ALPHA D3-TEVA CAPS - instructions for use

Pharmacological properties of the drug Alpha D3-teva

Alpha D3-Teva is a pro-D hormone (a highly effective active metabolite of vitamin D3) that regulates the metabolism of calcium and phosphorus. Alphacalcidol (1-alpha-hydrocholecalciferol) in the liver and bone tissue is very quickly transformed into calcitriol (1,25-dihydrocholecalciferol, D-hormone) in the liver. Calcitriol is the major metabolite of cholecalciferol (vitamin D3) and plays a key role in maintaining calcium and phosphorus homeostasis through intestinal calcium absorption and renal reabsorption. In the body, calcitriol (1,25(OH)2D3) is normally formed as a result of two successive reactions of hydroxylation of cholecalciferol (ergocalciferol) - initially in the liver and bone tissue into calcidol (25(OH)2D3) - a slightly active compound, and then in the kidneys involving 1 alpha-hydroxylase in 1,25(OH)2D3. In osteoporosis, there is a decrease in the activity of 1 alpha-hydroxylase in the kidneys, which leads to a decrease in calcitriol levels and impaired calcium absorption in the intestine. Alpha D3-Teva transforms into 1,25-dihydrocholecalciferol (D-hormone) and increases its level in the blood. This causes an increase in the absorption of calcium and phosphorus in the intestines, an increase in their reabsorption in the kidneys, increased bone mineralization, and a decrease in the level of parathyroid hormone in the blood. In patients with impaired alpha-hydroxylation in the kidneys that occurs with age, taking Alpha D3-Teva promotes sufficient formation of calcitriol, which neutralizes the deficiency of D-hormone. Alpha D3-Teva restores a positive calcium balance, as a result of which the intensity of bone resorption decreases, which helps reduce the incidence of fractures. Increases bone mineral density. With a course of use of the drug, there is a decrease in the severity of bone and muscle pain associated with impaired phosphorus-calcium metabolism, improved coordination of movements and balance support, increased muscle strength, as a result of which the frequency of falls decreases. Pharmacokinetics . After oral administration, Alpha D3-Teva is quickly absorbed into the gastrointestinal tract. The time to reach the maximum concentration of the drug in the blood plasma is 8–18 hours. The onset of action is after 6 hours, the duration of action is up to 48 hours. In the liver and bone tissue, alfacalcidol is quickly transformed into calcitriol (1,25-dihydrocholecalciferol, D-hormone). The rate of transformation of Alpha D3-Teva into D-hormone in the body is regulated by the feedback principle and depends primarily on the initial plasma level of D-hormone, as well as on the plasma levels of Ca and PGT. Unlike natural vitamin D3, the biotransformation of the drug does not occur in the kidneys, which allows its use in patients with renal pathology, as well as in all patients with osteoporosis, accompanied by a decrease in the activity of 1 alpha-hydroxylase.

Alpha D3-Teva® (Alpha D3-Teva®)

Attention should be paid to patients taking cardiac glycosides, since hypercalcemia can lead to the development of arrhythmia in such patients.

Attention should be paid to patients taking thiazide diuretics, as the risk of developing hypercalcemia may be increased in such patients.

The effectiveness of alfacalcidol is generally maintained in patients with reduced liver function. In severe liver failure, the concentration of the active metabolite 1,25-dihydroxyvitamin D may decrease due to a weakening of the hydroxylation process or due to decreased enterohepatic circulation. In this case, it may be necessary to prescribe the drug in higher doses.

When using the drug in older people, no dose adjustment is required.

The drug may contribute to the development of hypercalcemia, so patients should be informed about the clinical symptoms of this condition (see section "Overdose"). While using the drug Alpha D3-Teva®, it is necessary to regularly monitor the concentration of calcium, phosphate, calcium-phosphate compounds, alkaline phosphatase and the level of parathyroid hormone in the blood serum.

Calcium concentration should be determined once a week or month depending on the clinical situation. More frequent calcium measurements are required early in treatment, especially in conditions without significant bone damage, such as hypoparathyroidism, and if plasma calcium is already elevated, and later in treatment if there is evidence of bone regeneration. The risk of developing hypercalcemia is determined by factors such as: the degree of bone demineralization, renal function and the dose of Alpha D3-Teva®. The appearance of hypercalcemia may be due to the fact that the dose of the drug is not reduced in a timely and adequate manner in the presence of biochemical signs of restoration of bone tissue structure (normalization of alkaline phosphatase in the blood). The development of prolonged hypercalcemia, especially in chronic renal failure, should be prevented, focusing on such indicators as the concentration in the blood serum of calcium, alkaline phosphatase, parathyroid hormone, the amount of calcium excreted in the urine, radiological and biochemical data.

