According to the Law for Health Insurance (State Gazette 25/ March, 2000, last amended State Gazette 113/ July, 2014), the NHIF in RNM is a buyer of health services that include drugs from the list of the Health Insurance Fund. The health insured persons exercise their right to receive drugs from the Fund through the pharmacies, on the basis of a prescription form given by the chosen doctor of medicine, in accordance with the legal provisions and the contractual provisions of the Fund.

The reimbursed drugs in RNM are classified into two main groups: List A – List of medicines for primary health care (pre-hospital care) and List B – medicines for hospital care. The medicines from the List – A are paid by the NHIF in RNM and are prescribed on a prescription form sent for implementation in pharmacies that have a contract with the NHIF of RNM for outpatient care. One patient could receive one prescription per one medicine.

Reimbursable price of the drug is the maximum amount that the Fund provides for a particular drug. The reference price of the medicine is determined according to the lowest defined wholesale price of the medicines, which are put into circulation in the RNM, according to the Law on Medicines and Medical Devices, with comparative analysis of the reference prices of the funds for compulsory health insurance determined by Article 63-c of the Law for Health Insurance (Official Gazette of the R Macedonia 8/ January, 2008). The treatment of osteoporosis in RNM is paid 100% by the Health Insurance Fund.

Table 1 presents the number of prescriptions of antiosteoporotic drugs available in the Macedonian pharmacies and paid by NHIF for the period from 2015 to 2018. In general, the number of prescriptions is increasing from 218 to 256 thousands of Rp per year. The largest number of prescriptions was granted in 2018 for ibandronic acid, followed by cholecalciferol (20.000 IU)/ ml oral drops and the combination alendronate sodium/cholecalciferol. The highest percent of prescriptions belongs also to ibandronic acid tablets 150 mg with a declining tendency of prescribing from 41 to 39% during 2015–2018. The second most often prescribed drug is cholecalciferol oral drops (20.000 IU/ ml) from 21 to 25% of all prescriptions. If we add the prescriptions for the dosage form of 4.000 IU/ml it still is the second one in the list of the most often prescribed. All other medicines fall below 10% of all prescriptions.

The costs of the NHIF for the individual drugs used for the treatment of osteoporosis in R. N. Macedonia by years are presented in Table 2. Total cost is increasing from 1 to 1,2 mln Euro during 2015–2018 year. Ibandronic acid is the costliest accounting for 61% to 56% of the total cost with declining tendency. The cost for fixed dose combination alendronic acid/cholecalciferol is constantly increasing from near 16% to 24% of total cost in 2018 year, followed by alendronic acid monocompound that is declining from near 7% to 4% of the total cost for osteopathic medicines in RNM (Table 2).

The calculated average cost per prescription is almost steady for the period around 4,5 Euro (Table 2).

For the investigated period the NHIF of RNM has paid the largest amount (2 547 725.9 euro) for ibandronic acid tablets (150 mg) (Table 2). From the analysis by years, it is visible that the use of the drug in 2015 and 2016 was lower. 619,725.16 and 618,502.60 euro respectively were reimbursed for it. In 2017 and 2018, the use of this drug increased and the reimbursement value reached 654,466.95 and 654,649.97 euro, respectively (Table 2).

The combination of alendronate sodium/ cholecalciferol tablets (70 mg/ 5.600 IU) is on the second place with a total reimbursement value of 911,561.24 euro. For the cholecalciferol oral drops (20.000 IU/ml) the NHIF reimbursed 258,292.47 euro for the period 2015–2018 (Table 2).

The bisphosphonate alendronic acid (tablets 70 mg) is on the 4^th place with a total reimbursement value of 224,164.85 euro (Table 2). It is noteworthy that the cost of alendronic acid decreased. In 2015, the cost was 68,190.66 euro, and in 2018 this amount decreased to 47,241.56 euro (Table 2), which is a consequence to the reduced use of the drug most likely due to the specific application conditions of alendronic acid and its low oral bioavailability.

Calcium carbonate 1g is prescribed alone or in combination with other drugs, as additional therapy for the prevention and treatment of osteoporosis. For Calcium carbonate 1g 182,293 euros were reimbursed (Table 2). Costs were increased slightly but steadily over the years. In 2015, the reimbursement value was 40,237.15 euro. In the following years there was an increase in the use of the drug and in 2018 the reimbursement value paid by the NHIF increased to 50,326.93 euro (Table 2).

For clodronic acid 400 mg NHIF reimbursed 55,084.912 euros for the period from 2015 to 2018 (Table 2). The use of clodronic acid, as well as alendronic acid, has also decreased over the years. In 2015, NHIF reimbursed an amount of 17,614.16 euro, while in 2018 the reimbursement value decreased almost twice, to 9,971.89 euro.

Calcitriol 0.25 mcg and calcitriol 0.50 mcg were also prescribed for the treatment of osteoporosis and a total of 19,102.76 and 37,558.76 euros respectively were spent for them, for the period 2015–2018 (Table 2). Cholecalciferol drops for oral use (4.000IU / ml) were also classified in the present analysis and prescribed for the treatment of osteoporosis. The total reimbursement value for the period 2015–2018 was 176,570.18 euro (Table 2).

