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TREATMENT AND PREVENTION OF OSTEOPOROSIS. USE BISPHOSPHONATES

     Osteoporosis is often called the "creeping epidemic of the XXI century." According to some prognostic data up to 50% of the current female population aged 15-20 years after 20-30 years will be have a disability. And the situation is compounded by the fact that effective treatment against this disease there, as well as prevention of a serious challenge. Is this true? And whether or not to treat this condition?
     Osteoporosis (osteoporosis; osteo- + from Greek. poros – pore, perforation; syn.: bone loss) – degeneration of bone tissue with rearrangement of its structure, characterized by a decrease in the number of bone trabeculae per volume unit of bone tissue, bending and complete resorption of these elements. To refer to this phenomenon (but not the disease!), which is often observed locally in the various processes used another term – osteopenia. Is a fairly common condition that is caused by increased fragility of bones. And it is the increased frequency of fractures included in the clinical definition of the disease. By some estimates at least 200 million people worldwide have their low density – from -1.0 to -2.5 times (indices of densitometry) compared with the average adult. At the same time provides clinically significant osteoporosis density less than -2.5. A decrease in density less than this index is called preosteoporosis. Such separation is important and justified in terms of therapeutic measures. Densitometry with the definition of the coefficient of reduction of bone mass is the most informative method of diagnosis of osteoporosis [1, 2].
     Different fractures due to osteoporosis cause chronic pain, depression, disability and increased mortality. According to statistics, during the year after hip fracture die 12-24% of women and 30% of men. The contribution of osteoporosis – about 1.5 million fractures of the spine and hip in the U.S. annually. Referring to the problems of medication, it is worth noting that despite the high prevalence of this pathology, the vast majority of patients generally are not treated. According to the National Committee for Quality Health United States in the country for more than 90% of adults with cardiovascular disease receiving β-blockers and only 19% of adults with frequent fractures treated for osteoporosis. Now an urgent need to revise accepted views on the disease, as usual age factor [3, 4].
     Recommended currently individualization of treatment justifies the medication is in the presence of osteoporosis, where it is non-alternative, as well as the presence of preosteoporosis additional risk factors (older age, existing fractures, prolonged use of corticosteroids, menopause). At the same time preosteoporosis should correct the majority of cases the only diet and only in certain situations, the use of special drugs.
     Prevention of osteoporosis. In general, it can be expressed as risk factors for this disease and the use of a special or a balanced diet. In particular, the generally accepted factors that increase the risk of osteoporosis, are (in descending of importance):
• Family history (the presence of osteoporosis in parents and siblings);
• Smoking;
• Asthenic physique;
• Excessive use of alcohol;
• Fair skin;
• Excessive intake of caffeine (coffee, tea, chocolate);
• Early menopause;
• Sedentary lifestyle;
• Use of medications (corticosteroids, levothyroxine, anticonvulsants, heparin).
     Effective prevention involves the elimination of these factors. And literature data confirm the high effectiveness of this approach. To other factors of osteoporosis, of course, applies and unhealthy diet (low calcium), as well as low physical activity. Therefore, the second important component of prevention is a sufficient level of calcium intake. Recommended levels in the norm – at least 1 g per day (primary prevention). At the same time, it is necessary to increase at preosteoporosis intake to 2.0 g per day (secondary prevention). There are recommendations FDA in 2008 to a level of calcium intake for women at “risk groups" – pregnant women, as well as in pre- and postmenopausal age period [5, 6].
