatory effect; normalization of serum calcium levels was also observed. A number of mechanisms for the positive action of Xydifon in cases of calcium metabolism disorders in soft tissues have been shown, one of which is the membrane-protective effect of Xydifon and indirect protection of soft tissues from calcification. In addition, in an experiment on animals that lasted for 3 years, the anticarcinogenic effect of Xydifon was confirmed, which since the 80s of the 20th century has been successfully used for malignant bone tumors (metastases) and breast cancer abroad [1,2,16 ]. In addition, Xidifon provides an additional positive effect in dysmetabolic nephropathy and interstitial nephritis, consisting of a moderate anti-inflammatory, analgesic and fibrinolytic effect, which is especially important when associated with infection or a tendency to stone formation [15,17]. As a membrane protector, Xidifon has a powerful inhibitory effect on the release of inflammatory and allergic mediators - leukotrienes and platelet activating factor, reduces the degree of basophil degranulation, increases the content of T-suppressors, reduces the level of immunoglobulin E in plasma and the transmembrane movement of calcium ions in stimulated leukocytes [18]. When treating bronchial asthma, Xidifon improves the ventilation function of the lungs [19]. Many other effects of diphosphonates, in particular Xydifone, have been described. Evidence has been obtained that in animal cells, diphosphonates significantly reduce the effect of mutagens [20–23]. The immunomodulatory effect of bisphosphonates has been sufficiently studied. It has been shown that they have a pronounced tropism for the tissues of the immune system. Under the influence of methylene diphosphonic acid in the immune cells of animals, the level of biosynthesis of DNA, RNA, protein, and the activity of some enzymes of adenosine and AMP metabolism change. On the other hand, methylene diphosphonic acid has virtually no effect on the uptake and metabolism of adenosine in immune cells. It has also been shown that bisphosphonates lead to inhibition of the biosynthesis of antibodies to T-dependent antigens and inhibition of cellular immune responses, which is due to their influence on the functional activity of T cells. It is believed that the biochemical basis of the immunomodulatory action of bisphosphonates is the inhibition of inorganic pyrophosphatase activity in the cell. Apparently, the immunomodulatory effect of Xidifon reflects the summation of their effect on biochemical reactions occurring with the participation of inorganic pyrophosphates in immunocompetent cells, and that this effect is based on the accumulation of diphosphonates in the immune system and the structural similarity between them and inorganic pyrophosphate. Using models of cellular immune response, it has been established that diphosphonates prevent the development of both systemic and local forms of delayed-type hypersensitivity reactions and do not have a cytotoxic effect on immune cells [24,25]. This is the basis for the use of Xydifon in atopic bronchial asthma, and this also partially explains the anti-inflammatory effect in kidney diseases. It has been shown that Xidifon, both in vivo and in vitro, significantly reduces the content of serum and intracellular cholesterol, the proliferative activity of cells, and normalizes the enzymatic spectrum of lysosomes in adipocytes and platelets. Recommendations for the use of Xydifon as an antiatherosclerotic agent are based on this action [26]. Also, in the process of clinical studies, it was proven that, together with the use of Xydifon, daily intake of vitamin E (in physiological doses) is necessary throughout the course of treatment. The initial course of treatment is 14 days. If long-term treatment with Xydifon is necessary, repeat courses are carried out after 1.5–2 months. for years (dermatomyositis, urolithiasis, intoxication with salts of heavy metals, etc.). Xidifon is currently used in the form of a 2% solution. Prescribed at the rate of 10 mg per 1 kg of body weight per dose 30 minutes before meals 1-2 times a day for 2 weeks to 3 months. Contraindications to the use of this drug are hypersensitivity, hypocalcemia, pregnancy, and lactation. It should be used with caution in chronic enterocolitis and renal failure. Thus, Xidifon is a unique drug that regulates calcium metabolism in the body, which currently occupies a strong place in the treatment of various pathologies. Literature 1. Arkhipova O.G., Yuryeva E.A., Dyatlova N.M. Prospects for the use of complexones in medicine. Journal of the All-Union Chemical Institute named after. DI. Mendeleeva 1984; 29:3:316–320. 