Introduction

Osteoporosis is a serious public health problem, particularly in postmenopausal women. In Korea, the prevalence of osteoporosis has been reported to be 33.3% among females aged over 50 years in the national health insurance claims data for 2005 and 2008 [1], and 35.5% in the data for 2008 and 2009, as obtained from the Korean National Health and Nutrition Examination Survey (KNHANES) [2]. Thus, one in three women in Korea is likely to have weakened bones with an increased risk of fractures. According to the Statistics Korea, a government organization for statistics, the number of individuals older than 65 years of age is predicted to reach 14.3% by 2018, which is the rapidest aging of any national population in the world. Therefore, the prevalence of osteoporosis in elderly women in Korea is expected to rise, while currently, Korea is categorized as a country with a medium risk of hip fracture as compared to 62 other countries [3].

Bisphosphonate and raloxifene are the osteoporosis medications most commonly prescribed by clinicians. While bisphosphonate is in the lead in its use, its long-term risks such as atypical fracture or osteonecrosis of the jaw are a concern [4]. The fracture risks, with respect to the bone turnover markers or bone mineral density (BMD), of these two drugs have been compared in several clinical trials [5–7] and observational studies using claims databases [8–10]. However, while bisphosphonate decreased the fracture incidence more in most of the studies, raloxifene had beneficial effects on lipid metabolism and breast cancer [5,11]. While bisphosphonates and raloxifene share a common mechanism of antiresorptive therapy, bisphosphonates suppress the osteoclast metabolism and raloxifene decreases bone degradation, resulting in the development of a combination of the two [12]. The most appropriate selection of osteoporosis treatment for individual patients remains controversial; therefore, the different efficacy and safety features of the two medications should be considered to optimize the treatment of osteoporosis patients.

Previous drug utilization studies have shown that raloxifene users are younger and in a better overall health condition than bisphosphonate users [13,14]. However, these studies were conducted by only one research group by using the United States claims database, and there is a lack of published data, focusing on the Asian population, on the prescription pattern of the two drugs. Therefore, this study aims to describe the prescription pattern of bisphosphonates and raloxifene in Korean women with osteoporosis in order to identify the demographic and clinical characteristics of the two drug users in actual clinical practice.

Materials and Methods

Results

Of the 51,671 patients with 320,075 prescriptions who had been diagnosed with osteoporosis by clinicians at least once, 26,881 (52.0%) patients with 108,406 prescriptions (33.9%) had been prescribed with bisphosphonate or raloxifene. Among the 26,881 final study subjects, 26,032 (96.8%) and 849 (3.2%) received bisphosphonate and raloxifene, respectively (Fig 1). The raloxifene users were younger than the bisphosphonate users, and this trend was statistically significant (mean age = 69.3 years vs. 67.6 years, p < 0.0001). The proportion of patients who received bisphosphonate was higher in all three prevalent comorbid conditions; chronic gastritis/GERD (47.3% vs. 42.9%, p = 0.0112), chronic low back pain (39.9% vs. 31.7%, p < 0.0001), and osteoarthritis (29.0% vs. 25.0%, p = 0.0106). However, patients with rheumatic and autoimmune diseases (4.0% vs. 6.1%, p = 0.0024), hot flash (1.8% vs. 6.1%, p <0.0001), coronary artery disease (1.2% vs. 2.8%, p< 0.0001), and lipid metabolism disorders (16.0% vs. 22.1%, p< 0.0001) formed a relatively higher proportion of raloxifene users (Table 1).

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Fig 1. Flowchart of study subject selection.

In the 3% sample data of national health insurance claims database, 51,671 were diagnosed with osteoporosis and 26,881 were prescribed with bisphosphonate or raloxifene among them.

https://doi.org/10.1371/journal.pone.0127970.g001

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Table 1. The frequency and proportion of osteoporosis patients by age, comorbidities, fracture by site, concurrent medication, and medical insurance type in Korea in 2010.

https://doi.org/10.1371/journal.pone.0127970.t001

Primary care clinics were most frequent in the bisphosphonate group (59.2% vs. 36.7%, p < 0.0001), while tertiary care institutions were most frequent in the raloxifene group (21.6% vs. 44.7%, p < 0.0001). Clinicians in the orthopedics department most frequently prescribed both drugs; however, internal medicine and gynecology specialists prescribed raloxifene more frequently than bisphosphonates for osteoporosis (Table 2).

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Table 2. The frequency distribution of bisphosphonate and raloxifene prescriptions by health care institution type and specialty in Korea in 2010.

https://doi.org/10.1371/journal.pone.0127970.t002

Among bisphosphonates, alendronate was the most frequently prescribed in terms of the number of prescriptions, followed by risedronate, ibandronate, pamidronate, and zoledronate. Nevertheless, the DDDs/1,000 patients/day values revealed that 12.4% of the osteoporosis patients had risedronate daily, 11.6% ibandronate, 11.3% alendronate, 1.6% pamidronate, and 0.4% zoledronate. However, DDDs/1,000 patients/day was the highest for raloxifene, and 15.8% of the osteoporosis patients were prescribed raloxifene daily. Moreover, once a week (79.8%) was the most preferred interval among bisphosphonates (Table 3). Among 26,032 bisphosphonate users, 13,833(53.1%) were prescribed with the drug within 45 days of previous prescription, which was the average day of duration between each prescriptions per patient, and for raloxifene, 447(52.7%) were prescribed within 52days. Among these regular receivers, 94(0.7%) of bisphosphonate users changed to raloxifene and 75(16.8%) vice versa.

