Modern treatment of osteoporosis

Currently, the prevention and treatment of osteoporosis are based on the use of two main groups of drugs: those that stimulate bone formation and those that inhibit bone resorption (antiresorptives).

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

Drugs that stimulate bone formation

• Fluorides (sodium fluoride, monofluorophosphate)
• Anabolic steroid
• Ossein-hydroxyapatite complex
• Peptide (1-34) PTH
• Prostaglandin E ₂
• Somatotropic hormone

Drugs that inhibit bone resorption (antiresorptives)

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

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Combination treatment of osteoporosis

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

A drug that meets the following requirements can be considered “ideal”:

• increases the BMD of various parts of the skeleton, regardless of the age of the patients (both men and women);
• reduces the risk of development and frequency of skeletal fractures (primarily of the femoral neck and compression fractures of the vertebral bodies);
• does not disrupt the normal structure of bones;
• does not cause serious side effects;
• well tolerated by patients;
• has a convenient method of application and dosing;
• economically advantageous;
• combines well with other medications;
• has a positive effect on concomitant pathology (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 eliminating 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 (dynamics of the joint index, Stanford Health Questionnaire, wrist strength indices, 15 m walking speed);
• probability of occurrence of new fractures (expressed in %);
• the likelihood of side effects with an analysis of their impact on organs and systems, indications for discontinuing treatment (%), as well as the negative impact on standard treatment regimens for rheumatic joint diseases.

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Restoring the disturbed calcium balance

A universal approach to osteoporosis prevention is to restore the disturbed calcium balance towards increased intestinal absorption and decreased excretion from the body. A diet with increased calcium content 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 diet, in the presence of risk factors for osteoporosis, additional intake of calcium preparations is necessary to compensate for its deficiency. In patients with diagnosed osteoporosis, daily doses 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 the doses may vary depending on a number of factors.

The following calcium preparations are most commonly used.

The content of elemental calcium in some of its salts

Calcium salt	Elemental calcium content, mg/1000 mg salt
Glycerophosphate	191
Glyuconate	90
Carbonate	400
Lactate	130
Chloride	270
Citrate	211

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

Since the loss of mineral components from bone is accelerated at night (circadian acceleration of bone resorption processes), 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 taking GCS at risk of developing osteoleukemia

Age	Doses, mg
Children:
1 year - 10 years 11 - 18 years	600-800 1200-1500
Adults:
Men Women Receiving Estrogen Receiving Vitamin D	1000-1500 1500-2000 1000-1200 800-1200

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

Calcium absorption is promoted by lactose, citric acid, protein diet, phosphorus, magnesium. Calcium absorption is impaired by excess fat, protein deficiency, fasting, strict vegetarianism, magnesium, phosphorus and vitamin D deficiency, foods high in oxalic acid (sorrel, rhubarb, spinach, beetroot, chocolate), gastrointestinal diseases (gastritis, enteritis, colitis, peptic ulcer), pancreatic diseases (diabetes mellitus, pancreatitis), gallbladder and bile ducts, thyroid gland (goiter, thyrotoxicosis, thyroiditis), gynecological diseases, especially those associated with endocrine pathology, some drugs, especially GCS (prednisolone, betamethasone, dexamethasone), levothyroxine, etc.

Vitamins play an important role in optimizing the management of patients with osteoarthritis with the risk of developing or already developed osteopenic syndrome.

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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 basic substance of connective tissue;
• increases antihyaluronidase activity.

2. Bioflavonoids:

• They thicken and reduce the permeability of the walls of blood vessels, particularly capillaries.

3. Vitamin B ₅:

• participates in cellular oxidation-reduction 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 directions of drug treatment of secondary osteoporosis is the use of HRT (estrogens, gestagens or combination drugs, as well as 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 is converted in the body into estradiol and estriol (the effect lasts for another 1-2 months). Transdermal forms are also used in monotherapy, for example, estradiol in the form of a 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 hypercoagulation syndrome, which often occurs against the background of rheumatoid arthritis, systemic lupus erythematosus and other rheumatic diseases.

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

When prescribing estrogen HRT, it is necessary to remember the contraindications: 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 HRT there is none. HRT-neutral conditions include: varicose veins, phlebitis, epilepsy, bronchial asthma, systemic connective tissue diseases, systemic atherosclerosis.

