INTRODUCTION
Osteoporosis, a systemic skeletal disease characterized by decreased bone strength and increased risk of fractures, is a growing public health concern, especially in aging populations like that of South Korea.[1-4] The socioeconomic burden of osteoporosis is considerable, with the disease contributing to a significant increase in mortality rates following fractures compared to those observed in the general population.[5,6] This rise in mortality underscores the urgent need for a comprehensive understanding of anti-osteoporotic medication (AOM) patterns.[7,8] Early diagnosis and active treatment strategies are critical, yet the asymptomatic nature of osteoporosis prior to a fracture event often leads to underdiagnosis and undertreatment.[9,10] Addressing this gap necessitates a concerted effort to enhance awareness and intervention strategies.
The introduction of new pharmacotherapies for osteoporosis in recent years has significantly broadened the therapeutic landscape.[11,12] AOMs such as denosumab (DMAB) and romosozumab (ROMO), which provide novel mechanisms of action compared to traditional treatments, represent a significant advancement in the management of osteoporosis.[13-15] However, the rapid evolution of osteoporosis pharmacotherapy introduces complexities in prescription practices and patient adherence, highlighting the need for in-depth research on the actual usage patterns of these newer medications.[16] Understanding how these drugs are integrated into clinical practice is crucial for assessing their real-world effectiveness and identifying potential barriers to optimal treatment outcomes.
The Korea Society of Bone and Mineral Research (KS-BMR) has been instrumental in addressing the challenges of osteoporosis in Korea by publishing comprehensive fact sheets in 2017, 2018, and 2019.[17] These publications, based on data from the Korea National Health and Nutrition Examination Survey (KNHANES) and the National Health Information Database (NHID), provide crucial insights into the epidemiology, treatment, and prescription patterns of osteoporosis and related fractures in the country. Recently, there has been an increased focus on very high-risk populations, prompting an analysis of treatment management rates following fractures with imminent risk of recurrence.[15,18] This nationwide study aims to evaluate the usage trends of AOMs in South Korea from 2002 to 2020, including newer agents such as DMAB and ROMO. It also emphasizes the prescription trends immediately following fractures, providing a comprehensive understanding of how treatment patterns have evolved, both in post-fracture care and overall osteoporosis management. The study hypothesizes that substantial gaps remain in osteoporosis treatment adherence and post-fracture management, despite the availability of advanced therapeutic options. Furthermore, a transition toward injectable medications is projected, indicating changes in clinical practice patterns.
METHODS
1. Study cohort and subjects
This study was a retrospective, nationwide analysis using data from the Korean NHID. The NHID includes health information for over 50 million residents of Korea, covering the entire medically insured population. Individual-level follow-up data spans from 2002 to 2023, with participants undergoing health screenings every two years. Nearly 97% of the Korean population is included, with data provided by medical institutions nationwide. The database contains records of self-reported health behaviors, the International Classification of Diseases, Tenth Revision (ICD-10) diagnostic codes, prescription information, hospital stays, medical interventions, and routine health screening results, including physical measurements and laboratory tests. Death records are also included. The National Health Insurance Service, as the sole insurer, collects and manages this data to facilitate the reimbursement process. Further details on the cohort methodology are provided in previous documentation.[19]
Our study focused on individuals aged 50 and older, with data from 2002 to 2005 subject to limitations in interpretation due to the absence of records for patients covered by the Medical Aid Program during this period. This delineation ensures that analyses and results for the excluded years are presented separately.
