Rev Osteoporos Metab Miner. 2018; 10 (1) Supplement: 18-22
The decision regarding pharmacological treatment of osteoporosis should be based on three fundamental pillars: the proven anti-fracture effectiveness of the chosen drug, its safety that will condition patient tolerability and the adherence that ensures the therapy is maintained as long as necessary, presumably from the time of diagnosis.
Osteoporosis (OP) as a chronic disorder with a relatively long initial course and asymptomatic to its complications represents a major problem of individual health and public health due to the costs involved. In addition, the therapeutic regimens currently available are uncomfortable and, therefore, contribute to the patient’s low therapeutic adherence1. Adherence is defined as compliance with the exact prescription provided to the patient and extended over the time indicated. When treating a chronic disorder, nothing can be achieved in the long term without persistence. Factors that influence treatment adherence include the prescribing physician’s explanations, the characteristics of the disease and the patient’s attitudes, but also the therapeutic regimen.
Other authors have indicated that the factors that influence OP therapy adherence include the cost of medications, adverse effects, frequency of dosage, education about the disease, patient follow-up and participation in the treatment decisions2,3. As maintaining treatment adherence is fundamental, extensive follow-up studies report (9,851 postmenopausal women referred to 141 Italian centers for OP management) that, in general, 19.1% of patients discontinued the prescribed medication before attending re-evaluations of bone mass, more than half of them in the first 6 months. The interruption rate was significantly different among treatments. The most frequent reasons for interruption were side effects related to medications, insufficient motivation for treatment and fear of these side effects3. The best medication is ineffective if it is not taken as it should be and the benefits of the treatment are lost if the patient does not take the medication. We currently know that patients with gastrointestinal symptoms have less adherence to treatment and worse quality of life in relation to health than patients without gastrointestinal symptoms4.
OP treatment should be maintained. Non-adherent patients experience more limited decreases in bone resorption levels and worse bone mass results as well5. A recent meta-analysis (which included 236,540 patients) showed that adherence is finally necessary for the maintenance of anti-fracture efficacy with a 46% increase in fracture risk in non-adherent patients6. It has been observed that adhesions below 80% correlate with significant decreases in protection against fractures. Thus, when the adhesion is between 80 and 90%, the risk of fractures increases by 9%, but if it is between 50 and 80%, the risk increases by 18% and up to 21% when the adherence drops. beyond 50%7, according to data from the monitoring of a database of 38,120 women with OP with a mean age of 66 years and a mean follow-up of 1.7 years. This probably has a considerable impact on the quality of life and healthcare costs, since the improvement of compliance in real practice can significantly reduce the risk of OP-related fracture8.
Improvement of adherence as a therapeutic objective in OP
Much scientific evidence indicates that an adequate efficacy of the different treatments against OP has been achieved, improving adherence is one of the basic objectives to improve the long-term expectation of the disease9 and reduce the rate of fractures, a primary objective of any treatment1,2. It has also been shown that better adherence facilitates a better cost-effectiveness balance of OP10 drug treatment at a time in our history when efficiency is increasingly valued, sometimes even more than efficacy itself.
Bisphosphonates (BFs) are drugs of first choice in OP according to multidisciplinary clinical practice guidelines11. Surely, among all of them, alendronate (ALN) as paradigmatic, because it is probably the one with the most clinical research available. However, the frequent gastrointestinal side effects of the group tend to be a reason to abandon treatment in a high percentage of cases12. In fact, prescribers perceive it when they highlight in well-designed surveys a low therapeutic adherence, mainly associated with side effects, polypharmacy and lack of communication between professionals13. In this same study it is pointed out that the restriction of eating and drinking before and after the taking of the drug is the administration instruction more difficult to follow by the patients and stands out as basic to increase the safety of the drug, which may be contradictory. In this order of things, new formulations that improve the digestive tolerance of ALN seem a good contribution to improve the adherence of a first-line drug12.
Improved safety by making alendronate soluble
The basic aim should be to reduce gastrointestinal side effects in the general framework of improving both patient compliance and therapeutic persistence, since most of the treatment discontinuations related to secondary diseases are due to gastrointestinal problems. A microencapsulation of alendronate sodium was initially designed to reduce mucous damage in rats, with polymeric microparticles as a promising way to administer ALN orally12,14. Immediately afterwards this formula was produced as water soluble to facilitate intake even more14-16 and thus reduce the possible impact that a rather large tablet could have on contact with the digestive mucosa. This would eliminate, among other factors, the enormous variability that the disintegration of tablets could have in facilitating their absorption, which had been shown to be of paramount importance in previous studies17. In fact, some ALN tablets only dissolved 80% after 20 minutes, taking up to 30 minutes to dissolve about 88%. In this study, differences in the disintegration and subsequent dissolution of the tablets were found to reduce bioavailability and effectiveness in relation to what was expected by the original drug. In fact, longer or shorter disintegration times may increase the risk of esophagitis due to ALN. The soluble formulation could represent an accessory solution that would improve this aspect15,16.
