An analysis of the combination frequencies of constituent medicinal herbs in prescriptions for the treatment of bone and joint disorder in Korean medicine: determination of a group of candidate prescriptions for universal use.

BACKGROUND: This study aimed to select prescriptions (mixtures of medicinal herbs) used in the treatment of bone and joint disorders in Korean medicine, and through the analysis of medicinal herb combination frequencies, select a high-frequency medicinal herb combination group for further experimental and clinical research.
METHODS: We systematically searched for terms related to bone and joint disorder in the "Dongeuibogam (Dong yibaojian)", a seminal Korean medicine book. We reviewed the results of published papers regarding the effects in bone and joint disorders (especially in osteoporosis, osteomalacia, osteopenia, rheumatoid arthritis, and degenerative arthritis).
RESULTS: In total, 34 candidates of a medicinal herb combination for the treatment of bone and joint disorders(CMHCTBJDs) and nine candidates of a medicinal herb for the treatment of bone and joint disorders(CMHTBJDs) were selected.
CONCLUSION: : The candidates of a medicinal herb combination for the treatment of bone and joint disorders (CMHCTBJDs) and candidates of a medicinal herb for the treatment of bone and joint disorders(CMHTBJDs) proposed in this study can be useful material for text mining to develop natural products with the effects in BJDs and also it has the potential to reduce the experimental and developmental time period.

Introduction

Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. Although their application is often viewed with skepticism by the Western medical establishment, they are used in ancient medical traditions such as Ayurveda and traditional Chinese medicine (TCM) which are a rich source of therapeutic leads for the pharmaceutical industry. However, it is very difficult to get a ‘discovery’ from traditional medicine.

This study is a kind of ‘discovery’, namely ‘mining’ from Korean medicine(KM) that is one of traditional medicine.

We aimed to sort candidates of medicinal herb combinations which have a high probability of treatment effect for more than one disorder among high morbidity rate disorders such as osteoporosis, osteomalacia, osteopenia, rheumatoid arthritis, and degenerative arthritis by analyzing constituent herbs from prescriptions (mixtures of medicinal herbs) which are widely used for various kinds of bone and joint disorders (BJD) in KM.

Furthermore, in this study, the frequency of medicinal herb combinations comprising each prescription for the treatment of bone and joint disorder (PTBJD) was analyzed after selecting all of the prescriptions recorded in “Dongeuibogam (Dong yi bao gian)”, a principal piece of Korean medicine literature, for the treatment of BJDs.

Although commonly used prescriptions for specific symptoms are fixed in Western medicine, the prescription could be different for individuals in KM since the prescriptions are customized based on patient’s age, gender, etc. Therefore, many prescriptions exist for specific symptoms in KM, and that is why we combined all individual medicinal herbs from PTBJDs when analyzing the frequency of individual medicinal herbs and combinations of medicinal herbs from PTBJD.

Methods

This methodology assumed that the higher the dose within a PTBJD, the stronger the effect, and that the more frequently used medicinal herbs are in PTBJDs, the more important it is.

In this paper, we found frequency of individual medicinal herbs and combinations of less than seven medicinal herbs from PTBJD in “Dongeuibogam” and made a list of high-ranked combinations.

By assessing the efficacy of the medicinal herbs of the combinations via analysis of previous studies, we would like to suggest preliminary data for experimental and clinical researchers to develop new herbal formulae for osteoporosis, osteomalacia, osteopenia, rheumatoid arthritis, and degenerative arthritis.

Since it is practically hard to develop herbal formulae using more than six medicinal herbs, the number of medicinal herbs is limited from one to six.

This study is comprised of three steps. Each step was performed as described in the following section.

Establishing a list of PTBJDs and constituents of each item in “Dongeuibogam”

According to the medical information website produced by the National Library of Medicine (MedlinePlus; https://www.nlm.nih.gov/medlineplus/), definitions of osteoporosis, osteomalacia, osteopenia, rheumatoid arthritis, and degenerative arthritis are “a condition that affects especially older women and is characterized by decrease in bone mass with decreased density and enlargement of bone spaces producing porosity and brittleness”, “a disease of adults that is characterized by softening of the bones and is analogous to rickets in the young”, “reduction in bone volume to below normal levels especially due to inadequate replacement of bone lost to normal lysis”, “a usually chronic disease that is considered an autoimmune disease and is characterized especially by pain, stiffness, inflammation, swelling, and sometimes destruction of joints”, and “arthritis typically with onset during middle or old age that is characterized by degenerative and sometimes hypertrophic changes in the bone and cartilage of one or more joints and a progressive wearing down of apposing joint surfaces with consequent distortion of joint position and is marked symptomatically especially by pain, swelling, and stiffness” respectively.