     The diet. The main sources of calcium are eating: whole or skim milk, where its content is 300 mg per 200 ml, cheese (20 mg per 28.3 g), yogurt (350 mg per cup). At the same time in Europe, accounting calcium concentration should be allowed to fix the norms of 40% of the "additions" which are for dairy products made from soy, rice and potatoes. And in Ukraine, such a calculation would be adequate only for milk products expensive varieties. The second most important source of calcium include green leafy vegetables, nuts and seeds, fish products with bones (sardines, salmon). At the same time it should be noted that in some leafy vegetables such as spinach and kale, contain a lot of oxalic acid which binds calcium and thus prevents its absorption. Excess magnesium (e.g., in drinking water) leads to the fact that fat and bile acids, necessary for calcium absorption associated with magnesium and absorbed into the blood, and without the absorption of calcium is not possible. An excess of red meat (veal, beef) due to a significant amount of iron contained in it also gives a similar effect. In this respect interesting data that argue that any restrictive diet increases the risk of osteoporosis. And with plenty of meat (protein diet), and the shortage of dairy products (vegetarian), and "fractional power" (violation of the ratio of minerals). For the absorption of calcium is also important in the presence of adequate vitamin D nutrition and phosphorus [7, 8].
     It is important and sufficient level of physical activity, among which the most appropriate from a medical point of view (especially for the elderly) is hiking, swimming, dancing, jogging or any kind of sports, providing stay on his feet. In all cases we have in mind and load feasible for older people (working in the garden, etc.). Be sure to perform complex morning exercises. It has long been known that if a person completely immobilized, he lost for the year to 50% of the strength of the skeleton. A lack of exercise in the modern world has become widespread medical and social problem.
     For people with preosteoporosis also a number of specialists recommended limiting salt intake, which causes increased excretion of calcium. Recommended Institutes of Health U.S. level of daily consumption of 1.5 g – the number that corresponds to only eat unsalted food and excluding finished and packaged foods [5]. At the same time the recommendation was disputed by a number of specialists and can be considered accepted only in patients with concomitant diseases (hypertension, diabetes mellitus).
     We should also mention the prevention of falls and injuries, which is important at osteoporosis and is important at preosteoporosis.
     Recommendations FDA late in 2008 on a diet to compensate for calcium at preosteoporosis and as part of the treatment of osteoporosis in the background of drug therapy include daily administration:
A simple low-fat yogurt, 230 g – 452 mg Ca
Swiss cheese, 43 g – 336 mg Ca
Cheese provolone, 43 g – 321 mg Ca
Mozzarella cheese, 43 g – 311 mg Ca
Skim milk, 1 cup – 306 mg Ca [6]
     Such a diet provides, subject to permitted additives in dairy products about 1 g of calcium daily. According to some researchers who believe that not all people adequately use the "milk" calcium, some of the inaccessible components of these recommendations is justified to replace products from another list:
Sesame seeds
Almonds
Dried figs
Sunflower
Walnuts
Broccoli
Tofu
Oranges
     Older people are often observed hypovitaminosis D, particularly in autumn and winter, which requires further its purpose, together with calcium salts. For an adequate supply of vitamin D (800 IU or 20 mg per day for those over 50 years) in the same document, FDA recommended:
Fish oil, 1 table-spoon – 1360 IU
Salmon, 100 g – 345 IU
Mackerel, 100 g – 320 IU
Sardines, 50 g – 250 IU
Canned tuna (in oil only!) 85 g – 200 IU
     For optimal absorption of calcium from food requires the presence of phosphorus in them. Moreover, the optimum ratio of these elements is 1 to 1.3.
     In terms of prevention and treatment of pre- and osteoporosis are interest the diet DASH (Dietary Approaches to Stop Hypertension), which focuses on the use of fruits, vegetables and fat-free products, recommends avoiding processed foods, gives the optimal intake beneficial bone nutrients (Table 1). It provides the necessary individuals for up to 50 years the amount of calcium. Supplementing it is only necessary over the age of 50 years. Diet provides the optimal amount of alkali equivalents of potassium through the consumption of fruits and vegetables. The same can be said about the content of magnesium, vitamin C and other antioxidants, which play a role in the metabolism of bone. Polyphenols, such as in case (but in fruits and vegetables as well), also positively associated with bone health. In addition, the DASH diet provides a reasonable level of income without the need to give sodium from salt. Although the DASH diet designed to prevent hypertension, it has positive results in the prevention of osteoporosis [9-11].
