RU2799244C1 - Method of increasing bone mineral density in patients with osteoporosis and polyneuropathy in type 2 diabetes mellitus - Google Patents

Abstract

FIELD: medicine; endocrinology; traumatology; rheumatology; therapy; geriatrics.

SUBSTANCE: at the 1st stage, the initial creatinine clearance is assessed calculated according to the Cockcroft-Gault formula. With creatinine clearance >30 ml/min, calcium and vitamin D preparations are administered until their parameters normalize and they are maintained within the target range. At stage 2, pathogenetic therapy is carried out with alendronic acid at a dose of 70 mg 1 time per week with calcium preparations: cocaliciferol with the introduction of thioctic acid 2 times a year according to the scheme 600 mg— intravenously slowly by drips 5 days a week for 4 weeks — 20 droppers, with subsequent transfer to a tablet intake of 600 mg 1 time per day in the morning 30 minutes before meals for 3 months. From the third month, the initial levels of the following vitamins are determined: B1, B6, B12; followed by a course of 10 injections of neurotropic vitamins. Then the patient is switched to oral intake of neurotropic vitamins for 8 weeks; while monitoring the following vitamins: B1, B6, B12 every 3 months, after 6 months — once every six months. Then the patient is switched to prophylactic courses of oral administration of tablet forms of neurotropic vitamins for 8 weeks — 2 times a year.

EFFECT: method improves the quality of bone tissue in patients with osteoporosis and polyneuropathy on the background of type 2 diabetes mellitus, reduces the risk of fractures, expands motor activity and improves the patient's quality of life.

1 cl, 1 dwg, 1 tbl, 2 ex

Description

The invention relates to medicine, in particular to endocrinology, traumatology, rheumatology, therapy and geriatrics.

Osteoporosis and type 2 diabetes mellitus (DM2) are among the most significant global health problems. The prevalence of diabetes mellitus (DM) is increasing worldwide and has now reached epidemic proportions in many developing and most developed countries [Whiting DR et al, 2011; International Diabetes Federation; 2020].

The social significance of osteoporosis (OP) and diabetes mellitus is determined by their consequences. So in OP, these are fractures of the vertebral bodies and bones of the peripheral skeleton, which lead to large material costs in the field of healthcare and cause a high level of disability, including disability and mortality. Complications of DM include micro- and macrovascular complications, diabetic neuropathy (including osteoarthropathy) and diabetic foot syndrome. The above complications of diabetes are the causes of not only high disability and mortality, but are also triggers for the development of diabetoporosis - osteoporosis initiated and aggravated by diabetes mellitus. Currently, specialized treatment of osteoporosis and separately diabetes mellitus is being carried out.

Vitamins play an important role in the normal functioning of the body, as well as in the pathogenesis of certain diseases, many of which are indispensable participants in various metabolic processes. They are necessary for normal cellular metabolism and tissue trophism, normal performance and maintenance of vital body functions. A variety of causes lead to vitamin deficiency, such as diseases of the gastrointestinal tract, leading to malabsorption, malnutrition, alcoholism, metabolic disorders, etc.

B vitamins have a metabolic effect on axonal transport and myelination processes in peripheral nerve fibers. Among all the B vitamins, these properties are most inherent in three of them - thiamine (B1), pyridoxine (B6) and cyanocobalamin (B12). The effect of B vitamins, primarily thiamine, on the central nervous system is mediated through the metabolism of gamma-aminobutyric acid (GABA) and serotonin, which also provides an analgesic effect, which is manifested when they are used in high doses.

The treatment of diabetic neuropathy with B vitamins has a long history spanning several decades. An important discovery was made in 1952 by Japanese scientists who, studying the mechanisms of thiamine penetration into the cell and its biotransformation in the body, synthesized the lipophilic compound benfotiamine, which is not destroyed by intestinal thiaminases, is completely absorbed into the blood and circulates in the body for a long time. Due to its fat-soluble properties, benfotiamine freely penetrates the blood-brain barrier, as well as through the lipophilic membrane of nerve cells. Inside the cells, benfotiamine is more rapidly converted to thiamine pyrophosphate, which contributes to the energetically optimal utilization of glucose. The entire group of fat-soluble thiamines has been named allithiamins. Among them, benfotiamine had the highest bioavailability and ability to penetrate into the cell.