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Table 3. The defined daily dose per 1,000 patients per day (DDDs/1,000 patients/day) of study drugs in Korea in 2010.

https://doi.org/10.1371/journal.pone.0127970.t003

However, DDDs/1,000 patients/day examined by different intervals of bisphosphonate was the highest in once a day (17.8%), followed by once a month (17.0%) and once a week (11.6%). The capital area, that is, the Seoul metropolitan area, had the highest DDDs/1,000 patients/day of osteoporosis medication and the highest proportion of raloxifene as compared to the other regions (DDDs/1,000 patients/day = 10.2 in Seoul and 3.5 on average nationwide). Also, metropolitan cities including Busan and Daegu had higher raloxifene prescription than the provinces nearby (Fig 2).

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Fig 2. Regional distribution of proportion of raloxifene prescription standardized in DDDs/1,000 patients/day.

The Seoul metropolitan area had higher proportion of raloxifene prescriptions among Korean osteoporosis female patients. (The map came from the official site of Statistics Korea, https://sgis.kostat.go.kr/statbd/statbd_03.vw)

https://doi.org/10.1371/journal.pone.0127970.g002

Discussion

Using a national claims database, we found that 52% of patients diagnosed as osteoporosis were being prescribed with bisphosphonate or raloxifene, two main treatment of osteoporosis prescribed by clinicians. This is similar to 39% taking anti-osteoporosis medication among high risk women from an international cohort, since the risk in this study is from the Fracture Risk Assessment Tool (FRAX) and the diagnosis was made by BMD in the present study [21]. Moreover, bisphosphonate was far more prescribed than raloxifene in Korea, as compared to the relative proportions of the two drugs prescribed in the US. Raloxifene was prescribed less frequently in chronic diseases such as chronic gastritis/GERD, and osteoarthritis, while it was prescribed more frequently in lipid metabolism disorders, hot flash and coronary artery disorders than bisphosphonate. In addition, we observed that raloxifene use was more prevalent in tertiary care institutions and the Seoul metropolitan area.

In this study, 3.2% of osteoporosis patients were prescribed with raloxifene as compared to bisphosphonates. However, raloxifene use was more than six times higher (18.4%) than bisphosphonate use in the US claims data [13]. In a report from Taiwan, which compared alendronate, a type of bisphosphonate, and raloxifene, it was, in fact, ten times higher (32.5%) than our result [9]. The fact that raloxifene is approved for breast cancer risk reduction by the US Food and Drug Administration and not in Korea indicates that bisphosphonate is highly preferred by Korean clinicians for osteoporosis management. Raloxifene users were younger and less frequent in cases of prevalent chronic diseases such as chronic gastritis/GERD, and osteoarthritis, which is in line with the results of a previous study where raloxifene users were younger and had a better overall health status [13]. However, patients with lipid metabolism disorders had higher proportions of raloxifene prescriptions, since they are expected to benefit from raloxifene in their comorbid conditions. Although raloxifene is known to be weaker in decreasing bone turnover markers or fractures, it has been found to be better in improving the lipid profile [5,10,22]. Nevertheless, the proportion of hot flash and coronary artery disease which are well-known adverse drug events of raloxifene were higher among raloxifene users, and this draws an alert for clinicians.

The higher proportion of osteoarthritis in the bisphosphonate group correlated well with the higher proportion of bisphosphonate from orthopedics clinicians in primary care institutions who also frequently treat osteoporosis and are more familiar with bisphosphonates than raloxifene. Likewise, gynecologists who are more aware of hormone replacement therapies and female organ specific cancers were more likely to prescribe raloxifene than bisphosphonates, as in Foster’s research [14]. However, the raloxifene group had a higher prevalence of rheumatologic and autoimmune diseases including rheumatoid arthritis, ankylosing spondylitis, and lupus, which is in contrast to the findings of a previous study [13]. This can be explained by the higher proportion of tertiary health care institutions (57.8%, not presented in the table) among these patients because raloxifene was more commonly prescribed by clinicians in the tertiary referral hospitals. The interest in trying and accepting a relatively new and challenging drug might be higher in doctors of tertiary health care institutions than those at primary clinics. Even though previous studies do not show the difference according to the level of health institutions, our study showed these patterns comprehensively.

