Alendronate
Alendronate tablets should be taken only with plain water, as other drinks (including mineral water, tea, coffee, fruit juices) impair the absorption of the drug. Taking alendronic acid before bed or in a horizontal position increases the risk of developing esophagitis.
Alendronic acid may cause local irritation of the mucous membrane of the upper gastrointestinal tract. When treated with alendronic acid, there are known cases of adverse reactions from the esophagus (esophagitis, ulcer or erosion of the esophagus), sometimes severe and requiring hospital treatment, and in rare cases complicated by the formation of a stricture. It is necessary to monitor the possibility of any signs of adverse reactions from the esophagus. The patient should be informed of the need to stop taking the drug and consult a doctor if dysphagia, pain when swallowing, chest pain or heartburn develops.
It is necessary to inform the patient about the possible risk of damage to the mucous membrane of the esophagus if the instructions for use are not followed. The risk of severe adverse reactions from the esophagus is higher in those patients who violate the recommendations for taking the drug and/or continue to take it when symptoms of esophageal irritation appear. It is especially important to give the patient recommendations for taking the drug so that he understands that the risk of developing damage to the esophagus increases if these recommendations are not followed.
The drug Alendronate should be prescribed with extreme caution to patients with exacerbations of diseases of the upper gastrointestinal tract, such as dysphagia, diseases of the esophagus, gastritis, duodenitis, ulcers, as well as with active gastrointestinal bleeding, surgical intervention in the upper gastrointestinal tract, with the exception of pyloroplasty, because for the possible irritating effect of the drug on the mucous membrane of the upper gastrointestinal tract and worsening the course of the underlying disease. For patients diagnosed with Barrett's esophagus, the question of prescribing alendronate should be decided individually based on an assessment of the ratio of expected benefit to possible risk.
Although no increased risk was observed in extended clinical studies of alendronic acid, rare cases of gastric and duodenal ulcers, sometimes severe and complicated, have been reported in post-marketing reports.
There are cases of localized osteonecrosis of the jaw, associated mainly with previous tooth extraction and/or local infection (including osteomyelitis), often with slow recovery. In most cases, bisphosphonate-associated osteonecrosis of the jaw occurs in cancer patients receiving intravenous bisphosphonates. Many of the patients also received chemotherapy and corticosteroids. There are also known cases of osteonecrosis of the jaw in patients with osteoporosis who took oral bisphosphonates. When assessing an individual's risk of developing osteonecrosis of the jaw, the following risk factors should be considered: bisphosphonate activity (highest for zoledronic acid), route of administration and total dose; oncological diseases, chemotherapy, radiotherapy, taking glucocorticosteroids, smoking; history of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures, poorly fitted dentures.
Before starting therapy with oral bisphosphonates, patients with poor dental status are recommended to have a dental examination and preventive treatment measures. During a course of bisphosphonates, such patients are advised to avoid invasive dental procedures if possible. If a patient develops osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may worsen the condition.
It is unknown whether stopping bisphosphonates reduces the risk of osteonecrosis of the jaw in patients requiring dental procedures. In each case, the decision must be made by the attending physician based on an assessment of the ratio of the expected benefit to the possible risk for a particular patient. During bisphosphonate therapy, patients should be educated about the importance of good oral hygiene, oral health screenings, and to report any oral symptoms such as tooth mobility, pain, or swelling.
Bone, joint and/or muscle pain has been reported in patients receiving bisphosphonates. These symptoms are rarely severe and/or disabling. The time of onset of symptoms varies from one day to several months from the start of therapy. In most patients, symptoms resolved after cessation of treatment. In some of them, symptoms reappeared when they resumed taking the same drug or a different bisphosphonate.
If hypocalcemia is present, it must be corrected before starting treatment. Other disorders of mineral metabolism (for example, vitamin D deficiency) must also be corrected. Therapy should be combined with a diet enriched with calcium salts and vitamin D. In patients with these disorders, it is necessary to monitor blood calcium levels and symptoms of hypocalcemia.
During treatment, a slight asymptomatic decrease in serum calcium and phosphate concentrations is possible due to the positive effect of alendronic acid on bone mineral density, which is of particular importance for patients receiving glucocorticosteroid drugs, since they may experience reduced calcium absorption.
In rare cases, hypocalcemia can be severe, usually in patients with a predisposition to this complication (hypoparathyroidism, vitamin D deficiency, calcium malabsorption).
Pathologic (ie, low-force or spontaneous) subtrochanteric or proximal femoral shaft fractures have been reported in a small number of patients taking bisphosphonates, primarily in patients receiving long-term therapy for osteoporosis.
Some of the fractures were classified as stress fractures (also known as stress fractures, marching fractures, or Deutschlander fractures), which occur in the absence of trauma. Fractures are often bilateral, so in patients with a hip fracture taking bisphosphonates. the second (contralateral) hip should be examined. It is known that these fractures heal poorly. Some patients have experienced prodromal pain in the affected area for weeks or months before the onset of a complete fracture, often associated with the characteristic radiographic appearance of a stress fracture.