As shown by K. Schreeb et al., the level of thiamine in plasma is approximately 5-6 times higher with the introduction of benfotiamine than after using the water-soluble form of the drug. The absolute bioavailability of benfotiamine after a week was 3.6 times higher than that of thiamine. Moreover, among the lipophilic derivatives of vitamin B1, benfotiamine has the highest bioavailability. Penetrating into the nervous tissue, benfotiamine activates the glucose degradation enzyme transketolase, and pyridoxine directly prevents the excessive formation of advanced glycation end products in the nervous tissue.

A known method for the treatment of diabetes mellitus (the use of oral hypoglycemic drugs or insulin (according to the clinical recommendations "Algorithms for specialized medical care for patients with diabetes mellitus" ed. I.I. Dedov, M.V. Shestakova, A.Yu. Mayorova issue 9, 2019 g.) and its complications - diabetic polyneuropathy with the help of thioctic acid (Acidum thiocticum) or alpha lipoic acid (results of studies ALLADIN, ALLADIN I, SYDNEY, etc.) it belongs to the clinical and pharmacological group of drugs with antioxidant, hepatoprotective and lipid-lowering effects. -therapeutic group: Metabolic agent.

Pharmacological action of thioctic-alfalipoic acid

It is an endogenous antioxidant that binds free radicals. Thioctic (α-lipoic) acid is involved in the mitochondrial metabolism of the cell, it performs the function of a coenzyme in the complex of transformation of substances with a pronounced antitoxic effect. They protect the cell from reactive radicals arising from intermediate metabolism or from the breakdown of exogenous foreign substances, and from heavy metals. Thioctic acid exhibits synergism with respect to insulin, which is associated with an increase in glucose utilization. In diabetic patients, thioctic acid leads to a change in the concentration of pyruvic acid in the blood.

Consensus on the management of patients with diabetic neuropathy in general medical practice, approved by the Council of Experts on April 8, 2017 Compiled by: Honored Scientist of the Russian Federation, Professor Vertkin A.L. Professor Danilov Al.B. Honored Doctor of the Russian Federation, Professor Mkrtumyan A.M. recommends the use of neurotropic vitamins in patients with diabetes mellitus and diabetic polyneuropathy.

A known method for the treatment of osteoporosis (the use of antiresorptive drugs in conjunction with drugs of calcium and vitamin D) (Clinical recommendations Osteoporosis developers - Russian Association of Endocrinologists, Public Organization "Russian Association for Osteoporosis", Association of Rheumatologists of Russia, Association of Traumatologists and Orthopedists of Russia, Association of Gynecologists - Endocrinologists of Russia , All-Russian public organization "Russian Association of Gerontologists and Geriatricians", 2021 (https://cr.minzdrav.gov.ru/schema/87_4) Alendronic acid, as a "representative" of the bisphosphonate group, is the first-line drug of choice in patients with osteoporosis , in the absence of contraindications However, this does not take into account the pathogenetic contribution of hyperglycemia, atherosclerosis, neuropathy, micro- and macroangiopathy, nephropathy, hyperinsulinism, sex steroid deficiency against the background of hyperglycemia, and other manifestations of diabetes mellitus in patients with osteoporosis on the background of diabetes mellitus.

The disadvantages of these known methods of treating osteoporosis against the background of type 2 diabetes mellitus include:

• Lack of influence on the manifestation of diabetic polyneuropathy or its prevention, as one of the pathogenetic factors in the development of osteoporosis on the background of diabetes mellitus;

• Lack of influence on micro- and macroangiopathy, as one of the links in the pathogenesis of osteoporosis in diabetes mellitus;

• Lack of accounting for micro- and macronutrient deficiencies in patients with type 2 diabetes mellitus (with the exception of calcium and vitamin D levels);

• Lack of influence on other factors in the pathogenesis of osteoporosis in type 2 diabetes mellitus;

• No effect on the manifestations or prevention of sarcopenia.

