Pharmacodynamics and pharmacokinetics
Pharmacodynamics
Alendronic acid inhibits the destruction of bone tissue, which is caused by osteoclasts . Penetrates resorption zones and inhibits this process. The mechanism of action is explained by stimulating apoptosis of osteoclasts and suppressing their activity. New tissue formation and bone degradation are unrelated, but alendronic acid reduces bone formation to a lesser extent than bone resorption . In general, there is an increase in bone mass, an increase in its mineralization and an improvement in quality characteristics. In therapeutic doses it does not cause osteomalacia and healthy bone tissue is formed during treatment.
Pharmacokinetics
Taking immediately before or after meals leads to a decrease in bioavailability. Bioavailability when taken 2 hours before meals is 0.64%. When drinking coffee it decreases by 60%. The lowest concentration that can be determined by laboratory methods is determined in blood plasma. 78% protein bound. Alendronic acid is distributed first in soft tissues, then redistributed into bones. Not metabolized. A small amount is excreted through the intestines, and the main part is excreted by the kidneys. The half-life is up to 10 years, which is due to release from bone tissue.
Alendronic acid preparations in the treatment of osteoporosis
The most effective drugs for the treatment of osteoporosis are bisphosphonates - synthetic analogs of bone matrix pyrophosphates that are resistant to enzyme breakdown. The effectiveness of alendronate, which belongs to the second generation of bisphosphonates, has been confirmed by a large number of clinical studies. The drug Ostalon® Calcium-D, containing alendronic acid, colecalciferol and calcium carbonate, demonstrates good efficacy and tolerability by patients.
Rice. 1. Efficacy of Ostalon for osteoporosis (lumbar spine)
Rice. 2. Efficacy of Ostalon for osteoporosis (femoral neck)
Rice. 3. Tolerability of Ostalon when used for 6 and 12 months
Osteoporosis (OP) is a progressive systemic disease of the skeleton, characterized by a decrease in bone mass and disruption of the structure (microarchitecture) of bone tissue, leading to increased bone fragility and the risk of fractures [1]. AP is one of the most common diseases, being one of the main causes of fractures of the femoral neck and vertebral bodies, and consequently, disability of patients. According to WHO, among non-communicable diseases, AP ranks fourth in frequency after diseases of the cardiovascular system, cancer and diabetes mellitus. In Russia, according to the Research Institute of the Russian Academy of Medical Sciences, the incidence of AP and osteopenia in women over 50 years of age is 34% in the lumbar spine and 43% in the femoral neck; in men – 27% and 44%, respectively (the work was carried out within the framework of the European program for the study of osteoporosis of the spine - EVOS) [2]. When examining another large cohort of patients - 2155 women aged 55 years and older, observed in the clinic of the Central District of Moscow - the frequency of AP in the lumbar spine was 29.8% [3]. Data on fracture rates are also disappointing: about 40% of Caucasian women and 13% of Caucasian men aged 50 years and older have at least one clinically significant fracture [4]. And the fact that bone fractures in AP occur even as a result of a minor injury, for example, falling from one’s own height or lifting heavy objects, makes AP an important socio-economic problem.
Considering the above, treatment of AP should be aimed primarily at reducing the risk of skeletal fractures. Today there is a fairly wide range of drugs for the treatment of this disease. But the most effective drugs, undoubtedly, are bisphosphonates [5–7].
Despite the fact that the history of bisphosphonates dates back to the 19th century, their use in medicine is relatively recent, and they were originally used to soften water in irrigation systems. Subsequently, thanks to the discovery of their ability to prevent the dissolution of hydroxyapatite, attempts were made to use bisphosphonates to treat disorders of bone metabolism (Paget's disease and hypercalcemia of tumor origin). This happened only in the 1960s, and the real mechanism of action of bisphosphonates was demonstrated only recently - in the 1990s. – using alendronate as an example [8].