If hypercalcemia develops or a persistent increase in the level of calcium phosphate compounds beyond the clinical norm, the drug should be discontinued immediately, at least until these indicators return to normal (usually within one week), then the drug can be resumed at a dose that is half the previous dose.

Excessive suppression of parathyroid hormone should be avoided. For patients on dialysis, serum parathyroid hormone levels should be in accordance with current treatment guidelines.

To prevent the development of hyperphosphatemia in patients with bone lesions of renal origin, alfacalcidol can be used together with phosphate binders.

For osteoporosis, the use of Alpha D3-Teva® can be combined with estrogens and antiresorptive drugs.

The excipients of the drug include peanut oil. The drug is contraindicated in patients with an allergic reaction to peanut butter and soy.

Indications for use of the drug Alpha D3-teva

main types and forms of osteoporosis (postmenopausal osteoporosis;
osteoporosis associated with treatment with corticosteroids, senile);
osteomalacia as a consequence of insufficient absorption, for example in the case of malabsorption and post-gastroectomy syndrome;
hypoparathyroidism;
hypophosphatemic vitamin D-resistant rickets/osteomalacia (as additional therapy);
osteodystrophy in chronic renal failure;
with the goal of significantly reducing the incidence of falls among older people.

Use of the drug Alpha D3-teva

Inside. The capsule should be swallowed whole with plenty of water. The dose and duration of therapy is determined by the doctor individually and depends on the nature of the disease and the effectiveness of therapy. In some cases, the drug is used throughout life. Unless otherwise prescribed, the starting dose for adults is 1 mcg of alfacalcidol (4 capsules of 0.25 mcg or 2 capsules of 0.5 mcg or 1 capsule of 1 mcg) daily. For patients with more severe bone disease, higher doses are prescribed: 1–3 mcg alfacalcidol (4–12 capsules of 0.25 mcg or 2–6 capsules of 0.5 mcg or 1–3 capsules of 1 mcg) daily. Children over 6 years of age with body weight ≥20 kg - 1 mcg/day (except in cases of renal osteodystrophy). For patients with hypoparathyroidism, the dose should be reduced once normal blood calcium levels are achieved (22–2.6 mmol/L; 8.8–10.4 mg/100 ml) or when the product of plasma calcium × phosphate concentrations = 3. 5–3.7 (mmol/l). Alpha D3-Teva capsules 0.25 mcg : If the daily dose is 0.5 mcg of alfacalcidol, take 1 capsule morning and evening daily. If the daily dose is 1 mcg of alfacalcidol, take 2 capsules in the morning and evening daily. Alpha D3-Teva capsules 0.5 mcg : If the daily dose is 0.5 mcg, take 1 capsule in the evening daily. If the daily dose is 1-3 mcg of alfacalcidol (2-6 capsules of 0.5 mcg), it should be divided in half and taken one half in the morning and the other in the evening. Alpha D3-Teva capsules 1.0 mcg : If the daily dose is 1 mcg of alfacalcidol, take 1 capsule in the evening daily. If the daily dose is 3 mcg of alfacalcidol, take 1 capsule in the morning and 2 capsules of Alpha D3-Teva in the evening.

Alphacalcidolum

Individually. The daily dose for adults varies from 0.07 mcg to 20 mcg, for children 0.01-0.08 mcg/kg.

Inside. The recommended daily dose of the drug can be taken immediately in 1 dose, or the dose can be divided into 2 doses. Therapy can last from 2-3 months to 1 year or more. The duration of treatment is determined by the doctor for each patient individually.

Adults

For osteomalacia associated with malnutrition or malabsorption:

from 1 to 3 mcg per day for at least 2-3 months.

For hypoparathyroidism:

from 1 to 4 mcg per day.

For osteodystrophy in chronic renal failure:

from 0.5 to 2 mcg per day in courses for 2-3 months 2-3 times a year.

For Fanconi syndrome and renal acidosis:

from 2 to 6 mcg per day.

For hypophosphatemic osteomalacia:

Therapy begins with a dose of 4 mcg per day. The maximum daily dose can reach 20 mcg.

For osteoporosis (including postmenopausal, senile, steroid):

from 0.5 to 1 mcg per day. It is recommended to start treatment with a minimum dose, monitoring the content of calcium and phosphorus in the blood plasma once a week. The dose can be increased by 0.5 mcg per day until biochemical parameters stabilize.

Parenteral, intravenous. It is necessary to begin treatment with minimal doses, monitoring the level of calcium and phosphorus in the blood once a week. Orally, adults: initial dose 1 mcg per day, can be increased by 0.25-0.5 mcg per day until biochemical parameters stabilize.

