Analysis of utilization of bisphosphonates, strontium ranelate and denosumabe in Serbia, Finland, Norway and Denmark in the period 2013-2016

Analysis of Utilization of Bisphosphonates, Strontium Ranelate and Denosumabe in Serbia, Finland, Norway and Denmark in the Period 2013 – 2016 A Đurđa M. Cvjetković, Sara M. Cvjetković-Nedeljković, Nikola B. Martić, Ana J. Sabo, Zdenko S. Tomić, Boris Ž. Milijašević A Department of Pharmacology, Toxicology and Clinical Pharmacology‚ Faculty of Medicine Novi Sad, University of Novi Sad, Novi Sad, Vojvodina, Serbia


INTRODUCTION
Osteoporosis is the commonest metabolic bone disease. It is believed that almost every second woman and every fi ft h man above 50 years of age will suff er a fracture caused by osteoporosis [1]. All fractures are associated with greater morbidity, whereas hip fractures are associated with greater mortality. Every fi ft h woman above 50 years of age that has suffered hip fracture dies within one year aft er the fracture. Th erefore early detection, prevention, and rational treatment are of great importance not only for an individual but for the entire population -it should be one of the national health priorities at the primary health-care level [2].
According to the defi nition of the Consensus Development Conference from 1993, "osteoporosis is a progressive, systemic, skeletal disease characterized by low bone density and microarchitectural deterioration in the bone that predisposes patients to increased bone fragility and fracture". By the age of 35 or 40 bone density naturally begins to weaken. Th e rate of mineral loss is 0,3-0,5% per year. Besides postmenopausal estrogen defi ciency, major risk factors for osteoporosis include early natural or surgical menopause (before the age of 45), hysterectomy with at least one ovary retained before the age of 45, positive family history for osteoporosis and fractures (especially mother's hip fracture history), white race, gracile body type, long-term immobilization, long-term drug utilization (prednisone or equivalent 5mg/day for at least three months), low calcium and vitamin D intake, sedentary lifestyle, physical inactivity, smoking, alcohol utilization [1][2][3].
Th e most common osteoporotic fractures are those of the distal forearm, spine, and hip. Risk factors for fractures are low bone mineral density (BMD), advanced age, female gender, previous falls, weak muscles, poor balance, conditions and medications aff ecting cognitive function, gait and balance [1,4]. Th e gold standard for diagnosing osteoporosis, fracture risk prediction and for monitoring of treatment response is the evaluation of bone mineral density -BMD that is primarily determined by bone mineral content [1][2][3]5].
Along with nonpharmacological measures, pharmacologic therapy is indicated in patients with a T-score equal to or worse than -2.5, in patients who have had an osteo-porosis-related fracture or in patients with a T-score between −1.0 and −2.5 between −1.0 and −2.5 combined with or high fracture probability. Prior to initiating treatment, patients should be evaluated for secondary causes of osteoporosis [5]. Pharmacological interventions can be classifi ed into antiresorptive agents that prevent bone resorption and anabolic agents that help in the new bone formation. Antiresorptive agents include bisphosphonates, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERM), and denosumab [6]. Anabolic agents include teriparatide, bone growth factors, growth hormone. Th ere are also medications both with the antiresorptive and anabolic mechanism of action (strontium ranelate) [2,7]. Th e most commonly used agents in Europe are bisphosphonates (alendronic, ibandronic, risedronic and zoledronic acid), denosumab, teriparatide, strontium ranelate, raloxifene. Hormone replacement therapy (HRT) is used for both prevention and treatment of postmenopausal osteoporosis. However, it is not the fi rst-choice treatment. Considering the progressive development of pharmacotherapy, new eff ective osteoporosis treatment options are anticipated [8].

AIM
Th e aim of this study was to measure the utilization of drugs aff ecting bone structure and mineralization in Serbia from 2013 to 2016 and to compare with countries with well-developed pharmacotherapeutic practice, such as the Norway, Finland, and Denmark.