However, as there is no correspondent definition in “Dongeuibogam”, we tried to select specific indications which are the most similar to symptoms of Western medicine by analyzing terms describing effects and selected all prescriptions which have one of the specific indications.

To sum up, in the first step, after selecting all of the prescriptions recorded in “Dongeuibogam”, their indications were analyzed and the medicinal herbs constituting each of the PTBJD were selected (Fig. 1). Data of “Dongeuibogam” was obtained from a state-run website, “Korean traditional knowledge portal” (http://www.koreantk.com/ktkp2014/).

Fig. 1

First research step; establishing a list of PTBJDs and constituents of each item in “Dongeuibogam”.

PTBJD, prescription for the treatment of bone and joint disorder.

Selection of medicinal herb combinations from 64 PTBJDs in order of frequency

In the second step, the combinations with the highest repeat frequencies were selected as candidates of a medicinal herb combination for the treatment of bone and joint disorders (CMHCTBJD), and all medicinal herbs which comprise these combinations were selected as candidates of a medicinal herb for the treatment of bone and joint disorders (CMHTBJD). Only the medicinal herbs with doses in the upper 80% cumulative proportion per prescription were included in the CMHCTBJD (Fig. 2). This ensured that only main therapeutic medicinal herbs were selected.

Fig. 2

Second research step; selection of medicinal herb combinations from 64 PTBJDs in the order of frequency.

PTBJD, prescription for the treatment of bone and joint disorder.

Preliminary evaluation of the effects of CMHTBJDs via analysis of previous studies

Selection and analysis of previous studies regarding effects in BJDs

We searched for CMHTBJDs in the previous studies, and identified relevant studies.

Searching the database

In addition to commonly used scientific databases (such as PubMed, Cochrane, and Scopus), Korean databases (Ndsl, Oasis, and Riss) were used since we were searching specifically for studies related to KM. The starting period for these study searches was not defined; however, June 30, 2015, was set as the final time point.

Searching keywords

The final goal of this study was selecting CMHTBJDs which have treatment effects on at least one of BJDs, especially osteoporosis, osteomalacia, osteopenia, rheumatoid arthritis, or degenerative arthritis among various BJDs (Fig. 3). We used the following terms for the searches: “scientific names of CMHTBJD (and names of herbal medicine of CMHTBJD) + osteoporosis, osteomalacia, osteopenia, rheumatoid arthritis, degenerative arthritis”.

Fig. 3

Third research step; preliminary evaluation of the effects of CMHTBJDs via analysis of previous studies.

BJD, bone and joint disorder; CMHTBJD, candidates of a medicinal herb for the treatment of bone and joint disorder.

Results

Sixty-four PTBJDs in “Dongeuibogam”

In total, 64 PTBJDs were selected in “Dongeuibogam” and each PTBJD comprised an average of 7.9 medicinal herbs (Table 1).

Table 1

Sixty-four PTBJDs from “Dongeuibogam”

Name of PTBJDs (No. of constituents)

Baifuzisan (8)/Baihuguizhitang (5)/Baozhentang (20)/Busundangguisan (7)/Butianwan (1)/Cangzhufujiandang (9)/Cangzhugao (2)/Chaijianmeiliansan (4)/Dafangfengtang (13)/Dajupitang (4)/Dancangzhuwan (1)/Dangguigao (18)/Digupisan (9)/Dingtongsan (12)/Dixiansan (5)/Duhuojishengtang (15)/Ermiaocangbaisan (2)/Ermiaosan (2)/Ershenggao (3)/Fuzitang (8)/Guntanwan (4)/Hugusan (12)/Huoxuesan (1)/Jiangusan (2)/Jiaweilonghusan (5)/Jiaweiqianghuotang (9)/Jiegudan (10)/Jiegusan (7)/Jieguzijindan (9)/Liuweidihuangyuan (6)/Lurongsijinwan (9)/Maidousan (6)/Maijiansan (11)/Manjingsan (9)/Meiyaojiangshengdan (9)/Qianghuoxuduantang (15)/Qianghuoyufengtang (27)/Qianjinzhimiwan (4)/Qinggusan (9)/Qingshenganluwan (8)/Qizhixiangfuwan (1)/Quanshenghugusan (7)/Renshenqingjisan (9)/Ruxiangdingtongwan (7)/Ruxiangheihudan (9)/Shengxisan (6)/Shenxianjijidan (22)/Tianmawan (10)/Tietanyuan (5)/Tuanyusan (6)/Weishengtianhuayuan (12)/Wubishanyaoyuan (12)/Wuwutang (3)/Wuzhengtang (9)/Wuzhengwan (7)/Wuzhuwan (5)/Xialingwanshoudan (5)/Xianyiliangtang (8)/Yiziqingjinsan (10)/Yuhangao (4)/Yuzhenwan (4)/Zirantongsan (12)/Ziyindabuwan (13)