Table 3, presents the reimbursement value paid by the NHIF for all drugs in comparison with the cost for the antiosteoporotic drugs in RNM. It is visible that during the years of the study period, the reimbursement value increased from 1,019,236 euro paid in 2015, to 1,173,469 euro, paid in 2018 but the percent of total cost remains steady around 2,5% out of the total NHIF budget for medicines.

Similar to RNM in RBG the NHIF is a buyer of health services that include medicines from the list of the NCPR (https://portal.ncpr.bg/registers/pages/register/list-medicament.xhtml). The health insured persons receive prescriptions from their family physician for one or 3 months for their ambulatory therapy (National People Assembly. Law for health insurance, State Gazette 70/ 19 June, 1998, last amended State Gazette 54/ 16 June 2020).

The reimbursed medicines in RBG are classified into three main groups: Annex 1 – List of medicines for outpatients paid by the NHIF, Annex 2 medicines for hospital care paid by the hospital budgets or by the NHIF, and Annex 3 – list of medicines for infectious diseases and vaccines covered by the Governmental budget. One patient could receive one prescription per three medicines for the therapy of one ICD code of the disease (Ministry Council, Decree on conditions, rules, and order of regulation and registration of prices of medicinal products. State Gazette 40/30 April 2013; last amended State Gazette 19/ 6 March 2020).

Reimbursable price of the medicines is settled as the lowest price per define daily dose (DDD), out of all trade names and dosage forms belonging to the same INN. The treatment of osteoporosis in Bulgaria is reimbursed 50% by the Health Insurance Fund.

As can be seen in Table 4, the largest number of patients was registered with a diagnosis of M81.0 or “Osteoporosis after menopause”. Their share increased from 76 to 78% of all osteoporotic patients suggesting that the prevailing part of the patients are female (Table 4). The relative share of the peoples with OP with pathological fractures (ICD M80.0) is decreasing as part of all patients from 18% to 16% but the crude number of people and the respective trend is increasing from 2% in 2016 in comparison with 2015 to 8% in 2018 in comparison with 2017 (Table 4).

In 2015, the total number of patients with OP after menopause (ICD M81.0) was 13443 (Table 4) people, for whose treatment the health care fund reimbursed a total amount of 1,363,802 euro, and in 2018 the total number of patients was 18523 with a reimbursement amount paid by the NHIF 2,265,654.30 euro (Table 5). Comparing the number of patients with a complication of pathological fracture and the cost of treatment paid by the NHIF, it was found that the NHIF has paid for medicines 291,149.28 euro in 2015 and reached 501,686.09 euro in 2018 for the diagnosis M80.0 “Osteoporosis with a pathological fracture after menopause” (Table 5). Logically the cost of therapy of ICD M81.0 is the highest one accounting to 76% on average during the observed period. Second costly is the ICD M80.0 OP with pathological fractures accounting for 17% of total cost on average.

The total number of patients with osteoporosis in 2015 was 17691 people and increased to 23621 persons in 2018 (Table 4), for whose treatment the amount of 1,764,327.27 and 2,994,563,26 euro was reimbursed, respectively (Table 5).

The most commonly used medicines in Bulgaria for the treatment of osteoporosis and included in Annex 1 of the Positive Drug List – Medicinal products intended for the treatment of diseases, which are paid for under the Health Insurance Act are presented in Table 6 and Fig. 1. The total amount paid by the NNIF only for drugs in 2015 was 1,559,301,47 euro and reached 2,765,761.31 euro in 2018, which presents an almost 100% increase in the costs (Table 6).

It was found that the highest costs were spent on the monoclonal antibody denosumab, for which NHIF has paid 6,533,689.10 euro over a period of 4 years. The analysis of the value for denosumab for each year separately (Table 6) shows that the dynamics of costs were progressively increasing. From 1,055,097.20 euro in 2015 the costs doubled to 2,291,197.67 euro in 2018. It also increases as the relative share of the total cost paid for osteoporosis from 68 to 83% in 2018. Mostly evident is the increase in sales in 2017 comparing with 2016 when the rise of more than 2000% is pointed out (Table 6).

From the analysis of the drug use for osteoporosis in Bulgaria (Table 6), it was found that strontium ranelate was reimbursed 127,123.61 euro in 2015 and after this period the use of the drug sharply decreased due to side effects. The European Medical Agency (EMA/10206/2014) recommends limiting the use of strontium ranelate in patients with cardiovascular disease (Bolland and Grey 2016). Concerns about cardiac safety have led to a new contraindication to strontium ranelate in patients with uncontrolled hypertension and/or current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease. But this medicine remains a useful therapeutic alternative in patients with severe osteoporosis without cardiovascular contraindications who are unable to take another osteoporosis treatment (Reginster 2014). For the period of 4 years, the total reimbursement amount that the NHIF has paid for this drug was 285,539.16 euro (Fig. 1).

Figure 1. 

Total reimbursement value for antiosteoporotic drugs, granted under the NIHF in the RBG (2015–2018).