METHODS
We conducted a descriptive retrospective pharmacoepidemiological study based on data already placed in the public domain by the regulatory authorities, therefore no Ethical Committee or Agency approval for conducting the study was obligatory.
Drug utilization and price data in the Republic of Serbia in the period 2013 -2016 were collected from the offi cial website of Medicines and Medical Devices Agency of Serbia and offi cial website of National Health Insurance Fund of Serbia [9][10][11][12].
Drug utilization and price data in the Kingdom of Norway in the period 2013 -2016 were collected from the offi cial website of the Norwegian Institute for Public Health [13]. Drug utilization and price data in the Republic of Finland in the period 2013 -2016 were collected from the offi cial website of Finnish Medicines Agency -Fimea [14][15][16][17].
Drug utilization and price data in the Kingdom of Denmark in the period 2013 -2016 were collected from offi cial website of Th e Danish Health Data Authority -Sundhedsdatastyrelsen [18].
Th e utilization of drugs is estimated using the Anatomical Th erapeutic Chemical/ Defi ned Daily Dose (DDD) methodology. Defi ned Daily Dose (DDD) is a statistical measure that represents an assumed average maintenance dose per day for a drug used for its main indication in adults. Th e amount of total drug utilization has been expressed in the number of Defi ned Daily Dose on 1000 inhabitants per day (DDD/1000 inhabitants/day). Th e parameter DDD per 1000 inhabitants per day gives an insight into the number of inhabitants that used a certain drug and were exposed to its effect during one day [19]. Th e results regarding drug utilization in the Republic of Serbia, the Kingdom of Norway, the Republic of Finland and the Kingdom of Denmark are presented in a tabular form.
Th e Anatomical Th erapeutic Chemical (ATC) Classifi cation System is based on a combination of seven alphanumeric characters that represent the International Nonproprietary Name (INN) -an offi cial generic and non-proprietary name given to a pharmaceutical drug or an active ingredient [20].
Th is type of study includes data already placed in the public domain by the regulatory authorities, so no patient consent or agency approval for data protection is needed.
Apart from descriptive statistics, formal statistical analyses were not used. Data are presented in tables.

RESULTS
In Serbia, the utilization of bisphosphonates predominates and their utilization increased from 2.25 DDD/1000 inhabitants/day or 69.23% of the utilization of all drugs aff ecting bone structure and mineralization (M05B) in 2013 to 2.89 DDD/1000 inhabitants/day or 82.57% in 2015 (Table 1) In Norway, during the examined period, the utilization of bisphosphonates was high but with a downward tendency (Table  3 Th e bisphosphonates are the most consumed drugs among all drugs aff ecting bone structure and mineralization in Denmark (Table 4). Th eir utilization in 2013, 2015 and in 2016 it was stable -14.40 DDD/inhabitants/day, with a mild increase in 2014 -14.60 DDD/inhabitants/day. Th e utilization of alendronic acid in the examined period increased, whereas the utilization of ibandronic acid decreased. Th e utilization of other bisphosphonates was on a low level or immeasurable. As for denosumab, there was an increase tendency, starting from 2013 -2.10 DDD/1000 inhabitants/day or 12.5% to 2016 -4.00 DDD/1000 inhabitants/day or 21.62% of the total utilization od the M05B subgroup.
According to data from Medicines and Medical Devices Agency of Serbia, aver-