Bisphosphonates are synthetic analogues of bone matrix pyrophosphates that are resistant to enzyme degradation. The primary mechanism of action of all bisphosphonates is to inhibit bone resorption by inhibiting osteoclast activity, resulting in increased bone mass. Alendronate belongs to the second generation of bisphosphonates containing one nitrogen atom in its chemical structure. These nitrogen-containing bisphosphonates, which entered medical practice in the late 80s. 20th century, have a more active antiresorptive effect compared to first generation drugs (clodronate, etidronate). This is due to the peculiarity of the metabolism of first generation bisphosphonates, which are metabolized to form compounds - analogs of ATP. These compounds accumulate in osteoclasts and disrupt their function. Aminobisphosphonates have a fundamentally different mechanism of action: they themselves are not metabolized, but interfere with the process of mevalonate metabolism (by inhibiting the enzyme farnesyl pyrophosphatase), thereby disrupting the differentiation of osteoclast precursors, as well as stimulating apoptosis of mature cells. Penetrating into bone tissue, bisphosphonates create a high concentration in resorption lacunae and reduce their depth (as shown in in vitro studies).
In addition, bisphosphonates help increase the number of osteoblasts in cancellous and cortical bone, as well as reduce the secretion of osteoclast-stimulating factor by osteoblasts.
All of the above together helps restore bone volume and increase its strength, and therefore reduce the risk of fractures. The effectiveness of alendronate against all types of fractures has been confirmed by a large number of long-term clinical studies. Several large multicenter randomized placebo-controlled studies have been conducted to study the effectiveness of alendronate in AP:
- the FOSIT study, including 153 centers in 34 participating countries and 1908 postmenopausal women with AP, study duration 1 year [9];
- the FIT study, including 11 US centers and 3658 postmenopausal women, lasting 3 years [10];
- The FLEX study was a 10-year follow-up of patients who continued to receive 5 mg and 10 mg alendronate or were switched to placebo after 5 years of alendronate therapy [11].
In all studies, daily administration of 10 mg alendronate was highly effective, increasing bone mineral density (BMD) in the femoral neck and spine (Evidence A) and significantly reducing the incidence of fractures in the spine, femoral neck and forearm.
In the FLEX study, patients switched to placebo after 5 years of alendronate therapy had a decrease in proximal femoral BMD (-2.4%; 95% CI (-2.9) to (-1.8)%; p
Subsequently, data were published on the effectiveness of alendronate therapy compared with placebo in combination with calcium and vitamin D supplements. Thus, according to a Cochrane systematic review [12], analyzing the results of 11 RCTs (12,068 women) conducted from 1966 to 2007 There was a significant reduction in the absolute risk of vertebral fractures (by 6%), femoral neck (by 1%), and peripheral fractures (by 2%) in patients receiving alendronate therapy (level of evidence A).
Thus, the use of alendronate remains relevant to this day; according to many authors, the drug is the “gold standard” in the treatment of AP. Further direction in the use of alendronic acid is associated with the development of long-acting drugs that create the possibility of intermittent administration, which is more rational both from a medical point of view and for compliance reasons.
Several randomized, placebo-controlled studies have demonstrated that once-weekly alendronate 70 mg is therapeutically equivalent to a daily dose of 10 mg. In addition, this form of the drug showed better tolerability, in particular, a lower incidence of adverse events from the upper gastrointestinal tract [13–17].
Post-marketing non-interventional study of Ostalon (alendronate sodium trihydrate, 1 tablet of which contains 91.35 mg, corresponding to the content of 70 mg of alendronic acid) lasting 12 months (April 2006 - June 2007), conducted in 294 osteoporosis treatment centers in Hungary and including 4360 patients with osteoporosis, showed good efficacy and tolerability of the drug (Fig. 1–3).
It is these advantages that were taken into account when creating the drug Ostalon® Calcium-D, which is a combination of tablets containing alendronic acid in a dose of 70 mg (No. 4), and tablets containing colecalciferol - the active form of vitamin D - 400 IU (10 μg) and calcium carbonate containing 600 mg of ionized calcium (No. 28). This form of release is very convenient for patients, since it includes a full range of drugs necessary for the treatment of AP within a month, and, therefore, helps to increase compliance.
