Efficacy of combination therapy with unkeito and boiogito for menopausal arthralgia: A retrospective observational study

ABSTRACT

Context:

Arthralgia affects menopausal patients.

Aim:

Here, we report a retrospective observational study evaluating the therapeutic efficacy of a combination of unkeito and boiogito for menopausal arthralgia.

Settings and Design:

Patients treated with a combination of unkeito and boiogito for menopausal arthralgia between April 2020 and October 2022 at three Japanese Kampo outpatient clinics were retrospectively examined. Treatment effectiveness was determined based on the patient’s description of pain. Adverse events associated with this treatment regimen were also recorded. The study design was approved by the Tokai University Ethics Committee (Approval number: 22R196).

Methods and Material:

This study was conducted by retrospectively analysing the medical records of patients who attended the three medical facilities. All patients received Kampo medicines based on traditional medical diagnoses. Outpatients with a diagnosis of menopausal arthralgia were selected, and information on those who were treated with a combination of unkeito and boiogito was collected.

Statistical Analysis:

The age, height, and weight of all patients are represented as the mean ± standard deviation. Statistical analyses were not performed in this study as there was no comparison group.

Results:

During the study period, nine patients with menopausal arthralgia received the unkeito and boiogito combination. Four patients showed a “significant” response to the combination treatment, four showed an “effective” response, and one patient showed an “ineffective” response. One patient reported headache as an adverse event.

Conclusion:

The combination of unkeito and boiogito may be effective in the treatment of menopausal arthralgia.

Introduction

Traditional Japanese medicines, known as Kampo medicines, have been used in Japan to manage menopausal symptoms.[1,2] Among them, unkeito (Wen Jing Tang in Chinese) is a commonly used Kampo formula for menopausal disorders, and boiogito (Fang Ji Huang Qi Tang in Chinese) is a typical Kampo formula used to treat arthralgia. In this study, we investigated the potential benefits of co-administering these two formulae to better ameliorate menopausal arthralgia. This is because we have recently experienced three cases of menopausal arthralgia that improved with the combination of these two formulae.[3] Detailed information on these Kampo formulae is available on STORK (http://mpdb.nibiohn.go.jp/stork/), and information on the production and quality control of Kampo products is available on the Tsumura website (https://www.tsumura.co.jp/english/kampo/07.html).

Subjects and Methods

We conducted a retrospective analysis of the medical records of female patients aged 40–60 years who visited outpatient clinics at Tokai University Hospital, Tomai Atsugi Clinic, and Joetsu General Hospital, and requested treatment with Kampo medicine for menopausal arthralgia, from April 2020 to October 2022. We selected patients who were treated with a combination of unkeito (Tsumura unkeito Extract Granules for Ethical Use, TJ-106, Tsumura and Co. [Tokyo, Japan]) and boiogito (Tsumura boiogito Extract Granules for Ethical Use, TJ-20, Tsumura and Co. [Tokyo, Japan]). We collected the following patient information: age, duration from disease onset to treatment initiation, height, weight, body mass index, treatment effects, continuation of medication after 6 months, adverse events, and changes in prescription. This study was registered as UMIN000051156 in the UMIN Clinical Trials Registry (https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000058344). Menopausal arthralgia does not have diagnostic criteria; therefore, we performed an exclusion diagnosis for each case. Patients were not considered to have menopausal arthralgia if they were diagnosed as having rheumatoid arthritis, another collagen diseases, or osteoarthritis on x-ray. The effects of the treatment against arthralgia were investigated based on the patient’s description of pain, and treatment efficacy was evaluated 2 months after treatment initiation. The absence of pain was designated as a “significant” response. A reduction in pain was deemed “effective,” no change in pain was deemed “ineffective,” and an increase in pain was deemed “worsening.” We recorded the adverse events associated with the administration of unkeito and boiogito. Over the course of the study, nine patients with menopausal arthralgia received a combination of unkeito and boiogito extracts. All patients received unkeito (7.5 g) and boiogito (7.5 g) three times a day before each meal. The study design was approved by the appropriate ethics review board (Tokai University Ethics Committee; approval number 22R196) and conformed to the Code of Ethics of the Declaration of Helsinki and its later amendments. No patient identifiers were used, and all data were anonymised. As the study involved patients who had been seen in the past, it was difficult to obtain consent from individual research subjects. Therefore, information on “the fact that the research was being conducted, its contents, methods, the opportunity to refuse participation in the research, and contact details” was publicised at the three medical institutions through the publication of an information disclosure document.