The number of reports has been very small, and stress fractures with similar clinical features occur in patients not taking bisphosphonates. Patients with stress fractures should be assessed for known causes and risk factors (eg, vitamin D deficiency, malabsorption, corticosteroid use, history of stress fracture, arthritis or lower extremity fracture, excessive or increased exercise, diabetes mellitus, chronic alcoholism) and provided they receive proper orthopedic care. Pending evaluation results, consideration should be given to stopping bisphosphonates in patients with stress fractures based on a case-by-case assessment of the benefit/risk ratio. Patients should be advised to report any hip or groin pain during bisphosphonate therapy. All patients admitted with such complaints should be examined for an incomplete femoral fracture.
During post-marketing use, there have been rare reports of severe skin reactions, including Stevens-Johnson syndrome and Lyell's syndrome (toxic epidermal necrolysis).
An adverse event reported was osteonecrosis of the external auditory canal, which was predominantly associated with long-term use of alendronic acid. Possible risk factors for osteonecrosis of the external auditory canal include steroid use, chemotherapy, and trauma.
Causes of osteoporosis other than estrogen deficiency and age should be considered.
Patients should be warned that if they accidentally miss a once-weekly dose of Alendronate, they should take one tablet in the morning of the next day. You should not take two doses of the drug on the same day, but subsequently you should return to taking the drug once a week on the day of the week that was chosen at the beginning of treatment.
Treatment of osteoporosis: experience with alendronate
Using advanced, primarily radiological, research methods, the development and implementation of new methods of prevention and treatment, as well as active and purposeful educational activities of the International Osteoporosis Foundation (IOF) and its 186 national societies in 90 countries, including the Russian Association for Osteoporosis osteoporosis, the social and medical significance of the disease has increased significantly. Official registration of the incidence of AP began in the Russian Federation in 1999, and over the past 10 years (1999–2008) the total number of recorded cases of AP among adult residents of Russia increased almost 4 times (from 31,500 people in 1999 to 115,530 people . in 2008). An improvement in the technical basis for diagnosis, namely the supply of bone densitometers to medical institutions, which made it possible to measure bone mineral density (BMD) and make a diagnosis of AP, had a significant impact on the frequency of detection of the disease. In 2005, the Russian Association for AP developed clinical guidelines for the diagnosis, prevention and treatment of AP, including glucocorticoid AP, and in 2009 they were revised and supplemented. Recommendations are ranked according to a unified international system of levels of evidence. Despite general recommendations, treating AP in a particular patient is often a difficult task and depends both on the doctor’s interpretation of the patient’s condition and on the patient’s readiness for long-term therapy. There are two main types of AP – primary and secondary, with primary AP being the most common: the ratio of its frequency to the frequency of all possible forms of secondary AP reaches 4:1 [1]. Primary AP is conventionally divided into postmenopausal and senile. Postmenopausal AP is associated with accelerated bone loss in women after the cessation of the menstrual cycle, and is caused by estrogen deficiency. The main reasons for the development of senile AP in individuals of both sexes are a decrease in calcium intake, impaired absorption in the intestine and vitamin D deficiency, which can lead to secondary hyperparathyroidism and, as a result, accelerated bone remodeling. One of the factors influencing the development of senile AP is considered to be a decrease in physical activity in old age. It must be emphasized that during the aging process, the interaction of hormones with growth factors and other cytokines that influence the process of osteoblastogenesis undergoes significant changes, and the activity of many local factors decreases. AP develops gradually and is often clinically detected after fractures, which is the basis for calling it a “hidden epidemic.” It should be noted that the incidence of AP increases with age, therefore, the increase in life expectancy observed in recent decades in developed countries and the associated rapid increase in the number of elderly people, especially women, leads to an increase in the frequency of this disease, making it one of the most important health problems worldwide. world. Providing medical care to patients with primary AP is carried out on an outpatient basis, with the exception of cases requiring surgical treatment of complications of AP - fractures. Treatment and observation of the patient is long-term, over several years, and should be carried out by a primary care doctor - a local therapist or a general practitioner. If secondary causes of the possible development of AP are identified, the patient should be referred for consultation to a specialist (rheumatologist, endocrinologist, etc.). Among diagnostic measures, clinical examination methods come to the fore: studying the patient’s complaints and medical history in order to identify risk factors for AP and risk factors for falls, as well as clinical signs of bone fractures, including vertebral fractures. Identification of the presence of AP in a particular individual includes an assessment of the family history of AP, lifestyle (bad habits, physical activity, nutrition, etc.), the presence of fractures, reproductive history, the presence of diseases and drug therapy leading to the development of AP (Table 1). Falls are an independent risk factor for fractures because... most fractures of the proximal femur and distal forearm occur due to falls (Table 2). Physical examination of a patient with AP includes a general medical examination with measurement of height and weight. A decrease in