As the closest analogue, a combination was chosen: a pathogenetic first-line antiresorptive drug - alendronic acid (Acidum alendronicum) (70 mg - 1 time per week) with calcium and vitamin D (in an individually selected dosage according to the recommendations) and course use of thioctic acid Acidum thiocticum (according to the scheme, slow intravenous administration of 600 mg for 20 days, followed by a switch to a tablet regimen for 3 months) (both the original drug and Russian-made generics) and neurotropic vitamins. These schemes are used separately in the treatment of patients with osteoporosis - the first-line pathogenetic antiresorptive drug alendronic acid (Acidum alendronicum) with calcium and vitamin D preparations (Clinical guidelines Osteoporosis developers - Russian Association of Endocrinologists, Public Organization "Russian Association for Osteoporosis", Association of Rheumatologists of Russia, the Association of Traumatologists and Orthopedists of Russia, the Association of Gynecologists and Endocrinologists of Russia, the All-Russian Public Organization "Russian Association of Gerontologists and Geriatricians", 2021 (https://cr.minzdrav.gov.ru/schema/87_4) and separately for patients with diabetes - thioctic acid Consensus on the management of patients with diabetic neuropathy in general medical practice, approved by the Council of Experts on April 8, 2017 Compiled by: Honored Scientist of the Russian Federation, Professor Vertkin A.L. Professor Danilov A.B. Honored Doctor of the Russian Federation, Professor Mkrtumyan A.M. recommends the use of neurotropic vitamins in patients with diabetes mellitus and diabetic polyneuropathy.

The disadvantages of the closest analogue (prototype) include the lack of an integrated approach to the management of this category of patients.

The objective of the invention is to optimize the management of osteoporosis in type 2 diabetes mellitus and reduce the risk of fractures (when using therapy for at least 12 months, according to the proposed scheme).

EFFECT: improved quality of bone tissue in patients with osteoporosis on the background of type 2 diabetes mellitus, reduced risk of fractures, increased motor activity and improved quality of life of the patient.

The problem is solved due to the fact that in the method of treating osteoporosis in type 2 diabetes mellitus, including combined (by drugs) and sequential (first intravenous, and then tableted) use of pathogenetic antiresorptive therapy - first-line drugs of choice - bisphosphonates - alendronic acid - Acidum alendronicum ( both the original drug and generics) together with calcium preparations (carbonate or citrate or chelate form) (according to age norms of calcium intake at normal blood levels or replenishment of its deficiency with the transition to age-supporting associated doses) and vitamin D (colcaliciferol - vitamin D3 (especially in patients with obesity or overweight) or alfacalcidol) in an individually selected dose, as well as thioctic acid (used according to the scheme) (both the original drug and Russian-made generics) and neurotropic vitamins (according to the algorithm).

The following differences are provided:

• The use of pathogenetic therapy in patients who have reached normocalcemia and the optimal level of vitamin D (according to Russian clinical guidelines);

• The use of pathogenetic therapy with alendronic acid bisphosphonates (Acidum alendronicum) at a dose of 70 mg once a week;

• Together with calcium preparations and vitamin D (in maintenance doses, individually selected depending on the complications of diabetes mellitus, comorbid diseases and the therapy being taken);

• The use of thioctic acid (both the original drug and generics) 2 times a year according to the scheme 600 mg - in / in drip 5 days a week for 4 weeks, followed by transfer to tablet intake of 600 mg 1 time per day in the morning for 30 minutes before meals - 3 months;

• The use of neuronic vitamins (B1, B6, B12 according to the algorithm).

Identification of risk groups for the development of a deficiency of neurotropic vitamins (B1, B6 and B12), these may include:

- elderly people;

- patients taking medications for a long time with the active substance Metformin (more than 3 months), proton pump inhibitors, _H2 -histamine receptor blockers, antacids, acetyl salicylic acid, etc.;

- patients after bariatric treatments for obesity;

- people who abuse alcohol;

- persons adhering to a specific diet depleted in B vitamins;

- diseases of the gastrointestinal tract, including diabetic polyneuropathy - gastroforma.

Determination of levels B1, B6, B12

At the initial stage of treatment of diabetic polyneuropathy, in order to achieve a rapid therapeutic effect, a course of 10 injections of neurotropic vitamins (100 mg of thiamine, 100 mg of pyridoxine, 1000 μg of cyanocobalamin, 20 mg of lidocaine) is carried out (if it is impossible to use saline).

Then they switch to oral intake of neurotropic vitamins (100 mg of benfotiamine, 100 mg of pyridoxine) 1 tablet 3 times a day for 8 weeks.