Table 1.
Full-time intake of calcium, sodium, potassium, and protein in the diet DASH

Notes: * – use unsalted food reduces this number
     It should be noted that the use of a multivitamin does not provide sufficient for daily requirements of calcium dose as calcium salts, ensure its supply of 500 mg, increasing the volume of a single dose to a physically impossible to accept. A particularly calcium absorption, which sharp decrease with increasing the dose and by the need for compulsory presence of auxiliary substances posed by modern pharmacy has not yet fully resolved the problem.
     At present, many developed countries formally adopted by the following methods of drug treatment of osteoporosis:
1) bisphosphonates (alendronate, ibandronate and risedronate)
2) calcitonin
3) estrogens
4) teriparatide (parathyroid hormone derivative)
5) raloxifene
6) some other (vitamin K and isoflavones, a monoclonal antibody to RANK ligand, strontium ranelate, etc.)
     For most patients with osteoporosis treatment of choice is the use of oral bisphosphonates. And this method of drug delivery has received the greatest amount of evidence that demonstrate its effectiveness. As an alternative to it in some cases effectively prevents fracture treatment teriparatide (within 2 years). While these two types of drug treatment are essential, but, as noted by most researchers, the practice of treating osteoporosis will evolve in the near future. However teriparatide (Forteo) is still very expensive, inconvenient to use (includes daily injections) and is not registered in many countries.
     Calcitonin is a 32-aminoacid peptide – calcitonin salmon synthetic, administered nasal spray. Relatively modest increases in the density of the spine studies (by 1.0-1.5%), but reduces the incidence of vertebral fractures by about a third only in those patients who received 200 IU per day. The frequency of non-vertebral fractures has almost no effect. Similarly, as to be effective in preventing fractures. Is the development of injectable forms, but generally not regarded as first-line treatment of osteoporosis treatment [12, 13].
     The use of estrogen reduces the rate of bone loss by activating specific protein and its cytokine reducing bone resorption. WHI study on 27 347 postmenopausal women, which provided for receiving conjugated estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day) showed a reduction in the incidence of hip fractures by 34%. Appointment only at a dose of estrogen 0.625 mg/day gave a decrease of 39%. However, although the use of estrogen for 2-3 years from the beginning postmenopausal period gives a clear benefit in preventing fractures, there is an increased risk of developing breast cancer, myocardial infarction and thromboembolism. According to the recommendations of the FDA, hormone therapy is applicable to the prevention of osteoporosis, but should only be used in women with severe risk of its development and should be treated nonestrogenic agents [14,15].
     How the use of estrogen without the risks of natural background for their use is treatment of a specific antagonist of estrogen receptors raloxifene. In a study of MORE (Multiple Outcomes of Raloxifene Evaluation) drug in different doses (60 mg and 120 mg) increased the density of the lumbar vertebrae (2.6% and 2.7%, respectively) and reduced the frequency of vertebral fractures (30% and 50%, , respectively). At the same time, it did not reduce the risk of non-vertebral fractures. A study of CORE (Continuing Outcomes Relevant to Evista) has shown that an increase in bone density was maintained, and 7 years after treatment of raloxifene. But while the drug increased the risk of thromboembolism and the incidence of complications of arterial limb ischemia [15, 16].
     Strontium ranelate is composed of two atoms of stable strontium (a divalent cation, similar in their properties with calcium) associated with ranelic acid. Compound mainly distributed in the cancellous bone structure and less in the cortical layer of her, as well as the newly-formed than in the old bones. In vitro strontium stimulates bone formation and inhibits its resorption. At the same time, strontium, compared with calcium, absorbs more X-rays, which can lead to a reassessment of bone density and require its correction. The study SOTI (Spinal Osteoporosis Therapeutic Intervention trial) density of the lumbar spine increased by 6.8% over the three year period by 41% decreased risk of new vertebral fractures by taking 2 g of strontium ranelate daily. A 5-year study TROPOS (TReatment Of Peripheral OSteoporosis), which included 5091 postmenopausal women gave reduce the risk of all types of fractures, including hip fractures. In this case a bone biopsy is not revealed osteomalacia or of a violation of mineralization. However, in the treatment of strontium ranelate is a discrepancy between the markers and reconstructing its mechanism of action, as well as full safety profile is still not understood completely [17-19].