height by 2.5 cm per year or by 4 cm or more compared to height at 25 years of age may indicate AP complicated by vertebral fractures. If the fracture was recent, local pain in the vertebral area may be noted, and progressive changes in posture may be accompanied by paravertebral pain on palpation and tension of the paravertebral muscles, and limited mobility in the spine. To diagnose AP, various instrumental methods are used: bone radiography and measurement of bone mineral density using bone densitometry. Bone radiography remains the only research method that allows one to evaluate the anatomical features of bones and the structure of bone tissue, as well as various skeletal injuries. One of the disadvantages of radiography in diagnosing AP is the low sensitivity of the method, which makes it possible to detect a decrease in bone mass when the degree of decrease in mineralization reaches 20–40%. Currently, radiography is used to detect or confirm bone fractures of any location. To diagnose osteoporotic fractures of the vertebral bodies, the method of X-ray morphometry of the spine in the lateral projection is used. X-ray morphometric analysis of the vertebral bodies includes measurement of the anterior, middle and posterior heights with the calculation of indices: anterior/posterior index - the ratio of the anterior height of the vertebral body to the posterior; middle/posterior index – the ratio of the average height of the vertebral body to the posterior; posterior/posterior index – the ratio of the posterior height of the body of the vertebra under study to the posterior heights of one or two overlying and underlying vertebrae. To assess deformations, the quantitative method of H. Genant is used [3]. Vertebral body indices of more than 0.8 (80%) indicate a normal configuration of the vertebra, with any index of 0.75–0.79 – a 1st degree of deformity, with 0.6–0.74 – a 2nd degree , and if 0.59 or less – a severe osteoporotic vertebral fracture of the 3rd degree. The OP of the spine is characterized by such types of deformities as anterior or posterior wedge-shaped, unilateral or biconcave deformities, as well as a compression fracture. Indications for referral of patients for X-ray examination include back pain and decreased height to detect osteoporotic vertebral fractures. Currently, the “gold standard” for diagnosis is the measurement of BMD using dual-energy X-ray absorptiometry (DXA), which estimates the amount of mineralized bone tissue in the scanned area (g /cm2). Standard testing methods include densitometry of the lumbar spine and proximal femur (femoral neck and total hip index), since the prevalence of fractures has been shown to correlate with BMD in these areas based on numerous assessment methods. The diagnosis of AP is made in postmenopausal women and men aged 50 years and older by comparing the obtained BMD data with the apparatus’s abstract database (the average value of “peak bone mass” in young healthy people according to the T-criterion) using the WHO recommendation [WHO, 1994] , according to which normal BMD values include indicators above -1SD from the reference base according to the T-criterion, values from -1SD to -2.5SD are classified as osteopenia, deviations below -2.5 SD - as OP, and with the additional presence of one and more fractures – as severe AP. If it is not possible to study the spine and hip, the results of measurements of the distal forearm can be used. Indications for referring patients for densitometry are the presence of risk factors for AP in patients under 65 years of age and to assess the effectiveness of pathogenetic treatment of AP. For the differential diagnosis of primary AP and metabolic diseases of the skeleton, as well as before prescribing antiresorptive therapy, a mandatory study of calcium, phosphorus and alkaline phosphatase in the blood, calcium in daily urine or the ratio of calcium to creatinine in morning urine is recommended. It should be remembered that in primary AP, the level of the above indicators in the blood is within normal limits, but hypercalciuria is possible, especially for the variant of AP with increased bone turnover. In addition, additional laboratory methods can be used, the purpose of which is to establish a diagnosis of the underlying disease, one of the symptoms of which is osteopenia (for example, thyroid-stimulating hormone, parathyroid hormone, 25-hydroxyvitamin D, etc.). To assess the rate of bone turnover, markers of bone formation (osteocalcin OS, carboxy- and aminoterminal propeptides of procollagen type I - PICP, PINP, bone isoenzyme of alkaline phosphatase - bALP), as well as markers of bone resorption (oxy- and deoxypyridinolines - PYR, DPYR, hydroxyproline - OHPr in urine, N- and C-telopeptides of type I collagen molecules cross-linked - NTX, CTX in blood serum or urine, as well as tartrate-resistant acid phosphatase - TRACP in blood plasma). However, at present there is no evidence of the importance of determining the level of bone markers for individual diagnosis of AP and for predicting the risk of fractures in individual patients in clinical practice; they can be used to assess the therapeutic effect of the drug (a decrease in their level by 30% or more when taking antiresorptive therapy is predicted good treatment effectiveness) and improved patient adherence to treatment. Treatment of AP includes both non-drug therapies and pharmacological interventions. Among the first, it should be noted educational programs, giving up bad habits (smoking, alcohol abuse, caffeine, heavy physical activity), physical education (walking, gymnastics, isometric exercises, swimming), fall prevention (vision correction, treatment of concomitant diseases, assessment and change home environment, movement pattern training, balance training), patients with vertebral fractures should be recommended to wear rigid or semi-rigid corsets for up to 4–6 hours during physical activity, because they reduce the severity of pain. With AP, such types of loads as jumping and strength exercises, sudden bends and rotations of the body should be excluded. Drug treatment of AP is a difficult task, since it is diagnosed quite late, when there may already be