2. Definition of osteoporotic fracture
This study expanded the definition of osteoporosis-related fractures beyond the traditional four sites (vertebrae, hip, humerus, and distal radius) to include two additional anatomical locations: ankle and pelvis. Consequently, our analysis encompassed a total of six fracture sites, providing a more comprehensive assessment of osteoporotic fractures. Each fracture code was required to be accompanied by a physician’s claim for site-specific procedure codes. The operational definitions for osteoporotic fractures were established using ICD-10 codes and procedure codes from the NHIS data. The ICD-10 codes for vertebral fractures included S22.0 (fracture of the thoracic spine), S22.1 (multiple fractures of the thoracic spine), S32.0 (fracture of the lumbar spine), M48.4 (fatigue fracture of vertebra), M48.5 (collapsed vertebra, NEC), and M49.5 (collapsed vertebra). Hip fractures were identified by codes S72.0 (fracture of the femur neck) and S72.1 (trochanteric fracture). Humerus fractures were defined by codes S42.2 (fracture of upper end of humerus) and S42.3 (fractured shaft of humerus), while distal radius fractures were identified by S52.5 (fracture of lower end of radius) and S52.6 (fracture of lower end of both ulnar and radius).[17] In addition to these traditional sites, we incorporated ankle fractures, identified by codes S82.3 (fracture of lower end of tibia), S82.5 (fracture of medial malleolus), S82.6 (fracture of lateral malleolus), and S82.8 (fractures of other parts of the lower leg). Pelvic fractures were included using codes S32.1 (fracture of sacrum), S32.2 (fracture of coccyx), S32.3 (fracture of ilium), S32.4 (fracture of acetabulum), S32.5 (fracture of pubis), S32.7 (multiple fractures of lumbar spine and pelvis), and S32.8 (fracture of other and unspecified parts of lumbar spine and pelvis). The overall operational definition was carefully developed through extensive expert discussions and validated in South Korea, demonstrating reasonable accuracy with a receiver operating characteristic analysis showing an area under the curve of 0.706 (95% confidence interval, 0.688-0.724).[20,21]
3. Classifications of AOMs
To accurately assess the prescription patterns of osteoporosis medications in Korea, we utilized data from the NHID spanning from 2002 to 2022. This analysis included several AOMs approved and covered by health insurance for the primary treatment of osteoporosis and related fractures. Specifically, we examined the use of selective estrogen receptor modulators (SERMs) such as raloxifene and bazedoxifene, which were administered daily. For bisphosphonates (BPs), our study included daily doses of risedronate and alendronate, weekly doses of these drugs along with their cholecalciferol-combined formulations, and monthly ibandronate. Intravenous formulations were also analyzed, which comprised three-monthly ibandronate and yearly zoledronic acid injections. We expanded our scope beyond the 2019 fact sheet to include not only commonly prescribed medications but also newly covered treatments.[17] This includes DMAB, an antiresorptive agent administered every six months, which was not previously analyzed.[22,23] Additionally, we incorporated anabolic agents teriparatide (TPTD), given daily or weekly, and ROMO, administered monthly.[24]
4. Statistical analysis
Data are presented as means±standard deviations for continuous variables and as frequencies with percentages for categorical variables. We used descriptive statistics to evaluate the annual prescription trends of AOMs within the first year following a fracture. The distribution of AOM classes prescribed within this timeframe was elucidated by calculating the percentage prescribed for each class: BPs, DMAB, SERMs, TPTD, and ROMO. Time series analysis was applied to assess the trends in the use of AOMs among individuals aged 50 years and over, tracing the prescription volumes over a span from 2002 to 2022. In parallel, the medication possession ratio (MPR) was utilized as an index of medication adherence, presenting the variation in MPR across the study years, differentiated by gender and combined population metrics. The definition of MPR used in this study is consistent with that used in a previous fact sheet publication.[17] Additionally, prescription rates of AOMs post-fracture were examined relative to the initiation period after the fracture event and stratified by the fracture site. This was conducted to observe the patterns in immediate post-fracture medical response.
5. Ethics statement
The institutional review board (IRB) at Korea University Anam Hospital granted approval for this study (IRB no. 2024AN0172). The requirement for informed consent was waived because this study was based on the NHIS database, which was fully anonymized and deidentified for analyses.
RESULTS
1. Trends in medication preferences over 20 years
Figure 1 demonstrates the changing patterns of AOM utilization in Korean adults aged ≥50 from 2002 to 2022. BPs were the mainstay therapy in the early 2000s but declined notably after 2021. Conversely, DMAB surged significantly following its approval as a first-line therapy in 2019. SERMs showed a steady increase over the two decades, maintaining consistent utilization. Anabolic agents, including TPTD and ROMO, are showing a gradual increase in their prescription, with TPTD increasing from 2016 and ROMO from 2020. This trend aligns with data in Table 1, which illustrates a transition in administration routes. Oral medications peaked at 974,545 prescriptions in 2016 before decreasing to 814,956 by 2022. Injectable prescriptions rose steadily from 3,017 in 2002, surpassing oral medications in 2020 with 1,162,779 prescriptions by 2022. This shift was more pronounced in women, whose injectable usage increased from 2,606 in 2002 to 1,099,309 in 2022, compared to a smaller increase in men (1,039-67,459).
