Chinese herbal prescriptions for osteoarthritis in Taiwan: analysis of national health insurance dataset

Background Chinese herbal medicine (CHM) has been commonly used for treating osteoarthritis in Asia for centuries. This study aimed to conduct a large-scale pharmaco-epidemiologic study and evaluate the frequency and patterns of CHM used in treating osteoarthritis in Taiwan. Methods A complete database (total 22,520,776 beneficiaries) of traditional Chinese medicine (TCM) outpatient claims offered by the National Health Insurance program in Taiwan for the year 2002 was employed for this research. Patients with osteoarthritis were identified according to the diagnostic code of the International Classification of Disease among claimed visiting files. Corresponding prescription files were analyzed, and an association rule was applied to evaluate the co-prescription of CHM for treating osteoarthritis. Results There were 20,059 subjects who visited TCM clinics for osteoarthritis and received a total of 32,050 CHM prescriptions. Subjects between 40 and 49 years of age comprised the largest number of those treated (19.2%), followed by 50-59 years (18.8%) and 60-69 years group (18.2%). In addition, female subjects used CHMs for osteoarthritis more frequently than male subjects (female: male = 1.89: l). There was an average of 5.2 items prescribed in the form of either an individual Chinese herb or formula in a single CHM prescription for osteoarthritis. Du-zhong (Eucommia bark) was the most commonly prescribed Chinese single herb, while Du-huo-ji-sheng-tang was the most commonly prescribed Chinese herbal formula for osteoarthritis. According to the association rule, the most commonly prescribed formula was Du-huo-ji-sheng-tang plus Shen-tong-zhu-yu-tang, and the most commonly prescribed triple-drug combination was Du-huo-ji-sheng-tang, Gu-sui-pu (Drynaria fortune (Kunze) J. Sm.), and Xu-Duan (Himalaya teasel). Nevertheless, further clinical trials are needed to evaluate the efficacy and safety of these CHMs for treating osteoarthritis. Conclusions This study conducted a large scale pharmaco-epidemiology survey of Chinese herbal medicine use in OA patients by analyzing the NHIRD in Taiwan in year 2002.


Background
Osteoarthritis (OA) is a degenerative joint disease which relates to aging, and affects the joint of hands, hips, knees, spine, and feet [1,2]. OA is the most common form of joint disease in human sparing no race or geographic area [3][4][5]. It affected 33.6% older people in the United States [6], and the cost of artificial knee and hip replacements for severe OA were $42.3 billion in 2009 [7]. Patients with OA suffered from swelling and pain of joints, limitation of joint motion range, limitation in walking and stair climbing, and lower quality of life [8]. The managements for OA includes weight reduction, rehabilitation, and pharmacologic therapies [9]. The most common western medicine used in treating OA is non-steroidal anti-inflammatory drugs, but some people had adverse drug reactions like gastrointestinal ulcer, bleeding and renal insufficiency [10]. OA is one of the most common musculoskeletal diseases in Taiwan. The incidence rate of OA was 37% among people aged over 50 years old in Taiwan [11].
The etiology of OA is still not fully clear, but the age, genetic, biomechanical, inflammatory, and metabolic changes of joints are the main factors [12,13]. And obesity may alter daily biomechanical exposures and make a damage effects on inflammation in OA joints [14]. Several literatures have elucidated that proinflammatory cytokines and anti-inflammatory cytokines like IL-1, IFN-γ, IL-6, IL-7, IL-10 and TNF-α were elevated in the OA joints [15][16][17]. In addition, the osteoporosis is highly associated with the prevalence of OA in menopausal women [18][19][20]. And the subchondral bone loss was a feature of osteoporosis and the early stage of OA [21].
Since there are many adverse side effects of conventional western medication in treating OA [22], more and more OA patients use complementary and alternative medicine (CAM) to improve the symptoms and signs of the disease joints [23]. Chinese herbal medicine [24,25], acupuncture [26], dry cupping [27], herbal patch [28] or other CAM therapies [29] were the common CAM widely accepted by OA patients.
National Health Insurance (NHI) is a universal health insurance program executed since 1995 in Taiwan which covers both western medicine and traditional Chinese Medicine (TCM) [30]. Near 98% of all inhabitants in Taiwan were covered in the NHI program at the end of 2002 [31]. However, there were no nationwide population based surveys of CHM used in treating OA so far.

