Modern treatment of osteoporosis

Currently prevention and treatment of osteoporosis are based on the use of two main groups of drugs: stimulating bone formation and inhibiting bone resorption (antiresorbents).

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Groups of drugs used in the treatment of GCS-induced osteoporosis

Drugs that stimulate bone formation

• Phthomid (probiotic fluid, monofluorophosphate)
• Anabolic steroid
• Ossein-hydroxyapatite complex
• Peptide (1-34) PTH
• Prostaglandin E ₂
• Somatotropic hormone

Drugs that inhibit bone resorption (antiresorbents)

• Calcium
• Vitamin D and its active metabolites
• Thiazide diuretics
• Ossein-hydroxyapatite complex
• Calcitonin
• Bisphosphonates (etidronic acid, clodronic, pamidronic, alendronic, tiludronic)
• Anabolic steroids (nandrolone, stanozolol, oxandrolone, etc.)
• HRT (estrogens, progestogens, combination drugs, etc.)

[10], [11], [12], [13]

Combined Osteoporosis Treatment

Experimental drugs (integrin antagonists, proton pump inhibitors, amylin).

"Ideal" can be considered a drug that meets the following requirements:

• increases the BMD of different parts of the skeleton, regardless of the age of the patients (both men and women);
• reduces the risk of development and the frequency of skeletal bone fractures (primarily the femoral neck and vertebral body compression fractures);
• does not disturb the normal structure of the bones;
• does not cause serious side effects;
• well tolerated;
• has a convenient method of use and dosing;
• cost effective;
• combines well with other drugs;
• positive effect on comorbidities (atherosclerosis, etc.).

A standard assessment of the effectiveness of each antiosteoporotic drug in a patient with a rheumatological profile (against the background of complex therapy with NSAIDs, basic agents, GCS, etc.) should include:

• the effectiveness of the drug in the elimination of pain syndrome (characterized by the dynamics of pain syndrome, expressed by the pain index);
• the effectiveness of the drug in restoring the functional status of patients (the dynamics of the articular index, the Stanford health questionnaire, carpal force indices, the rate of passage of 15 m);
• the likelihood of new fractures (expressed in%);
• the likelihood of side effects with an analysis of their effect on organs and systems, indications for stopping treatment (%), as well as a negative effect on standard regimens for the treatment of rheumatic diseases of the joints.

[14], [15], [16], [17], [18], [19], [20]

Recovery of impaired calcium balance

A universal approach to the prevention of osteoporosis is the restoration of impaired calcium balance in the direction of increasing intestinal absorption and reducing excretion from the body. A diet with a high content of calcium is a necessary component of complex treatment. Sources of calcium are dairy products (especially hard cheese, containing from 600 to 1000 mg of calcium per 100 g of product, as well as processed cheese, to a lesser extent cottage cheese, milk, sour cream), almonds, hazelnuts, walnuts, etc.

Along with a diet, if there are risk factors for osteoporosis, an additional dose of calcium supplements is needed, which can compensate for its deficiency. In patients with diagnosed osteoporosis, the daily intake of calcium, taken in addition to food, should be 1500-2000 mg; for the prevention of osteopenia in patients taking GCS - 1000-1500 mg, and doses may vary depending on a number of factors.

The following calcium supplements are most commonly used.

The content of elemental calcium in its some salts

Calcium salt	Content of elemental calcium, mg / 1000 mg of salt
Glycerophosphate	191
Gutunate	90
Carbonate	400
Lactate	130
Chloride	270
Citrate	211

The effectiveness of calcium preparations depends on their bioavailability (the lowest - in chloride and calcium gluconate, higher - in carbonate and phosphate, the highest - lactate and calcium citrate).

Since at night the loss of mineral components by bone is accelerated (circadian acceleration of resorptive processes in bone), it is advisable to take calcium supplements in the evening, which will prevent this process in the second half of the night.

Daily doses of calcium, recommended for patients who have received GCS, with the threat of developing osteoleniya

Age	Doses mg
Children:
1 year-10 years old 11-18 years old	600-800 1200-1500
Adults:
Men women receiving estrogens receiving vitamin D	1000-1500 1500-2000 1000-1200 800-1200

It must be remembered that with increased calcium intake there is a certain risk of developing urolithiasis, which is correlated with an increase in the dose of the drug (especially when using doses higher than 2000 mg / day). Practitioners should recommend such patients to increase fluid intake (1.2-1.5 l / day).