a history of fractures of various locations. Treatment must be long-term, since the effect may take many months to appear. In this regard, there is a constant search for highly effective and inexpensive drugs. The goal of therapy is to slow down and, if possible, stop bone loss, prevent bone fractures, improve the patient's condition, reduce pain, and improve his quality of life. Today, the range of drugs for the treatment and prevention of AP has expanded significantly; their use reduces the risk of fractures from 30 to 70%. The drugs of first choice for pathogenetic therapy are drugs of the bisphosphonate (BP) class and strontium ranelate. The action of BP is based on reducing the rate of bone turnover due to its effect on osteoclasts - cells that destroy old bone - while maintaining bone microarchitecture and increasing bone mineral density (BMD). One of the drugs in the BF class is alendronate, which has been widely used in clinical practice throughout the world for almost 15 years. When treated with alendronate, resorption processes by osteoclasts are suppressed and bone metabolism processes are restored to premenopausal levels and prevents microarchitectural disorders and bone loss. The processes of bone metabolism remain stable during long-term treatment with alendronate for 10 years, while the accumulation of the drug in the bone does not lead to excessive suppression of bone turnover, but, on the contrary, demonstrates that bone turnover remains at premenopausal levels, and bone quality remains normal throughout the treatment period . Data from pharmacokinetic studies have confirmed that the effectiveness of BP on bone mass and strength depends on the cumulative dose of these drugs. Thus, the same amount of alendronate is absorbed with a single dose of 70 mg once a week. or 10 mg 7 times/week. The effectiveness of alendronate in patients with AP has been proven in several randomized clinical double-blind placebo-controlled studies (RCTs) [4,5,6]. Taking alendronate showed high efficiency: it significantly reduced the incidence of vertebral fractures by 47%, hip fractures by 51–56%, and forearm fractures by 48% [5,7]. Currently, alendronate is the first drug that has a 10-year study duration that assessed the dynamics of BMD in groups of patients who took alendronate throughout this period or were switched to placebo after the first 5 years of active therapy. In women who continued to receive 10 mg/day. alendronate, there was a gradual increase in spine BMD to 13.7% (p<0.001), and hip BMD to 6.7% (p<0.001) relative to the initial level. As a result of alendronate administration, the level of bone turnover markers decreased to premenopausal levels, which remained stable over the entire 10-year period without signs of oversuppression. Compared with the study group, individuals who took placebo over the past 5 years showed a decrease in total hip BMD (–2.4%; 95% CI –2.9%; –1.8%; p<0.001) and lumbar spine (–3.7%; 95% CI –4.5%; –3.0%; p<0.001), however, mean BMD values remained above baseline at study entry. At 5 years, the overall risk of peripheral fracture was not significantly different between groups (RR 1.00; 95% CI 0.76, 1.32). Those who continued alendronate therapy had a significantly lower risk of clinically significant vertebral fractures: for example, in the placebo group they occurred in 5.3% of patients, and in the alendronate group – in 2.4% (OR 0.45; 95% CI 0.24; 0.85). For fractures detected by X-ray morphometry of the spine, such a pattern was not found (11.3 and 9.8%, respectively; RR 0.86; 95% CI 0.60, 1.22). A small number of iliac biopsies did not reveal any qualitative bone pathology. In summary, this study showed that stopping treatment after 5 years does not significantly increase the risk of fractures, but women at high risk of clinical vertebral fractures should continue treatment beyond 5 years [6]. When taking oral bisphosphonates, much attention is paid to adverse events (AEs) associated with damage to the gastrointestinal tract. It should be noted that during the studies, the frequency of all adverse events when taking 10 mg of alendronate per day did not exceed that in the placebo group [5]. Currently, all over the world, due to the problem of treatment compliance, preference is given to another dose of the drug 70 mg 1 time/week. RCTs have shown that this dosage of alendronate provides therapeutic equivalence to a daily dose of 10 mg of the drug, while at the same time better tolerability and ease of use [8–10]. Thus, the increase in BMD was 6.8 and 7.4%, respectively, in the spine, 4.1–4.3% in the hip. A two-year follow-up of patients receiving various doses of alendronate showed that the incidence of fractures in the 70 mg group once a week. was 7.3%, and in the group 10 mg/day. – 7.0% (p>0.05). There is clear evidence of a reduction in fracture risk with alendronate 10 mg daily, and the lack of difference in fracture incidence at both doses, comparable increases in BMD, and similar changes in bone turnover marker levels suggest a similar effect on fracture risk at these dosages. The biopsy material showed no signs of osteomalacia when taking both doses of the drug. In a comparative study, it was shown that the frequency of gastrointestinal AEs (esophagitis, erosion, hemorrhage, reflux, gastritis, stomach ulcer, etc.) in groups receiving different doses of alendronate was similar, i.e. an increase in a single dose of 7 times did not increase the risk of developing AEs [10,11]. The RI RAMS conducted a study of the effectiveness and safety of alendronate 70 mg/week. in an open-label, one-year controlled study [11]. After a year of therapy, a significant increase in BMD in the spine and femoral neck was obtained in patients receiving alendronate compared to the comparison group (p=0.00001 and p=0.030, respectively). When assessing the number of patients with a significant increase in the MPC in the spine and the proximal thigh department, it was revealed that in the group that received treatment with alendronate, 85.7% of patients had an increase in more than 2% in the spine and 42.8% of people - in the field of the hip neck, and 38.8% had a significant increase in both areas of