2. Veltishchev Yu.E., Yuryeva E.A., Arkhipova O.G. Some prospects for the clinical study of the therapeutic use of phosphonic compounds. Vopr Med Chem 1975; 5:451–461. 3. Veltishchev Yu.E., Yuryeva E.A., Kudrin A.N. Biologically active phosphonic acids and their derivatives. Chem Pharm J. 1983; 17:3:282–290. 4. Fleisch H. Bisphosphonates in bone disease. New York, London 1997; 184. 5. Yuryeva E.A., Alekseeva N.V. Xidifon is a calcium-regulating drug. Russian Bulletin of Perinatology and Pediatrics, N4–1999, pp. 45–49. 6. Veltishchev Yu.E. (ed.) Xidifon is a new means of regulating calcium metabolism in the body in pathology. Dep. VNIIMI N 72–13–85 1985; 180. 7. Veltishchev Yu.E. Problems of membrane pathology in pediatrics. Vopro okhr mat i det 1981; 27:4:3–9. 8. Veltishchev Yu.E., Kapustyan A.M. Problems of childhood pathology in terms of disruption of the structure and function of biological membranes. Scientific review of VNIIMI. M 1982; 82. 9. Marchenko S.N., Burdyga F.V., Babich L.G., Yuryeva E.A. The effect of xydiphone and AMOC on Ca++ transport in subcellular fractions of smooth muscle and its contractility. In: Multiorgan membrane pathology. Ed. Yu.E. Veltishchev et al. M 1991; 181–191. 10. Yurieva EA, Osmanov JM, Raba GP, Matkovskaya TA Pharmacological characteristics of xydiphone. Bone 1996; 17: 6: 618. 11. Cherenko S.M. Primary hyperparathyroidism: modern view on prevalence, diagnosis and surgical treatment. Health of Ukraine 2007; 22/1; on pp. 50–53. 12. Zahrani AAI, Levine M. Primary hyperparathyroidism. Lancet 1997;349:1233–1238. 13. Yuryeva E.A., Simanina L.V., Alekseeva N.V., Vozdvizhenskaya E.S. Xidiphone as a means of pharmacological diagnosis in urolithiasis. In Sat.: a new helating agent - Xidiphone. Ed. Yu.E. Veltishchev et al. M 1990; 52–57. 14. Yuryeva E.A., Vozdvizhenskaya E.S., Alekseeva N.V., Simanina L.V. Clinical aspects of dimitabolic nephropathy, interstitial nephritis, urolithiasis in calcifilaxia. Pediatrics 1989; 1: 42–48. 15. Yuryeva E.A., Dunaeva I.P., Kulakova T.I., Korovina N.A. The effectiveness of xidiphone, depending on the method of its use in dispmetabolic nephropathy and interstitial nephritis. In Sat.: a new helating agent - Xidiphone. M 1990; 62–70. 16, Chalov MB, Arkhipova O.G., Krinitskaya L.V., Alekseeva N.V. The anticandine activity of xidiphone in experimental animals. In Sat.: a new helating agent - Xidiphone. Ed. Yu.E. Veltishchev et al. M 1990; 70–74. 17. Yuryeva E.A., Dunaeva I.P., Kulakova G.I., Korovina N.A. Dimitabolic nephropathy and interstitial nephritis combined with polyorgan membrane pathology in children. In Sat.: Polorgan membrane pathology. M 1991; 77–83. 18. Svyatkina O.P., Round B.I. A change in the release of leukotrienes in children with atopic bronchial asthma. Department VNIIMI AMN USSR. N 10328. M 1986; 2. 19. Svyatkina O.P. Leukotrienes are a new class of highly active biological substances. Successes of modern biology 1984; 99: 3: 413–425. 20. Veltishchev Yu.E., Seleznev Yu.S. Antimutagenic effect of xidiphone. Genetics 1978; 14: 1276–1278. 21. Veltishchev Yu.E., Yuryeva E.A., Dyatlova N.M. Helating agents in pharmacology, toxicology and therapy. In Sat.: a new helating agent - Xidiphone. Ed. Yu.E. Veltishchev. M 1990; 2–12. 22. Veltishchev Yu.E., Yuryeva E.A., Alekseeva N.V. Polyorgan membrane pathology as a result of oxidative stress in the body. In Sat.: Polorgan membrane pathology. Ed. Yu.E. Veltishchev. M 1990; 2–13. 23. Ablev S.K., Dyatlova N.M., Krinitskaya L.V., Chalov M.B. The antimutagenic activity of xidiphone in the experiment. In Sat.: a new helating agent - Xidiphone. Ed. Yu.E. Veltishchev et al. M 1990; 74–78. 24. Komissarenko S.V., Fomovskaya G.N., Penesina O.P., Borisova A.N. Bisphosphone complexes in immunjective molecules for diagnosing receptors on the surface of the cell. In Sat.: a new helating agent - Xidiphone. Ed. Yu.E. Veltishchev et al. M 1990; 28–29. 25. Fomovskaya G.N., Komissarenko S.V. The biochemical mechanisms of the immunotropic effects of methylenebospherfospherent acid. In Sat.: a new helating agent - Xidiphone. Ed. Yu.E. Veltishchev et al. M 1990; 24–28. 26. Knyazev Yu.A., Turkina T.I., Yuryeva Yu.A. The hypocholesterolemic effect of xidiphone. VOPR honey chem 1983; 29: 72–74.