It should be noted that the bioavailability of colecalciferol in combination with alendronic acid is similar to its bioavailability when taken alone. The bioavailability of alendronic acid when taken on an empty stomach (2 hours before meals) is 0.64%, T1/2 - 72 hours, final T1/2 (removal from bone tissue) - more than 10 years.
Indications for use of the drug Ostalon® Calcium-D are:
- osteoporosis in postmenopausal women (reduced risk of fractures, including femoral fractures and compression fractures of vertebral bodies);
- osteoporosis in men (reducing the risk of fractures);
- osteoporosis caused by long-term use of glucocorticosteroids.
The dosage of the drug is traditional: tablets containing alendronic acid are prescribed 70 mg once a week. Tablets containing the combination of “colecalciferol + calcium carbonate” are prescribed 1 pc. daily, no earlier than 3 hours after taking alendronic acid. The presence of vitamin D3 (colecalciferol) in Ostalon® Calcium-D is an undeniable advantage of the drug. Vitamin D is the main regulator of calcium and phosphorus homeostasis in the human body and is necessary for normal bone mineralization. Vitamin D enhances the absorption of calcium and phosphorus ions in the small intestine and reduces their excretion by the kidneys. It is known that calcium ions are absorbed mainly in the proximal part of the small intestine, with only 10% being absorbed passively, and the vast majority of calcium - 90% - through an active mechanism controlled by vitamin D. In turn, vitamin D3 comes from food of plant origin, and is also formed in the skin from vitamin D2 under the influence of ultraviolet rays. However, vitamin D supplied with food is absorbed only by 50%, and a small number of sunny days in most European countries and the northern regions and central Russia leads to its deficiency. According to German researchers (N. Breijawi et al.) [18], 84.7% of patients with AP and osteoarthritis examined by the authors had a deficiency of vitamin D3.
Thus, it is obvious that patients with AP need an additional supply of vitamin D3, which undergoes further transformation in the body: in the liver - into 25-hydroxycolecalciferol and then in the kidneys - into the active form 1,25-dihydroxycolecalciferol.
Further studies have shown that a decrease in the level of 1,25-dihydroxyvitamin D can lead not only to impaired mineral metabolism, but also to the development of myopathy, manifested in weakness of the proximal muscles, changes in gait, and difficulty getting out of bed and from a chair. H. A. Bischoff et al. [19] showed in 1999 that in older adults (over 65 years of age), there is an inverse correlation between serum 1,25-dihydroxyvitamin D concentrations and knee extension strength. Later, the same authors found an association between normal vitamin D levels and higher arm muscle strength, better ability to rise from a chair, and a lower risk of falls [20]. This once again confirms the advisability of using vitamin D supplements in patients with AP in order to optimize neuromuscular function and prevent falls, which in most cases lead to fractures.
A recent study by SH Scharla et al. [21] describe the effects of vitamin D (alfacalcidol) on bone metabolism, cytokine levels, muscle strength and pain in elderly patients with rheumatoid arthritis and osteopenia. When analyzing the results, it was found that in the group of patients taking 1 mcg of alfacalcidol + 500 mg of calcium daily, the level of bone resorption marker (NTX) in the urine was significantly reduced. In addition, taking alfacalcidol was accompanied by a significant decrease in TNF-α levels. This fact confirms preliminary data published by G. Hein and P. Oelzner, who noted a decrease in the levels of TNF-α and IL-6 in patients with rheumatoid arthritis [22]. In the work of SH Scharla et al. an increase in muscle strength was confirmed in patients taking alfacalcidol, and an improvement in the total pain score was also noted, which can be explained by a decrease in the content of TNF-α (correlating with the severity of pain) and an improvement in muscle function.
Thus, the calcium and vitamin D preparation included in Ostalon® Calcium-D complements the action of alendronic acid, increasing the effectiveness of the drug.
