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Drugs Used in the Treatment of Osteoporosis Osteoporosis

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Drugs Used in the Treatment of Osteoporosis Osteoporosis Drugs used in the treatment of osteoporosis Osteoporosis • Osteoporosis is a systemic disease of the skeleton in which the amount of bone is decreased and the structure integrity of trabecular bone is impaired. Cortical bone becomes more porous and thinner. This makes bones weaker and more likely to fracture. 2 3 Classification of osteoporosis Osteoporosis may be of primary or secondary type. There are two types of primary osteoporosis: type 1 – postmenopausal, age 50 – 75 and type 2 – senile osteoporosis, age 70 and above. Type I of primary osteoporosis • Regarding gender differences, type 1 osteoporosis occurs 6 times as often in females as in males. In this type of osteoporosis, an increased rate of bone loss (2-3% per year) is observed as a result of bone resorption and the increased activity of osteoclasts at the beginning of menopause. • In this form of the disease the loss of trabecular bone is three times greater than the loss of cortical bone. Typical fracture site: vertebrae, distal radius. 4 Classification of osteoporosis Type II of primary osteoporosis (senile osteoporosis) In type 2 osteoporosis, occurring in old age, the loss of trabecular and cortical bone is similar and is caused by the decreased osteoblast activity and bone formation, and decreased GI Ca absorption. Typical fracture site: femoral, neck, hip. Rate of bone loss: 0,3-0,5% per year. 5 Classification of osteoporosis Secondary osteoporosis (type III) accompanies certain diseases in which bone creation is decreased or resorption is increased or both dysfunctions appear together. Secondary osteoporose (type III) Typical age of diagnosis: any age Gender ratio: 1:1 vomen/men Bone morphology: decreased cortical bone Typical fracture site: vertebrae, hip, extremities. Rate of bone loss: variable. 6 Risk factors for osteoporosis The following factors increase the risk of osteoporosis: • lifestyle (smoking cigarettes, lack of exercise, long-term low- calcium consumption, vegetarian diet, excessive consumption of coffee, alcohol and protein, and products increasing calcium elimination, insufficient supply of vitamin D) • genetic factors (white or yellow race, gender, mother’s osteoporosis, low body mass, slight body frame, early menopause, lack of the enzyme which decomposes lactose). 7 Causes of secondary (type III) osteoporosis The following factors are recognized to cause secondary osteoporosis: • endocrinologic disorders (hypophysis, hyperthyroidism, hyperparathyroidism, adrenal gland diseases, gonad hypofunction) • gastroenterologic disorders (malabsorption syndromes, liver diseases, states after resection of the gastrointestinal tract, amyloidosis) • kidney disorders (uremia, hypercalciuria, renal failure) • rheumatologic disorders (rheumatiod arthritis, ankylosing spondylitis, systemic lupus) • hematologic and oncologic disorders (leukemia, lymphoma, multiple myeloma, breast carcinoma, sarcoidosis, pernicious and hemolytic anemia, hemophilia) • eating disorders (anorexia, bulimia) • long-term use of certain drugs, such as glucocorticoids, preparations of thyroid, anticoagulants, anticonvulsants, oncologic drugs, drugs binding phosphates and drugs with aluminium) 8 • metal ion poisoning (cadmium poisoning). Quantification of bone mineral density (BMD) Recomended method DEX (priviously DEXA) - Dual energy X- ray absorptiometry Two X-ray beams with differing energy levels are aimed at the patient's bones. When soft tissue absorption is subtracted out, the BMD can be determined from the absorption of each beam by bone. Dual energy X-ray absorptiometry is the most widely used and most thoroughly studied bone density measurement technology. The recomended site of the test: the neck of the femoral bone. 9 T-score The T-score is a comparison of a patient's BMD to that of a healthy thirty-year-old of the same sex and ethnicity. This value is used in post-menopausal women and men over aged 50 because it better predicts risk of future fracture. The criteria of the WHO are: Normal is a T-score of -1.0 or higher Osteopenia is defined as less than -1.0 and greater than -2.5 Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty year old woman. 10 Remodeling of bone tissue • Bone tissue, like any living tissue, undergoes permanent remodeling. Part of bone tissue is resorbed and in its place new bone tissue is created. In the remodeling of bone tissue an important role is played by osteoclasts (bone cells responsible for bone resorption), osteoblasts (cells creating new bone stroma) and osteocytes (crucial for the rapid and accurate exchange of mineral ingredients between blood and bone). • In young individuals the process of creating new bone tissue dominates, while in older people the process of bone loss prevails. • The bone tissue that participates in bone remodeling is subject to endocrine, paracrine and autocrine regulation. 