Figure 2 highlights the annual change in the mean 1-year MPR for osteoporosis treatments between 2003 and 2021. The MPR, indicative of patient adherence, increased from 35.4% in 2003 to 73.2% by 2021. Women consistently demonstrated higher MPRs than men. Analysis also revealed that individuals in their 60s had the highest average MPR, followed by those in their 70s.
2. Trends in post-fracture osteoporosis medication utilization
Figure 3 shows the annual trend in AOM prescriptions within the first year post-fracture from 2002 to 2021. Prescription rates increased from 31.1% in 2006 to 39.9% in 2021 with data from 2002 to 2005 potentially less reliable due to the exclusion of patients under medical aid. Table 2 reveals notable disparities in treatment initiation rates. Within the first month post-fracture, 25.5% of women initiated treatment compared to 10.9% of men. Within one year post-fracture, treatment initiation rates reached 41.7% in women and 16.2% in men. Prescription rates varied by fracture site, with vertebral fractures having the highest rate (52%), followed by femur (39%) and hip (27%). Humerus (26%), wrist (23%), and ankle (15%) fractures showed considerably lower rates, highlighting gaps in post-fracture management for non-vertebral sites.
Figure 4 illustrates the distribution of AOM prescriptions within the first year post-fracture. BPs remained the most commonly prescribed medication (30.8%), followed by DMAB (3.3%) and SERMs (2.9%). Anabolic agents like TPTD (0.7%) and ROMO (0.1%) were prescribed at markedly lower rates.
DISCUSSION
This comprehensive analysis of AOM usage trends in South Korea from 2002 to 2022 revealed significant shifts in treatment patterns and patient adherence. BPs usage declined after 2021, while the prescription of DMAB had been increased following its approval as a first-line therapy in 2019. SERMs maintained consistent utilization, and anabolic agents such as TPTD and ROMO showed gradual increases in their prescription rates. A notable transition occurred in administration routes, with injectable medications surpassing oral medications in 2020. Over the study period, patient adherence, as measured by the MPR, improved significantly, with women demonstrating better adherence than men. Post-fracture AOM prescription rates increased from 2006 to 2021, with differences observed between genders and fracture sites. Women were more likely to initiate treatment within the first year post-fracture compared to men, while vertebral fractures had the highest treatment initiation rate. In post-fracture AOM prescriptions, anabolic agents were prescribed at the lowest rates, while BPs still remained the most commonly prescribed medication.
Based on these findings, South Korea has seen a significant shift over the past two decades from oral to injectable AOM agents, a trend also observed in Japan, where intravenous and subcutaneous injections have notably increased among osteoporosis patients.[25] The Japanese study highlights a decline in oral prescriptions, emphasizing the superior efficacy of injectables to prevent fractures. Similarly, in South Korea, injectable BPs and DMAB have become increasingly prescribed,[26] largely due to their improved compliance profiles and effectiveness in managing osteoporosis. This shift is further facilitated by the inclusion of DMAB in national insurance coverage, demonstrating the influence of policy on treatment patterns. The preference for injectable form is due to several factors: less frequent dosing, which may enhance patient adherence compared to daily or weekly oral medications,[27] and the growing availability of DMAB, which became more accessible following insurance adjustments.[28] This transition has contributed to improved MPR, suggesting better adherence to prescribed regimens. These findings, consistent with international trends, reflect a broader shift in osteoporosis management towards injectable therapies, driven by advancements in drug development and an increasing focus on patient compliance.
Despite these improvements, this study reveals that significant challenges remain. The treatment rate remains under 50%, highlighting significant under-treatment in osteoporosis management even following fractures. Although this rate is comparatively higher than in many countries, it still points to substantial gaps in care. For example, in the US, treatment rates following hip fractures were as low as 6.87%, with no notable improvements from 2011 to 2018. [29] Similarly, in Belgium, only 6% of patients received osteoporosis treatment within a year post-hip fracture, and in a broader European analysis, only 23.4% of women over 70 initiated treatments after a fragility fracture.[30] In Japan, a mere 25.5% of patients received anti-osteoporotic treatment during their index hospitalization for osteoporotic fractures, with only 21.1% continuing treatment post-discharge.[31] These figures underscore the global challenge of under-treatment, even in advanced healthcare systems.