     Bisphosphonates (diphosphonates) as a drug for bone remodeling occurred about 20 years ago in connection with the search for pharmacological agents to treat osteopenia [1, 10]. And now they recognized the leading role in the practice of treating and preventing osteoporosis, in particular, its complications (fractures of the vertebrae, hip, etc.). They also play an important role in medical treatment of other diseases of the musculoskeletal system with an abnormal (focal) bone resorption. To those include glucocorticoid-induced osteoporosis (at rheumatoid arthritis, asthma, etc.), Paget's disease, metastatic lesions, various forms of osteal fibrous dysplasia, primary hyperparathyroidism, certain forms of congenital osteogenesis imperfecta, etc. This allows us to focus on this group of drugs in more detail. Although bisphosphonates have no direct therapeutic effect as blocking these processes are effective for relief of pain in these conditions, reducing the use of analgesics, the maintenance patient’s activity and its overall status. It should be stressed that so far no evidence of adverse effects of bisphosphonates on the processes of natural healing of bone fractures.
     Bisphosphonates cause suppression or block bone resorption by osteoclasts. However, despite the fact that the currently used drugs of this group are chemically similar – they are chemically analogous to the natural pyrophosphate – different mechanisms of action they are represented in different ways. Moreover, some details remain to the end of the researched. In this regard remains a special interest in clinical studies recently [3, 20].
     Bisphosphonates are mainly absorbed by osteoclasts at sites of active bone reconstruction in connection with which this group of drugs may be considered as selective drugs. Osteoclasts then significantly slow down its activities, which reduces the process of bone destruction. Different drugs are to varying degrees, an additional:
• controls the formation of osteoclasts
• make them self-destructive or early death
• change the alarm between osteoclasts and osteoblasts
• configure the chemical barrier between the bone and osteoclasts.
     Chemically, bisphosphonates are divided into two groups (classes) of the content in a molecule of nitrogen balance (Table 1). At the same aminobisphosphonates have a more pronounced effect than the "simple" bisphosphonates. This is due to the fact that they are not digested by osteoclasts and, thus, have an additional effect. In particular, they inhibit the mevalonate pathways by blocking an enzyme-diphosphate synthetase famesil that destroys a specific protein. The destruction of the latter leads to the accumulation of anomalies in osteoclasts, which accelerates their apoptosis and leads to an additional reduction of the effect of bone resorption. Antiresorptive effect of different aminobisphosphonates increases is based on the ability to interfere with this enzymatic pathway (Fig. 1) [8, 21].
     In addition, the mechanism of action of individual drugs plays a role reduction geranil-geranil-diphosphate, which is required for the synthesis of protein binding of osteoclasts and the regulation of local blood supply to the bone. Also reduced cholesterol biosynthesis, required for the newly formed cell membranes of this type.
Fig. 1. Lots enzyme inhibition with bisphosphonates
     
     Statins are another class of drugs that inhibit the reductase HMG-CoA-pathway (mevalonic) (Fig. 1). Unlike bisphosphonates, statins have tropism to the bone, characteristic of pyrophosphate, and therefore their effect on it is nonspecific. Although some studies have reported a decrease in the incidence of fractures in osteoporosis and/or increasing bone mineral density in patients taking statins, their efficacy in the treatment of osteoporosis remains controversial [22, 23]. 