DISCUSSION
Th e modern approach to the treatment of osteoporosis relies mostly on several groups of medications: bisphosphonates, denosumab, teriparatide, strontium ranelate, and raloxifene. Our analysis has included drugs from the ATC M05 subgroup and those are: bisphosphonates, combination of alendronic acid and cholecalciferol, denosumab and strontium ranelate. Th ey diff er from each other in dosage regimens: bisphosphonates are available in oral formulations, with daily, weekly and monthly dosage schedules and in intravenous formulations administered in three-month intervals, denosumab treatment is given subcutaneously at intervals of six months, whereas strontium ranelate is administered orally every day.
Although expressing the utilization in Defi ned Daily Doses has made major progress towards the evaluation of the medicine utilization, there are some limitations. Th e extent of prescribed or sold drugs does not necessarily correspond to the extent of the drugs actually consumed by the patients.
In Serbia, the utilization of bisphosphonates predominates. In the group of bisphosphonates, the most frequently used drug in Serbia in the beginning of the examined period was alendronic acid and its utilization represented approximately 46.77% of the total utilization of the ATC M05 subgroup. Th e combination of alendronic acid and cholecalciferol ranked second (28.61%), followed by ibandronic acid -with 22.46% of the total utilization of the ATC M05 subgroup. Nevertheless, in 2016, ibandronic acid made more than half (67%) of the total M05 subgroup utilization. In the same year, the combination of alendronic acid and cholecalciferol ranked second (22.68%), whereas the utilization of alendronic acid was on a surprisingly low level, making no more than 7.90% of the total utilization of the drugs aff ecting bone structure and mineralization. Th is shift at the top of the utilization pyramid may be due to price changes of the drugs. Namely, in 2013 the price of DDD of ibandronic acid was higher than the price of alendronic acid's DDD. However, in 2016 it was the opposite. Th e diff erences regarding dosage regimen should also be considered: alendronic acid is administered once a week and ibandronic acid is administered orally once a month. Th is advantage of ibandronic acid has been also confi rmed by Table 6. The average cost per defi ned daily dose (DDD) of most commonly used drugs affecting bone structure and mineralization expressed in euros. and patient's participation in the cost expressed in percentage (%) in the period 2013-2016 in the Republic of Serbia. based on data from the National Health Insurance Fund of Serbia www.hophonline.org BALTO study, according to which signifi cantly more women with postmenopausal osteoporosis preferred once-monthly ibandronate therapy in comparison to once-weekly alendronate therapy, and once-monthly regimen is more convenient. Ease of complying with a treatment regimen for a long time was the most common reason given for the patients' preferences [21]. Th e level of other bisphosphonates' utilization in Serbia, as well as the utilization of strontium ranelate, is constantly low compared to other drugs. Th e same applies to Norway and Denmark as well, with the exception of Finland where except alendronic acid, zolendronic and risedronic acid are also consumed.
Th e combination of alendronic acid and cholecalciferol in Serbia ranked second in the examined period, unlike other three countries, where it was at the bottom. Moreover, in Norway this combination has not been registered at all. However, between 2013 and 2016 its utilization slightly decreased, unlike its price. According to data from National Health Insurance Fund of Serbia, the price of DDD of this combination was 0.21 euros in the year 2013, and in the year 2016 it was 0.27 euros. Th is increase in price was also followed by an increase in patients' share of medication costs from 45% to 55%. Th at could at least partially explain the decrease of the utilization of this combination in Serbia.
Unlike Serbia, in Norway and Denmark the utilization of alendronic acid was constantly high and the highest among all drugs belonging to the ATC M05B subgroup in the examined period. However, there was a slight decrease registered over these four years. On the other hand, the utilization of denosumab increased. Th e same applies for Serbia, where the utilization of denosumab also increased in the examined period although it was signifi cantly lower compared to bisphosphonates and generally on a low level compared to other three countries. Regarding the utilization of denosumab, Finland is the country that certainly stands out, since the utilization of this medication made up 39.84% in 2013 and 58.95% of the total utilization of drugs aff ecting bone structure and mineralization in 2016.
By analyzing the utilization of osteoporosis medications from the fi nancial standpoint, one can conclude that in Serbia, Norway and Denmark the most consumed drugs -bisphosphonates, are at the same time the cheapest ones. It might be the demand that determines the price of drugs. On the other hand, the most consumed drug in Finlanddenosumab is the most expensive one among the analyzed drugs. However, an increase in the utilization of denosumab, as well as relative decrease in the utilization of bisphosphonates was registered in all four countries between 2013 and 2016, even in Serbia, where this medication is not on a list of medicines payable by the National Health Insurance Fund.
Opinions regarding which drug should be used as an initial therapy diff er between experts. Some experts believe that denosumab should not be used as initial therapy for postmenopausal women with osteoporosis at high risk for fracture because of the availability of oral bisphosphonates, for which there are long-term safety and fracture prevention data. In addition, the bisphosphonates are less expensive. However, some other experts disagree and would use denosumab as initial therapy for women at high risk for fracture who have diffi culty with the dosage requirements of oral bisphosphonates or are unwilling to take bisphosphonates. In addition, denosumab may have a role in patients with high risk fracture who are intolerant of or unresponsive to other therapies [22].
According to a 2-year DAPS study, postmenopausal women with osteoporosis were more adherent, compliant, and persistent with subcutaneous denosumab injections every 6 months than with once-weekly alendronate tablets [23]. Because of its every-sixmonths subcutaneous dosage regimen, denosumab is particularly attractive for patients who are intolerant or in whom there is concern about gastrointestinal absorption of oral agents, for elderly patients taking many other medications and for patients known to comply poorly with osteoporosis drugs. Treatment with denosumab is also appropriate in patients whose BMD is still in the osteoporosis range aft er several years of bisphosphonate therapy or who have completed a course of teriparatide therapy [22,24].
Depending on patients' comorbidities and other used medications, oral bisphosphonates may be correlated to low absorption, adverse eff ects on the gastrointestinal tract (upper gastrointestinal mucosal irritation, esophagitis, esophageal ulcer or erosion, rarely esophageal stricture), musculoskeletal pain, infl ammation of the ocular structures and in the long run they can cause jaw osteonecrosis, as well as atypical subtrochanteric fractures of the femur [25][26]. In 2010, Th e U.S. Food and Drug Administration warned about the possible risk of atypical thigh bone (femoral) fracture in patients who take bisphosphonates [27]. On the other hand, adverse eff ects of denosumab include urinary tract infections, upper respiratory tract infection and rarely jaw osteonecrosis [28].
Furthermore, the main diff erence between denosumab and bisphosphonates is that the fi rst one does not accumulate in bones and its eff ects are reversible [29]. Unlike bisphosphonates, the skeletal eff ects of denosumab are quickly and completely reversible and there is no accumulation in bones. Due to that, there is no justifi cation for a temporary interruption of therapy (so-called "drug holiday") with denosumab. If therapy is discontinued, either because of intolerance or the patient has met a treatment goal, it would be very prudent to take pharmacological measures to prevent the rapid bone loss and the return of fracture risk [24,30].
Th ere are some limitations to this study. One of them is the lack of individual patient data like age and link to patient health registers with the outcome of osteoporosis therapy. Another setback is the defi ciency of prescriber's information (primary vs secondary sector).
In the absence of defi nitive data comparing osteoporosis therapies, treatment decisions for patients with osteoporosis should be individualized. Th e individual risk for fracture, presence of comorbidities, and personal preference, are important for weighing the potential benefi ts and risks of osteoporosis therapies [22].