The first description of an oral drinking solution of ALN is more than 14 years old. Each bottle contained 70 mg of ALN, with citrate as a buffer, with an artificial raspberry flavor, parabens as preservatives and saccharin as a sweetener. With this formulation, more extra water (drinkable ALN was bioequivalent to 70 mg tablets), a 6-month placebo-controlled clinical study was conducted that treated 392 postmenopausal women. Adverse events were generally mild to moderate and did not result in treatment interruption, with most patients considering the taste of the drink that could be acceptable18. Subsequently, different formulas of soluble ALN were developed and tested, all of them bio-equivalents. The results showed that the drinkable ALN was a bioequivalent formulation to the tablets in terms of absorbed ALN (they were within the acceptance limits of between 80 and 125%) and may be advantageous in patients in which the transit or disintegration of the tablets were not adequately attained15.
In a subsequent prospective clinical study, the rhythm of gastric emptying was evaluated with scintigraph study by labeling with 99mTc-DTPA and pH using direct nasogastric tubes, after administering “conventional” ALN tablets and effervescent form with a buffer to improve safety. Neither form affected the esophagus and there were no relevant or statistically significant differences in gastric emptying. The mean pH measured at the time of 50% gastric emptying of the radiolabel was significantly higher in the subjects treated with effervescent formulation compared with those treated with the tablets18. The new ALN form was found to reduce the exposure of the gastric mucosa to a pH level <3, which per se represents a risk factor for irritation of the gastro-esophageal mucosa12,19.
In 2013, a soluble ALN product with 70 mg weekly (called bonasol in Austria, Belgium, Czech Republic, Denmark, Finland, France, Greece, Hungary, Ireland, Italy, the Netherlands) was approved in decentralized countries by decentralized procedure. Norway, Portugal, Romania, Slovak Republic and with other trade names in Sweden, Germany and the United Kingdom, as well as in Spain – soludronate), whose objective is to provide a friendlier way with ALN patients, which will lead to greater compliance and with a cost similar to that of generic ALN tablets 15,20,21.
This new water-soluble form has potential advantages since it avoids the adhesion of the conventional tablet to the gastric mucosa, also overcoming all the motility obstacles (for example, those present in the hernia, the spasms, the position of the patient’s body during the transit) and thus eliminating the variability in the tablet’s disintegration rate with the consecutive irritation by reflux of particles and control of the pH of the gastric fluid20. The bio-equivalence of this drinking solution of ALN 70 mg in 100 ml was compared and confirmed by means of a randomized controlled study against reference tablets in 104 healthy volunteers. The transit time was also compared according to 24 male and female healthy volunteers (average age 52 years) standing or lying prone on the right side during the intake of the product, by means of a video recording of the swallowing with X-rays, to characterize the esophageal passage time of the two ALN formulations. When taken in the standing position (Figure 1A), both formulations had equal mean transit times from mouth to stomach, but the dispersion was significantly less with the liquid form. When taken lying down (Figure 1B), the drinkable ALN had shorter and less variable average transit times compared to conventional tablets. These results show that soluble and drinkable ALN is bioequivalent to the tablets and can be advantageous in patients with delayed transit or in whom the disintegration of the tablets causes some damage20.
Different clinical trials of casuistry collection4,6,9,16 report clinical adherence of 34.5% (with n of 245 patients) (Figure 2A) and up to 60% for the first year of treatment with BFs, specifically with ALN. A prospective follow-up study16 finally showed with 118 patients who took soluble ALN, that none had discontinued the therapy after 3 months from the start of their treatment; after 6 months, 6 patients (5.08%) had discontinued their therapy (p=n.s). After 12 months, the therapy was suspended for 9 subjects (7.63% of the initial number). Therefore, 109 subjects were still receiving therapy (92.37% of the total they started) (p<0.2=n.s) (Figure 2B). Finally, the goal of significant improvement in adherence was achieved.
• ALN is a drug of first choice in the management of osteoporosis11,22.
• A high percentage of patients abandon the treatments in their first year of therapy1-3.
• Most treatment withdrawals are related to gastrointestinal problems and the recommended posology4,13.
• The poor adherence of patients to treatments suggests identifying new alternatives to improve that7-9.
• New formulations of effervescent or soluble ALN have shown better safety indices12,14,15.
• Soluble and drinkable ALN reduces gastrointestinal side effects and is shown as a valid alternative to improve adherence15,20.
• Soluble ALN has been shown to be prospectively effective in increasing adherence at one year, from 34.5% with conventional tablets up to 92.37%16.
Conflict of interests: The authors declare no conflict of interests.
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21. Ficha técnica de Soludronate Semanal 70 mg solución oral. Accesible en: https://cima.aemps.es/cima/dochtml/ ft/73232/FT_73232.html. Último acceso, 21.12.2017.
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