Secondary hyperparathyroidism: symptoms, causes, treatment

There are many causes for hypocalcemia and hyperphosphatemia. But secondary hyperparathyroidism, which develops in patients receiving renal replacement therapy, deserves special attention. A progressive decrease in the number of functioning nephrons in chronic renal failure causes disruption of all links in the regulation of phosphorus-calcium metabolism.

When hyperphosphatemia occurs, there is a response decrease in ionized calcium. Hyperphosphatemia and hypocalcemia directly stimulate the synthesis of parathyroid hormone (PTH) by the parathyroid glands. Calcium affects the processes of PTH synthesis through calcium receptors present in the parathyroid glands, the number and sensitivity of which decrease. As the decline in renal function progresses, a deficiency of calcitriol, the active metabolite of vitamin D3 synthesized in the kidneys, also occurs, and the number of calcitriol receptors in the parathyroid glands decreases. As a result of these processes, the inhibitory effect of calcitriol on the synthesis and secretion of PTH is weakened, and skeletal resistance to the calcemic effect occurs, which is also accompanied by hypersecretion of PTH.

Causes and symptoms of secondary hyperparathyroidism

Secondary hyperparathyroidism differs from primary hyperparathyroidism in that it is not a direct consequence of changes occurring directly in the parathyroid glands. The main causes of development are pathological processes in other organs and systems of the body.

The appearance of secondary hyperparathyroidism can be caused by:

• renal pathologies: chronic renal failure (hereinafter chronic renal failure), tubulopathy, renal rickets;
• intestinal pathologies: malabsorption syndrome, Crohn's disease;
• bone pathologies: osteomalacia, Paget's disease;
• lack of vitamin D, various liver diseases, hereditary fermentopathy;
• malignant diseases including myeloma.

As a rule, secondary hyperparathyroidism develops as a result of various renal pathologies, in particular chronic renal failure, and the clinical picture is dominated by the symptoms of this particular disease. Characteristic symptoms:

• arthralgia, bone pain,
• weakness in the proximal muscles,
• spontaneously occurring fractures are possible,
• softening of bones and their curvature,
• various skeletal deformities.

Often, patients may develop extraosseous calcifications; this process can acquire a variety of clinical signs. The result of arterial calcification can be the appearance of ischemic changes. Periarticular calcifications form on the arms and legs. The process of calcification of the cornea with the conjunctiva, as well as recurrent conjunctivitis, causes red eye syndrome.

Under the influence of a large amount of PTH, a complex of complications develops, which is characteristic of secondary hyperparathyroidism:

• Renal osteopathies, the manifestations of which are skeletal deformation, bone pain, pathological fractures.
• Extraskeletal calcification, primarily damage to the valves and blood vessels of the heart.
• Itching.
• Spontaneous tendon rupture.
• Calciphylaxis.

How does this happen?

As a result of prolonged and uncontrolled effects of PTH on osteoclasts, hyperplasia (an increase in the number of cells) and activation of the latter occurs. Due to the uncontrolled activation of osteoclasts, the same uncontrolled destruction of bone tissue and proliferation of connective tissue occurs. Often this process takes on a cystic-fibrous character: bone tissue is replaced by closed cavities, among which there is an accumulation of cells (osteoclasts, fibroblasts) and connective tissue fibers.

Methods for diagnosing secondary hyperparathyroidism

To diagnose secondary hyperparathyroidism and its complications, a number of laboratory and instrumental research methods are required. Diagnosis can be carried out by specialists in various fields of medicine. This is explained by the wide variety of clinical manifestations of the disease. The disease is diagnosed using:

• anamnestic information (questioning, detailed study of the medical record, examination),
• analysis of characteristic symptoms,
• X-ray examinations of the bones of the arms, legs, skull and spine,
• studying the results of general, biochemical and specific blood tests for the concentration of parathyroid hormone, calcium, phosphorus,
• urine analysis,
• Ultrasound of the thyroid gland,
• studies of the composition of gastric juice,
• fibrogastroduodenoscopy (gastric walls and duodenum).

Of the laboratory data, the most important are the following studies:

• PTH concentrations,
• levels of ionized calcium, inorganic phosphorus,
• markers of bone resorption in the patient's blood serum.

Bone changes and extraskeletal calcification are assessed using densitometry, parathyroid scintigraphy, echocardiography, and MRI.
In the case of secondary hyperparathyroidism, it is very important to conduct a comprehensive diagnosis of the primary disease. The main directions of prevention and treatment of secondary hyperparathyroidism are the impact on all parts of the pathogenesis of the disease.