Control of vitamins B1, B6, B12 at the initial stages every 3 months, after 6 months - once every six months.

The transition to supporting forms - Multivitamins with trace elements.

In order to maintain the achieved clinical effect, prophylactic courses of oral administration of tablet forms of neurotropic vitamins (100 mg of benfotiamine, 100 mg of pyridoxine) 1 tablet 3 times a day for 8 weeks - 2 times a year.

The essence of the proposed method is as follows:

Stage 1:

1) assessment of the initial creatinine clearance, calculated according to the Cockcroft-Gault formula, with creatinine clearance ˃30 ml/min administration of the drug;

2) normalization of calcium and vitamin D values, according to clinical guidelines (https://www.mediasphera.ru/issues/problemv-endokrinologii/2016/4/1037596602016041060).

Stage 2:

- the use of pathogenetic therapy (bisphosphonates - alendronic acid (Acidum alendronicum) at a dose of 70 mg 1 time per week (orally, without chewing, 2 hours (at least 30 minutes) before the first meal, drinking only water) together with calcium preparations ( carbonate, or citrate, or chelate form) (according to the age norms of calcium intake - in a maintenance dosage) and vitamin D - colecalciferol - vitamin D3 (especially in patients with obesity or overweight) or alfacalcidol (in an individually adjusted dose, depending on the data laboratory studies - 25 OHD3 (by mass spectrometry), against the background of individually selected hypoglycemic therapy, using courses of thioctic acid (both the original drug and generics) 2 times a year according to the 600 mg scheme - intravenously drip 5 days a week for 4 weeks, followed by transfer to a tablet intake of 600 mg once a day in the morning 30 minutes before meals - 3 months From 3 months, the addition of neurotropic vitamins according to the algorithm:

• Identification of risk groups for the development of deficiency of neurotropic vitamins (B1, B6 and B12), these may include:

- elderly people

- patients taking long-term medications with the active ingredient Metformin (more than 3 months), proton pump inhibitors, _H2 -histamine receptor blockers, antacids, acetyl salicylic acid, etc.,

- patients after bariatric treatments for obesity,

- alcohol abusers

- persons adhering to a specific diet depleted in B vitamins,

- diseases of the gastrointestinal tract, including diabetic polyneuropathy - gastroforma.

• Definition of levels B1, B6, B12.

• At the initial stage of treatment of diabetic polyneuropathy, in order to achieve a rapid therapeutic effect, a course of 10 injections of neurotropic vitamins (100 mg of thiamine, 100 mg of pyridoxine, 1000 μg of cyanocobalamin, 20 mg of lidocaine) is carried out (if it is impossible to use saline).

• Then they switch to oral intake of neurotropic vitamins (100 mg of benfotiamine, 100 mg of pyridoxine) 1 tablet 3 times a day for 8 weeks.

• Control of vitamins B1, B6, B12 at the initial stages every 3 months, after 6 months - once every six months.

• Transition to supporting forms - Multivitamins with trace elements.

• In order to maintain the achieved clinical effect, prophylactic courses of oral administration of tablet forms of neurotropic vitamins (100 mg benfotiamine, 100 mg pyridoxine) 1 tablet 3 times a day for 8 weeks - 2 times a year.

The invention allows:

• To increase the effectiveness of antiresorptive therapy in patients with osteoporosis on the background of type 2 diabetes mellitus.

• Reduce the risk of falls and prevent the development of traumatic fractures in patients with osteoporosis associated with type 2 diabetes.

• Improve the quality of life of patients with osteoporosis associated with type 2 diabetes.

• Identify and eliminate possible deficiencies - vitamins D, B1, B6, B12, calcium.

The possibility of carrying out the claimed invention is shown by the following examples.