PTBJD, prescription for the treatment of bone and joint disorder.

Selection of medicinal herb combinations from 64 PTBJDs by frequency order

The following medicinal herb combinations were selected: 53 combinations of one medicinal herb; 141 combinations of two medicinal herbs; 209 combinations of three medicinal herbs; 246 combinations of four medicinal herbs; 232 combinations of five medicinal herbs; and 169 and combinations of six medicinal herbs. By focusing on the top five of each of these (plus ties) selection of the following occurred: five combinations comprising one medicinal herb, 13 combinations of two medicinal herbs, 10 combinations of three medicinal herbs, five combinations of four medicinal herbs, and one combination of five medicinal herbs. These comprise the CMHCTBJD with a highest probability of efficacy in the treatment of BJD. Also, it is noted that all CMHCTBJDs comprised only nine medicinal herbs (Table 2).

Table 2

Medicinal herb combinations from 64 PTBJDs in the order of frequency (80%)*

No of constituents in each combination; name of constituents (frequency)
1; E(13)/A(6)/D(4)/F(4)/G(4)
2; A, D(4)/A, E(4)/C, D(3)/A, B(3)/A, C(3)/B, C(3)/B, D(3)/E, I (3)/B, E(3)/C, E(3)/E, G(3)/E, H(3)/D, E(3)
3; A, D, E(3)/A, B, C(3)/A, B, D(3)/A, B, E(3)/B, C, D(3)/A, C, D(3)/B, D, E(3)/E, D, C(3)/A, C, E(3)/B, C, E(3)
4; A, B, D, E(3)/A, B, C, D(3)/B, C, D, E(3)/A, C, D, E(3)/A, B, C, E(3)
5; A, B, C, D, E(3)
9 CMHTBJDs: Angelica gigas Nakai., root (A), Atractylodes japonica Koidz. ex Kitam., rhizome (B), Poria cocos (Schw.) Wolf., sclerotium (C), Paeonia lactiflora Pall., root (D), Rehmannia glutinosa (Gaertn.) DC., root (E), Dioscorea polystachya Turcz., rhizome (F), Gypsum(G), Panax ginseng C.A.Mey., root (H), Saposhnikovia divaricata (Turcz.) Schischk., root (I)

*Selecting CMHCTBJDs as the top five on the basis of frequency, only including frequencies >3, and including ties for 5th place.

CMHTBJD, candidates of a medicinal herb for the treatment of bone and joint disorder; PTBJD, prescription for the treatment of bone and joint disorder.

Preliminary evaluation of the effects of nine CMHTBJDs via analysis of previous studies

A total of 496 studies of nine CMHTSs were found; of these, 80 studies were concerned with effects in at least one of osteoporosis, osteomalacia, osteopenia, rheumatoid arthritis, and degenerative arthritis, resulting in an average of 8.9 publications per candidate herb (Fig. 4).

Fig. 4

Number of previous studies on nine CMHTBJDs.

CMHTBJD, candidates of a medicinal herb for the treatment of bone and joint disorder.

Studies were specifically divided into in vitro studies (VT), in vivo studies (VV), clinical studies (C), and reviews (R). A number of previous studies on each medicinal herbs are 13 for Angelica gigas Nakai., root (VT:6, VV:‘4, R:3), five for Atractylodes japonica Koidz. ex Kitam., rhizome (VT:1, VV:3, R:1), two for Poria cocos (Schw.) Wolf., sclerotium (VV:1, R:1), 10 for Paeonia lactiflora Pall., root (VT:3, VV:6, R:1), nine for Rehmannia glutinosa (Gaertn.) DC., root (VT:5, VV:4), 10 for Dioscorea polystachya Turcz., rhizome (VT:4, VV:6), one for Gypsum (VV:1), 28 for Panax ginseng Mey., root (VT:13, VV:13, R:1, C:1), and two for Saposhnikovia divaricata (Turcz.) Schischk., root (VT:2). According to these, nine CMHTBJDs have been subjects of research studies on osteoporosis, osteomalacia, osteopenia, rheumatoid arthritis, and degenerative arthritis (Table 3).