Calcium absorption is promoted by lactose, citric acid, protein diet, phosphorus, magnesium. Excessive amounts of fat, lack of protein, starvation, strict vegetarianism, lack of magnesium, phosphorus and vitamin D, foods high in oxalic acid (shavel, rhubarb, spinach, beets, chocolate), diseases of the digestive organs (gastritis, enteritis, colitis, peptic ulcer), diseases of the pancreas (diabetes mellitus, pancreatitis), gallbladder and biliary tract, thyroid gland (goiter, thyrotoxicosis, thyroiditis), gynecological diseases, especially those associated with endocrine pathology, otorye drugs, especially GKS (prednisone, betamethasone, dexamethasone), levothyroxine, etc.

An important role in optimizing the management of patients with osteoarthritis with a threat of development or already developed osteopenic syndrome is played by vitamins.

[21], [22], [23], [24], [25], [26],

Vitamins in the treatment of osteoarthritis and osteopenic syndrome

1. Ascorbic acid:

• enhances the synthesis of GCS in the body;
• reduces vascular permeability;
• participates in the formation of the main substance of connective tissue;
• increases antihyaluronidase activity.

2. Bioflavonoids:

• condense and reduce the permeability of the walls of blood vessels, in particular capillaries.

3. Vitamin B ₅ :

• participates in cellular redox reactions;
• improves capillary blood flow;
• normalizes the secretory function of the stomach.

4. Tocopherol (vitamin E):

• prevents oxidation of unsaturated fatty acids in lipids;
• affects the biosynthesis of enzymes;
• improves the functions of the vascular and nervous systems.

5. Vitamin D and its active metabolites

One of the areas of medical treatment of secondary osteoporosis is the use of hormone replacement therapy (estrogens, gestagens or combination drugs, and androgens.

Among estrogens, estradiol is most often used either in the form of esterified forms (estradiol valerate 20 mg, estradiol sulfate) or conjugated forms containing estrone, which turns into estradiol and estriol in the body (the effect lasts another 1-2 months). In monotherapy, transdermal forms are also used, for example, estradiol in the form of 0.1% gel, a single dose of which is 0.05 or 0.1, which corresponds to 1 mg of estradiol (daily dose), which works well, like other transdermal estrogens, in women with hypercoagulable syndrome, often occurring on the background of rheumatoid arthritis, systemic lupus erythematosus and other rheumatic diseases.

In addition, HRT with estrogen reduces the risk of coronary heart disease and recurrence of myocardial infarction (50-80%), menopausal disorders (90-95% of women), improve the condition of muscle tone, skin, reduce the likelihood of hyperplastic processes in the uterus and mammary glands, urogenital disorders, etc.

In the appointment of hormonal hormone estrogen it is necessary to remember about contraindications: indications of a history of breast cancer, endometrial cancer, acute liver disease, porphyria, estrogen-dependent tumors. It should be remembered that an increase in the level of blood triglycerides is a contraindication to the oral use of HRT drugs, even against the background of normal cholesterol levels; whereas for transdermal - it is not. ZGT-neutral conditions include: varicose veins, phlebitis, epilepsy, bronchial asthma, systemic diseases of the connective tissue, systemic atherosclerosis.

Experts believe that all postmenopausal women taking GCS should receive HRT in the absence of contraindications, and the course (for the prevention and treatment of osteoporosis) is 5-7 years.

Men with gonadal deficiency (and in some cases, women) may be recommended by hormone replacement therapy with androgens - testosterone propionate 100–200 mg intramuscularly 1 time in 2–4 weeks, testosterone enanthate, etc.

Gestagen preparations include: Cycloproginum (1-2 mg of estradiol valerate + 0.5 mg of norgestrel), Klimonorm (2 mg of estradiol valerate + 0.15 mg of levonorgestrel), derivatives of 17-OH progesterone - Klimene (2 mg of estradiol valerate + 1 mg cyproterone acetate), Divin (1-2 mg of estradiol acetate + 10 mg of medroxyprogesterone), implantation dosage forms, etc. A contraindication to the prescription of drugs in this group is meningioma.

Densitometric monitoring during HRT is needed every 3 months.

Copiconin (an endogenous polypeptide containing 32 amino acid residues) also has the ability to prevent bone loss, and in high doses it increases the mineral content in the skeleton. The antiresorptive effect of the drug is due to specific binding to calcitonin receptors expressed on osteoclasts. However, the nature of the effect of calcitonin on trabecular and cortical bone, as well as its effectiveness in osteopenic conditions in patients with PAD (especially while receiving GCS) in domestic and foreign literature, until recently, were little studied.

Currently, four types of calcitonin are used in clinical practice: natural porcine calcitonin, synthetic human calcitonin, eel, and salmon. The latter has found wide application in Ukraine in various fields of medicine, including rheumatology.