measurement, which was significantly higher than in the comparison group (p = 0.01). At the same time, the increase in MPCT more than 6% in the spine was found in 53% of women who received alendronate, and in the neck of the thigh - an increase of more than 3% - in 30.6%. In addition, when taking alandronate, it was reliably more women who positively responded to treatment than women whose effect was absent (p <0.001). Our study showed high efficiency of alendronate at a dose of 70 mg 1 time/week. In the treatment of primary OP in women in postmenopausa: it had a positive effect on the MPC, reduced the pain syndrome and, as a result, reduced the restriction of the physical activity of patients. It is noted quite good tolerance of the drug, side effects in the treatment group were comparable to those in the comparison group. An analysis of the action of alendronate showed that it has a path for the 12 -month period after the end of treatment in relation to the MPC of the spine. Alendronate is effective in both men and women, for the prevention and treatment of glucocorticoid (Civil Code) OP both in relation to the increase in the IPC and a reduction in risk of fractures. The fundamental evidence of the effectiveness of the alendronate was obtained in a randomized clinical study with a placebo control, in which men and women (n = 477) with newly prescribed Civil Code (34% of patients) or with Civil Code of therapy that lasted more than 4 months. (66% of patients), were under observation of more than 48 weeks. Positive effects of treatment for 12 months. At the MPC, they were statistically reliable in the lumbar spine and the hip neck. It is noted that in the Alendronate group of new vertebral fractures during the observation period, there were less than the placebo group (2.3 and 3.7%, respectively, P> 0.05). Subsequently, observation of 208 patients showed the effectiveness of therapy with alendronate during the 2nd year and a significant decrease in the number of new vertebral fractures in the Alendronate group (0.7%) compared to the placebo group (6.8%; p = 0.026) [ 13]. Alendronate must be taken on an empty stomach immediately after lifting from bed, the tablet must be washed down with 1 cup (180–240 ml) of pure water, and after receiving you should be in an upright position (sitting or standing) for at least 30 minutes. BF can cause side effects associated with the defeat of the gastrointestinal tract, as well as headache, muscle pain and bones, a decrease in calcium and phosphorus in the blood serum, in rare cases - a rash and erythema. With an overdose of BF - hypocalcemia and hypophosphatemia, gastrointestinal tract disorders. Compliance with recommendations for taking the drug significantly reduces the risk of gastrointestinal nia. Contraindications to their purpose: hypersensitivity to the drug, stricture and esophagus ahalazia, severe renal failure (creatinine clearance below 35 ml/min.), Hypocalcemia, pregnancy and breastfeeding, children's age, severe hypoparastic, calcium malabsorption. It should be remembered that taking drugs affecting pathogenesis of the OP should take place against the background of sufficient intake of calcium and vitamin D with food or in the form of drugs. Active metabolites (alfacalcidol and calcitriol) can be used as a vitamin D donator, the combined use of them with BF leads to an increase in the MPC of the spine and the hips of the thigh, a decrease in the risk of falling and peripheral bones [14].
Literature 1. Guide to osteoporosis / Ed. Prof. L.I. Benevolenskaya. M.: BINOM, 2003. 524 p. 2. Clinical recommendations “Osteoporosis. Diagnostics, prevention and treatment / Ed. prof. L.I. Benevolenskaya and Prof. O.M. Lesnyak. M.: GEOTAR-Media, 2009; 272 pp. 3. Genant HK, Wu C, van Kuijk et al. Vertebral fracture assessment using a semiquantitative technique // JBMR 1993;9:1137–1148. 4. Pols HA, Felsenberg D, Hanley DA, et al. Multinational, placebo–controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Fosamax International Trial Study Group. Osteoporos Int. 1999; 9:461–468. 5. Black DM, Thompson DE, Bauer DC and FIT research group. “Fracture risk reduction in women with osteoporosis: the Fracture Intervention Trial.” J Clin Endocrinol Metab 2000; 85:4118–24. 6. Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long–term Extension (FLEX): a randomized trial. JAMA. 2006 Dec 27;296(24):2927–38. 7. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995; 333:1437–43. 8. Schnitzer T., Bone H. G., Crepaldi G. et al. Therapeutic equivalence of alendronate 70 mg once–weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging Clin Exp Res 2000;12:1–12. 9. Rizzoli R, Greenspan SL, Bone G III et al. Two–Year Results of Once–Weekly Administration of Alendronate 70 mg for the Treatment of Postmenopausal Osteoporosis // J Bone Mineral Research, 2002, Nov 17(11):1988–96 10. Greenspan S, Field–Munves E, Tonino R, Smith M, Petruschke R, Wang L, Yates J, de Papp AE, Palmisano J. Tolerance of once–weekly alendronate in patients with osteoporosis: a randomized, double–blind, placebo–controlled study//.Mayo Clin Proc. 2002 Oct;77(10):1044–52. 11. Lanza F, Sahba B, Schwartz H, Winograd S, Torosis J, Quan H, Reyes R, Musliner T, Daifotis A, Leung A. The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo–controlled endoscopy study//Am J Gastroenterol. 2002 Jan;97(1):58–64 12. Toroptsova N.V., Nikitinskaya O.A., Demin N.V., Benevolenskaya L.I. Results of a study of the effectiveness of weekly administration of alendronate (Fosamax®) in patients with primary osteoporosis // Osteoporosis and Osteopathy. 2006;1: 22–25. 13. Adachi JD, Saag KG, Delmas PD, Liberman UA, Emkey RD, Seeman E. Two–year effects of alendronate on bone mineral density and vertebral frac¬ture in patients receiving glucocorticoids: a randomized, double–blind, placebo–controlled extension trial. Arthritis Rheum 2001;44:202–211. 14. Ringe JD, Farahmand P, Schacht E, Rozehnal ASuperiority of a combined treatment of Alendronate and Alfacalcidol compared to the combination of Alendronate and plain vitamin D or Alfacalcidol alone in established postmenopausal or male osteoporosis (AAC–Trial). Rheumatol Int. 2007 Mar;27(5):425–34.