Intravenously, during hemodialysis at the end of each session in the form of a bolus (within 30 s). The injection should be carried out in the return line of the device (as close as possible to the patient - to eliminate the risk of absorption of alfacalcidol by the plastic). The initial dose is 1 mcg, the maximum is 6 mcg per dialysis, but not more than 12 mcg within 1 week.

Children over 3 years old

For rickets and osteomalacia associated with malnutrition or malabsorption:

from 1 to 3 mcg per day for at least 2-3 months.

For osteodystrophy in chronic renal failure:

from 0.5 to 1 mcg per day in courses for 2-3 months 2-3 times a year.

For Fanconi syndrome and renal acidosis:

from 2 to 6 mcg per day.

For hypophosphatemic rickets and osteomalacia:

Therapy begins with a dose of 1 mcg per day.
Parenteral, intravenous.
Hypophosphatemic rickets, persistent hypocalcemia due to hypo- and pseudohypoparathyroidism. 1 month-12 years: intravenously at a dose of 25-50 ng/kg per day (maximum dose 1 mcg). 12-18 years: 1 mcg per day. Persistent neonatal hypocalcemia. Newborns are prescribed intravenously at a dose of 50-100 ng/kg per day (up to 2 mcg/kg in resistant cases).

Prevention of vitamin D deficiency in patients with kidney disease or cholestatic liver disease. Newborns are prescribed intravenously at a dose of 20 ng/kg per day. 1 month-12 years with body weight up to 20 kg 15-30 ng/kg per day (maximum dose - up to 500 ng), with body weight over 20 kg - at a dose of 250-500 ng per day; children 12-18 years old: at a dose of 250-500 ng per day.

Side effects of the drug Alpha D3-teva

If the dose of alfacalcidol is not adjusted, there may be an increase in calcium levels in the blood, which disappears when the dose is reduced or the drug is temporarily stopped. Signs of a possible increase in calcium levels in the blood are fatigue, gastrointestinal disorders (vomiting, heartburn, abdominal pain, nausea, epigastric discomfort, constipation, diarrhea), anorexia, dry mouth, moderate muscle pain, bone pain, joints. During therapy with alfacalcidol, the following adverse reactions are possible: rarely (1/10,000 and ≤1/1000) - a slight increase in the level of phosphates in the blood, in order to prevent which the patient can be prescribed phosphate absorption inhibitors (such as aluminum compounds); tachycardia; weakness, headache, dizziness, drowsiness; very rarely (≤1/10,000) , including isolated cases - heterotopic calcification (cornea and blood vessels), disappearing after discontinuation of the drug; a slight increase in HDL in the blood plasma. In patients with severe renal impairment, hyperphosphatemia may develop; allergic skin reactions (itching) and anaphylactic shock, the latter can be caused by peanut oil, which is part of the drug.

Alpha d3-Teva Capsules, box, 30 pcs., 1 mcg, for oral administration

special instructions

When using the drug Alpha D3-Teva® in children and in patients with chronic renal failure, it is necessary to regularly monitor the calcium and phosphate levels (at the beginning of treatment - once a week, when Cmax is reached in the blood plasma and during the entire treatment period - every 3 -5 weeks), as well as alkaline phosphatase activity (for chronic renal failure - weekly monitoring) in the blood plasma.
In chronic renal failure, preliminary correction of hyperphosphatemia is required. When normal ALP activity in the blood plasma is achieved, the dose of Alpha D3-Teva® must be reduced, which will avoid the development of hypercalcemia.

At the beginning of treatment with Alpha D3-Teva®, it is recommended to measure calcium levels, especially in conditions without significant bone damage, for example, with hypoparathyroidism and in cases where plasma calcium levels are already elevated, and also at later stages of treatment - if there are signs of recovery bone tissue structure.

The risk of developing hypercalcemia is determined by factors such as the degree of bone demineralization, renal function, and drug dose.

Hypercalcemia or hypercalciuria is corrected by reducing the dose of Alpha D3-Teva® and reducing calcium intake until its content in the blood plasma is normalized. Typically this period is 1 week. After normalization, therapy is continued using half of the last dose used.

If hypercalcemia develops or a persistent increase in the content of calcium phosphate compounds beyond the clinical norm, the drug should be immediately discontinued, at least until these indicators return to normal (usually within a week), then use of the drug can be resumed at a dose , which is half the previous one.

The development of long-term hypercalcemia should be prevented, especially in chronic renal failure, focusing on indicators such as calcium content in blood serum and urine, alkaline phosphatase activity, parathyroid hormone concentration, radiological and histological data.