Relevance of the problem

The social significance of any disease is determined by its prevalence, difficulties of diagnosis and therapy, and significant impact on disability and mortality rates.
According to these criteria, diseases caused or accompanied by disorders of phosphorus-calcium metabolism absolutely correspond to the status of socially significant ones. In the practice of an endocrinologist, diseases accompanied by impaired calcium metabolism occupy a significant place. Severe disturbances of mineral metabolism are observed in diabetes mellitus, pathology of the thyroid gland and adrenal glands, hyper- and hypoparathyroidism, peri- and postmenopause, and age-related androgen deficiency. Clinical manifestations of calcium and phosphorus metabolism disorders are quite varied, but the most well known manifestations are those associated with damage to bone tissue, including osteoporosis. As a cause of disability and mortality in patients from bone fractures, osteoporosis ranks fourth among non-communicable diseases [1]. According to statistics, only 25% of patients are completely cured after a hip fracture, 50% of patients remain disabled, and in 25% of cases, a fracture due to osteoporosis leads to the death of patients. In Russia, osteoporosis has been detected in 10% of the population (more than 14 million people) [3, 4]. Every year, 3 million vertebral fractures are recorded, more than 150 thousand of the radius and more than 40 thousand of the proximal femur.

In the medical literature, osteoporosis is sometimes figuratively called a “silent epidemic.” The disease is asymptomatic for a long time and is first diagnosed after a fracture occurs. The term “osteoporosis” as the name of a pathological process is usually used when talking about primary osteoporosis (Fig. 1). The pathology of the endocrine system is usually associated with manifestations of secondary osteoporosis, which is observed in patients against the background of increased secretion of parathyroid hormone (PTH), caused by secondary causes, incl. endocrine diseases (Fig. 2). From the group of diseases designated as primary osteoporosis, the scope of activity of endocrinologists includes osteoporosis caused by postmenopause, and, in our opinion, osteoporosis caused by androgen deficiency can be rightfully included.

The state of phosphorus-calcium metabolism in normal and pathological conditions

The level of calcium in the human body is one of the most significant constants. Reliable proof of this is the minimal spread of the values ​​of the given indicators. Laboratory criteria for the normal level of total calcium in the blood serum are 2.1–2.6 mmol/l; ionized – 1.1–1.3; protein-bound – 0.9–1.1; complexed – 1.18 mmol/l. In the blood, calcium is presented in three forms. About 40% of it is in the form of protein-bound compounds, almost half is free (including ionized) calcium, 10% is complexes with citrates and phosphates.

As a rule, extracellular calcium regulates muscle contractile activity, synaptic signal transmission in nervous tissue, platelet and erythrocyte aggregation, the coagulation process, and the secretion of hormones and biologically active compounds. Intracellular calcium regulates the processes of the cell cycle and growth, the permeability of cell membranes, the strength of muscle contractions, as well as the secretion of hormones and biologically active factors.

Calcium is an important component in regulating the functioning of the cardiovascular system (contractile function, maintaining normal rhythm and conduction, blood pressure control), and has antioxidant, anti-inflammatory, anti-edematous and anti-atherosclerotic effects.

The metabolism of calcium and phosphorus in a healthy body is in dynamic equilibrium; compensatory mechanisms regulate it in hyper- or hypocalcemic conditions.

The implementation of this control is ensured by adequate levels of PTH, calcitonin, vitamin D and other hormones:

• PTH: regulates bone resorption indirectly through osteoclasts;
• calcitonin: inhibits bone resorption by acting directly on osteoclasts;
• insulin: stimulates matrix synthesis and cartilage formation, normalizes mineralization;
• somatotropic hormone: maintains overall bone mass by regulating the synthesis of insulin-like growth factor type 1 (IGF-1), stimulates the synthesis of 1,25-dihydroxy vitamin D;
• vitamin D is responsible for bone mineralization, stimulates the synthesis of osteocalcin by osteoblasts and increases the concentration of IGF-binding proteins;
• glucocorticoids: stimulate bone resorption, reducing calcium absorption in the intestine (decreased PTH secretion);
• Thyroid hormones: stimulate bone resorption;
• estrogens: suppressing the production of interleukins (IL-1, -6), reduce bone resorption, maintain bone mass by regulating the activity of the TGF-β gene;
• androgens: have an anabolic effect on bone tissue.

The vital activity of the skeletal system is based on two interrelated processes: the creation (formation) of new bone and the process of destruction (resorption) of old bone. These processes in the skeletal system occur at different rates throughout a person’s life. From 1–2 to 10% of bone mass is exchanged annually. The latter reaches its maximum value by the age of 16–20 years, therefore childhood and adolescence are critical periods for the formation of a strong, healthy skeleton. Upon reaching the peak, a balance between the processes of synthesis and resorption occurs, which continues until 40–45 years in women and 50 years in men. Then bone loss begins, which is more significant in women after menopause [3, 4].