Alendronic acid, instructions for use (Method and dosage)
For osteoporosis , Alendronic acid 70 mg is taken once a week. If the drug dose is 10 mg, then daily administration is necessary. It is recommended to take it in the morning 2 hours before meals and not go to bed for an hour. It is necessary to take the tablet with plain water, since other drinks (including mineral water) reduce the absorption of the drug. The tablet must be swallowed whole, as sucking or dissolving it may cause ulcers in the throat or mouth.
Taking the drug before bedtime carries a risk of developing esophagitis . If you miss taking the drug once a week, resume taking it at the usual dose the next day. For elderly people, dose adjustment is not carried out. The optimal duration of treatment for this disease is 3–5 years. If esophageal irritation occurs ( dysphagia , chest pain, heartburn ), you should consult a doctor and decide on the possibility of continuing treatment.
For glucocorticoid osteoporosis, 10 mg daily is prescribed.
For prophylactic purposes in early menopause - 5 mg daily.
Alendronate
Alendronate may cause local irritation of the mucous membrane of the upper gastrointestinal tract. In this regard, while taking Alendronate, caution should be exercised when prescribing the drug to patients with diseases of the upper gastrointestinal tract, for example, dysphagia, diseases of the esophagus, gastritis, duodenitis, ulcers, serious gastrointestinal disease suffered in the previous 12 months , for example, for peptic ulcers, as well as for active gastrointestinal bleeding, surgery on the upper gastrointestinal tract, with the exception of pyloroplasty. 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.
When treating 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. Therefore, clinicians should pay particular attention to any signs or symptoms indicating possible esophageal problems, and patients should be warned to stop taking Alendronate and seek medical attention if symptoms of esophageal irritation, such as dysphagia, pain with swallowing, or pain behind the sternum, the appearance or worsening of heartburn.
The risk of severe adverse events from the esophagus is higher in patients who violate the recommendations for taking the drug: you cannot take a horizontal position after consuming the drug and/or take it without washing it down, according to the recommendations, with a full glass of water (at least 200 ml), and/or Continue taking it if symptoms of esophageal irritation occur. Patients who are unable to follow dosage instructions due to mental illness should be treated with Alendronate under appropriate supervision.
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.
In the presence of hypocalcemia, the level of calcium in the blood must be normalized before starting treatment with Alendronate. Vitamin D deficiency must also be corrected. In patients with these disorders, serum calcium levels and symptoms of hypocalcemia should be monitored during treatment with Alendronate.
Due to the fact that alendronic acid increases bone mineral content, small asymptomatic decreases in serum calcium and phosphate concentrations may occur, especially in Paget's disease of bone, with an initially significantly increased bone turnover rate, as well as in patients receiving glucocorticoids, which is accompanied by a possible decrease in calcium absorption. Usually this decrease is small and asymptomatic. However, there are rare cases of symptomatic hypocalcemia, which sometimes reaches a severe degree and develops in patients with a corresponding predisposition (for example, hypoparathyroidism, vitamin D deficiency and calcium malabsorption). It is especially important to ensure adequate calcium and vitamin D intake in these patients.
Dentistry
Cases of local osteonecrosis of the jaw, associated primarily with previous tooth extraction and/or local infection (including osteomyelitis), often with slow recovery, have been reported in patients taking bisphosphonates, including alendronic acid.
In most cases, local osteonecrosis of the jaw due to bisphosphonates occurs in cancer patients receiving intravenous bisphosphonates. There are also known cases of osteonecrosis of the jaw in patients with osteoporosis who took oral bisphosphonates.
Risk factors for localized osteonecrosis of the jaw include invasive dental procedures (eg, tooth extraction, dental implants, bone surgery), cancer, concomitant therapies (eg, chemotherapy, radiation therapy, corticosteroids), poor oral hygiene, comorbidities ( for example, periodontal and/or other dental diseases, anemia, coagulopathy, infection, ill-fitting dentures) and smoking. There is evidence that the risk of osteonecrosis of the jaw increases with the combined use of bisphosphonates and angiogenesis inhibitors.