Methods
In this study, we use the complete NHI database of 2002 which covered the entire population of 22,520,776 beneficiaries in Taiwan to survey the utilization and patterns of CHM for TCM outpatients' clinics.

Data sources
National Health Insurance Research Dataset (NHIRD) is an electronic claim data that contains nationwide medical records of National Health Insurance (NHI) since 1995 in Taiwan. We collected the information including genders, ages, birthdays, dates of encounters, and disease diagnosis of patients from the NHIRD in the year 2002 from outpatient visiting file (CM_CD2002.DAT) and the corresponding prescription files (CM_OO2002.DAT) were also identified. And this study was assessed to the TCM outpatient visits in the NHRID was approved by the Taipei Veterans General Hospital. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) was used to define the study population with the diagnosis of OA (ICD code: 715). Patients and institutional privacies were protected by scrambling cryptogram. Data of Chinese herbal formulae and Chinese single herbs were provided in prescription files, which could reveal the prescription and the utilization patterns.
The details of NHIRD data have been described in previous prescription patterns and the utilization analysis of CHM in different diseases like insomnia [32], constipation [33], chronic hepatitis [34], inflammatory bowel disease [35], liver cancer [36] and allergic rhinitis [37].

Study design
Although "pattern identification as the basis for determining treatment" is the key concept for treating patients in TCM which is different from that of Western medicine doctors, the TCM doctors in Taiwan still have to use ICD-9-CM codes to make a diagnosis for outpatient visits. Since OA has several types, the ICD-9-CM codes 715.0 (Osteoarthrosis, generalized), 715.1 (Osteoarthrosis, localized, primary), 715.2 (Osteoarthrosis, localized, secondary), 715.3 (Osteoarthrosis, localized, not specified whether primary or secondary), 715.9 (Osteoarthrosis, unspecified whether generalized or localized), 716.1 (Traumatic arthropathy) and 716.9 (Arthropathy, unspecified) were all extracted as target study subjects among the outpatients visits in this study.

Data analysis
We used the Structure Query Language (SQL server 2008, Microsoft Corp., Redmond, WA USA) for data linkage analysis and processing. Frequency and patterns of Chinese formulae or Chinese single herbs use were taken into regular statistics by the Statistical Package for Social Science version 19.0 (SPSS Inc., Chicago, IL USA). Association rule was applied when we used International Business Machines DB2 8.1 (IBM, Armonk, NY USA) for co-prescribing prescriptions. As the support factor and confidence factor were the main determining factors, in this study, we set 0.4% as the minimum support factor and 30% as the minimum confidence level.

Results
There were totally 6,221,426 TCM outpatients (27.6%) treated by CHM among the 22,520,776 beneficiaries under the NHI in 2002. Among these TCM outpatients, 37,163 (0.6%) patients were diagnosed with OA. In this study, we extracted 20,059 patients (54.0%) who visited the TCM outpatient clinics with the single diagnosis of OA. There were totally 32,609 CHM prescriptions for these 20,059 patients. Female patients preferred using CHM for OA more than male patients (female: male = 1.89: 1). Patients' age between 40 and 49 years had the highest prevalence rate (19.2%), followed by age 50-59 years (18.2%), 60-69 years (18.2%) and 70-79 years (15.9%). Table 1 demonstrates the age-sex-specific frequency of CHM used in OA patients.