To prevent the development of hyperphosphatemia in patients with bone lesions of renal origin, alfacalcidol can be used together with phosphate binders.

It must be taken into account that sensitivity to vitamin D varies from patient to patient, and sometimes the use of even therapeutic doses may be accompanied by symptoms of hypervitaminosis.

Children who receive vitamin D for a long time are at increased risk of stunted growth.

To prevent hypovitaminosis D, a balanced diet is most preferable. In old age, the need for vitamin D may increase due to a decrease in the absorption of vitamin D, a decrease in the skin's ability to synthesize provitamin D3, a decrease in sun exposure, and an increase in the incidence of renal failure.

The excipients of the drug include peanut oil. The drug is contraindicated in patients with an allergic reaction to peanut oil and soybean oil.

Impact on the ability to drive vehicles and machinery

Caution should be exercised when driving vehicles and mechanisms that require increased concentration and speed of psychomotor reactions, since dizziness and drowsiness may develop when using the drug Alpha D3-Teva®.

Special instructions for the use of Alpha D3-teva

The drug should be prescribed with caution to patients predisposed to hypercalcemia, especially those with urolithiasis. During the period of use of the drug, it is necessary to regularly (at least once every 3 months) monitor the level of calcium in the blood plasma and urine, monitor the development of the therapeutic effect and, if necessary, adjust the dose of alfacalcidol to avoid the development of hypercalcemia and hypercalciuria. If there are biochemical signs of normalization of bone structure (normalization of alkaline phosphatase in the blood plasma), an appropriate reduction in the dose of Alpha D3-Teva is necessary, which helps to avoid the development of hypercalcemia. Hypercalcemia or hypercalciuria can be eliminated by discontinuing the drug and reducing calcium intake until its plasma concentration normalizes. As a rule, this period is 1 week. Therapy can then be extended, starting with half the last dose used. During pregnancy and breastfeeding . Although no negative effects on the fetus or infant have been proven, the drug should not be used during pregnancy and lactation. Due to the possible risk of developing persistent hypercalcemia, which can cause delayed physical and mental development, supravalvular aortic stenosis, retinopathy in infants, overdose of a vitamin D analogue during pregnancy should be avoided. The use of Alpha D3-Teva during breastfeeding may increase the level of calcitriol in breast milk. Considering this, the drug is not used during breastfeeding. The ability to influence reaction speed when driving vehicles or working with machinery . The effect of the drug on the ability to drive vehicles and operate complex mechanisms has not been identified, but the possibility of adverse reactions such as drowsiness and dizziness should be taken into account. Children. Used in children over 6 years of age with body weight ≥20 kg.

ALPHA D3-TEVA

special instructions

In children and patients with chronic renal failure (CRF), it is necessary to regularly monitor the content of calcium and phosphate in the blood plasma (at the beginning of treatment - once a week, when Cmax is reached, and throughout the entire treatment period - every 3-5 weeks), as well as alkaline phosphatase activity (for chronic renal failure - weekly monitoring).
In case of chronic renal failure, preliminary correction of hyperphosphatemia is required. When the activity of alkaline phosphatase in the blood plasma is normalized, the dose of Alpha D3-Teva® must be reduced, which will avoid the development of hypercalcemia. At the beginning of treatment with Alpha D3-Teva®, it is recommended to measure calcium levels, especially in conditions without significant bone damage, for example, with hypoparathyroidism and in cases where calcium levels in the blood plasma are already elevated, as well as at later stages of treatment - if there are signs of structural restoration bone tissue. The risk of developing hypercalcemia is determined by factors such as the degree of bone demineralization, renal function, and drug dose.

Hypercalcemia or hypercalciuria is corrected by reducing the dose of Alpha D3-Teva® and reducing calcium intake until the calcium level in the blood plasma is normalized. Typically this period is 1 week. After normalization, therapy is continued using half of the last dose used. If hypercalcemia develops or a persistent increase in the content of calcium phosphate compounds beyond the clinical norm, the drug should be immediately discontinued, at least until these indicators return to normal (usually within a week), then the drug can be resumed at a dose , which is half the previous one.

Patients with severe bone damage (as opposed to patients with renal failure) can tolerate higher doses of the drug without signs of hypercalcemia. The absence of a rapid increase in serum calcium in patients with osteomalacia does not always mean that the dose of the drug should be increased, since calcium can penetrate into demineralized bone due to its increased absorption in the intestine. The development of prolonged hypercalcemia, especially in chronic renal failure, should be prevented, focusing on indicators such as calcium levels in the blood serum and urine, alkaline phosphatase activity, parathyroid hormone concentration, radiological and histological data.