Table 3

Preliminary evaluation of the effects of nine CMHTBJDs in bone and joint disorder via analysis of the previous studies

Name of CMHTBJD/classification of the study (No.)/source database/main outcome
Angelica gigas Nakai., root	VT (6)	(1) P/Prevents cartilage destruction in osteoarthritis & favor cartilage repair4
		(2) P, S/Demonstrates inhibitory effects on RANKL-mediated osteoclast differentiation in bone marrow macrophages in vitro5
		(3) P/Inhibits IL-1β-induced rheumatoid synovial fibroblast proliferation & COX-2, PGE2, & MMPs production6
		(4) P/Stimulates UDP-sugar synthase genes through promoting gene expression of IGF-1 & IGF1R in chondrocytes7
		(5) P/Decreases the hydrogen peroxide-induced IL-1beta, TNF-alpha, MMP-1 & MMP-13 & increases SOX9 gene expression8
		(6) R/Shows inhibitory effect on osteoclast differentiation & function9
	VV (4)	(1) P/Less trabecular bone loss & thick cortical areas were observed10
		(2) P/Prevents the OVX-induced bone loss in rats via estrogen-independent mechanism11
		(3) P/APS-3c can improve the proteoglycans synthesis of chondrocytes in vivo & IL-1 β-stimulated chondrocytes in vitro12
		(4) R, O/Has a suppressing inflammation effect on Freund‘s adjuvant arthritis in rats13
	RW (3)	(1) P, S/Has potent binding affinity with IL6R protein14
		(2) P, S/Has strong antiinflammatory & antiarthritic effects15
		(3) R/Turns out to be the most frequently used herb for the treatment of osteoporosis since 200016
Atractylodes japonica Koidz. ex Kitam., rhizome	VT (1)	(1) N, O, R/Has beneficial effect on osteoporosis by inhibition of osteoclast differentiation & by inhibition of functioning osteoclast17
	VV (3)	(1) S/Increases the growth & differentiation of osteoblastic MC3T3-E1 cells18
		(2) S/Inhibits osteoclast differentiation from its precursors19
		(3) N, R/Decreases the arthritic scores & inhibits pathological changes of knee joint tissues in CIA mice20
	RW (1)	(1) P/Consists one of the most used herbal drugs prescription cluster for osteoporosis treatment21
Poria cocos (Schw.) Wolf., sclerotium	VV (1)	(1) N, R/Inhibits RANKL-induced osteoclast differentiation in bone marrow-derived macrophages22
	RW (1)	(1) P, S, N/Triterpenoids are known to have a pivotal influence on rheumatoid arthritis23
Paeonia lactiflora Pall., root	VT (3)	(1) N, S/Reduces or prevents osteoblast degeneration in osteoporosis24
		(2) S/Contributes to the prevention for osteoporosis25
		(3) R/May be useful as potential sources of therapeutic agents against postmenop- ausal osteoporosis26
	VV (6)	(1) P, N, S/Inhibits RANKL-induced osteoclastogenesis by inhibiting ERK, p38 & NF-κB pathway27
		(2) N/Negatively regulates osteoclast differentiation & formation28
		(3) N, S/Suppresses inflammatory process by reducing the production of prostaglandin E2, leukotriene B4, nitric oxide, reactive oxygen species, proinflammatory cytokines & chemokines29
		(4) N, R/Relieves arthrocele & arthralgia & elevates the contents of L-ENK, beta-END, IL-2 & degrades the contents of SP, IgG, IL-1beta, IL-6 & inhibits abnormal secretion accentuation of synovial cell like fiber30
		(5) S/Inhibits abnormal proliferation of synoviocytes & treats the rheumatoid arthritis31
		(6) S/Total glucosides of paeony treats rheumatoid arthritis32
	RW(1)	(1) P/The beneficial effects of total glucosides of peony in treating rheumatoid arthritis were verified by randomized controlled trials33
Rehmannia glutinosa (Gaertn.) DC., root	VT (5)	(1) N, R, S/Has potential as a therapeutic material to attenuate the inflammatory disease such as rheumatoid arthritis34
		(2) N/Contains active ingredients involved in bone tissue metabolism & may be effective in improving osteoporosis35
		(3) N, S/Improves the osteoporosis resulted from augmentation of osteoblast proliferation36
		(4) R/Shows remarkable inhibitive effect on RANKL-treated osteoclast differentiation without cytotoxicity37
		(5) P, N/Enhances the bone metabolism in osteoporosis38
	VV (4)	(1) N, R/Can be used for prevention & curing the postmenopausal obese39
		(2) N, C, S/Controls rapid reduction of bone turnover in postmenopausal women40
		(3) P, S/Prevention of bone loss41
		(4) N, R/Decreases the serum level of cholesterol & increases the serum level of ALP42