Results

Table 1 presents the data collected during the study. The mean age (± standard deviation) of the patients was 48 ± 6.78 years, and the mean duration from disease onset to treatment initiation was 7.33 ± 6.46 months. The mean height, weight, and body mass index of the nine patients were 163.11 ± 5.78 cm, 54.78 ± 7.26 kg, and 22.0 ± 3.41 kg/m², respectively. No cases had received hormone replacement therapy in the past. Out of the nine patients, four showed a “significant” response. Treatment was “effective” in four patients and “ineffective” in one patient. One patient reported headache as an adverse event, which persisted even after treatment discontinuation, but improved after the administration of tokishakuyakusan (7.5 g/day, Tsumura and Co., Tokyo, Japan). After 6 months, four patients continued to take unkeito and boiogito, one patient continued taking unkeito only, one patient continued taking boiogito only, and three patients stopped taking both formulae. Notably, no patient presented with pseudoaldosteronism after 6 months of treatment.

Table 1.

Data of menopausal arthralgia cases receiving a combination of unkeito and boiogito

Case	Age (years)	Height (cm)/Weight (kg)/Body mass index (kg/m2)	Duration from disease onset to Kampo treatment initiation (months)	Effects of treatment	Patients continuing/stopped medication after six months	Any adverse events	Prescription changes
1	54	158/42/16.82	3	Effective	Continuing unkeito only	None
2	47	162/50/19.05	5	Ineffective	Stopped	Headache	Tokishakuyakusan
3	50	164/52/19.33	4	Significant response	Continuing unkeito and boiogito	None
4	46	168/52/18.21	6	Effective	Stopped	None
5	40	168/64/22.68	12	Significant response	Continuing boiogito only	None
6	60	162/55/20.95	24	Significant response	Continuing unkeito and boiogito	None
7	38	169/60/21.01	3	Significant response	Continuing unkeito and boiogito	None
8	51	166/53/19.23	6	Effective	Continuing unkeito and boiogito	None
9	46	151/65/28.51	3	Effective	Stopped	None

Discussion

Menopause is a major health problem in women.[4,5] Vasomotor symptoms, such as hot flashes, anxiety, and irritability, are typically observed in menopause and treated with hormone replacement therapy (HRT) and complementary and alternative medicines.[6] Despite menopausal arthralgia being another frequent symptom,[7,8] it is relatively less recognised compared to hot flashes and psychiatric symptoms in Japan. Because the onset of menopausal arthralgia coincides with the age of susceptibility to rheumatic diseases such as rheumatoid arthritis[9] and patients visiting orthopaedic and rheumatology outpatient clinics may not be considered in need of medical care because of the absence of inflammatory or other pathological findings on diagnostic imaging or blood tests. Additionally, there is no established treatment for menopausal arthralgia, although some reports indicate the usefulness of HRT.[10,11,12,13] Symptomatic treatment with acetaminophen and (or) nonsteroidal anti-inflammatory drugs (NSAIDs) is often initiated; however, these medications are ineffective in most cases. Moreover, due to the lack of a diagnosis, antirheumatic drugs, such as salazosulfapyridine and steroids, were inappropriately administered in a few cases of early rheumatoid arthritis, causing side effects.

In the present study, we report nine patients with menopausal arthralgia who were prescribed unkeito and boiogito extracts. Treatment for menopausal arthralgia with the unkeito and boiogito combination showed remarkable efficacy in all patients following their diagnosis with a condition that indicated taking this regimen by a specialist in Kampo medicine. Therefore, this study examined the efficacy of unkeito and boiogito only in patients with an indication for both medications as shown in Table 2. Table 2 also shows which of these items the nine cases met.