Recent guidelines highly recommend anabolic agents as first-line therapies for patients at very high risk of fractures, particularly those with recent fractures. These agents have demonstrated superior efficacy in increasing bone mineral density and reducing fracture risk, especially when initiated early in the treatment course.[14,32] However, anabolic agents remain under-prescribed in our study population, with treatment regimens still largely dominated by antiresorptive therapies such as BPs and DMAB. Barriers to the use of anabolic agents, including high costs, limited insurance coverage, and insufficient physician familiarity, may contribute to their underuse. Strategies to expand insurance coverage and enhance clinician education are needed to improve access to these therapies. While injectable treatments such as BPs and DMABs have seen increased adoption in South Korea, the use of anabolic agents continues to lag behind, despite their demonstrated benefits. Strategies to expand insurance coverage and enhance clinician education are needed to improve access to these therapies.[33]
This study has several limitations that should be acknowledged. First, its reliance on an insurance claims database introduces potential biases, including inaccuracies in diagnostic coding and the omission of prescriptions not covered by insurance. It should be noted that the operational definition for osteoporotic fractures was carefully developed and validated to ensure accuracy. While the inclusion of the ICD-10 code M49.5 (Collapsed vertebra in diseases classified elsewhere) might include fractures caused by metastatic tumors, this potential misclassification was minimized through our operational definition. Specifically, the definition required the presence of physician claims for site-specific procedures related to osteoporosis management. Furthermore, a validation study using the same definition reported acceptable performance and suggested that malignancies were present in only a small proportion (8.8%) of incidental vertebral fractures. Nonetheless, this remains a limitation of claims-based research, and future studies incorporating clinical and patient-specific data are needed to provide a more comprehensive evaluation of fracture etiology and outcomes. Regarding pharmacological treatments, the insurance policy in South Korea only recently expanded to include DMAB as a first-line treatment for osteoporosis in 2019, while TPTD and ROMO remain approved exclusively as second-line therapies. Given that this study is based on insurance claims data, the analysis is inherently limited to prescriptions reimbursed under insurance coverage, potentially excluding instances where these newer agents were prescribed off-label or obtained through out-of-pocket payment. Furthermore, data from 2002 to 2005 excluded patients receiving medical aid, potentially underrepresenting certain subsets of the population during that period. Additionally, as this study is based on large-scale administrative data, it is not possible to directly assess the clinical effectiveness of AOMs in terms of patient outcomes such as fracture risk reduction or bone mineral density improvements. Future studies incorporating clinical and patient-specific data are necessary to provide a more comprehensive evaluation of treatment efficacy.
Despite these limitations, the study has notable strengths. The use of a nationwide cohort provides findings that are highly representative of South Korea’s population, ensuring a broad and reliable epidemiological perspective. The expanded fracture site analysis, which includes nontraditional locations such as the ankle and pelvis, offers a more comprehensive assessment of treatment patterns in the aging population. Additionally, incorporating anabolic agents into the analysis reflects the evolving treatment landscape and underscores the increasing use of proactive therapies for patients at very high risk of fractures. The longitudinal examination of treatment trends over 20 years delivers important insights into the long-term shifts in osteoporosis management practices. This study provides a comprehensive nationwide analysis of osteoporosis treatment trends over the past two decades, presenting meaningful data that may contribute to the development of clinical guidelines and healthcare policies. The findings demonstrate progress in treatment strategies while identifying ongoing gaps in post-fracture care. These observations may help guide targeted interventions to improve treatment adherence and accessibility, ultimately supporting better patient outcomes and future public health initiatives.
In conclusion, this 20-year analysis highlights improvements in osteoporosis management in South Korea, including increased use of injectable AOMs. However, prescription rates remain low among post-fracture patients, even within the first year following fractures, revealing substantial gaps in treatment initiation. These findings underscore the need for enhanced clinical strategies and policy interventions to address under-treatment and improve care for individuals with recent fractures.
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