Factors that influence bone formation and strength include:

• genetic;
• growth factor;
• nutritional factors;
• physical activity;
• environmental factors.

The bone of a healthy person is living, active tissue. It is strong, able to withstand significant loads without breaking, but at the same time flexible, able to absorb energy, deform and not break. Such contradictory properties of bone are achieved due to the special composition and structure (weaving type 1 collagen into a triple helix). With disturbances in phosphorus-calcium metabolism, the situation changes. The effect of loading on a bone with insufficient mineralization causes the bone to bend excessively and fracture, however, if loading occurs on a bone with excessive mineralization, it will underflex and also fracture.

Hypercalcemia, accompanied by excessive production of PTH, is observed in primary, secondary hyperparathyroidism, multiple endocrine neoplasia, pseudohyperparathyroidism (ectopic production of PTH) and familial isolated hyperparathyroidism. Hypercalcemia syndrome can develop against the background of other endocrinopathies - thyrotoxicosis, hypothyroidism, eosinophilic pituitary adenoma (acromegaly), hypercortisolism, pheochromocytoma, VIPomas. In addition to endocrine diseases, the causes of hypercalcemia and objects for differential diagnosis are an overdose of vitamin D, malignant tumors, acute and chronic renal failure, immobilization after bone fractures, and certain medications. Excessive calcium intake (more than 2 g/day) can also lead to the development of hyperparathyroidism.

Hypocalcemia is a condition associated with primary or secondary deficiency of PTH production, vitamin D deficiency and resistance to PTH (pseudohypoparathyroidism). The main reasons: autoimmune process in the parathyroid glands, postoperative or radioiodine hypoparathyroidism, diabetes mellitus.

Dysfunction of the parathyroid glands can manifest itself as a component of various genetic syndromes (DiGeorge syndrome, Wilson's disease, hemochromatosis, etc.) and autoimmune polyglandular syndrome type I (hypoparathyroidism, chronic generalized granulomatous candidiasis and chronic adrenal insufficiency). Calcium deficiency is accompanied by endocrine disorders associated with age-related changes in the reproductive system - androgen deficiency in men and postmenopausal processes in women.

In addition to endocrine disorders, calcium deficiency may be accompanied by diseases of the gastrointestinal tract, kidneys, hypovitaminosis D, increased levels of magnesium in the blood serum, and the use of medications (hormonal, laxatives, antacids, diuretics, adsorbents, anticonvulsants, tetracycline).

Factors that contribute to calcium deficiency in the body include a sedentary lifestyle, consumption of a lot of proteins, sugar, salt, animal fats, acidic foods (spinach, rhubarb, etc.) [5].

An imbalance of phosphorus-calcium metabolism contributes to the progression of atherosclerosis, the development of arthrosis and dorsopathy, arterial hypertension, but the main manifestation remains osteoporosis, leading to a significant increase in the risk of bone fractures [6, 7].

Primary hyperparathyroidism

The most common cause of hypercalcemia and hypophosphatemia. The disease has been repeatedly presented since 1981 in the scientific medical literature under various names: Recklinghausen's disease, Burnett's syndrome, fibrous osteodystrophy, primary hyperparathyroidism. The prevalence of the disease is 0.05–0.10% of the population and is observed approximately 4 times more often in women than in men.

In 80–89% of cases, the cause of the disease is a solitary adenoma of the parathyroid gland; multiple adenoma (2–3%), hyperplasia of the parathyroid glands (2–6%) and cancer (0.5–3.0%) are much less common.

Primary hyperparathyroidism is observed in 90% of patients with multiple endocrine neoplasia type I (MEN I) and in 50% of patients with MEN type IIa. Excessive production of PTH and lack of suppression of secretion in response to hypercalcemia lead to accelerated bone resorption and leaching of calcium from bones, reducing the threshold for phosphorus reabsorption. Glomerular filtration of calcium and urinary excretion of phosphorus increases. Hypercalcemia is maintained by increased tubular reabsorption of calcium and increased intestinal calcium absorption. The symptoms of the disease are quite varied. Patients complain of general weakness, loss of appetite, nausea, vomiting, constipation, weight loss, bone pain, arthralgia, bone deformation, muscle weakness, convulsions, polyuria, polydipsia, memory impairment, depression, calcifications of soft tissues and cornea, swelling of the face, dysfunction of the cardiovascular system. The predominance of certain symptoms makes it possible to conditionally classify the manifestations of the pathology of a particular patient as bone, visceral or renal forms of hyperparathyroidism. The least difficult form to diagnose is the “bone” form, in which variants of damage such as systemic osteoporosis, osteitis fibrosa or Paget’s disease are possible. X-ray examination allows us to record typical bone changes in the form of osteoporosis, pathological fractures, subperiosteal bone resorption, cystic formations in the area of ​​the epiphyses, and skeletal deformities. Hyperparathyroidism is quite common, but, unfortunately, diagnosing this disease is quite difficult.