Dioscorea polystachya Turcz., rhizome	VT (4)	(1) P/Inhibits the IL-1β-induced expression of inflammatory mediators43
		(2) P, N, R/Reduces the proliferation of human fibroblast-like synovial cells44
		(3) P/Potents inhibitory activities on bone resorption45
		(4) P/Potents inhibition against bone resorption46
	VV (6)	(1) P/Might prevent bone loss during aging & provide beneficial effects in osteoporosis in elderly people47
		(2) P/Lies in the synchronous inhibitory effects on both the bone formation & the bone resorption48
		(3) N/Counteracts the progression of osteoporosis & augments bone mineral density49
		(4) P/Inhibits bone loss in bone mineral content50
		(5) P/Inhibits the decrease in cancellous bone mineral content, cancellous bone mineral density, & cortical bone mineral content51
		(6) N, O, R/Shows inhibitory effect on bone loss in osteoporetic condition, & reduces the increase of ALP activity & osteocalcin level in serum52
Gypsum	VV (1)	(1) P/Improves amount, density & biomechanical performance of bone trabeculae in osteoporotic vertebra53
Panax ginseng C.A.Mey., root	VT (13)	(1) P/Promotes the differentiation of bone marrow mesenchymal stem cells & mononuclear cells into osteoblasts & osteoclast54
		(2) P, S/Reduces receptor activator of nuclear factor kappa B ligand-induced tartrate-resistant acid phosphatase activity, pit formation (actin rings), & TRAP-positive multinucleated cells development in RAW264.7 cells55
		(3) P/Inhibits osteoclastogenesis by suppressing MAPK in LPS-activated RAW264.7 cells56
		(4) P, S/Plays an important therapeutic role in osteoporosis patients by improving osteogenic differentiation of Bone marrow stromal cells57
		(5) P/Has therapeutic potential for preventing cartilage collagen matrix breakdown in diseased tissues such as those found in patients with arthritic disorders58
		(6) P/Protects the cell against the development of chondrocyte senescence in osteoarthritis59
		(7) P/Exerts a protective effect against the cartilage degradation of osteoarthritis60
		(8) P/Can be a potential alternative to the current antiTNF-alpha therapeutics for rheumatoid arthritis61
		(9) P, S/Reduces cell infiltration & cartilage destruction in the arthritic joint62
		(10) N, R/Has osteogenic & antiosteoclastogenesis properties & regards as potential therapeutic agents for management of osteoporosis63
		(11) N, R/Has beneficial effects against arthritis without any adverse effects64
		(12) S/Inhibits dexamethasone-induced apoptosis through promotion of GPR120 induction in bone marrow-derived mesenchymal stem cells65
		(13) R/Can be applicable for the improvement of arthritic symptoms as a new diet-supplement66
	VV (13)	(1) P/Prevents loss of cell viability caused by Dex-induced apoptosis in MC3T3E1 cells67
		(2) P, S/The serum levels of TNF—a, IL—1β, & IL—6 were increased68
		(3) P/The bone-modulating effects of PNS may be due to the increased bone formation & decreased bone resorption69
		(4) P/Protects against bone loss in rat model by increasing the serum levels of TNF—α, IL—1β, & IL—668
		(5) P/Enhances bone mineral density, bone strength, & prevents the deterioration of trabecular microarchitecture without hyperplastic effect on uterus70
		(6) P, S/Can ameliorate arthritis in mice with CIA by targeting pathogenic Th17 & osteoclast differentiation71
		(7) P/Alleviates autoimmune arthritis by suppressing T cell activation72
		(8) N, R/Alternative medicine for the relief & prevention of rheumatoid arthritis symptoms73
		(9) S/Prevents postmenopausal bone loss by inhibiting osteoclast differentiation, a process controlled by estrogen74
		(10) S/Inhibits osteoclastogenesis by modulating NF-κB & MAPKs pathways75
		(11) S/Inhibits differentiation & maturation of osteoclasts76
		(12) S/Reduces the carrageenan-induced paw edema & suppresses the production of serum IL-677
		(13) P/The expression levels of chondrogenic genes, such as type II collagen & SOX9, were increased in the presence of ginsenoside Rb178
	RW (1)	(1) P, N, R, S/Most important therapeutic agent for the treatment of osteoporosis79
	CS (1)	(1) P/Enhances the therapeutic effect in treating rheumatoid arthritis80
Saposhnikovia divaricata (Turcz.) Schischk., root	VT (2)	(1) P/Reduces the inflammatory responses in the joints of collagen-induced arthritis rats81
		(2) N, R/Reduce osteoblast activity82