Table 2.

Indication patterns of unkeito and boiogito combination therapy, and the case numbers of cases matching those items

Indication patterns of unkeito and boiogito combination therapy	The case numbers of cases matching the item
1. Onset during menopause	All caes
2. Polyarthralgia, mainly in fingers, wrists, elbows, and shoulders	All caes
3. Morning stiffness in hands	All caes
4. Hypersensitivity to cold	All caes
5. Prone to redness and/or frostbite	All caes
6. Rather emaciated	Excluding cases 5, 6 and 9
7. Burning or redness of palms	All caes
8. Dry lips	All caes
9. Tendency to sweat spontaneously	All caes
10. Weak pulse	All caes
11. No abdominal symptoms such as fullness and discomfort in chest and hypochondrium or epigastric stuffiness and resistance	All caes

Unkeito, a prescription that was first introduced in the book Jin Gui Yao Lue, is indicated for “A women about 50 years of age suffers from vaginal bleeding for several tens of days without stopping, with heat effusion at dusk, lesser abdominal urgency, abdominal fullness, vexing heat in palms of the hand, and dry lips and mouth”. Boiogito, used for treating arthralgia, was also first mentioned in Jing Gui Yao Lue for “Wind-damp with a floating pulse, heavy body, sweating, and aversion to wind is governed Fang Ji Huang Qi Tang” and “For wind water that presents with a floating pulse, heavy body, sweating, and aversion to wind Fang Ji Huang Qi Tang governs. For abdominal pain, add peony”. These classical descriptions are an important basis for the indications of unkeito and boiogito as listed in Table 2.

Yokoyama et al.[14] reported that unkeito alone was effective in five out of seven cases of menopausal arthralgia, and our report suggests a higher efficacy of the combination of unkeito and boiogito. Kogure et al.[15] also reported the treatment of menopausal musculoskeletal symptoms using a combination of keishikaryojutsubuto and boiogito. Kampo medicine is accepted by many patients in Japan,[16] and vasomotor symptoms and psychosomatic disorders associated with menopause are often treated with Kampo formulae.[2,17] Kampo formulae are also used to treat painful conditions, such as arthralgia and neuralgia.[18,19,20] Although Kampo formulae have some adverse effects,[21,22,23] they are relatively safe and effective in the treatment of menopausal arthralgia. In addition to cases reported by Yokoyama as mentioned above.[14]

Several studies have suggested that menopausal arthralgia is caused by a decrease in oestrogen level[8,9,22]; unkeito has been reported to regulate the secretion of female hormones, thereby alleviating arthralgia.[24,25] Unkeito suppresses bone loss and promotes osteoclast apoptosis and may reduce arthralgia by regulating the secretion of female hormones and preventing bone fragility.[26,27]

A study involving 50 patients diagnosed with knee osteoarthritis with joint effusion randomly assigned them to two groups: one receiving a combination of boiogito/loxoprofen (25 patients) and the other receiving only loxoprofen (25 patients). The patients were evaluated after 12 weeks.[28] The study reported that the ability to ascend and descend stairs based on the functional score of the Knee Society Rating System was markedly improved in the boiogito/loxoprofen group compared with that in the loxoprofen group. In addition, evaluation using the Short Form 36 Health Survey Questionnaire (SF-36) showed considerable improvement in physical function scores in both groups after 12 weeks. The investigators reported substantial reduction in joint fluid volumes at weeks 4, 8, and 12 in the boiogito/loxoprofen group compared with those at baseline (before initiating drug treatment).

Another study investigated patellar tendon elasticity, knee soft tissue swelling, and local heat sensation in three groups of patients with knee osteoarthritis with oedema.[29] Group A consisted of 31 patients treated with boiogito, Group B consisted of 33 patients treated with boiogito and NSAIDs, and Group C consisted of 20 patients treated with NSAIDs. Group B showed a major improvement in patellar elasticity and knee joint swelling over Group C and a remarkably better local heat sensation than Groups A and C. This indicates the usefulness of combining boiogito and NSAIDs for treating knee osteoarthritis.