Secondary hyperparathyroidism

A condition associated with increased PTH production in response to prolonged hypocalcemia. In patients with thyrotoxicosis, increased catabolic processes lead to increased bone tissue resorption, because Thyroid hormones activate predominantly osteoclasts. The predominance of bone resorption over its formation can lead to hypercalcemia and calciuria, and with long-term uncompensated hyperthyroidism, the development of osteopenia can be considered an expected complication, especially in young patients.

The occurrence of osteoporosis against the background of hypothyroidism is possible, but this is associated with hormonal replacement therapy (overdose of thyroid drugs). For patients with hypercortisolism, both primary and iatrogenic, excess production of glucocorticoids is accompanied by suppression of osteoblast activity and inhibition of calcium absorption in the intestine. Hypocalcemia leads to increased production of PTH, development of secondary hyperparathyroidism and activation of osteoclasts.

A decrease in insulin secretion in patients with type I diabetes mellitus is accompanied by a decrease in the activity of osteoblasts and suppression of the secretion of 1,25(OH)2D3 in the kidneys. Bone loss is also influenced by increased glucocorticoid secretion in response to hypoglycemia and decreased physical activity.

Primary hypoparathyroidism

Insufficiency of PTH secretion by the parathyroid glands, decreased calcium resorption in the renal tubules, decreased calcium absorption in the intestine, leading to hypocalcemia. The main causes are surgical interventions on the thyroid and parathyroid glands, treatment with radioactive iodine, developmental disorders of the parathyroid glands (congenital hypoplasia, DiGeorge syndrome, etc.), autoimmune processes and idiopathic hypoparathyroidism. The disease can occur in acute and chronic forms. The leading syndromes include tetany and autonomic dysfunction. Confirmation of the diagnosis involves conducting provocative tests: Trousseau, Chvostek, Schlesinger, Weiss.

Postmenopausal osteoporosis

Postmenopausal osteoporosis occurs most often in clinical practice and is characterized by rapid development. Postmenopausal women experience a 15–20% decrease in bone mass over 5–10 years. The main reason is estrogen deficiency, which leads to an increase in the number and activity of osteoclasts. Increased resorption leads to irreversible bone loss. High activity of osteoclasts promotes perforation of trabeculae at the site of resorption, and the microarchitecture of the bone is disrupted. The trabecular bone is primarily affected, so the localization of early osteoporetic fractures is the carpal bones and vertebrae.

Multiple endocrine neoplasia

This name combines a group of syndromes caused by tumors (rarely hyperplasia) of several endocrine glands simultaneously. Most tumors are of neuroectodermal origin and have a malignant course. In the middle of the 20th century. P. Wermer described a syndrome that included a combination of a tumor of the parathyroid glands, pituitary glands and pancreas, and called it multiple endocrine adenomatosis (now MEN I). A little later, JH Sipple described the syndrome of combined symptoms of thyroid cancer and pheochromocytoma (MEN IIa). Among 50% of these patients, parathyroid adenoma and hyperparathyroidism are observed. Difficulties in diagnosis are due to the fact that symptoms of damage to different endocrine organs do not appear simultaneously. Sometimes the disease begins with hyperparathyroidism with characteristic clinical symptoms, and symptoms of damage to other endocrine glands manifest much later, so it takes much more time to establish a final diagnosis.

Problems of diagnosing disorders of phosphorus-calcium metabolism

The problem of diagnosing disorders of phosphorus-calcium metabolism is associated with the characteristics of the disease. The absence of pronounced clinical manifestations in the initial stages of the disease leads to the fact that a visit to an endocrinologist is far from the first position in the diagnostic chain. Therefore, the diagnosis of disorders of phosphorus-calcium metabolism of an endocrine nature is made quite late. As a rule, the first signal to begin examining a patient is the occurrence of a pathological fracture. Densitometry does not always immediately provide an unambiguous answer. Among women aged 50 years and over, 50% have fractures but do not have osteoporosis, as measured by bioenergetic X-ray absorbitiometry (Wainwright SA et al., 2005). In a population of women aged 50 years and older, 96% of typical fractures can occur without a decrease in bone mineral density (BMD) (Kanis JA et al., 2001).