CMHTBJD, candidates of a medicinal herb for the treatment of bone and joint disorder; CS, Clinical study; C, Cochrane; N, Ndsl; O, Oasis; P, PubMed(); (), RW, Review; R, Riss; S, Scopus, VT, in vitro study, VV, in vivo study.

Discussion

In this paper, medicinal herbs which have high probability of treatment effect for more than one disorder among five BJDs in KM were selected from “Dongeuibogam” by analyzing frequency and effectiveness. Then, analysis of the previous studies was done.

According to Table 3, an average of 8.9 studies per CMHTS that described their effects in at least one of five BJDs was obtained. We found that more than 10 researches on four items such as Angelica gigas Nakai. (root), Paeonia lactiflora Pall. (root), Dioscorea polystachya Turcz .(rhizome), and Panax ginseng Mey. (root) have already been performed, although one or two studies on two CMHTS including gypsum and Poria cocos (Schw.) Wolf. (sclerotium) were done.

Looking at the possible mechanisms of nine CMHTSs in Table 3 the final results found were: (1) Angelica gigas Nakai, root: Angelica gigas Nakai prevents cartilage destruction and bone loss via inhibitory effect on osteoclast differentiation, also beneficial effect on inflammatory and arthritic diseases; (2) Atractylodes japonica Koidz. ex Kitam., rhizome: Atractylodes japonica Koidz is effective on osteoporosis by inhibiting differentiation and function of osteoclast; (3) Poria cocos (Schw.) Wolf., sclerotiu: Poria cocos (Schw.) Wolf. inhibits osteoclast differentiation, and triterpenoids, which are obtained from Poria cocos, are known to have crucial influence on rheumatoid arthritis; (4) Paeonia lactiflora Pall, root: Paeonia lactiflora Pall regulates osteoclast differentiation and formation, and suppresses inflammatory process, as its effect in curing rheumatoid arthritis is shown in other previous studies; (5) Rehmannia glutinosa (Gaertn.) DC., root: Rehmannia glutinosa (Gaertn.) DC. is capable of moderating inflammatory disease and ameliorating osteoporosis via osteoblast proliferation, as well as preventing obese and bone loss on postmenopausal women; (6) Dioscorea polystachya Turcz., rhizome: Dioscorea polystachya Turcz. inhibits bone resorption and functions as an efficient treatment for osteoporosis; (7) gypsum (VV:1): gypsum improves amount, density, and biomechanical performance of bone trabeculae in osteoporotic vertebra; (8) Panax ginseng Mey., root: Panax ginseng Mey. promotes bone differentiation through improving osteogenic abilities and inhibiting osteoclastic functions, prevents bone loss and enhances bone density and strength, and protects the cell against cartilage degradation, consequently showing potential as highly effective therapeutic agent for osteoarthritis, osteoporosis, and rheumatoid arthritis; and (9) Saposhnikovia divaricata (Turcz.) Schischk., root: Saposhnikovia divaricate (Turcz.) Scischk. reduces inflammatory responses and osteoblast activity.

However, in spite of the explanations so far, there could be a few fundamental questions regarding methodology and results of this study since the research method we used was not general.