Another animal study reported that boiogito ameliorated the increased knee joint effusion in a rat model of knee osteoarthritis by suppressing the production of the inflammatory cytokine, interleukin (IL)-1β, in the joint cavity and modulating water transport in the synovial membrane.[30] Moreover, boiogito increases hyaluronic acid levels in the synovial fluid and has a preventive effect against early post-traumatic knee osteoarthritis when administrated orally in rats.[31] Boiogito decreases the mobilisation of macrophages and helper T cells to the synovium of the ankle joints in adjuvant arthritic rats (AA rats), suppresses the production of tumour necrosis factor (TNF)-α, and increases the production of IL-10, which is mainly released by macrophages. It also suppresses the mobilisation of type 1 T helper (Th1) cells in the synovium of AA rats and regulates the Th1/Th2 ratio.[32]

Our study findings suggest that the combination of unkeito and boiogito has a synergistic effect in treating menopausal arthralgia as the former reduces menopausal hormonal imbalance and the latter reduces arthralgia. However, further high-quality research is required to validate these results.

It is worth mentioning that the treatment has no specific adverse effects, except for the potential for pseudoaldosteronism, which may be caused by the presence of glycyrrhiza in both unkeito and boiogito. According to a review by Yoshino et al.,[33] high daily dosage, prolonged administration over 30 days, constipation, hypoalbuminemia, hyperbilirubinemia, older age, and being female are all risk factors for liquorice-induced pseudoaldosteronism. Furthermore, concomitant use of thiazide diuretics, loop diuretics, and glucocorticoids may increase the risk of pseudoaldosteronism. A dose containing 7.5 g each of unkeito and boiogito extracts, which corresponds to a daily administration of 3.5 g of glycyrrhiza, should be carefully monitored, since a dose greater than 2.5 g of glycyrrhiza is associated with an increased risk of pseudoaldosteronism.

The present study has some limitations. First, it was a retrospective, not a prospective, intervention study with no control group assigned. Second, the study examined the efficacy of the combination of unkeito and boiogito only in patients treated with these medicines according to the traditional diagnosis listed in Table 2, which limits the generalizability of the findings. Last, the effectiveness of treatment was based solely on patient self-reports and not on objective measures. Therefore, more research is needed to confirm the positive effects of the combination of unkeito and boiogito for menopausal arthralgia.

Concluding Remarks

The combination of unkeito and boiogito has high therapeutic efficacy against menopausal arthralgia. These findings pave way for more research into combinational Kampo therapy in alleviating various symptoms experienced by menopausal women. However, further high-quality research with a larger sample is still required to validate the results of our study.

Postscript

The main objective of this study was presented at the 40^rd Annual Meeting of the Japan Society of Medical and Pharmaceutical Sciences for Traditional Medicine held from August 26 to 27, 2023.

Author contributions

TN treated the patients and collected the data. DT and TN prepared the manuscript. NM and TT reviewed the case from a gynaecological perspective. MA supervised this study. All authors significantly contributed to data interpretation and manuscript preparation.

Financial support and sponsorship

Nil.

Conflicts of interest

TN and MA received lecture fees from Tsumura and Co.; however, this was not related to this study.

Ethical policy and Institutional Review board statement: The present study was carried out in compliance with the Helsinki Declaration, the clinical research law of Japan, and the study protocol.

Data Availability statement: The data set used in the current study is available (tick the appropriate option and fill the information)

• Evaluation of the usefulness of Unkeito together with Boiogito for arthralgia in menopausal patients.

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• UMIN Clinical Trials Registry

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• Provided the responsible author is contacted.

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• available on request from (contact name/email id)

  Co-responding author, Tatsuya Nogami/t-nogami@tsc.u-tokai.ac.jp_____________________________

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Reporting guidelines: The study adheres to the STROBE reporting guidelines