For the drug teriparatide, the Bulgarian NHIF reimbursed a total of 238,766.8 euro for the period of 4 years (Fig. 1). The analysis by years shows that the cost paid by the NHIF of the drug increased from 1,935.32 euro in 2015 to 153,385.46 euro in 2017. As relative share this increase is from 0.12% in 2015 to 4,37 in 2016, to 6,51% in 2017 and drop to 4,72% in 2018 year. In 2018 the total amount paid by the NHIF for this drug decreased slightly and reached 130,485.42 euro.

In the Republic of Bulgaria for the treatment of osteoporosis, raloxifene and calcitonin were the least commonly used drugs, for which the NHIF has reimbursed 218.09 and 394.12 euro, respectively. Some restrictions for calcitonin, due to the increased risk of malignancies, are also known. In view of the new safety concerns in relation to the risk of cancer in long-term use and the limited efficacy of calcitonin in the treatment of osteoporosis, EMA is of the opinion that the benefit-risk balance of the intranasal formulations of calcitonin-containing medicinal products is not positive under normal conditions of use. Therefore the Committee recommended the suspension of the Marketing Authorisations for the intranasal formulation of calcitonin. EMA recommends do not use it in osteoporosis (EMA/109665/2013), which affects its consumption in Bulgaria. Since 2016, the sale of calcitonin (salmon synthetic) in RBG has been suspended. EMA therefore considered the benefit-risk balance of injectable calcitonin-containing products for the treatment of Paget’s disease, for the prevention of acute bone loss due to sudden immobilisation such as in patients with recent osteoporotic fractures, and for the treatment of hypercalcaemia of malignancy for the shortest possible time using the minimum effective dose (EMA/109665/2013).

Concerning the use of bisphosphonates in the RBG for the period 2015–2018, it was established that the use of alendronic acid (tablets of 70 mg) throughout the period was very low. During the same period, the use of the other two drugs alendronate sodium/ cholecalciferol tablets (70 mg/ 5.600 IE) and ibandronic acid (tablets 150 mg and solution for injection, 3 mg/ 3 ml) was higher. The use and the reimbursement value of the drug alendronate sodium/ cholecalciferol, increased over the years from 157,050.22 euro in 2015 to 203,729.32 euro in 2018. With ibandronic acid, a different situation was observed. Its use, respectively reimbursement value decreased over the years. In 2015 214,645.75 euros were reimbursed and by 2018 the value was decreased to 131,229.99 euro (Table 6).

Comparative analysis of the reimbursement policy and financing the anti-osteoporotic medicines between RBG and RNM revealed some similarities as well as differences.

On the first place in both countries the access to anti-osteoporotic medicines is granted via the reimbursement system although the level of reimbursement is higher in RNM (100%) and lower in RBG (50%).

It was found that in Bulgaria, as well as in Macedonia, the number of people suffering from osteoporosis is progressively increasing during the years of the study period, which leads to an increase in the cost of treatment of this disease, paid by the health insurance fund.

Comparing to RBG, the NHIF of RNM has reimbursed a higher value for bisphosphonates for the period 2015–2018 (Fig. 2). Probably this difference is due to the higher reimbursement rate for osteoporosis drugs in Macedonia – 100%.

Figure 2. 

The total reimbursement amount for the three bisphosphonates paid by the NHIF in the RBG and RNM (2015–2018).

Bisphosphonates alendronic acid, alendronate sodium/ cholecalciferol and ibandronic acid tablets of 150 mg were dispensed under the NHIF in both countries. In Bulgaria, the NHIF provides also ibandronic acid solution for injection, 3 mg/ 3 ml.

The NHIF of RBG reimbursed a total of EUR 1,401,646.71 for that three BP for the period 2015–2018. During the same period, the NHIF of RNM reimbursed a total of EUR 3,682,575.11 for these medicines. We might suppose that the prices of medicines are also higher but this needs further evaluation. The use of bisphosphonates in the RNM has been constantly increasing over the years, while in Bulgaria the use of bisphosphonates has slightly decreased or remained relatively constant for the last two years of the analysis.

The lower costs of the NHIF in Bulgaria for bisphosphonates, compared to RNM, are most likely due to the huge costs for denosumab, as well as due to the lower rate of reimbursement by the NHIF for ICD-osteoporosis – 50% compared to 100% in Macedonia.

Denosumab has not been registered in Macedonia, but it was approved for placing on the market in certain cases аccording to article 31 (Chapter III.I Marketing authorization) of the Law on Medicines and Medical Devices (Official Gazette of RM 106/ September 2007), in exceptional cases and justified reasons related to the health of patients (rare diseases, ethical aspects, vital hazardous diseases), if appropriate medication is not available, it may issue a conditional marketing authorization containing obligations for the holder of the approval, and for the longest period of one year.

Unlike Macedonia, vitamin D derivatives and calcium products, widely used in our western neighboring country, are not reimbursed in Bulgaria for the treatment of osteoporosis whereas strontium ranelate, teriparatide and raloxifene are not reimbursed in RNM.