Bisphosphonates are pharmacological preparations in the chemical composition of which esters of phosphonic acids are present. The main therapeutic effect of drugs is the prevention of bone loss observed in osteoporosis. Bisphosphonates reduce the risk of spontaneous fractures characteristic of this pathology of the musculoskeletal system. Drugs are used both for pathogenetic therapy and for prevention.
Any bisphosphonate is characterized by a wide range of contraindications. In violation of the dosage regimen or as a result of prolonged use, systemic and local side effects often occur. Only after a series of instrumental studies, the doctor concludes that it is advisable to include bisphosphonates in treatment regimens.
A bit of history
Initially, bisphosphonates were not synthesized for the needs of the pharmaceutical industry. Moreover, this area of their application has not been considered for almost 100 years. Phosphonic acid esters were produced for agriculture. Mineral fertilizers were created on their basis, water for subsurface irrigation was softened. The textile and oil refining industries did not do without bisphosphonates and still use them actively.
At the same time, doctors and pharmacists tried to find ways to strengthen bone mass. A breakthrough in this area is a discovery made by Astley Cooper. In 1824, this English physician and court surgeon of the royal court put forward a hypothesis about the relationship between increased fragility of bones in the elderly and a certain pathology developing in their body. The disease was discovered, systematized and received a scientific name in the early twentieth century. But to eliminate osteoporosis, to prevent its dangerous complications at that time was not possible.
Swiss Herbert Fleisch experimented with chemical compounds for a long time. In 1968, he discovered that when inorganic pyrophosphate comes into contact with a biological fluid, a significantly lower amount of calcium precipitates. So that the enzymes do not aggressively affect pyrophosphate, the phosphorus atom in its molecule was replaced by a carbon atom. It also significantly increased the biological activity of the chemical compound.
But before synthesizing the first pharmacological preparation based on bisphosphonates, there were still 30 long years. In 1995, after lengthy clinical trials, large-scale production of agents for the treatment of bone osteoporosis began.
Mechanism of action
Bisphosphonates are still actively used in the treatment of osteoporosis, despite a number of deficiencies found. For example, it was found that drugs increase bone density, but do not make them stronger. The structure of bone tissue becomes similar to some metal alloys – with a certain physical impact, they break into small pieces. Therefore, in therapeutic schemes, in addition to bisphosphonates, preparations for strengthening bones are included.
Bisphosphonate, or diphosphonate, is an artificially synthesized chemical compound that is close in structure to pyrophosphonate. This substance is responsible for the adhesion of calcium to bone tissue. But unlike natural biological pyrophosphonates, synthetic bisphosphonates have a higher clinical activity. They have a wider spectrum of pharmacological action.
In healthy bone tissues, metabolic processes proceed smoothly, and in case of any malfunction, compensatory mechanisms for updating and regenerating damaged areas instantly turn on. The main structural units of bone tissue:
- osteoblasts – young bone cells with a diameter of 15-20 microns, synthesizing intercellular substance. As the matrix accumulates, they are walled up in it and become osteocytes;
- osteoclasts are giant multinucleated cells that remove bone tissue by dissolving the mineral component and destroying collagen.
In the human body there are approximately the same number of osteoclast utilizers and osteoblast creators. If the number of destroyers begins to increase, then apoptosis occurs – a regulated process of programmed cell death. Otherwise, an imbalance will cause serious consequences, one of which is osteoporosis. Bisphosphonates stimulate the self-destruction of osteoclasts, restoring the natural balance of bone cells. After penetration into the body, they bind calcium molecules that accumulate in the bone tissue. Chemical compounds reliably hold a microelement, being exposed to continuous attacks of the multiplied osteoclasts. But, before being destroyed, bisphosphonates completely cope with their task – increasing the density of bone mass.
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In the international classification, bisphosphonates are divided into two large groups depending on the molecular structure, or rather, the content of the nitrogen molecule in the chemical structure. For the treatment of osteoporosis, eight main compounds are used, which are the active ingredients of domestic drugs and their imported structural analogues:
nitrogen-free – clodronate, tiludronate, et >
Nitrogen-free medicines are first-generation drugs that served as the basis for further progressive developments. But their use is still relevant in the treatment of osteoporosis. Embedding in bone tissue, nitrogen-free bisphosphonates are transformed into compounds – analogues of ATP. They accumulate in high concentration in osteoclasts and significantly reduce their destructive activity. Before the final destruction of the drug occurs, he manages to partially restore the disturbed balance due to the destruction of osteoclasts.