Among all the drugs used in the treatment of osteoporosis (OP), drugs from the bisphosphonate (BP) group are currently most commonly used. Clinical recommendations and guidelines consider BP as first-line drugs for the treatment of AP [1]. The first BF (etidronate) was synthesized in 1897 by von Baeyer H. and KS Hoffmann, but their active use in medicine began in the 1960s. The effectiveness of etidronate in the treatment of AP was insufficient, and in some cases its use was accompanied by disruption of the processes of bone tissue mineralization. All this limited the widespread use of the drug in clinical practice. In 1995, alendronate was registered as the first nitrogen-containing BP for the treatment of AP. Its effectiveness was higher than that of the first generation BF, and the safety profile was significantly more favorable. Currently, a doctor has a number of BPs in his arsenal, but alendronic acid preparations are still widely used in the treatment of AP, being as effective and safe as other BPs.
In terms of their chemical structure, BPs are analogues of pyrophosphate, structurally similar to hydroxyapatite and capable of adsorption on the surface of hydroxyapatite crystals in bone tissue. BFs are not metabolized in the body of mammals and are excreted unchanged. The bioavailability of BF is low and in most of them does not exceed 1%. After entering the bloodstream, from 20 to 60% of BPs in circulation are adsorbed by bone tissue, and the remainder is quickly excreted from the body through the kidneys. The removal of BP from bone is associated with remodeling processes and occurs during resorption. However, the released molecules can be reincorporated into bone tissue, which determines the rather long half-life of BP from the body, reaching 10 years or more [2]. The main mechanism of action of BP is associated with their direct effect on osteoclasts, leading to disruption of their formation, metabolism and functional activity, induction of apoptosis and, as a consequence, suppression of bone resorption. There are indications of the ability of BP to have a stimulating effect on the formation of new bone tissue [1].
Alendronate is one of the most studied BPs used in the treatment of AP. Its effectiveness and safety have been demonstrated in a number of studies. Alendronate significantly increases bone mineral density (BMD). In the multicenter placebo-controlled study FOSIT (Fosamax International Trial), postmenopausal women with AP (n=1908) took 10 mg of alendronate daily for a year [3]. After a year, patients receiving the drug significantly (p<0.001) increased BMD indicators: in the spine - by 5.6% (95% confidence interval [CI] - 4.6–5.2%), in the trochanteric region - by 3. 6% (95% CI – 3.2–4.1%), in the femoral neck – by 2.6% (95% CI – 2.0–2.8%), in the proximal femur – overall by 3.0% (95% CI – 2.6–3.4%). The increase in BMD in the main group was significantly higher compared to the placebo group (p<0.001). In this study, individuals taking alendronate also showed a 47% reduction in the risk of peripheral fractures (95% CI - 10-70%; p = 0.021).
The effect of alendronate therapy on the risk of fractures was studied in the FIT (Fractiure Intervention Trial) program [4]. It consisted of two randomized, double-blind, placebo-controlled studies. The program included postmenopausal women aged 55–88 years (n=6457) with low proximal femoral BMD. One subgroup (n=2023) assessed the ability of alendronate to reduce the risk of new vertebral fractures in individuals with a history of such fractures. Therapy continued for 3 years. Another subgroup (n=4432) assessed the ability of alendronate to prevent symptomatic fractures in individuals without a history of fractures. The concept of “fractures with clinical symptoms” is of particular importance in AP, since in some cases slowly increasing compression of the vertebrae may not have a clinical picture. The duration of the study for this subgroup was 4 years. Initially, alendronate was used for 2 years at a dose of 5 mg/day, later the dose was increased to 10 mg/day as it was more effective and had a good level of safety.