Materials and methods: 46 case histories of patients (45 women and 8 men, mean age 61±3.2 years) with verified diagnoses of type 2 diabetes mellitus (experience from 2 to 28 years) and osteoporosis were analyzed. All patients received antiresorptive therapy with alendronic acid (original or generic drug) according to the standard scheme - at a dose of 70 mg once a week (by mouth, without chewing, 2 hours (at least 30 minutes) before the first meal, drinking only water) in in combination with calcium citrate or carbonate and active forms of vitamin D), as well as thioctic acid (TA) (according to the scheme - 20 intravenous infusions and 60 days of taking a tablet form of 600 mg). Neurotropic vitamins according to the algorithm. Statistical data processing was carried out using the Statistica 10.1 program using parametric and nonparametric methods. The results were recognized as statistically significant at p<0.05.

results

When analyzing the case histories, it was found that 51.4% received TC course treatment 2 times a year, 43.9% received TC once a year, 1.7% periodically (less than 1 time in 12 months) and 3% did not receive never received this type of therapy.

Patients were prescribed neurotropic vitamins according to the algorithm:

• Identification of risk groups for the development of deficiency of neurotropic vitamins (B1, B6 and B12);

• Definition of levels B1, B6, B12.

At the initial stage of treatment of diabetic polyneuropathy, in order to achieve a rapid therapeutic effect, a course of 10 injections of neurotropic vitamins (100 mg of thiamine, 100 mg of pyridoxine, 1000 μg of cyanocobalamin, 20 mg of lidocaine) is carried out (if it is impossible to use saline).

Then they switch to oral intake of neurotropic vitamins (100 mg of benfotiamine, 100 mg of pyridoxine) 1 tablet 3 times a day for 8 weeks.

Control of vitamins B1, B6, B12 at the initial stages every 3 months, after 6 months - once every six months.

The transition to supporting forms - multivitamins with trace elements.

In order to maintain the achieved clinical effect, prophylactic courses of oral administration of tablet forms of neurotropic vitamins (100 mg of benfotiamine, 100 mg of pyridoxine) 1 tablet 3 times a day for 8 weeks - 2 times a year.

Hypervitaminosis B12 was detected in 1 patient, he was excluded from observation.

The increase in bone mineral density (according to dual-energy X-ray absorptiometry or DEXA) with 2 times a year of course use of TC + vitamins B1, B6, B12 during treatment with Alendronic acid preparations was + 2.9% - 1.4%.

Example 1

Patient A., born in 1938. Type 2 diabetes mellitus 15 years (Table 1)

- elderly people

- patients taking medications for a long time with the active substance Metformin (more than 3 months),

- persons adhering to a specific diet depleted in B vitamins,

- diseases of the gastrointestinal tract, including diabetic polyneuropathy - gastroforma.

• Determination of levels B1, B6, B12 - the norm.

• At the initial stage of treatment of diabetic polyneuropathy, in order to achieve a rapid therapeutic effect, a course of 10 injections of Cocarnit is carried out.

• Next, they switch to oral administration of Neurobion, 1 tablet 3 times a day for 8 weeks.

• Control of vitamins B1, B6, B12 at the initial stages every 3 months, after 6 months - once every six months. When monitoring the levels of neurotropic vitamins, there were no increases in the levels of B1, B6 and B12.

• Transition to supporting forms - Multivitamins with trace elements (B-50 Now Foods USA).

• In order to maintain the achieved clinical effect, prophylactic courses of oral administration of tablet forms of neurotropic vitamins (100 mg benfotiamine, 100 mg pyridoxine) 1 tablet 3 times a day for 8 weeks - 2 times a year.

Treatment of osteoporosis in patient M.

2015 - DEXA data spine L1-L4 Total - 2.5 Tscore, BDM 0.776;

Left femoral neck Total -2.9 Tscore, BDM 0.649, Neck - 2.9 Tscore, BDM $0.632

250HD3 - 24 nmol/l, ionized calcium is normal. Creatinine clearance over 40

Appointed by Binosto ((ATX code: M05 BA04), SwissCo Services AG, Bahnhofstrasse 14, 4334 Sisseln, Switzerland), calcium carbonate and vitamin D

2016 - no pathological fractures were detected. The pain syndrome did not disturb;

2017 data DEXA spine L1-L4 Total - 2.3 Tscore, BDM 0.779;

Left femoral neck Total -2.6 Tscore, BDM 0.654, Neck - 2.7 Tscore, BDM 0.641;

2019 data DEXA spine L1-L4 Total - 2.1 Tscore, BDM 0.780;

Left femoral neck Total -2.5 Tscore, BDM 0.659, Neck - 2.5 Tscore, BDM 0.648;

During the entire observation period, no pathological fractures were observed, although there were 3 falls from the height of one's own height, and no decrease in body length (height) was noted. The pain syndrome did not disturb.