Bisphosphonates in the treatment of postmenopausal osteoporosis

Osteoporosis is a progressive systemic disease of the skeleton, characterized by a decrease in density and disruption of the microarchitecture of bone tissue with a constant increase in bone fragility and the risk of fractures. The relevance of the problem of osteoporosis in modern medicine is caused primarily by the social and economic consequences of fractures. At the same time, the problem of osteoporosis in the future should become even more global, since in modern society there is an increase in life expectancy and a general aging of the population.

The majority of people susceptible to osteoporosis are women. In the first 5 years after menopause, a woman’s bone loss can amount to up to 1/3 of the bone mass lost throughout her life [7, 11]. Nearly 30% of postmenopausal women have osteoporosis and approximately 54% have osteopenia, making them vulnerable to osteoporosis and osteoporotic fractures. Thus, for a 50-year-old woman, the risk of a fracture of the spine is on average 15.5%, of the femoral neck - 17.5%, of the wrist bones - 16.0%, and of any of the three parts of the skeleton - 39.7%. In addition, 50% of women over 50 years of age will experience an osteoporotic fracture during their later lives [18].

Osteoporosis is the leading cause of hip fractures, which are common in women over 65 years of age. In elderly people, 90% of hip fractures, as international studies have shown, occur due to osteoporosis [7, 11]. Unfortunately, there has been a clear trend towards an increase in the incidence of hip fractures against the background of osteoporosis and in the age group of 50–60 years. The consequences of hip fractures are catastrophic: 20% of patients die within six months, half of those who survive a hip fracture have a reduced quality of life, and a third require long-term care and find themselves in a dependent state [1, 2, 11]. Fractures of the proximal femur are considered the most costly because, among other things, they require hospitalization. According to WHO, it is fractures of the proximal femur that place osteoporosis in 4th place among all causes of disability and mortality [1, 11, 18].

Currently, there are effective programs for the prevention and treatment of osteoporosis, including a combination of non-pharmacological methods with modern anti-osteoporotic drugs. Early prevention and treatment of osteoporosis can slow down the progression of the disease, reduce the incidence of bone fractures and improve the patient’s quality of life. The main goals of treatment for osteoporosis are to slow or stop bone loss, prevent fractures, reduce pain, and improve quality of life. Among the means of pathogenetic pharmacotherapy of osteoporosis, depending on the predominant mechanism of action, three main groups are distinguished: drugs that slow down bone resorption; drugs that stimulate bone formation; drugs with multifaceted action.