Still, some symptoms of osteoporosis are present. These include pain in the back and lower back, forward curvature of the spine, a decrease in height by several centimeters over the course of a year, leg cramps, brittle nails, and the appearance of early gray hair. Typically, the appearance of these symptoms leads patients not to an endocrinologist, but to a neurologist and therapist. Osteoporosis should be suspected if height has decreased by more than 2 cm in one year or by 4 cm over several years.

The traditional approach to diagnosing osteoporosis is based on assessing the risk of fracture. Risk factors for osteoporosis and fractures are usually divided into major and minor.

Big risk factors:

• age over 65 years;
• history of previous fractures (during daily physical activity in persons over 40 years of age);
• vertebral compression fractures;
• family history of osteoporetic fractures;
• long-term use of glucocorticoids (more than 3 months);
• female;
• low BMD;
• estrogen deficiency: early menopause (up to 40–45 years), surgical menopause (up to 40–45 years);
• primary hyperparathyroidism;
• predisposition to falls (muscle weakness, decreased visual acuity, decreased proprioceptive sensitivity, use of benzodiazepines);
• malabsorption syndrome;
• long-term immobilization;
• osteopenia;
• hypogonadism.

Minor risk factors:

• rheumatoid arthritis, diabetes mellitus;
• history of clinical hyperparathyroidism;
• continuous anticonvulsant therapy;
• insufficient calcium intake;
• vitamin D deficiency;
• long-term immobilization;
• smoking (decreased estrogen production);
• alcohol abuse (inhibits osteoblasts, suppresses bone resorption, disrupts vitamin D metabolism, increases age-related androgen deficiency);
• body mass index <20 kg/m2, weight <57 kg;
• weight loss of more than 10% at age 25;
• caffeine abuse;
• long-term heparin therapy.

Osteoporotic (minimal trauma fracture) is defined as a fracture that occurs spontaneously or from a fall from a height no higher than one's own height, including fractures caused by activities such as coughing, sneezing, or sudden movement (for example, opening a window). And also in a situation where a patient’s x-ray reveals a vertebral compression fracture, regardless of whether symptoms of compression are detected or not.

Laboratory diagnostics involves determining blood levels of calcium, phosphorus, other microelements, biochemical markers of bone formation (alkaline phosphatase, osteocalcin, PINP N (terminal propeptide of type 1 procollagen) and markers of bone resorption. Markers of bone resorption (beta-cross laps) indicate on accelerated bone turnover, decreased BMD, and fractures.The combination of a high level of bone resorption markers (for example, the degradation products of type I collagen - N-telopeptide [NTX] in the urine or C-telopeptide in the blood serum) with a low level of BMD on densitometry or previous fractures indicates an increased risk of new fractures. Repeated BMD studies during therapy are usually carried out at intervals of 1–2 years. Treatment is considered effective if no negative dynamics are observed in BMD indicators within a year.

Determination of the level of PTH and osteocalcin is a mandatory component of the examination for any form of osteoporosis. In the diagnosis of disorders of phosphorus-calcium metabolism, histomorphometry uses both methods of X-ray examination, densitometry, and standard radiography.

Any adult patient who has sustained a vertebral, proximal femoral, or radial fracture due to minimal trauma should be considered at high risk for fracture development and a candidate for treatment for osteoporosis (even if BMD values ​​do not meet criteria for a diagnosis of osteoporosis). Women over 70 years of age with a previous fracture are candidates for treatment of osteoporosis without densitometry.

The choice of treatment tactics for various types of phosphorus-calcium metabolism disorders

The main goal of treating patients with diseases accompanied by hypercalcemia, in addition to the etiopathogenetic treatment of the underlying disease, is to reduce the leaching of calcium from the bones or increase the flow of calcium into the bone.

In the treatment of primary hyperparathyroidism, the main and most radical method is adenomectomy of the parathyroid gland. However, not in all cases this operation can be performed quickly or radically. If the patient refuses surgery, if there are absolute or relative contraindications, or if the operation is unsuccessful, drug treatment should be prescribed. Synthetic phosphate binders are used in short courses (2–4 weeks), which eliminates hypercalcemia and prevents the formation of kidney stones.

Positive results from the use of estrogen-gestagen drugs have been obtained from postmenopausal women. A good effect is ensured by the use of active metabolites of vitamin D and bisphosphonates, the importance of which increases in the presence of contraindications to hormone replacement therapy. The use of bisphosphonates in standard doses allows normalization of calcium levels in 80% of patients. Treatment of osteoporosis in patients with age-related androgen deficiency involves prescribing testosterone replacement therapy.