To prevent the development of hyperphosphatemia in patients with bone lesions of renal origin, alfacalcidol can be used together with phosphate binders. It must be taken into account that sensitivity to vitamin D varies from patient to patient, and sometimes taking even therapeutic doses can cause symptoms of hypervitaminosis.

Children who receive vitamin D for a long time are at increased risk of stunted growth.

The excipients of the drug include peanut oil. The drug is contraindicated in patients with an allergic reaction to peanut butter and soy.

Interactions of the drug Alpha D3-teva

In the treatment of osteoporosis, Alpha D3-Teva can be prescribed in combination with antiresorptive drugs of different groups and estrogens. The effect of alfacalcidol is enhanced by the simultaneous use of estrogens in pre- and postmenopausal women. Vitamin D and its derivatives should not be used concomitantly with Alpha D3-Teva due to the possibility of additive interactions and an increased risk of hypercalcemia. With the simultaneous use of Alpha D3-Teva with digitalis preparations, the risk of developing arrhythmia increases. When used simultaneously with barbiturates, anticonvulsants and other drugs that activate microsomal oxidation enzymes in the liver, it is necessary to take Alpha D3-Teva in a higher dose. GCS may also reduce the effect of alfacalcidol. The absorption of alfacalcidol is reduced when used with cholestyramine, colestipol, sucralfate, and antacids with a high aluminum content. Alpha D3-Teva and aluminum-based antacids cannot be used simultaneously; the interval between doses should be at least 2 hours. When used simultaneously with Alpha D3-Teva, magnesium-based antacids increase the risk of developing hypermagnesemia. With the simultaneous use of calcium supplements and thiazide diuretics, the risk of developing hypercalcemia increases.

The use of alfacalcidol in the treatment of osteoporosis

Osteoporosis (OP), a systemic skeletal disease from the group of metabolic osteopathies, is characterized by a decrease in bone mass and disruption of the microarchitecture of bone tissue, which leads to a decrease in bone strength and, as a consequence, an increased risk of fractures [1]. The goal of drug therapy for AP is to reduce the incidence and risk of fractures, increase bone mineral density (BMD) and improve the quality of life of patients [1].

Among the drugs used for the treatment and prevention of systemic AP, antiresorptive drugs occupy an important place, which include vitamin D and its active metabolites - alfacalcidol and calcitriol [2, 3]. Postmenopausal AP is characterized by increased peri- and postmenopausal bone loss, which can occur with normal or initially low peak bone mass. The leading pathogenetic mechanism of AP is estrogen deficiency and the associated decrease in the activity of the renal enzyme 1α-hydroxylase, accompanied by a decrease in the synthesis of calcitriol in the kidneys [4]. This results in calcium (Ca) leaching from bone tissue, concomitant parathyroid hormone (PTH) suppression, Ca malabsorption, and vitamin D receptor (VDR) deficiency, primarily in the classic target tissues (intestine, bone, kidney, and parathyroid glands). It is important that in postmenopausal AP, a decrease in calcitriol activity is always secondary to estrogen deficiency [5, 6]. The rate of bone formation in this type of AP, as a rule, remains within the normal range or is slightly reduced [7–11].

The main mechanism for the development of senile (involutive) AP is a decrease in the synthesis of calcitriol as a result of deficiency of renal 1α-hydroxylase, as well as a deficiency and decrease in the affinity of receptors for calcitriol in target organs: the gastrointestinal tract (GIT), bones and parathyroid glands. Increased Ca malabsorption and, accordingly, its leaching from the bone, as well as a decrease in the expression of genes responsible for the synthesis of matrix proteins produced by osteoblasts, ultimately have a negative effect on the mass and quality of bone tissue [6, 7, 12, 13].

Deficiency of sex hormones (estrogens/testosterone), as well as somatopause, accompanied by a decrease in insulin-like growth factors (IGF) and their binding proteins (IGFBP-4↑, IGFBP-3/5↓), in senile AP have an additional effect on the reduction of cofactors 1α-hydroxylase [14–16].

As a result, a decrease in the synthesis, reception and activity of D-hormone stimulates the synthesis of PTH with the development of parathyroid hyperplasia and tertiary hyperparathyroidism [15, 17]. Moreover, an increase in PTH levels in patients over 70 years of age with osteoporosis is accompanied by an increase in endocortical resorption, especially in the area of the proximal femur, intracortical porosity, and underlies the patients’ susceptibility to fractures. Moreover, bone resorption induced by PTH is not accompanied by an adequate increase in bone formation [9, 18–20].