The rather high efficacy in the treatment of osteoporosis of calcitonin salmon (the trade name of the drug registered in Ukraine is Miakalcik®) in combination with calcium supplements, vitamins of group D and diet in patients with RZS and osteoporosis is confirmed by the results of studies conducted on the basis of the Institute of Cardiology. N.D. Strazhesko, URZ.

Recently, the concept that the basis of the action of antiosteoporotic drugs is their ability to positively influence not only the "quantity", but also the "quality" of bone tissue. This concept turned out to be particularly important for explaining the mechanisms of action and the high clinical efficacy of synthetic salmon calcitonin, which is one of the most effective drugs, the anti-osteoporetic activity of which is associated with the suppression of bone resorption. Moreover, along with high antiosteoporotic activity, salmon calcitonin has a wide range of systemic effects, which makes its use particularly appropriate for osteoporosis, which develops against other diseases, including osteoarthritis.

Of particular interest is the study of the analgesic effects of calcitonin. Immunoreactive calcitonin was identified in the brain, spinal fluid, pituitary, etc. Labeled ¹²⁵ 1 calcitonin is irreversibly associated with specific receptors localized in various brain structures, especially in those areas of the hypothalamus that are involved in the transmission and perception of pain. It is noteworthy that the central analgesic effects of calcitonin resemble those of opioid analgesics. The analgesic potential of calcitonin may be associated with the stimulation of the release of an endogenous opioid receptor agonist, beta-endorphin. Against the background of intranasal calcitonin, an increase in the level of beta-endorphin in plasma is observed. The analgesic effect of calcitonin has been demonstrated in clinical studies with pain syndrome of various etiologies, including rheumatic. Moreover, data from recent experimental studies suggest that in experimental osteoarthritis of dogs in vivo, calcitonin effectively suppresses Pir and D-Pir products, inhibits the progression of morphological changes in cartilage and stimulates the synthesis of proteoglycan in vitro. These data indicate not only symptomatic, but also, possibly, modifying effect of myacalt on the progression of osteoarthritis. Thus, calcitonin is the drug of choice for osteoporosis, accompanied by pain of various origins, including osteoarthritis, as well as a combination of osteoporosis and osteoarthritis. In addition, the ability of calcitonin to inhibit gastric secretion, an important property of the drug in relation to the prevention and treatment of "drug" ulcers (NSAIDs-gastropathy) in patients with osteoarthritis, long-term NSAIDs.

One of the promising classes of anti-osteoporotic drugs are bisphosphosta - analogues of inorganic pyrophosphate, an endogenous regulator of bone metabolism. The preparations of this group are stable, not metabolized, but have a high affinity for calcium phosphate and, therefore, for bone, which contributes to their rapid removal from the blood and makes it possible to be included in calcium tissues. Their distribution in the bone is inhomogeneous: they are deposited mainly in the places of formation of the new bone.

In pharmacotherapy of osteoporosis associated with inflammation, bisphosphonates play a significant role as drugs with specific anti-inflammatory properties that suppress the development of articular inflammation and destruction of joints in various experimental models of arthritis. For some bisphosphonates, it has been shown that they are able to reduce the synthesis of TNF-a, IL-1, IL-6.

Proven efficacy and safety of these drugs in the maintenance of skeletal bone mass and the prevention of fractures. However, the different structure of drugs of this class causes their different antiresorptive capabilities and the ratio of efficacy and toxicity. It has been established that they have an inhibiting property against osteoclast mediated bone resorption. However, strong and prolonged inhibition of resorption, achieved by long-term use of bisphosphonates, can cause impaired bone formation and, consequently, an increase in its fragility, increase the risk of fractures (as has been proven for etidronate, etc.). The more potent bisphosphonates with a significant therapeutic gap between the doses that inhibit bone resorption and those potentially disrupting mineralization include alendronic and tiludronic acid — bisphosphonates of new generation, which have a strong inhibitory activity on bone resorption and a positive effect on bone formation.

The most common side effects of bisphosphonates are minor dysfunctions of the digestive tract, which do not require discontinuation of drugs. In addition, when using bisphosphonates of the first generation, phenomena of mineralization defects and osteomalacia may occur, i.e. Impaired bone quality.

With regard to the interaction of antiosteoporotic drugs with the most frequently used in the treatment of NSAIDs, it has been shown that there is no interaction with the pharmacokinetics of bisphosphonates and NSAIDs, with the exception of indomethacin. Very important is the optimal choice of NSAIDs. On the basis of the URC, a comparative study of the efficacy and safety of using NSAIDs — Meloxicam (Movalis), Diclofenac sodium, and Flurbiprofen — was used in the complex therapy of patients with RZS (osteoarthrosis and rheumatoid arthritis), which included examination of patients with the EFA method at the beginning of treatment and after 12 months.