First of all, one may wonder if it is possible to match today’s BJDs and BJDs written in the classical literature. Of course, the definition of BJDs in KM and Western medicine is different, nevertheless we tried to select specific indications which are the most similar to symptoms of today’s BJDs by analyzing terms describing effects and selected all prescriptions which have one more of specific indications. As shown above, we tried to select information from classical literature that is the closest to today’s theory but inconsistency of definition still remained. This has inevitable consequences because we select information from the classical literature which has a different theoretical system compared with today’s system. Although carrying out follow up experiments or clinical research, we think we should solve problems that are derived from inconsistency of definition such as “the different terminology between ancient and modern disease” and “inclusion and exclusion criteria”. Therefore, even though inconsistency of definition is existed, it is worthwhile to try to select CMHCTBJDs and CMHTBJDs by matching today’s BJDs and BJDs written in the classical literature.

Second of all, one may wonder why 80% of medicinal herbs in PTBJD are only included in CMHCTBJD in the second step of method. In Korean traditional prescription, a little amount of herbs, such as Zingiber officinale Roscoe so-called “Guide herb (shǐyào)” are added for balance of medicinal herbs or to improve digestive functions. These “Guide herb (shǐyào)” do not have major treatment effects but frequently added in prescriptions; which means just frequently used medicinal herbs in prescriptions does not mean that the herbs are principle ingredients. Therefore, the minor herbs were excluded from CMHCTBJD and only 80% of medicinal herbs in PTBJD were included in CMHCTBJD. The other doubt in the second step of the method is that instead of selecting the most frequently used medicinal herbs in 64 PTBJD as CMHTBJD, why CMHTBJD is selected after sorting CMHCTBJD out. The reason is that prescriptions are not simply a quantitative addition of the individual medicinal herbs, instead they produce a superior efficacy to single medicines.83, 84 Therefore, proposing medicinal herbs of possible combinations instead of single medicines to a clinical researcher could be more useful for follow-up experiments.

Third, since definitions are different as shown above, main clinical signs are different; and therefore you might want to know which steps of which disease among five BJDs medicinal herbs or medicinal herb combinations can be used, and how to distinguish five BJDs from similar other diseases and use medicinal herbs or medicinal herb combinations. Also one might wonder how optimum component ratio of medicinal herbs of the combination can be decided after selecting medicinal herb combinations. As the purpose of this study is a selection of information from classical literature, it seems that these kinds of problems are beyond research range and thus it is hard to answer in this paper. These problems should be solved during follow-up experiments or clinical research.

Fourth, because previous research is not done for all of nine CMHTBJDs and type and result of the previous research is a little different, you may think that there are some different results between ancient and modern literature analysis. But, the reason for doing modern literature analysis in this study is not to compare to ancient literature analysis. Instead it is because proposing candidates of medicinal herb to experimental and clinical researchers by discovering from the classical literature is also the final purpose of this study. By summarizing previous studies for experimental and clinical researchers, it is expected to motivate researchers to conduct follow-up study and help to establish research direction using candidates of medicinal herb selected from this research. Therefore, instead of comparing previous research and ancient literature analysis and discussing the difference, we think that it is a more productive way to refer to previous research and find a direction of follow up study of 34 CMHCTBJDs and nine CMHTBJDs.

The fundamental questions discussed above are not only key points but also characters of this paper. Therefore, if you do not agree with the authors’ answers, you may criticize this paper as the paper lacks methodological structure. The answer regarding the criticism is as below. We have done “text mining and literature review” regarding “cognitive-enhancing herbal formulae” and “medicinal herbs in prescriptions for the treatment of stroke” using similar methodology that this research used.85, 86 Subsequently, we have done experimental research on efficacy of medicinal herbs using the result we gotobtained.87, 88 As a result, although it is hard to conclude since there are only two cases, we provisionally conclude that the methodology (text mining and literature review) is very useful for selection of medicinal herbs which had the specific efficacy we were looking for.

In the present study, we finally selected 34 CMHCTBJDs and 9 CMHTBJDs from “Dongeuibogam” and reviewed the results of previous studies regarding the effects in BJDs (especially in osteoporosis, osteomalacia, osteopenia, rheumatoid arthritis, and degenerative arthritis). In order to develop universally applicable PTBJDs, it will be necessary to conduct longer and more complex experiments and clinical trials. However, the methodology used in this study is regarded as a meaningful challenge to discover “a hidden treasure” for BJDs from classical literature. The result of this study, 34 CMHCTBJDs and 9 CMHTBJDs, will be certainly valuable as fundamental data for experiment and clinical research.

Conflicts of interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.