Nitrogen-containing drugs are characterized by greater resistance to aggressor cells. They steadily withstand destructive attacks of osteoclasts, which explains their prolonged pharmacological effect. Amino-containing bisphosphonates are third-generation drugs with less toxic effects on internal organs.
|Cons of bisphosphonates in the treatment of osteoporosis||Characteristics|
|Aggressive effect on the digestive system||With prolonged use of drugs, the likelihood of developing peptic ulcer and gastritis as a result of ulceration of the mucous membranes increases|
|Long therapeutic course||To increase the density of bone tissues or prevent their resorption, it is necessary to take bisphosphonates for 3-5 years, and after their cancellation, a deterioration in the therapeutic result is observed|
|The possibility of only pathogenetic treatment||Medicines eliminate the effects of osteoporosis, but are not able to get rid of its cause – metabolic disturbances, decrease in the rate of osteoblast formation|
|Low absorption of active ingredients||After penetration into the body, 10% of bisphosphonates are absorbed. The non-adsorbed portion is rapidly evacuated by the kidneys|
|The need for other medicines||Typically, in therapeutic regimens, bisphosphonates are combined with glucocorticosteroids and calcium preparations. This seriously increases the pharmacological burden on the patient’s body.|
Types of Bisphosphonates
When choosing a drug for the treatment of osteoporosis, the doctor relies on the results of instrumental studies, general blood and urine tests. It takes into account the stage of the disease, the degree of tissue damage, the patient’s history and age, and the cause of bone resorption. Preference is given to drugs with a more gentle effect. But sometimes more aggressive means are needed to quickly suppress the attacks of osteoclasts.
In the treatment of osteoporosis, the following drugs are used:
- Clodronate. It inhibits osteoclasts, reduces the severity of pain in the late stages of osteoporosis, retains calcium in the bones, lowering its concentration in the systemic circulation. Clodronate is also prescribed to prevent the development of hypercalcemia and demineralization, which provokes the dissolution of bone tissue;
- Tiludronate. Actively stimulates mineralization, increasing bone density. It is prescribed to patients for quick recovery after complex fractures, treatment of Paget’s disease, or osteodystrophy, with characteristic fragility of bones as a result of metabolic processes disturbance;
- Et >
- Pamidronate Prevents the reproduction of osteoclasts, reducing the rate of catabolic processes and stimulating regenerative biochemical reactions;
- Risendronate Bisphosphonate is characterized by high clinical activity in the absence of a pronounced toxic effect on the body. Risendronate often becomes the first choice in the treatment of osteoporosis, provoked by prolonged use of glucocorticosteroids;
- Ibandronate An effective prophylactic against spontaneous vertebral fractures. Slows down the reproduction of osteoclasts, prevents bone resorption, retaining calcium in bone structures.
Zoledronate inhibits bone resorption, inducing apoptosis of osteoclasts. Therefore, this drug is prescribed for progressive osteoporosis, when the primary goal of treatment is to slow down and stop the destructive processes.
Contraindications and side effects
Each drug is characterized by certain side effects and contraindications for use. But the similarity of pharmacological properties allows combining pathological conditions in which the bisphosphonates are not prescribed:
- acute and chronic renal failure;
- recurrent ulcerative lesions of the stomach and duodenum;
- hypocalcemia, or lack of calcium in the body.
Contraindications to treatment with these drugs are pregnancy, breastfeeding, and individual intolerance to active and auxiliary ingredients. If the dosing regimen is violated or as bisphosphonates are deposited, adverse reactions may develop. From the digestive system, dyspeptic disorders are possible: nausea, vomiting, excessive gas formation, diarrhea or constipation, epigastric pain. Neurological disorders are manifested by a decrease in visual acuity, headaches, dizziness. Cases of cardiac arrhythmia, atrial fibrillation, development of osteonecrosis of the jaw joints are described. Sometimes fever occurs, complicated by chills, weakness, apathy, arthralgia, muscle pain. The characteristic symptoms of a local allergic reaction are swelling and redness of the skin, the appearance of itching and rashes.
Shishkevich Vladimir, orthopedic and traumatologist, project editor-in-chief ExpertNews.
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