CONCLUSION
Based on the results, the following conclusions can be drawn: -Th e consumption of drugs used for the treatment of bone diseases including drugs used to treat osteoporosis in Serbia in the period 2013-2016 is multiple times lower in comparison to the other three analyzed countries. In Norway and Finland, the consumption of these medicines in the examined period is three to four times, whereas in Denmark even fi ve to six times greater than in Serbia.

Volume 6 • Number 3 • December 2019 • HOPH
-In Serbia, the consumption of bisphosphonates predominates and their share in the total consumption of drugs aff ecting bone structure and mineralization (M05B) represents around 75%. Bisphosphonates make around 40% in Finland and around 80% in Norway and Denmark of the total consumption of the M05 subclass.
-In the group of bisphosphonates the most frequently used drug in Serbia at the beginning of the examined period, was alendronic acid. However, at the end of the examined period the consumption of ibandronic acid takes the lead. In between-country comparisons, the alendronic acid has the highest rate of consumption amongst bisphosphonates.
-Th e consumption of the combination of alendronic acid and cholecalciferol in Serbia ranked second in the examined period, which diff ers from Finland and Denmark, where its consumption is on a low level, whereas in Norway this combination is not even registered.
-In comparison to other countries, the consumption of denosumab in Serbia is multiple times lower, making only 0.8% of the total consumption of the drugs aff ecting bone structure and mineralization. Th is percentage is much higher in other countries: in Norway and Denmark 18%, and in Finland -50%. Th ere is an upward trend of denosumab consumption registered in all four countries in the examined period