Thus, restoring calcitriol levels is a key area of prevention and treatment for AP and requires the mandatory use of vitamin D or its active forms (calcitriol and alfacalcidol).

Both regular vitamin D3 and the D-hormone prodrug alfacalcidol (1α,25(OH)D3) act through a common biologically active metabolite, calcitriol (1α,25(OH)2D3; D-hormone). Moreover, in the body, alfacalcidol (Alpha D3-Teva®) is converted into calcitriol, bypassing endogenous regulation and without the participation of the renal enzyme 1α-hydroxylase [21].

As already noted, the effect of alfacalcidol (via the active metabolite calcitriol) in maintaining calcium and bone homeostasis is through interaction with nuclear VDR in target organs, primarily the intestine, bones, kidneys and parathyroid glands [14, 22, 23]. In conditions of vitamin D3 deficiency, the main effects of physiological and pharmacological concentrations of calcitriol (1α,25(OH)2D3) are thought to be:

increasing the level of Ca in the blood plasma by stimulating its absorption in the intestine and reabsorption in the distal renal tubules;
a decrease in the content of PTH in the blood plasma, which occurs in two ways: firstly, due to direct inhibition of PTH gene transcription due to binding to the VDR of the parathyroid glands, and secondly, as a result of indirect inhibition of PTH secretion due to an increase in the concentration of Ca in the blood plasma [14 –23];
decrease in resorption and increase in bone tissue formation due to a decrease in PTH content and an effect on Ca and phosphate homeostasis [24–26].

Data on the effects of calcitriol from randomized prospective clinical trials vary widely. Some studies have shown a significant effect of calcitriol (1α,25(OH)2D3) on the increase in BMD in postmenopausal osteoporosis [21, 23, 26], while others have not obtained similar effects [27], which may be due to the use of lower doses of the drug. Additionally, a 3-year prospective multicenter study of 622 women with vertebral compression fractures found that treatment with calcitriol (1α,25(OH)2D3) resulted in a reduction in the incidence of new vertebral fractures [28].

A feature of vitamin D preparations is their good tolerability. Supplementation of regular vitamin D and Ca in elderly patients with natural vitamin D deficiency and concomitant low levels of 25OHD3 substrate is in most cases sufficient to overcome clinical or even subclinical osteomalacia. According to some studies, in patients with natural vitamin D deficiency and low Ca intake, vitamin supplements reduce the severity of osteoporosis and the incidence of non-vertebral fractures [17, 29]. Meanwhile, the use of regular vitamin D in physiological daily doses of 400–3000 IU (or 15 μg of 25OHD3) is not always effective in the treatment of osteoporosis [21, 30]. Moreover, in elderly people, correction of disturbances in the synthesis, reception and activity of calcitriol requires the administration of vitamin D in doses that significantly exceed not only physiological, but also pharmacological, which can lead to vitamin D intoxication due to its long-term retention in soft tissues.

A study using the D-hormone precursor alfacalcidol, compared with native vitamin D3 in combination with calcium supplements, revealed an increase in BMD and a decrease in the incidence of vertebral fractures [21, 24, 31].

Bone effects and safety of the use of 1 mcg/day alfacalcidol (Alpha D3-Teva®) and a combination of vitamin D 880 IU/day and Ca carbonate 1000 mg/day, in the treatment of white patients with postmenopausal AP and the absence of vitamin D deficiency in the blood plasma, evaluated in a multicenter randomized comparative study. After 12 months from the start of treatment, in the group of patients taking alfacalcidol, there was an increase in BMD of the lumbar spine (from the initial level) by 2.33%, and after 18 months - by 2.87% (p < 0.001); in the group taking vitamin D and calcium - only by 0.7%. Moreover, the statistical differences between the groups were significant (p = 0.018; 0.005).

The main mechanisms of action of alfacalcidol in AP are the normalization of reduced calcitriol synthesis and, accordingly, the correction of Ca malabsorption by stimulating the expression of estrogen receptors in bone cells, mediated by calcitriol [14–26]. Although calcitriol synthesized from alfacalcidol is not directly involved in the regulation of mineralization, but rather increases Ca levels, this does not exclude its effects on the organic matrix of bone or on bone growth factors. On the contrary, the effects of alfacalcidol can also include an increase in the secretion of calcitonin and the normalization of disconnected processes of bone tissue remodeling by increasing the level of transforming growth factor beta (TGF-β) and osteoprotegerin (OPG), which, in turn, determines the inhibition of postmenopausal production of bone-resorbing cytokines tissue, especially tumor necrosis factor alpha (TNF-α), and an increase in the release of TRF-β, which ensures restoration of weakened osteoclast apoptosis and slowdown of resorption processes [9, 32–34].