Among drugs that suppress bone resorption, bisphosphonates are most widely used in the treatment of osteoporosis and other bone pathologies [4, 20, 22]. This is a class of drugs created on the basis of inorganic pyrophosphates, synthetic derivatives of phosphonic acids, which differ in their chemical structure by replacing the oxygen atom in the pyrophosphate molecule with a carbon atom - P-C-P. In addition, the structure of the side chains of bisphosphonates contains two radicals, one of which facilitates the physicochemical binding of bisphosphonates to hydroxyapatite, and the other determines the biological effect of the drugs on bone cells [2, 7]. The selective effect of bisphosphonates on bone tissue is associated with their high affinity for bone hydroxyapatite crystals. This property determines their ability to be deposited in places where new bone is formed. Bisphosphonates remain in places of new bone formation until the old bone is replaced by new bone [1, 8]. The main pharmacological effect of bisphosphonates is a decrease in bone remodeling with a more pronounced inhibition of bone resorption than bone formation, as well as a decrease in the frequency of activation of remodeling. The drugs reduce or prevent the negative effects on bone of almost all known resorption stimulants [4, 14]. Penetrating into bone tissue, bisphosphonates concentrate around osteoclasts, creating a high concentration in resorption lacunae. In vitro studies have shown that bisphosphonates affect the depth of resorption lacunae, reducing it.

The antiresorption activity of individual drugs from this group varies significantly, which is associated with the characteristics of the chemical structure.

Below we list bisphosphonates depending on their activity.

1 x — etidronate acid (xidifon, didronel);

10 x - clodronic acid (Bonefos, Lodronate, Ostak), tiludronic acid (Skelid);

100 x - pamidronic acid (Aredia, aminomax);

1000 x - alendronic acid (fosamax, osteotab);

10,000 x - risedronic acid (Actonel), ibandronic acid (Bonviva), zoledronic acid (Zometa, Aklasta).

The first generation of bisphosphonates - etidronate, disodium clodronate and tiludronate, which do not contain nitrogen atoms in their structure, are metabolized intracellularly by osteoclasts to cytotoxic analogues of adenosine triphosphate. By blocking the synthesis of farnesyl diphosphate synthase, nitrogen-containing bisphosphonates reduce the formation of mevalonate, which is necessary to maintain normal cytoarchitecture and vital activity of osteoclasts [21, 22]. The latter are stronger inhibitors of osteoclastic activity and osteolysis than drugs that do not contain nitrogen in their structure [24]. Structural differences in the nitrogen chain of bisphosphonates also influence their effectiveness in inhibiting bone resorption.

Bisphosphonates are taken up by osteoclasts, where they disrupt the formation of the cytoskeleton necessary for osteoclast attachment to bone tissue, and also reduce the secretion of lysosomal enzymes. The cellular mechanism of action of bisphosphonates is to directly inhibit the activity of osteoclasts, their mobility, as well as blocking the binding of osteoclasts to bone tissue [20, 21]. The presence of a nitrogen atom in the side chain explains the special mechanism of action of nitrogen-containing bisphosphonates, associated with the ability to inhibit the process of protein modification in osteoclasts, which leads to apoptosis of mature cells and is confirmed by the appearance of specific changes in the cell and nuclear structure [13, 24]. The action of nitrogen-containing bisphosphonates, in addition, leads to the loss of the ability of osteoclast precursor cells to differentiate and mature, which subsequently entails a decrease in the osteoclast population. However, the exact molecular mechanism of action of bisphosphonates is still unclear.

Along with antiresorption effects, bisphosphonates have an inhibitory effect on the processes of mineralization of skeletal and soft tissues [2, 21]. Osteoblasts are also potential targets for bisphosphonates because they affect the functional activity of osteoclasts. In vitro data indicate that, under the influence of bisphosphonates, osteoblasts reduce the secretion of osteoclast-stimulating factor [1, 13, 14].