Treatment of secondary hyperparathyroidism is determined by the underlying pathology that caused its formation and the stage of medical care. In the treatment of secondary osteoporosis, calcitriol, calcium supplements and bisphosphonates are used. Parathyroidectomy may also be the treatment of choice for the treatment of secondary hyperparathyroidism. The absolute indications are the occurrence of osteitis fibrosa, failure of conservative therapy, persistent hypercalcemia with an increased PTH value, disseminated skin necrosis, and soft tissue calcifications.

Treatment of hypoparathyroidism involves a diet rich in calcium (mainly milk-vegetable), calcium salts, replacement therapy with PTH and its analogues, as well as the use of vitamin D and combination drugs (vitamin D + calcium supplements, dehydrotachysterol, AT-10, etc. ).

Treatment of osteoporosis due to both primary and secondary causes has common approaches.

Non-drug therapy:

• physical exercise;
• reducing the risk of falls;
• diet;
• to give up smoking;
• food enriched with calcium and vitamin D.

Drug therapy:

• hormone replacement therapy;
• tibolone (synthetic steroid);
• selective estrogen receptor modulators;
• bisphosphonates;
• calcitonin;
• calcium preparations.

Among the non-drug treatments listed, the patient can be responsible for quitting smoking and reducing the risk of falls. As for physical exercises, there should be a mandatory consultation with a specialist and an individual complex of physical therapy developed for each patient.

Whatever the origin of the disease that leads to the development of osteoporosis, diet is an important component of treatment. Under normal conditions of the body, to ensure the basic processes regulated by phosphorus-calcium metabolism, a person should receive 0.5 g of calcium per day. However, many guidelines recommend 1 g of calcium per day, this is due to the fact that only 50% of the consumed dose is absorbed in the intestines due to the low ability of calcium to form soluble compounds. It is for this reason that calcium is better absorbed from foods that have not been subjected to heat treatment. When foods are heated, calcium forms stable compounds and is practically not absorbed by the body. Higher doses of calcium under physiological conditions are required by a growing body, a woman during pregnancy, people during significant physical and mental stress, and in winter. Patients with osteoporosis must consume foods rich in calcium, vitamins (D, A, E), and microelements (magnesium, copper, zinc, selenium).

As people age, the skin's ability to produce D3 and absorb it in the intestines decreases. Older people are less likely to be outdoors in direct sunlight, which, of course, cannot but affect the formation of endogenous vitamin D.

Drug correction of phosphorus-calcium metabolism disorders is not an easy task. A fairly limited group of drugs has been identified that are used as pathogenetic therapy. In the practice of an endocrinologist, bisphosphonates, calcium and vitamin D preparations are successfully used [8, 9].

Criteria for assessing the effectiveness of drugs for the treatment of osteoporosis: reduction in the incidence of fractures during 3-5 years of treatment (main criterion), increase in bone mineral density, normalization or improvement of the profile of markers of bone metabolism, improvement in bone quality (histomorphological studies), improvement in the quality of life of patients (increased physical activity, pain reduction).

Calcium preparations have been used for a long time in the treatment of primary osteoporosis. Tablet forms of calcium supplements are more often used; the main means that promote better absorption of calcium from the gastrointestinal tract are well known:

• protein foods (amino acids improve calcium transport into the cell);
• lemon juice (increases the absorption of calcium salts);
• choleretic agents (bile acids improve calcium utilization in the small intestine);
• sufficient amount of fluid (1.5–2.0 l/day).

Ionized calcium has physiological activity; it activates the plastic function of osteoblasts and osteocytes, participates in the formation of bone tissue, and forms the mineral basis of the skeleton. Calcium preparations compensate for ion deficiency, inhibit the activity of osteoclasts and reduce bone resorption. Calcium salts are effective in the treatment of osteoporosis if they enter the body in an amount of at least 1500 mcg/day (in terms of ionized calcium). The lowest calcium content in 1 g of salt is found in calcium gluconate, the highest in calcium carbonate and calcium phosphate. In addition to monocomponent preparations of calcium salts, two-component preparations are used: calcium salts + vitamin D3.

Vitamin D is used for various disorders of phosphorus-calcium metabolism - in the complex therapy of osteoporosis, hypoparathyroidism, osteomalacia, Fanconi syndrome. The concept of “vitamin D” combines two natural forms – D2 (ergocalciferol) and D3 (colecalciferol), their structural analogues and active metabolites. Native products (colecalciferol, ergocalciferol) and a vitamin D2 analogue (dihydrotachysterol) have moderate activity. Currently, active metabolites are more often used for therapeutic purposes - calcitriol [1α,25-(OH)2D3], alfacalcidol [1α-(OH)D3], calcipotriol. All vitamin D preparations in the body are converted into calcitriol and provide the same pharmacological effect: increased calcium absorption in the intestine (formation of calcium-binding proteins inside enterocytes), inhibition of increased bone resorption, normalization of remodeling processes and leaching of calcium from bones, suppression of PTH secretion, improvement of muscle tissue function . Under the influence of calcitriol and alfacalcidol, there is also an increase in the synthesis of type 1 collagen and matrix proteins (osteocalcin and osteopontin) in osteoblasts, which play an important role in the processes of formation and mineralization of bone tissue. The use of calcitriol helps suppress the activity of 1α-hydroxylase and stimulates the activity of another renal enzyme - 24α-hydroxylase, increases the formation of the active metabolite - 24α,25(OH)2D3, which plays an active role in the healing processes of microfractures and the formation of microcalluses in bones, increases bone tissue density .