Experts believe that all postmenopausal women taking GCS should receive HRT unless there are contraindications, with the course (for the prevention and treatment of osteoporosis) lasting 5-7 years.

Men with gonadal insufficiency (and in some cases women) may be recommended HRT with androgens - testosterone propionate 100-200 mg intramuscularly once every 2-4 weeks, testosterone enanthate, etc.

Progestogen preparations include: Cycloproginova (1-2 mg estradiol valerate + 0.5 mg norgestrel), Klimonorm (2 mg estradiol valerate + 0.15 mg levonorgestrel), 17-OH progesterone derivatives - Klimen (2 mg estradiol valerate + 1 mg cyproterone acetate), Divina (1-2 mg estradiol acetate + 10 mg medroxyprogesterone), implantable dosage forms, etc. A contraindication to the use of preparations of this group is meningioma.

Densitometric monitoring during HRT is necessary every 3 months.

Copcitonin (an endogenous polypeptide containing 32 amino acid residues) also has the ability to prevent bone loss, and in high doses increases the content of minerals in the skeleton. The antiresorptive effect of the drug is due to specific binding to receptors for calcitonin 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 RZS (especially against the background of taking GCS) have been poorly studied in domestic and foreign literature until recently.

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

The sufficiently high efficiency of salmon calcitonin (trade name of the drug registered in Ukraine - Miacalcic®) in the treatment of osteoporosis in combination with calcium preparations, vitamins of group D and diet in patients with RZS and osteoporosis is confirmed by the results of studies conducted at the N.D. Strazhesko Institute of Cardiology, URC.

Recently, the concept has become widespread that the action of antiosteoporotic drugs is based on their ability to positively influence not only the "quantity" but also the "quality" of bone tissue. This concept has proven to be especially important for explaining the mechanisms of action and high clinical efficacy of synthetic salmon calcitonin, which is one of the most effective drugs whose antiosteoporotic activity is associated with the suppression of bone resorption. Moreover, along with its high antiosteoporotic activity, salmon calcitonin has a wide range of systemic effects, which makes its use especially appropriate for osteoporosis developing against the background of other diseases, including osteoarthrosis.

Of particular interest is the study of the analgesic effects of calcitonin. Immunoreactive calcitonin has been identified in the brain, cerebrospinal fluid, pituitary gland, etc. Labeled with ¹²⁵ 1, calcitonin irreversibly binds to specific receptors localized in various brain structures, especially in those areas of the hypothalamus that participate 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 stimulation of the release of the endogenous opioid receptor agonist, beta-endorphin. Intranasal administration of calcitonin is accompanied by an increase in the beta-endorphin level in the blood plasma. The analgesic effect of calcitonin has been demonstrated in clinical studies of pain syndromes of various etiologies, including rheumatic pain. Moreover, data from recent experimental studies indicate that in experimental canine osteoarthrosis in vivo, calcitonin effectively suppresses the production of Pyr and D-Pyr, inhibits the progression of morphological changes in cartilage, and stimulates proteoglycan synthesis in vitro. These data indicate not only a symptomatic, but also, possibly, a modifying effect of myacalcic on the progression of osteoarthrosis. Thus, calcitonin is the drug of choice for osteoporosis accompanied by pain of various origins, including osteoarthritic, as well as for a combination of osteoporosis and osteoarthrosis. In addition, the ability of calcitonin to inhibit gastric secretion is an important property of the drug in relation to the prevention and treatment of "drug-induced" ulcers (NSAID gastropathy) in patients with osteoarthrosis who have been taking NSAIDs for a long time.

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

In the pharmacotherapy of osteoporosis associated with inflammation, bisphosphonates play a significant role as drugs with certain anti-inflammatory properties, suppressing the development of joint inflammation and joint destruction 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.

The efficacy and safety of these drugs in maintaining skeletal bone mass and preventing fractures have been proven. However, the different structure of drugs in this class determines their different antiresorptive capabilities and the ratio of efficacy and toxicity. It has been established that they have an inhibitory property with respect to osteoclast-mediated bone resorption. However, strong and prolonged inhibition of resorption, achieved by long-term use of bisphosphonates, can cause a violation of bone formation and, consequently, an increase in its fragility, and increase the risk of fractures (as proven for etidronate, etc.). More potent bisphosphonates with a significant therapeutic interval between doses inhibiting bone resorption and doses potentially capable of disrupting mineralization include alendronate and tiludronic acid - new-generation bisphosphonates with strong inhibitory activity on bone resorption and a positive effect on bone formation.