Table 2
Bisphosphonates are used in medical practice


     Pamidronate. Intravenous pamidronate is frequently used to treat osteoporosis in patients who have intolerance to oral bisphosphonates, although it has not received formal approval by FDA. The drug significantly increases bone density, but its effect on the prevention of fractures in osteoporosis while not clearly established. At the same time, pamidronate has established a meaningful activity for bone metastases [21, 24]. In many countries popularity of the drug is caused by a low cost and yet sufficiently effective generics. Side effects may include flu-like symptoms, including myalgia and transient subfebrilitet.
     Alendronate. In several randomized controlled clinical trials has been shown the ability to use oral alendronate increased bone density and reduce fracture risk in osteoporosis in postmenopausal women. It is also proved some efficacy in osteoporosis in men, glucocorticoid-induced osteoporosis in both sexes and in the prevention of osteoporosis in women [22, 25]. Daily treatment (10 mg) was equivalent to the impact and incidence of adverse reactions, the introduction of weekly (70 mg). Since 2005 the market for weekly alendronate reception there is also a combination pill with 2.800 IU of vitamin D3.
     The required duration of treatment alendronate, as well as some other aminobisphosphonates is currently being studied. It is believed that long-term drug treatment causes excessive bone mineralization and increases of fracture risks [26]. At the same time, the available clinical trial data have not yet confirm these concerns, since there is evidence of increasing density of vertebrae in the treatment of alendronate for 10 years. The density of the femoral neck grew the first 3 years and then remained stable [3, 27].
     In large-scale study of women in FLEX postmenopausal age determined the influence of breaks in the alendronate on bone density. After 5 years of therapy with their randomized for placebo and alendronate continuation of treatment. After 3 and 5 years of placebo was not detected differences between groups in the incidence of all fractures. However, it is vertebral fractures were 50% lower in the group, who continued alendronate [28]. These data suggest that patients can safely discontinue enough alendronate after 5 years of therapy. However, officially this conclusion and the recommendations have not yet been adopted.
     Ibandronate. Ibandronate was recently approved in the U.S. is to prevent and treat postmenopausal osteoporosis. Three-year randomized double-blind controlled study in 2946 women investigated the efficacy of different treatment doses of the drug (2.5 mg daily, 20 mg daily for 12 doses every 3 months, etc.). It has been shown to increase the density of the lumbar spine, decreased markers of bone resorption and decrease the incidence of fractures [29]. At the same time, not decreased it non-vertebral fractures, which leaves room for further studies of this drug.
     Risedronate. Several controlled studies have shown that risedronate significantly increases bone density and prevent hip fractures in the spine and postmenopausal period in women [2, 30]. Weekly receiving 35 mg risedronate well tolerated and is now a standard regimen used. Mellstrom et al. [2] showed that after 6-7 years of treatment with the density of the lumbar spine continued to increase and the frequency of fractures in osteoporosis has remained stable. Risedronate effective in glucocorticoid-induced osteoporosis. In a one-year comparative study of postmenopausal women with weekly alendronate (70 mg) or risedronate (35 mg) gave the first big rate of increase in bone density and reduce the trend of the exchange markers than risedronate [23]. At the same time, there is currently no sufficient long-term studies in terms of the required duration of treatment.
     Zoledronic acid is currently the most powerful of the available bisphosphonates. It is approved by the FDA for the treatment of hypercalcemia syndrome in malignant tumors, multiple myeloma and metastatic tumors in bone. At the Annual Research 351 postmenopausal women zoledronic acid compared with placebo increased the density of the lumbar vertebrae at 4,3-5,1% and femoral neck – at 3.1-3.5%. Five modes of the drug for a year (4 mg once, 2 mg twice as well as 1, 0.5 and 0.25 mg four times) gave identical results. Markers of bone turnover were reduced during follow-up rates. As the side effects were observed subfebrilitet, malaise, myalgia, nausea [31].
     The three-year study of the effectiveness of postmenopausal osteoporosis therapy in Reclast (Stady 2301) in 7737 women were shown to decrease the risk of hip fractures compared with placebo for the first year more than doubled (from 3.7% to 1.5%), while the second and third – more than three times (respectively, from 7.7% to 2.2% from 12.8% to 3.8%). Used once per year through introduction of 5 mg [4].