Vitamin D preparations have been used for a long time to prevent and treat osteoporosis. Physiological replacement doses of native vitamin D range from 400–800 to 1000–2000 IU/day. In case of metabolic disorders, dosages can be increased from 10 thousand to 25 thousand IU/day. Therapy is carried out over several months or years.

Calcitriol has proven effectiveness in the treatment and prevention of secondary hyperparathyroidism. The use of calcitriol lowers PTH levels and improves bone structure. The dose depends on the severity of the patient’s condition and the route of administration (oral, intravenous).

However, the risk of developing hypercalcemia and hypercalciuria should be taken into account during long-term treatment with high doses of vitamin D. Alfacalcidol is safer with long-term use and can be used in patients with kidney disease.

Bisphosphonates are the “gold” standard in the treatment of osteoporosis, regardless of whether it is primary or secondary [8]. The name of this group of drugs was formed due to the presence in the chemical structure of a carbon atom bonded to two phosphorus atoms (non-hydrolyzable PCP bond). The structure of bisphosphonates is close to endogenous pyrophosphate. First-generation bisphosphonates inhibited the resorptive activity of osteoclasts due to the formation and accumulation of metabolites that disrupt the normal functioning of osteoclasts. The first generation bisphosphonates (etidronate, clodronate and tiludronate) were used primarily to treat Paget's disease (osteitis deformans) and later in the treatment of osteoporosis. Today, etidronate, tiludronate, pamidronate, ibandronate and zoledronate are practically not used in the treatment of osteoporosis; the main indications for their use remain Paget's disease and tumor forms of hyperthyroidism.

The formula of new generation bisphosphonates - aminobisphosphonates - contains a nitrogen atom (alendronate, risendronate), which changes their mechanism of action, and due to the inhibition of farnesyl pyrophosphatase and other stages of mevalonate metabolism, the differentiation of osteoclast precursors is disrupted and osteoclast apoptosis is enhanced. As a result, the level of bone resorption markers decreases, bone mineral density increases and the risk of fractures decreases.

All of the above has expanded the horizons of use of new generation bisphosphonates. Alendronate is effectively used both for juvenile and immobilization osteoporosis, and for osteoporosis caused by endocrine disorders (hyperthyroidism, hypercortisolism, estrogen and androgen deficiency).

The use of bisphosphonates must be accompanied by certain precautions: the drugs must be taken on an empty stomach with plenty of water. The most common side effects are: abdominal pain, dyspeptic disorders (constipation or diarrhea, flatulence), dysphagia, heartburn; muscle pain, bone pain. Bisphosphonates are not metabolized in the body, so they are excreted in the urine almost unchanged.

Bisphosphonates are contraindicated during pregnancy, lactation, severe renal impairment (creatinine clearance less than 30 ml/min), and hypersensitivity. One should also remember about the “rebound phenomenon” - increased bone resorption during treatment with calcium salts after discontinuation of bisphosphonates.

Forosa® is the drug of choice in the treatment of phosphorus-calcium metabolism disorders in patients with endocrine pathology

In the treatment of phosphorus-calcium metabolism disorders in patients with endocrine pathology, the requirements for choosing a drug for their correction are increasing. Not all drugs used in the treatment of primary osteoporosis are sufficiently effective in secondary osteoporosis of endocrine origin. On the other hand, according to the requirements of modern medicine, the effectiveness of any drug must be proven by multicenter randomized studies. In accordance with these criteria, the activity of nitrogen-containing bisphosphonates (alendronate, risendronate) has been confirmed [3], so they are the first-line drugs for the treatment of osteoporosis.

One of the most optimal bisphosphonate formulas that we use today is Forosa® - sodium alendronate trihydrate, a non-hormonal specific inhibitor of osteoclastic bone resorption that suppresses osteoclast activity. Forosa® stimulates osteogenesis, restores a positive balance between bone resorption and restoration, increases bone mineral density (regulates phosphorus-calcium metabolism), promotes the formation of bone tissue with a normal histological structure. The advantages of the drug are associated with the frequency of use (70 mcg once a week), high effectiveness for osteoporosis of any type, both in women and men. And this is a very important aspect in the treatment of secondary osteoporosis against the background of age-related androgen deficiency and the prevention of fractures.