Along with this, data have now been accumulated that can be used to justify the advantages of using alfacalcidol over vitamin D in osteoporosis, also in the context of bone effects, but not associated only with stimulated calcium absorption and a reduced content of endogenous PTH as the only necessary conditions for the anabolic action of these drugs.

Studies evaluating the relationship between the ability of alfacalcidol and vitamin D3 to increase calcium levels and have a protective effect on bones in osteoporosis caused by estrogen deficiency have shown that both drugs increase bone mineral density. Moreover, the increase in MIC is accompanied by a slight (within the normal range) increase in the Ca content in the blood plasma and directly depends on the dose of the drugs. However, at a fixed plasma calcium concentration, alfacalcidol increases BMD more effectively than vitamin D3, and higher doses of vitamin D3 are required to achieve comparable levels of BMD.

Similar patterns can be traced in terms of an increase in bone strength when taking both drugs. Of course, the effect depends on the rate of increase in the concentration of Ca in the blood. However, at the same plasma Ca level, alfacalcidol is more effective than vitamin D3 in increasing bone strength, which is reduced in estrogen deficiency. Moreover, the study showed that the effect of vitamin D3 on bone strength reached a plateau at a dose of 200 μg/kg, and a dose of 400 μg/kg did not lead to a corresponding increase in BMD at all [35].

When comparing the effect of drugs depending on the excretion of Ca in the urine, unidirectional trends are also observed: at the same level of Ca in the urine, alfacalcidol is more effective than vitamin D3 in increasing bone mass and strength, which is reduced with estrogen deficiency.

A comparison of the bone effects of alfacalcidol and vitamin D3 at a well-defined plasma calcium concentration of less than 10 mg/dl (that is, at dosages that do not cause hypercalcemia) shows that bone strength increases with alfacalcidol, but does not change with vitamin D3. Obviously, in order to cause an increase in BMD comparable to alfacalcidol, large doses of vitamin D3 may be required, and this is fraught with the development of hypercalcemia.

An assessment of the effect of drugs on the urinary excretion of deoxypyridinoline (a marker of bone resorption) against the background of a decrease in estrogen concentrations shows that both alfacalcidol and vitamin D3 dose-dependently reduce the content of deoxypyridinoline in the urine, but alfacalcidol inhibits bone resorption more effectively than vitamin D [21, 35] . A comparison of the same effects of the drugs, but with a given low Ca content in plasma, shows that the administration of alfacalcidol leads to a decrease in the excretion of deoxypyridinoline in the urine, while the administration of vitamin D3 in doses that maintain the concentration of Ca in the blood plasma below 10 mg/dl, is not accompanied by significant suppression of deoxypyridinoline excretion.

Thus, both alfacalcidol and vitamin D3 increase BMD and bone strength while increasing plasma and urinary Ca levels. It is reasonable to conclude that the bone effects of these drugs are directly dependent on their calcium effects. However, correlation of the bone and calcium effects of both drugs obtained at a given Ca level suggests that alfacalcidol increases bone mass and improves bone quality more effectively than vitamin D3. It is obvious that the implementation of the protective effect of alfacalcidol on bones occurs partly independently of its normalizing effect on calcium balance. Of course, the mechanisms of the protective effect of alfacalcidol on bone remain not fully understood, however, there is convincing evidence of its suppression of bone resorption caused by estrogen deficiency.

Since, as studies show, the protective effect of alfacalcidol on bones is not due solely to the normalization of calcium balance, it is possible that suppression of endogenous PTH is also not the only necessary condition for the development of bone effects of the drug.

This is confirmed by the results of a study in which the effect of alfacalcidol on bones and calcium metabolism was assessed in an experiment on animals that had undergone parathyroidectomy [35]. Postoperative hypocalcemia and hyperphosphatemia were reversed by continuous infusion of human parathyroid hormone (hPTH) (amino acid sequences 1–34 responsible for the calcemic effects of PTH). Thus, against the background of a fixed PTH level and relative normocalcemia, the dose of alfacalcidol was titrated upward, but, and this was the main condition, it was not accompanied by the development of hypercalcemia. Then, at the end of the study, the animals were killed and the bones were examined. The study showed that over a 2-week period, alfacalcidol dose-dependently increased proximal tibial BMD and trabecular bone volume. The bone surface of alfacalcidol-treated animals was lined with large cuboidal cells resembling active osteoblasts [29, 35].

The main conclusion that the study allowed us to draw is that the protective effect of alfacalcidol on bones does not depend on the level of PTH and is partly carried out independently of its effect on Ca absorption and the resulting suppression of PTH secretion.