Bisphosphonate, but not raloxifene, is recommended for prevention of corticosteroid-induced osteoporosis, a condition taken into account when corticosteroids are prescribed for more than three months. However, the use of corticosteroid did not differ between the two groups in this study. Among the corticosteroid prescribers, patients with diagnosis of secondary osteoporosis (ICD-10 code: M82) were nine and among them only one patient was prescribed with raloxifene who also had gastritis. All of the corticosteroid users were prescribed within less than 50 days and 72.5% were prescribed less than 3 times. Thus, even though corticosteroid is a well-known risk for osteoporosis, majority of them were not recognized as corticosteroid-induced osteoporosis but primary osteoporosis. However, among patients who had osteoporotic fracture during 2010, there was no one who had been prescribed with bisphosphonate or raloxifene before their fracture occurred. Among 2,550 fracture events, 2,496 patients had at least one fracture and 2,000 (81.0%) started to receive either bisphosphonate or raloxifene at the same time with osteoporotic fracture incidence. It is reported from a national survey that among Korean osteoporosis patients over 50 years old, 23.5% receive pharmacological treatment [23]. Low treatment rate thus explains the lack of patients who were receiving bisphosphonate or raloxifene before fracture actually happened. This raises an attention in the low treatment rate of osteoporosis and its negative consequences once again.

In terms of DDDs/1,000 patients/day, raloxifene was the highest in total, and risedronate was the highest among bisphosphonates. Surprisingly, although only 3% of the patients were prescribed raloxifene, it had the highest DDDs/1,000 patients/day among the study drugs. This implies a good adherence to raloxifene, same as in a previous study which reported that raloxifene had better adherence and more patient satisfaction than bisphosphonate [24]. In number of prescriptions, alendronate and once-a-week basis were the most preferred treatment. However, in terms of DDDs/1,000 patients/day, risedronate and once-a-day basis had the highest ranking. This must have resulted from the dominantly high number of recipients in alendronate or once-a-week basis because DDDs/1,000 patients/day is calculated by dividing the patient number of each drug. To sum up, even though alendronate was the most favored prescription, risedronate was the most adherent one, and while once-a-week basis was more commonly prescribed, once-a-day basis was more compliant. Furthermore, alendronate and risedronate are known to have similar absolute fracture rates [25]. Among regular receivers of bisphosphonate or raloxifene, while less than 1% of bisphosphonate users were switched to raloxifene, 17% changed from raloxifene to bisphosphonate. Among these switchers of raloxifene, 33 patients were due to visiting another specialty for arthritis or intervertebral disc disorders which were mainly orthopedics. Also, nine patients changed to bisphosphonate due to osteoporotic fracture, and two patients due to diabetes which is a risk factor for stroke. Therefore, switching from raloxifene to bisphosphonate seemed to take place mainly owing to clinicians’ preference determined by their specialties. This could be a problem in the consistency of treatment since patients tend to change their hospitals often without a family doctor system in Korea.

While there was a large regional variation, DDDs/1,000 patients/day was higher near the capital area. In Korea, the Seoul metropolitan area including Seoul and Gyeonggi is considered to have the highest level of economic status in the country. The management of osteoporosis by clinicians must have been more active by clinicians in the capital area, suggesting more attention in the rural area, where the prevalence of osteoporosis is known to be higher [23]. It is said that a physician-specific tendency was the strongest determinant in osteoporosis patient care variation [26]. Furthermore, the physician factor is known to be affected by academic activities conducted by pharmaceutical companies or the physician’s number of years of practice [27]. However, in this database, 42.3% of the health care institutions were tertiary referral hospitals in the Seoul metropolitan area, which tend to exist in economically developed regions. This has resulted in a high proportion of raloxifene prescriptions in these regions, implying that patient care can be somewhat different among regions due to the different distribution of health care institutions nationwide.

The strength of this study comes from the nationally representative database. HIRA-NPS is sampled from the nationwide health insurance claims database, which consists of 97% of the whole 50 million Korean population [28]. The representativeness and the effectiveness of the healthcare utilization database in studying the real world are well known [29], and the validity and the generalizability of the HIRA-NPS database have been assessed in advance [17]. Therefore, this result can be generalizable to the entire population. Second, since this database is formed in the process of reimbursement, a misclassification of the prescribed drugs is less likely to happen, reflecting the actual clinical practice taking place in the clinics [29]. However, this study has some limitations. First, it lacks laboratory examination data such as BMD, bone turnover markers, or body mass index, and a consideration of lifestyle factors such as smoking, alcohol consumption, or diet. However, even though BMD is used in the diagnosis of osteoporosis, it alone is considered imperfect for predicting fracture vulnerability [30]. Moreover, in the case of vertebral fractures, factors associated with behavioral patterns such as obesity, alcohol intake, or smoking have been found to have little or no effect among Koreans [31].

In conclusion, with a high preference for bisphosphonate in osteoporosis management in Korea, bisphosphonate and raloxifene users among Korean women had different patterns of prescription in different comorbid conditions, concurrent medications, health care institution types, clinicians’ specialties, and regions. The potential adverse drug events of bisphosphonate and raloxifene such as gastrointestinal disorders, coronary artery disease, or hot flash should be examined prior to giving prescriptions. However, we cannot draw a conclusion on the appropriateness of this clinical practice since the current guidelines suggest these two medications not strictly for specific situations but as generic medications for osteoporosis. Thus, it is required to conduct a long- term comparative effectiveness study in order to provide a detailed guide for the appropriate management of osteoporosis.