In the first study, the primary endpoint was the development of new fractures. A vertebral fracture without clinical symptoms was determined using X-ray morphometry. A fracture was diagnosed when the vertebral height decreased by more than 20% and/or by more than 4 mm. A fracture with clinical symptoms was determined based on the patient’s complaints and confirmed radiographically. Analysis of the data obtained showed that the use of alendronate by women with a history of fractures, and therefore who had a high risk of developing fractures in the future, led to a significant reduction in this risk. Thus, the reduction in the risk of morphometrically detected vertebral fractures reached 67% (hazard ratio [RR] – 0.53; 95% CI – 0.41–0.68), vertebral fractures with clinical symptoms – 55% (RR – 0. 45; 95% CI – 0.27–0.72), any “clinical” fractures – 28% (OR – 0.72; 95% CI – 0.58–0.90), fractures of the proximal femur – 51 % (RR – 0.49; 95% CI – 0.23–0.99) and fractures of the distal forearm – 48% (RR – 0.52; 95% CI – 0.31–0.87) [5] .
A second study, which assessed the effectiveness of alendronate in individuals without a history of vertebral fractures, found that treatment over 4 years (average data) increased spinal BMD by 8.3% (difference from placebo - 6.6%; p<0.001), in the femoral neck - by 3.8% (difference with placebo - 4.6%; p<0.001), in the proximal femur - by 3.4% (difference with placebo - 5.0%; p<0.001), in the proximal femur - by 3.4% (difference with placebo - 5.0%; p<0.001). The relative risk of fractures with clinical manifestations of all locations (except for the skull bones and phalanges) was significantly reduced by 36% in women with BMD ≤ -2.5 SD (95% CI - 0.5–0.82; difference with placebo - 6. 5%; NNT – 15). In individuals with higher BMD values, there was a tendency to reduce the risk of fracture, which did not reach statistical significance. Using a post hoc analysis, alendronate was shown to reduce the risk of proximal femur fracture in women with femoral neck BMD <-2.5 SD by 56% (RR 0.44; 95% CI 0.18–0.97 ). The risk of radiographically detected vertebral fractures was reduced by 44% (RR, 0.56; 95% CI, 0.39–0.80) [6].
Thus, it has been shown that in people suffering from AP, alendronate therapy significantly increases BMD and reduces the risk of fractures in a variety of locations.
The duration of use of BF in patients with a moderate risk of fractures is 3–5 years. Further continuation of therapy may be considered if there is a negative change in BMD or the occurrence of new fractures [7]. Determining the content of bone turnover markers can provide some assistance in deciding whether to continue treatment. The use of BP is accompanied by a decrease in their level to 30% after the first 3 months of therapy. If marker levels remain low (more than a 25% decrease) after stopping treatment, the patient may not need further treatment.
In general, the main criteria for continuing therapy include the appearance of new fractures during therapy, the presence of risk factors for AP, low BMD (<-2.5 SD), and progressive loss of BMD [8]. For persons at high risk of fractures, therapy should be continued for up to 10 years. Due to the accumulation of data on the pharmacokinetics, pharmacodynamics of BP and a number of rare but potentially serious complications with their use, such as atypical fractures, some authors suggest taking breaks in treatment after 3, 5 and 10 years, depending on the clinical situation. Moreover, the duration of such “medicinal holidays” for people at high risk of fractures should not exceed 1–2 years. During this period, it is possible to prescribe other groups of drugs for the treatment of AP [9, 10].
The efficacy and safety of long-term use of alendronate was assessed in the FLEX (Fracture Intervention Trial Long-term Extension) study [11]. It included 1099 women who had previously participated in the FIT program and received alendronate for 5 years. Some women continued taking alendronate up to 10 years, the rest were included in the comparison group. Among patients who stopped taking the drug after 5 years, there was a decrease in BMD in the proximal femur (total hip) by 2.4% (95% CI - 1.8–2.9%; p <0.001), in the spine - by 3.7% (95% CI - 3.0-4.5%; p < 0.001), but BMD values still remained significantly higher compared to their values before the start of therapy 10 years ago. Discontinuation of alendronate treatment was also accompanied by an increase in the level of markers of bone turnover compared with persons who continued therapy: C-telopeptide of type 1 collagen (a marker of bone resorption) by 55.6% (p <0.001), N-propeptide of type 1 collagen (a marker of bone formation) by 59.5% (p<0.001) and bone alkaline phosphatase (a marker of bone formation) by 28.1% (p<0.001). However, the levels of these markers 5 years after stopping treatment remained significantly lower compared to the levels when alendronate was started 10 years ago.
At the end of the study, the cumulative risk of non-vertebral fractures did not differ significantly between the comparison groups (RR – 1.00; 95% CI – 0.76–1.32). For individuals who continued taking alendronate, the risk of vertebral fractures accompanied by clinical symptoms was significantly lower (5.3% in the placebo group and 2.4% in the alendronate group; RR - 0.45; 95% CI - 0.24–0. 85), while differences in the risk of vertebral fractures detected by radiological morphometry were not significant (11.3% in the placebo group and 9.8% in the alendronate group; RR - 0.86; 95% CI - 0.60 –1.22).
During the work, bone biopsy specimens (n=18) obtained from the iliac wing were examined using microcomputed tomography. There were no differences in bone quality between the comparison groups.