Thus, the phenomenon of stimulation of osteoclastic bone resorption observed in vitro (as a result of induction of the formation of osteoclastogenesis-supporting molecules (RANKL/TRANCE) in bone marrow stromal cells), while taking large doses of 1α,25(OH)2D3, contradicts the data obtained in vivo , indicating that in doses that do not lead to the development of hypercalcemia, the active metabolite of vitamin D3 increases bone mass, at least by suppressing bone resorption [14. 15, 36–38]. Given that the protective effects of alfacalcidol on bone are observed at constant PTH levels, it is reasonable to assume that the active metabolite of vitamin D3 inhibits bone resorption independent of PTH suppression. Further studies are certainly needed to shed light on the mechanisms by which the active metabolite of vitamin D3 inhibits bone resorption [34, 35].

Another target organ for the effects of calcitriol [14–17] is the muscular system. Activation of VDR by alfacalcidol on the membrane of muscle cells, where they regulate the transport of calcium and phosphate, as well as in the cell nucleus, where they participate in the production of energy for muscle contraction, contributes to the improvement of motor activity, optimization of motor coordination and, as a result, preventing the risk of falls in elderly patients. In addition, alfacalcidol regulates the expression of nerve growth factor (NGF), and also promotes a dose-dependent increase in the effect of IGF-1, one of the most significant factors of muscle activation [15, 27]. It is obvious that some pathogenetic factors of age-related sarcopenia can be balanced by alfacalcidol therapy.

Clinical data have been obtained on the effectiveness of alfacalcidol in terms of increasing muscle strength [24] and reducing the incidence of vertebral and femoral neck fractures by 50–70%, reducing the intensity of back pain compared to native vitamin D [33].

An estimate of the relative risk of falls in postmenopausal women receiving vitamin D showed a small beneficial effect of cholecalciferol on falls risk reduction of 0.92 (95% CI 0.75–1.12). However, no differences were observed with those patients who did not receive vitamin D supplementation. A randomized, placebo-controlled clinical trial involving 9,440 home-dwelling older women and men over the age of 75 years found that annual intramuscular administration of 300,000 IU vitamin D for 3 years failed to reduce falls and thus the risk of hip fractures and hip fractures. non-vertebral fractures. Daily oral supplementation of native vitamin D (800 IU) and/or calcium (1 g) in a group of 5292 women (85%) and men aged 70 years and older with established AP and follow-up at 24 and 62 months was also not confirmed reducing the risk of falls and fractures of the vertebrae and femoral neck [9, 22, 29, 39, 40, 41].

Along with this, a comparative meta-analysis of the effectiveness of two treatment regimens - alfacalcidol and native vitamin D (14 studies with a total number of patients 21,268) showed a statistically significant reduction in the absolute risk of falls by 3.5 times on therapy with active metabolites compared with vitamin D preparations 0, 79 (95% CI 0.64–0.96) vs. 0.94 (95% CI 0.87–1.01) (p = 0.049). Moreover, the number of patients who needed to be treated to prevent 1 fall was 12 for alfacalcidol, and 52 for vitamin D [41].

Thus, alfacalcidol (Alpha D3-Teva®) not only effectively increases BMD, improves the quality of bone tissue, but also improves neuromuscular conduction and contractility of motor muscles, as well as coordination of movements, which ultimately reduces the tendency to fall, and therefore, and risk of fractures.

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M. I. Shupina1, Candidate of Medical Sciences G. I. Nechaeva, Doctor of Medical Sciences, Professor

State Budgetary Educational Institution of Higher Professional Education Omsk State Medical Academy of the Ministry of Health of the Russian Federation, Omsk

1 Contact information

Overdose of the drug Alpha D3-teva, symptoms and treatment

With a single overdose (25–30 mcg) of alfacalcidol, no harm to health is observed. Subsequent cases of alfacalcidol overdose may cause hypercalcemia. Symptoms : weakness, lethargy, dizziness, headache, nausea, dry mouth, constipation, diarrhea, heartburn, vomiting, abdominal pain, bone pain, itching, tachycardia. Polyuria, polydipsia, nocturia, proteinuria may occur if renal function is impaired. Treatment : stop taking the drug. Depending on the severity of hypercalcemia, you can adhere to a calcium-free or low-calcium diet, take fluids, perform dialysis, use loop diuretics, corticosteroids and calcitonin. In case of acute overdose, a positive effect is possible with gastric lavage and/or the use of mineral oil (which helps reduce absorption and increase excretion of the drug in feces). There are no specific antidotes for alfacalcidol.