Example 2

Patient K., 76 years old.

First diagnosed diabetes mellitus in 2016, diabetic polyneuropathy (2016), osteoporosis since 2018.

2016 - glycemia in the detection of type 2 diabetes mellitus 12 mmol / l, HbA1c - 18%. Insulin therapy - glargine 16 units at 18 hours, metformin 1000 mg at bedtime.

• 2016 the patient was transferred to oral tablet therapy GalvusMet 50/1000 mg + Metformin 1000 mg in the evening before bedtime. Thioctic acid was also added in courses 2 times a year according to the scheme of 600 mg - in / in slowly drip 5 days a week for 4 weeks (20 droppers), followed by transfer to a tablet intake of 600 mg 1 time per day in the morning 30 minutes before meals - 3 months,

• concentrate for solution for infusions 30 mg/ml, LSR-001808/08, valid from 17.03.2008 Pharmstandard-UfaVITA (Russia),

• film-coated tablets 600 mg, LP-001863, effective from 09/28/2012 Pharmstandard-Leksredstva (Russia).

And neurotropic vitamins according to the algorithm.

The patient is at risk for deficiency of neurotropic vitamins:

- elderly people

- patients taking medications for a long time with the active substance Metformin (more than 3 months),

- persons adhering to a specific diet depleted in B vitamins,

- diseases of the gastrointestinal tract, including diabetic polyneuropathy - gastroforma.

• Determination of levels B1, B6, B12 - the norm.

• At the initial stage of treatment of diabetic polyneuropathy, in order to achieve a rapid therapeutic effect, a course of 10 injections of neurotropic vitamins - Kombilepen is carried out.

• Further transition to oral administration of neurotropic vitamins Kombilepene 1 tablet - 3 times a day.

• Control of vitamins B1, B6, B12 at the initial stages every 3 months, after 6 months - once every six months, while monitoring the levels of neurotropic vitamins, no increase was detected.

• Transition to supporting forms - Multivitamins with trace elements (B-50 Now Foods USA).

• In order to maintain the achieved clinical effect, prophylactic courses of oral administration of tablet forms of Neurotropic vitamins (100 mg benfotiamine, 100 mg pyridoxine) 1 tablet 3 times a day for 8 weeks - 2 times a year.

2018, a patient with a hip fracture was diagnosed with osteoporosis according to DEXA - L1-L4 Total -3.5 IUD (g) 39.35.

Vitamin D deficiency was found in normocalcemia and normocalciuria. The treatment was carried out and after 1.5 months the level of vitamin D reached normal values, which made it possible to start the basic therapy of osteoporosis - Fosomax 70 mg - 1 time per week together with calcium and vitamin D in maintenance doses.

2019 DEXA - L1-L4 Total-3.4 IUD (g) 39.5 therapy continued.

On FIG. 1 shows a treatment regimen for a patient with osteoporosis associated with type 2 diabetes mellitus.

Claims (1)

A method for increasing bone mineral density in patients with osteoporosis and polyneuropathy in type 2 diabetes mellitus, consisting of two stages, where at stage 1, the initial creatinine clearance is assessed, calculated according to the Cockcroft-Gault formula, with creatinine clearance> 30 ml / min, administration is carried out calcium and vitamin D preparations until their parameters normalize and maintain them within the target range, and at stage 2, pathogenetic therapy with alendronic acid at a dose of 70 mg once a week is carried out with calcium preparations: cocaliciferol with the introduction of thioctic acid 2 times a year according to the scheme: 600 mg intravenously slowly drip 5 days a week for 4 weeks - 20 droppers, followed by transfer to tablet intake of 600 mg 1 time per day in the morning 30 minutes before meals - 3 months; from the third month determine the initial levels of vitamins: B1, B6, B12; followed by a course of 10 injections of neurotropic vitamins; then switch to oral intake of neurotropic vitamins for 8 weeks; at the same time, vitamins are monitored: B1, B6, B12 every 3 months, after 6 months - 1 time in six months; then they switch to prophylactic courses of oral administration of tablet forms of neurotropic vitamins for 8 weeks - 2 times a year.

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