In addition to the antiresorption effect, bisphosphonates have a number of anabolic effects, since they block the apoptosis of osteoblasts and osteocytes and stimulate the formation of new bone [19, 21]. It is important to note the positive effect of bisphosphonates on the mechanical strength of bone. Long-term use of bisphosphonates is accompanied by positive changes in bone microarchitecture and an increase in the thickness of trabeculae. Thus, a histomorphometric study of bone biopsies showed that the microarchitecture of bone in women treated with bisphosphonates for 5–10 years corresponds to the microarchitecture of premenopausal women [19]. Absorption of drugs occurs partially in the stomach, and mainly in the small intestine [2, 6]. When bisphosphonates are taken orally, 1–10% of the drug is absorbed, but 20 to 50% of the absorbed drug is deposited in the bones. The absorption process is reduced when taken simultaneously with food, as well as in the presence of calcium and iron salts. Also, the absorption process is reduced by antacids. They are stored in bone tissue for a very long time, almost the entire rest of the individual’s life [1, 2, 20]. Bisphosphonates are not metabolized in the body and are excreted unchanged in the urine.

Side effects of bisphosphonates when used orally include primarily disorders of the gastrointestinal tract (6–30% of cases): nausea, vomiting, dyspepsia, abdominal pain, ulceration of the mucous membrane of the esophagus and stomach [6, 10, 15]. The risk of side effects from the gastrointestinal tract increases when administered simultaneously with non-steroidal anti-inflammatory drugs. Muscle and headaches, skin allergic reactions and transient fever are rarely observed. When administered intravenously, especially if the rule of slow infusion of the solution is not observed, kidney damage may occur. Since drugs in this group cross the placenta and can adversely affect the fetus, they should not be used during pregnancy.

One of the conditions for effective treatment of osteoporosis with bisphosphonates in the presence of hypocalcemia in a patient is its mandatory correction before starting therapy. Long-term therapy with bisphosphonates is effective with additional intake of calcium salts (1–1.5 g/day) and 500 IU of vitamin D [6, 8, 17]. The interval between taking bisphosphonates and other medications should be at least 1 hour.

In clinical practice, bisphosphonates are effectively used for the treatment of almost all forms of osteoporosis, as well as the treatment of hypercalcemia, osteolytic conditions in malignant tumors and bone metastasis [4, 21, 23].

Until now, in osteoporosis, etidronic and alendronic acids have been mainly used in practice as the most studied drugs. The greatest experience in treating patients with osteoporosis has been accumulated with first-generation drugs (ethidronic acid). Alendronic acid, a member of the group of aminobisphosphonates, for osteoporosis is prescribed 70 mg once a week or 10 mg daily. The drug, like other bisphosphonates, should be taken 60 minutes before meals. It is necessary to maintain an upright body position for an hour after administration.

Therapy for osteoporosis, which is a severe chronic disease, must be carried out over a long period of time. In this regard, in practice, the problem of patient adherence to treatment often arises, which is closely related to the effectiveness of therapy. The new generation bisphosphonate bonviva (ibandronic acid) has broad clinical prospects, the main advantage of which is not only greater antiresorptive activity, but also the possibility of using 1 tablet once a month in the treatment of patients with osteoporosis [15, 16, 23]. Thus, when studying the possibility of ibandronic acid to cause inhibition of bone resorption in a model of retinoid-induced bone resorption, its significant advantage over pamidronic and alendronic acids was shown [21].

Bonviva (ibandronic acid) is a third-generation nitrogen-containing bisphosphonate and is used in the treatment of osteoporosis at a dose of 150 mg orally once a month [16, 22, 24]. Once absorbed, Bonviva is rapidly distributed and 40–50% of the drug dose in the systemic circulation binds to and accumulates in bone tissue, consistent with the concept of high affinity of the drug for bone hydroxyapatite. Once bound to bone minerals, the release of the drug is extremely slow. Bioavailability is not reduced if food is taken no earlier than 1 hour after taking the drug. Like other bisphosphonates, Bonviva is not metabolized in the body and is excreted unchanged in the urine. The clearance of ibandronic acid depends on renal function. The portion of the drug that is bound to bone tissue is not eliminated from the body until the process of bone remodeling is completed in that area of ​​the bone. According to experimental studies, the half-life of Bonviva from bones is about 1 year.