     Among the studies in clinical trials in recent years, bisphosphonate from zoledronic acid (Zometa) has shown the best efficacy in treatment of several common cancers, in connection with which the FDA approved it, along with pamidronate (Aredia), for use in oncology. At the same time in the ongoing clinical trials have clarified a number of important issues. Thus, "Myeloma IX” is intended to clarify the effect of clodronate and zoledronic acid for multiple myeloma. Another ongoing clinical trials exploring ways to extend the remission of bisphosphonates flow of breast cancer, as well as their efficacy in relapse after various treatments (surgery or medications). The potential ability of bisphosphonates to prevent or slow the development of multiple myeloma and bone metastases of solid tumors are currently being actively investigated in various models. It is hoped that the process of blocking bone resorption could have a positive effect on the progression of cancer in general. This is an area for further research [20, 21, 24]. 
     Complications and side effects of treatment with bisphosphonates: Use of bisphosphonates involves a number of risks. Osteonecrosis of the jaw was observed in patients treated with pamidronate, zoledronic acid and, less frequently, oral bisphosphonates. The prevalence of this serious complication in cancer patients who receive higher doses of intravenous bisphosphonates compared with the treatment of osteoporosis, and more often (10-12 times) is 6-10%. Recognized risk factors for osteonecrosis of the mandible are the recent removal of a tooth, jaw trauma or active dental infection. Alleged reason is to block the processes of recovery of bone on the background of increased physiological stress. Similar explanations have noted in the literature and an increased frequency of hip fracture. Almost exclusively in all cases of these two events were linked in cancer patients with zoledronic acid [20, 21]. Ongoing studies are now aim to improve understanding of the pathophysiology occurring during this process. In November 2008, the FDA released a new version of the safety review regarding potential increased risk of atrial fibrillation during treatment with bisphosphonates. Data were studied 19 687 patients treated with bisphosphonates and 18 358 patients taking placebo, which were investigated in terms of 6 months to 3 years. Cases of atrial fibrillation was rare for each group, in most cases, including not more than two such events. In all studies, a clear link between bisphosphonates and incidence of atrial fibrillation was not observed. Increasing the dose or duration of treatment with bisphosphonates were also not correlated with an increase in frequency of this complication. At the same time review concludes on the need strict adherence to the recommended regimen of drugs.
     Indications, contraindications and precautions: Reception of a particular drug of bisphosphonates provides a clear compliance with relevant regulations, which differ only slightly for each of them. Common to them at the time of the treatment period is sufficient intake of calcium (1000-1500 mg daily) and vitamin D (400 IU).
     All oral bisphosphonates are poorly absorbed from the gastrointestinal tract. To improve the absorption and prevention of dyspepsia (usually gastroduodenal reflux and heartburn) medications must be taken on an empty stomach – at least 30 minutes before eating. In the same context are contraindicated using of calcium-containing products for several hours after ingestion. The more calcium should not be taken concurrently with oral bisphosphonates.
     In addition to dyspepsia, oral bisphosphonates may trigger inflammatory changes in mucosal GI erosions of the esophagus. Prevention of these effects is the vertical position of the patient for 30-60 min after ingestion.
Intravenous bisphosphonates can be used after the first injection cause fever, transient muscle pain and various flu-like symptoms. It is considered that this is a direct consequence of excessive activation of T lymphocytes. Symptoms usually do not recur with subsequent infusions and, in most cases require no treatment.
     A relative contraindication to the use of bisphosphonates in the clinic is renal failure. At the same time, provided the expected prevalence of positive results over the potential risks of treatment, according to the recommendations of the FDA, in this case can be used pamidronate. Typically, this requires dose adjustment in the direction of its reduction, and self intravenous carried out much more slowly.
     If you are using Zometa in all cases it is necessary to investigate renal function before each drug administration. Recommendation based on insufficient knowledge of side effects of the drug against a background of impaired renal function.

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