The most common side effects of bisphosphonates are minor gastrointestinal disturbances that do not require discontinuation of the medication. In addition, mineralization defects and osteomalacia, i.e., bone quality disorders, may occur with first-generation bisphosphonates.

With regard to the interaction of antiosteoporotic drugs with the most commonly used NSAIDs in treatment, the absence of mutual influence on the pharmacokinetics of bisphosphonates and NSAIDs, with the exception of indomethacin, has been proven. The optimal choice of NSAIDs is very important. A comparative study of the efficacy and safety of using NSAIDs in the complex therapy of patients with rheumatoid arthritis (osteoarthrosis and rheumatoid arthritis) was conducted at the Ural Regional Center - meloxicam (Movalis), sodium diclofenac and flurbiprofen, which included examination of patients by the OFA method at the beginning of treatment and after 12 months.

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

Dynamics of MPC according to OFA data (A%) in patients with RZS

NSAIDs	Spongy bone tissue	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 rheumatoid arthritis can be explained by their reduction in the activity of the inflammatory process accompanied by an autoimmune component, i.e. their anti-inflammatory properties can additionally provide a protective effect on bone tissue demineralization, especially against the background of the use of GCS.

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

1. Reducing the negative impact of such factors in the development of osteoporosis as smoking, alcohol abuse, a sedentary lifestyle, prolonged fasting, etc.
2. Timely treatment of concomitant pathology affecting bone metabolism - hyperthyroidism, hyperparathyroidism, etc.
3. Maintaining and maintaining a positive calcium balance (diet, additional intake of calcium supplements in combination with vitamin D or its active metabolites).
4. In the absence of contraindications, prescribing HRT drugs to women in the postmenopausal period; in the premenopausal period, in case of ovarian-menstrual cycle disorders - monitoring of 17beta-estradiol and, if necessary, HRT (including androgens taking into account the hormonal profile).
5. In men - control of testosterone levels; if necessary - androgen HRT.
6. Conducting a control densitometric examination of patients with osteoarthritis belonging to the risk group.
7. Annual densitometric monitoring of MNC and MPK indices in patients with osteoarthritis and diagnosed osteoporosis.

Monitoring of antiosteoporotic therapy for osteoporosis

R. Civitelly et al. (1988) noted a significant increase in spine 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 with respect to calcitonin therapy. The greater effectiveness 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 bone resorption and formation. Based on accurate measurement of bone mass by densitometric methods and the expected level of change in bone mass induced by antiresorptive therapy, it is only after 2 years that it can be determined whether the treatment in a particular patient is effective, i.e. whether bone mass increases reliably. Many studies have shown a significant correlation between early changes (after 3-6 months) in markers of bone formation and/or resorption and delayed (more than 1 year - 2 years) changes in bone mass according to densitometric studies (in the radius, spine or in the whole skeleton) in patients treated with antiresorptive agents such as estrogens or bisphosphonates. The correlation coefficients in these studies were consistently around -0.5. This led the authors to suggest that at the individual level, bone turnover markers may not be able to accurately predict delayed changes in bone mass. However, by introducing a limiting threshold for a reliable decrease in bone markers after 6 months (30-60% or more depending on the accuracy of the measurement), it is possible to identify immediately after the start of treatment most patients who will respond with an increase in bone mass after 2 years with a very low rate of false positive and false negative results.

Thus, repeated measurements of sensitive and specific markers (formation or resorption) 3-6 months after the start of antiosteoporotic therapy are probably acceptable for monitoring rheumatological patients with osteoporosis, especially since the effects of such treatment can be detected even before the appearance of changes in BMD.

The above literature data, as well as the results of our studies, confirm the relevance of the problem of osteopenic syndrome in osteoarthrosis. The combined development of osteoporosis and osteoarthrosis significantly worsens the quality of life, and probably the life expectancy of patients, especially the elderly and old.

We emphasize the importance of conducting densitometric and biochemical monitoring of the state of bone marrow to assess the dynamics, as well as the effectiveness of the drugs used, primarily NSAIDs.

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