Compliance with the dosage and administration regimens of the drug is the most important condition for quality treatment of any chronic disease. While maintaining effectiveness and safety, lengthening the intervals between drug doses can increase patient adherence to therapy and, accordingly, improve the outcome of the disease. After registration and introduction of alendronate into clinical practice, it was used at a dosage of 10 mg daily. However, subsequent studies showed that the use of the drug at a dose of 70 mg once a week is characterized by similar effectiveness and safety.
T. Schnitzer et al. [12] conducted a one-year, multicenter, double-blind study comparing the effectiveness and safety of different doses and regimens of alendronate in postmenopausal women. Patients received alendronate 70 mg once a week (n=519), 35 mg twice a week (n=369) and 10 mg daily (n=370). After a year of therapy, the average increase in BMD in the spine in these groups was 5.1% (95% CI – 4.8–5.4%), 5.2% (95% CI – 4.9–5.6%) and 5.4% (95% CI – 5.0–5.8%), respectively, without significant differences between groups. Indicators of increased BMD in the proximal femur with different drug administration regimens also did not differ significantly. The groups showed similar decreases in the levels of markers of bone resorption and bone formation. When assessing the tolerability of therapy, the frequency of adverse events in the comparison groups was comparable. Similar data were obtained in other studies [13, 14].
The use of alendronate 70 mg once a week increases adherence to treatment, since the majority of patients choose this particular drug regimen. JA Simon et al. [15] conducted a multicenter, randomized, open-label study (n=324) to assess preference for alendronate in two regimens: 70 mg once weekly and 10 mg daily. Each group of patients took alendronate at the appropriate dosage for four weeks, then the regimen changed between groups. When analyzing the data, it turned out that the vast majority of patients preferred to take the drug weekly (86.4 vs. 9.2%; p < 0.001), because, as study participants noted, this regimen was more convenient.
The use of BF may be accompanied by the development of a number of side effects. In general, the use of BF for the treatment of AP is well tolerated and the development of serious adverse reactions is rare. In the large international studies FOSIT, FIT and FRAX, the incidence of adverse events in the alendronate groups was comparable to that in the placebo groups. However, in real clinical practice, when using any drug, an increase in the frequency of adverse events is observed. We will look at some of them.
When taking BF, various dyspeptic symptoms may occur, including the development of esophageal erosion. When analyzing data from post-marketing studies, it turned out that the most serious complications occurred in case of non-compliance with the instructions for use of the drug: taking BF against the background of an existing lesion of the esophagus, taking a horizontal position immediately after taking the pill, in some cases, patients did not take the drugs at all or took a small amount water [16]. Compliance with the recommendations significantly reduces the risk of adverse events from the upper gastrointestinal tract.
From 10 to 30% of patients after the first infusion of BP experience manifestations of acute phase reactions (APR): fever, general malaise, myalgia, arthralgia, bone pain [17, 18]. These phenomena occur 1–3 days after administration of the drug and can last up to 7–14 days. However, with subsequent infusions, the frequency and severity of ARF sharply decrease. The use of BF orally is rarely accompanied by such reactions, therefore, when using alendronate, RRFs are not common. In most cases, paracetamol is sufficient to relieve ARF.
In 2002, the US FDA reported several episodes of osteonecrosis of the mandible (ONJ) when patients with cancer were treated with zoledronic acid. When analyzing repeated reports, it was revealed that the main risk factors for ONJ include radiation therapy of the face and neck area, periodontal disease, dental surgical procedures, constant trauma to the oral mucosa with poorly fitting dentures, and the infusion method of using BP in high doses [19]. It should be noted that the risk of developing ONJ when using oral forms is very small and is more likely to develop with long-term use of BP: more than three years [19]. Prevention of ONJ includes examination by a dentist before prescribing BF and every 6 months during treatment. If a patient is expected to undergo invasive treatment procedures, bifid therapy should, if possible, be prescribed after completion of the procedure.
Another very rare but serious potential complication is an atypical femur fracture. Currently, there is no unambiguous confirmation of the connection between taking BF and the risk of atypical fracture; however, the attending physician should pay special attention to the occurrence of unexplained pain in the hip area in patients taking BF and, if necessary, conduct an X-ray examination.
Compliance with the rules for taking alendronate is important. As noted above, orally taken BFs are characterized by very low absorption. Food intake has a significant impact on absorption rates. Thus, when taking alendronate at a dose of 70 mg on an empty stomach 2 hours before breakfast, its bioavailability was 0.64% in women and 0.59% in men. If the drug was taken one hour or 30 minutes before breakfast, bioavailability decreased to 0.46 and 0.39%, respectively. When taken with food or within the first two hours after a meal, the bioavailability of adendronate becomes extremely low. Taking alendronate together with coffee or orange juice reduces bioavailability by 60%. Therefore, according to the instructions, it is recommended to take the drug on an empty stomach with a sufficient amount of water (at least 200 ml). Once alendronate enters the circulation, it is quickly redistributed into bone tissue or excreted in the urine. Its concentration remains insignificant in the blood plasma (<5 ng/ml).
So, alendronate is a first-line treatment for patients suffering from AP and at high risk of fractures. It has high efficacy and a favorable safety profile.