In patients treated with meloxicam or diclofenac, the rate of loss of bone tissue of the mineral component (in both spongy and compact matter) was lower than in those treated with flurbiprofen, which correlated with a more pronounced positive dynamics of laboratory indicators of inflammatory activity.

The dynamics of the BMD according to the OFA (A%) in patients with OCR

NPVP	Spongy bone	Compact bone tissue
Meloxicam (15 mg / day)	-6.2%	-2.5%
Diclofenac (150 mg / day)	-4.7%	-2.7%
Flurbiprofen (200 mg / day)	-8,0%	-5.1%

Thus, the protective effect of NSAIDs on bone tissue in OCR can be explained by their reduced inflammatory activity, accompanied by an autoimmune component, i.e., their anti-inflammatory properties can additionally provide a protective effect on bone demineralization, especially when using GCS.

In conclusion, we formulate some principles of preventive and curative measures in secondary osteoporosis in patients with osteoarthritis:

1. Reducing the negative impact of such factors of osteoporosis development as smoking, alcohol abuse, sedentary lifestyle, long-term starvation, etc.
2. Timely treatment of comorbidities affecting bone metabolism - hyperthyroidism, hyperparathyroidism, etc.
3. Maintaining and maintaining a positive calcium balance (diet, supplementation with calcium supplements in combination with vitamin D or its active metabolites).
4. In the absence of contraindications, the appointment of post-menopausal women with HRT drugs; in the premenopausal period with violations of the ovarian-menstrual cycle - control of 17beta-estradiol and, if necessary, HRT (including androgens taking into account the hormonal profile).
5. In men, testosterone levels are controlled; if necessary - HRT androgens.
6. Carrying out a control densitometric examination of patients with osteoarthritis at risk.
7. Annual densitometric monitoring of OLS and MP K parameters in patients with osteoarthrosis and osteoporosis.

Monitoring anti-osteoporotic therapy for osteoporosis

R. Civitelly et al. (1988) noted a significant increase in the spinal BMD after calcitonin therapy for 1 year, whereas in individuals with low bone metabolism, similar therapy did not lead to an increase in bone mass. The authors suggested that patients with increased bone metabolism, characterized by increased levels of osteocalcin and hydroxyproline, have a more favorable prognosis regarding calcitonin therapy. The high efficacy of other antiresorptive agents (estrogen-replacement therapy, bisphosphonates) in the treatment of osteoporosis in patients with increased bone metabolism remains unproven.

Antiresorptive agents such as estrogen replacement therapy and bisphosphonates induce a significant but reversible decrease in markers of resorption and bone formation. Based on an accurate measurement of bone mass by the densitometric method and the expected level of bone mass change induced by antiresorptive therapy, only after 2 years can it be determined whether the treatment is effective in a particular patient, i.e. Whether bone mass increases significantly. Many studies have shown a significant correlation between early changes (after 3-6 months) of indicators of markers of bone formation and / or resorption and delayed (more than 1 year to 2 years) changes in bone mass according to densitometric studies (in the radial bone, spine, or throughout skeleton) in patients treated with antiresorptive agents such as estrogen or bisphosphonates. The correlation coefficients in these studies were constantly around -0.5. This allowed the authors to suggest that, at an individual level, markers of bone metabolism may not be able to accurately predict delayed changes in bone mass. However, by introducing a limiting threshold of a significant decrease in bone markers after 6 months (30-60% or more depending on measurement accuracy), most patients who will respond with an increase in bone mass after 2 years with a very low frequency of false positives can be identified immediately after the start of treatment. False negative results.

Thus, repeated measurements of sensitive and specific markers (formation or resorption) 3-6 months after the start of anti-osteoporotic therapy are likely to be suitable for monitoring rheumatologic patients with osteoporosis, especially since the effects of such treatment can be detected even before the appearance of BMD changes.

The above literature data, as well as the results of our research, confirm the urgency of the problem of osteopenic syndrome in osteoarthritis. The combined development of osteoporosis and osteoarthrosis significantly impairs the quality of life, and, probably, the life expectancy of patients, especially elderly and senile.

We emphasize the importance of conducting densitometric and biochemical monitoring of the condition of the bone can for the assessment of the dynamics, as well as the effectiveness of the drugs used, primarily NSAIDs.

[27], [28], [29]