Discussion
This study is the first nationwide population based survey of the CHM use for OA patients in Taiwan. Females used CHM for OA higher than males (1.89:1), and the female aged 50-69 years had the highest prevalence of CHM use for OA. Menopause, higher percentage of obesity and osteoporosis in female may be the factors accounting for this phenomenon [38][39][40].
OA patients were treated with the thought of "pattern identification as the basis for determining treatment" by TCM physicians, and the prescriptions were different among TCM doctors according to their individual personal experience and their knowledge of Traditional Chinese herbs. There were few large-scale pharmaco-epidemiologic surveys of OA patients with CHM use. By analyzing the nationwide TCM outpatient clinic medical record from the NHIRD, we can evaluate the utilization and prescription patterns of CHM in treating OA. The results showed "Du-huo-ji-sheng-tang" was the most common used Chinese herbal formula for OA. Lai et al. [41] conducted a prospective clinical study to observe 68 patients with OA knees who were treated with "Du-huo-ji-sheng-tang" for 4 weeks in 2005. They evaluated the knee condition with the Western Ontario and McMaster Universities Arthritis Index (WOMAC) [42], which is widely used in evaluating knee and hip OA with three dimensions including pain, disability and joint stiffness. They concluded that the WOMAC index scores were decreased after treatment, and the patients' pain and stiffness in knees were released. In addition, their physical function were improved after treatment. Chen et al. [43] used "Du-huo-ji-sheng-tang" , osaminethacine and placebo in an anterior cruciate ligament transection inducing experimental OA rabbits model, and proposed that histological degeneration of cartilarge in "Du-huo-ji-sheng-tang" group was lower than the osaminethacine group and the control group. In this animal model, Du-huo-ji-sheng-tang" could inhibit chondrocytes apoptosis and could also regulate the expression of vascular endothelial growth factor (VEGF) mRNA, hypoxia-inducible factor (HIF) -1α mRNA.
"Xu-duan" was the second most commonly used Chinese single herb for OA. It was shown to increase bone mineral density and also had osteo-protective effect in animal model [49,50]. "Xu-dan" can also improve degeneration of cartilage and bone in the OA mice model [51]. The third common one to treat OA was "Nui-xi". It could improve bone mineral density and relieve the swelling joint in the OA rat model [52].
TCM doctors in Taiwan frequently prescribe a combination of Chinese herbal formulae and Chinese single herb with the concepts of "pattern identification as the basis for determining treatment" and "sovereign, minister, assistant, and courier" [33,35,37]. Mostly, there were six items of CHM in a prescription for OA. Since female OA patients usually combined with menopausal syndrome and osteoporosis, the TCM doctors might combine use these CHM formulae more frequently in order to treat these two diseases.
There were some limitations in this study: (1) The diagnosis of OA among TCM doctors might mix with rheumatoid arthritis and other arthropathy or connective tissue disease, since the joint pain or arthralgia were similar. This might explain that the highest prevalence of OA in our study was 40-49 years, while OA is known to be a degenerative disease which commonly seen in elderly. (2) We only analyzed the utilization of CHM for treating OA, the utilization of acupuncture and Chinese tuina in treating OA were not included. (3) Since the therapeutic effectiveness of TCM for OA is not evaluated in this study, further efficacy studies will be executed in the future.

Conclusions
This pharmaco-epidemiological study showed higher utilization of Chinese herbal medicine use of OA patients in the 40-49 age group and female patients, with Du-zhong (Eucommia bark) and Du-huo-ji-sheng-tang being the most commonly prescribed single herb and herbal formula, respectively.
The most common single herb and Chinese herbal formula are "Du-zhong" and Chinese "Du-huo-ji-sheng-tang." The most common combination of two CHMs and triple CHMs are "Shu-jiang-hou-xie-tang plus Du-huo-ji-shengtang" and "Du-huo-ji-sheng-tang, Gu-sui-pu plus Xuduan." However, the therapeutic effects and safety of these CHM in treating OA still need to elucidate with welldefined randomized, double-blind, placebo-controlled clinical trials for further study. Table 5 The most common prescription patterns for the triple drug combination of Chinese herbs for subjects with osteoarthritis in Taiwan during 2002 (total prescription numbers = 32,050) Chinese herbal formulae or single herbs Support (%)