11 Contrôle du remodelage osseux par le système OPG/RANKL. La liaison de RANKL à son récepteur RANK sur les précurseurs des ostéoclastes induit la différenciation ostéoclastique et la survie des ostéoclastes. L’OPG produite par les ostéoblastes se lie au RANKL, antagonise sa liaison à RANK et inhibe l’ostéoclastogenèse. Les hormones et facteurs régulateurs du remodelage osseux agissent en contrôlant positivement ou négativement la production d’OPG et de RANKL par les ostéoblastes. RANK = Receptor Activator for Nuclear Factor . 12 RANKL = RANK ligand; OPG = Osteoprotegerin Endocrinology Vol. 142, No. 12 5050-5055 Biomed. Papers 145(2), 61–64 (2001) 61 PTH-CALCITONIN-VITAMIN D-BONE OSTEOPROTEGERIN, RANK, RANKL Minireview: The OPG/RANKL/RANK System David Stejskala, Josef Bartekb, Radmila Sundeep Khosla Pastorkováa, Viktor Růžičkaa, Ivo Orala, Dalimil Horalíka RANKL, expressed on the surface of preosteoblastic/stromal cells, binds to RANK on the osteoclastic precursor cells. M-CSF, which binds to its receptor, \ c-Fms, on preosteoclastic cells, appears to be necessary for osteoclast development because it is the primary determinant of the pool of these precursor cells. RANKL, however, is critical for the differentiation, fusion into multinucleated cells, activation, and survival of osteoclastic cells. OPG puts a brake on the entire system13 by blocking the effects of RANKL. A number of proresorptive cytokines, such as TNF- and IL-1, modulate this system primarily by stimulating M-CSF production (thereby increasing the pool of preosteoclastic cells) and by directly increasing RANKL expression. In addition, a number of other cytokines and hormones, such as TGF-ß (increased OPG production), PTH (increased RANKL/decreased OPG production), 1,25- dihydroxyvitamin D3 (increased RANKL production), glucocorticoids (increased RANKL/decreased OPG production), and estrogen (increased OPG production) exert their effects on osteoclastogenesis by regulating osteoblastic/stromal cell production of OPG and RANKL. 14 However, not all regulation of the osteoclast is exclusively via the osteoblast because calcitonin acts directly on osteoclastic cells, and estrogen has been shown to induce apoptosis of osteoclasts as well as inhibit osteoclast differentiation by interfering with RANK signaling, principally RANKL-induced JNK activation and c-Jun activity and expression. Moreover, TGF-ß can also stimulate RANK expression on preosteoclastic cells, and thus enhance osteoclastic sensitivity to RANKL. 15 Hormones participating in bone tissue remodelling • The main hormones that participate in the metabolism and remodeling of bone tissue are parathormone (PTH; parathyroid hormone), calcitonin (CT), vitamin D, estrogens, glucocorticoids, the growth hormone, insulin and the thyroid gland hormone. • PTH, CT and vitamin D maintain at a constant level the concentration of calcium ions in plasma and of phosphates in the extracellular fluid. • PTH is released as a result of the low level of calcium in plasma and has an opposite effect to calcitonin. PTH decreases renal elimination of calcium, indirectly stimulates absorption of calcium in the intestines, together with active vitamin D stimulates the resorption of calcium from bone tissue and stimulates the transformation of 25(OH)D3 to 1,25(OH)2D3 in the kidneys. 16 17 • Parathormone is a one-chain polypeptide which contains 84 amino acids. • The sequence that causes the full activity of PTH has 27 amino acids. • PTH is synthesized in the cells of the parathyroid gland and stored in its vesicles. • The principal factor controlling PTH secretion is the reverse relationship between hormone concentration and the concentration of ionized calcium and magnesium in plasma. • There is a relationship between the amount of released PTH and the concentration of cAMP (cyclic adenosine monophosphate) in the parathyroid glands. 18 • Protein membrane receptors participate in the mechanism of action of PTH. They are present in the cells of bone and in the kidneys. • The interaction of PTH with receptors initiates a typical cascade reaction: the activation of adenyl cyclase (leads to an) → increase in the intracellular concentration of cAMP → an increase in the intracellular concentration of calcium → phosphorylation of specific proteins by kinases → activation of intracellular enzymes or proteins. • The reaction complex induced by PTH, similarly to other peptide hormones, leads to a decrease in the number of receptors (down regulation of receptor number) and in the concentration of effector hormones. 19 • Parathormone (PTH) is an important physiological regulator
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