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. Patients who develop localized osteonecrosis of the jaw during bisphosphonate treatment should be monitored by a dental surgeon. The need to discontinue bisphosphonate therapy should be considered based on an assessment of the expected benefit versus potential risk for the individual 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.
Musculoskeletal pain
Severe, sometimes disabling bone, joint and/or muscle pain has been reported in patients taking bisphosphonates (including alendronic acid) prescribed for the treatment of osteoporosis, most often in postmenopausal women. Symptoms appear anywhere from one day to several months after starting the drug. If severe symptoms develop, the drug should be discontinued. In most patients, symptoms resolve after stopping the drug.
If severe musculoskeletal pain occurs, the patient should inform the doctor.
Atypical subtrochanteric and diaphyseal fractures of the femur
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 fractures are 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 the other (contralateral) hip should be evaluated in patients with a hip fracture taking bisphosphonates. 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, discontinuation of bisphosphonates in patients with stress fractures should be considered 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.
There have been rare reports of severe skin reactions with alendronic acid, including Stevens-Johnson syndrome and Lyell's syndrome (toxic epidermal necrolysis).
This medicinal product contains lactose. Patients with rare hereditary diseases of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this drug.
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.
Overdose
An overdose is manifested by dyspeptic disorders, abdominal pain, dysphagia , and heartburn. Esophagitis and gastritis develop . Biochemical tests show hypophosphatemia and hypocalcemia .
Symptomatic treatment is carried out. The intake of milk and antacids to bind alendronate . Do not induce vomiting as there is a risk of damage to the esophagus.
Alendronic acid analogues
Level 4 ATC code matches:
Tevanat
Rizendros
Zolerix
Aklasta
Forosa
Bonviva
Xydiphone
Zometa
Ibandronic acid
Fosamax
Ostalon
Alendronate
Alendronate , Alental , Lindron , Ostalon , Osteotab , Tevanat , Ostealen , Osterepar , Strongos , Forosa , Fosamax .
Reviews about Alendronic acid
Treatment of osteoporosis includes drugs that slow down bone resorption ( calcitonins and bisphosphonates) , enhance bone formation (anabolic steroids, parathyroid hormone , androgens, growth hormone ) and have a multifaceted effect ( osteogenone , vitamin D and its metabolites).
The first-line drugs in the treatment of osteoporosis are bisphosphonates , which include alendronic acid . Fosamax , Forosa , Alendronate , Ostalon , Alental and others are registered in Russia They have been well studied, their high effectiveness and tolerability have been proven. It is the intake of bisphosphonates that maintains bone mass at the existing level and even increases it by up to 10%. By increasing bone strength, they reduce the risk of fractures. However, it should be noted that these drugs only control the course of osteoporosis , not cure it.
Most often there are reviews about the use of these drugs for osteoporosis during menopause , but there is also information about their use for glucocorticoid osteoporosis in young people. It is known that the use of glucocorticoids, even in small doses, is accompanied by a risk of developing fractures.
“... Alendronic acid tablets 70 mg were prescribed after studying bone mineral density. I took it once a week, followed the instructions exactly and there were no side effects.” “... I drank prophylactically for only a month. The impressions are neutral - I didn’t feel any harm or effect.” “... There are no problems with the stomach and intestines, so I tolerated taking this drug well for 2 years. Helped me."
Negative reviews are left by patients who have gastrointestinal diseases . Even if this remedy was prescribed during a period of stable remission, then after 3-4 months, and for some even earlier, complaints of pain in the stomach and intestines, heartburn , belching and pain along the esophagus appeared. These phenomena forced me to stop taking the drug.
Recently, bisphosphonate based on ibandronic acid - Bonviva , the advantage of which is its greater antiresorptive activity and the possibility of using a 150 mg tablet once a month. Most women prefer monthly dosing.
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.