There are no restrictions for its use in elderly patients and patients with impaired liver function or moderate renal impairment (Cl creatinine > 35 ml/min). The drug is of particular value for endocrinological practice due to the proven effectiveness of its use in patients with hypercortisolism, incl. for the treatment of osteoporosis caused by long-term use of corticosteroids. Forosa does not affect concentration or the ability to drive.

Conclusion

The clinical effectiveness of alendronate has been repeatedly proven in randomized studies in patients with osteoporosis (recommendation level A). It is effective not only for primary forms of hypoparathyroidism, but also for disorders of phosphorus-calcium metabolism in patients with hyperparathyroidism, hypercortisolism, thyrotoxicosis, and diabetes mellitus. On average, Forosa reduces the risk of fractures of various locations by 50%, and the risk of multiple vertebral fractures by 90%. Of course, the drug is also endowed with some common disadvantages of all bisphosphonates: low bioavailability of tablet forms, nephrogenic route of elimination, limited use in patients with impaired renal function, side effects in the form of dyspeptic disorders, pain in bones and muscles, allergic reactions, but subject to the recommendations for use The drug Forosa® allows for high efficiency in the correction of phosphorus-calcium metabolism disorders in endocrine diseases.

Prevention

There is no specific prevention of the primary form of the disease. To reduce the risk of pathology it is important:

• Maintain the level of vitamin D in the body. If there is a deficiency, taking vitamin-mineral complexes is recommended.
• Regular exercise.
• Eating enough calcium, however, should not take calcium supplements without determining its level.
• Drinking enough fluids reduces the risk of kidney stones.
• When taking diuretics, check the level of calcium in the blood.
• Persons with a hereditary tendency to this disease should undergo examinations.
• Menopausal women undergo annual densitometry examination to detect osteoporosis.

Prevention of secondary hyperparathyroidism is possible. For kidney diseases, diet therapy, medications that adsorb phosphorus and active vitamin D preparations are prescribed. In the later stages of the secondary form of the disease, hypertrophy of the parathyroid glands develops. In order not to miss this condition, you need to regularly do ultrasound, and if a pathological enlargement of the glands is detected, the patient should be recommended for surgical treatment.

Pathogenesis

The activity of the parathyroid glands is regulated by the principle of feedback between the level of calcium in the blood. When the calcium content in the plasma decreases, the production of parathyroid hormone is stimulated, the action of which is aimed at increasing the level of calcium by releasing it from bone tissue, increasing the reabsorption (reabsorption) of calcium in the kidneys and increasing the production of calcitriol (a metabolite of vitamin D3) by the kidneys. Under the influence of vitamin D3, calcium is absorbed in the intestines.

With adenoma, the feedback between the calcium level and the production of parathyroid hormone is disrupted, and the decrease in parathyroid hormone production with elevated calcium levels is also disrupted. This is due to the fact that the sensitivity of calcium-sensitive receptors on the surface of parathyroid cells is reduced or absent, so the synthesis of parathyroid hormone increases.

With glandular hyperplasia, there is an increase in the number of cells producing parathyroid hormone and its production becomes unregulated.

Excessive hormone production causes:

• Increased bone resorption and loss of calcium. Calcium, being washed out of bone tissue, passes into the blood. The bone matrix is ​​destroyed and cavities and granulomas form in them.
• Reduced reabsorption of phosphates in the kidneys - this leads to hypercalcemia , hypercalciuria , hypophosphatemia .
• Strengthening the absorption of calcium in the intestines.

With primary hyperparathyroidism, target organs are affected: the gastrointestinal tract (ulcerative lesions develop), the skeletal system ( osteoporosis ), the urinary system (stone formation, secondary pyelonephritis ) and the cardiovascular system ( calcification of blood vessels and heart valves).

Consequences and complications

The main complications of the disease are:

• The formation of kidney stones due to increased excretion of calcium in the urine, its deposition in the kidney tissue ( nephrocalcinosis ).
• Vascular calcification with the development of arterial hypertension , myocardial infarction , stroke , circulatory failure.
• Neuropsychiatric disorders ( depression , memory impairment).
• Stomach ulcer.
• Secondary osteoporosis and fractures.
• Hypercalcemic crisis.
• Postoperative complications include: hypocalcemia , hungry bone syndrome, laryngeal nerve damage. To eliminate the “hungry bone” syndrome after surgery, high doses of calcium and vitamin D are prescribed.