The clinical effectiveness of Bonviva was confirmed by data from a number of multicenter studies examining the effect of different doses of ibandronic acid on bone mineral density (BMD) and bone quality, the risk of developing new fractures and tolerability of the drug [16, 22, 24]. The results of the MOBILE study (multicenter, randomized, double-blind) showed that when ibandronic acid was administered once a month in women with postmenopausal osteoporosis, bone mineralization of the lumbar spine increased as effectively as when taking 2.5 mg daily [16 ]. The study included 1609 women (age 55–80 years) with a postmenopausal duration of 5 years or more who had diagnosed osteoporosis in the lumbar spine (BMD T-score from –2.5 CO to –5.0 CO). Patients were prescribed several regimens for taking bonviva or placebo: 2.5 mg bonviva per day orally and placebo once a month; Bonviva 100 mg orally once a month and placebo daily; 100 mg of Bonviva orally once a month, 50 mg/day for 2 days in a row (50/50 mg) and daily placebo; Bonviva 150 mg orally once a month and placebo daily. In addition, all study participants took calcium (500 mg) and vitamin D (400 IU) supplements daily. The primary endpoint for evaluating efficacy was the change in lumbar vertebrae BMD after 1 year of treatment compared to baseline. Secondary efficacy endpoints included changes in BMD of the lumbar vertebrae after 2 years, BMD of the proximal femur after 1 and 2 years of therapy, changes in the level of bone turnover markers (C-telopeptide α-chain of type I collagen (CTx) serum) after 1 and 2 years . After 1 year, there was a significant increase in BMD of the lumbar spine relative to baseline values ​​by 4.3% when taking 50 mg/50 mg Bonviva, by 4.1% when taking 100 mg, by 4.9% when taking 150 mg monthly and by 3.9% with a daily dose of 2.5 mg Bonviva [9]. The increase in BMD of the lumbar vertebrae after 2 years of the study was 5.3%, 5.6% and 6.6% when taking 50 mg/50 mg, 100 mg and 150 mg of Bonviva, respectively, and by 5.0% when taking the drug daily [25 ]. A significant increase in BMD of the hip as a whole, femoral neck and greater trochanter area was observed in all treatment groups 1 year after therapy and persisted during the second year of treatment. (rice.). Compared with the daily dosing regimen, Bonviva 150 mg once a month was associated with the largest and most progressive increase in BMD at all proximal femoral sites (p < 0.05 at 2 years). A study of the level of bone turnover markers showed a decrease after 3 months of treatment. The decrease continued throughout the observation period. After 2 years, the reduction in serum CTX levels was 56.1–61.5% in the treatment groups, with the greatest reduction in the group receiving 150 mg ibandronic acid.

The BONE study conducted histological and histomorphometric analyzes of bone biopsies in a subgroup of patients participating in a program to evaluate the effects of intermittent and daily ibandronic acid dosing on bone quality and microarchitecture [6]. The results showed that both intermittent and daily oral administration of Bonviva were associated with new bone formation without evidence of disruption of bone matrix mineralization, while there were signs of improvement in bone microarchitecture.

As noted above, the effectiveness of therapy for any chronic disease is closely related to the patient’s adherence to treatment. The results of the multicenter BALTO study, dedicated to the comparative assessment of patient adherence to treatment, showed that 66.1% of women with postmenopausal osteoporosis prefer monthly intake of 150 mg of Bonviva to weekly intake of 70 mg of alendronic acid [9].

The results of these and a number of other studies also indicated that the relatively large dose that was necessary to take the drug once a month did not have a significant effect on the tolerability of Bonviva. In addition, Bonviva was not associated with an increased risk of upper gastrointestinal side effects [16, 22, 24].

In conclusion, it should be noted that Bonviva is an effective treatment for osteoporosis. Its long-term use in the complex treatment of various forms of osteoporosis leads not only to a progressive increase in BMD in the lumbar spine and proximal femur, but also reduces the risk of vertebral fractures.

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A. M. Mkrtumyan , Doctor of Medical Sciences, Professor E. V. Biryukova MGMSU, Moscow