Effectiveness of Boswellia and Boswellia extract for osteoarthritis patients: a systematic review and meta-analysis

Background Osteoarthritis (OA) is the commonest form of inflammatory joint disease. Unfortunately, to date, there is no appropriate treatment for OA. Boswellia serrata was considered as a potent anti-inflammatory, anti-arthritic and analgesic agent that may be a drug for OA. Methods In this meta-analysis, data from randomized controlled trials were obtained to assess the effects of Boswellia or its extract versus placebo or western medicine in patients with OA. The primary outcomes included visual analogue score (VAS), WOMAC pain, WOMAC stiffness, WOMAC function and lequesne index. Result Seven trials involving 545 patients were included. Compared with the control group, Boswellia and its extract may relieve the pain [VAS: (WMD -8.33; 95% CI -11.19, − 5.46; P<0.00001); WOMAC pain: (WMD -14.22; 95% CI -22.34, − 6.09; P = 0. 0006)] and stiffness [WOMAC stiffness: (WMD -10.04; 95% CI -15.86, − 4.22; P = 0. 0007)], and improve the joint’s function [WOMAC function: (WMD -10.75; 95% CI -15.06, − 6.43; P<0. 00001); lequesne index: (WMD -2.27; 95% CI -3.08, − 1.45; P<0. 00001)]. Conclusion Based on current evidence, Boswellia and its extract may be an effective and safe treatment option for patient with OA, and the recommended duration of treatment with Boswellia and its extract is at least 4 weeks.


Background
Osteoarthritis (OA) is an inflammatory joint disease that mainly damages articular cartilage. It is characterized by the degradation of articular cartilage and involving the entire joint tissue, which eventually leads to joint degeneration, fibrosis, fracture, defect and damage to the entire articular surface [1][2][3]. Epidemiological studies show that there are currently 355 million people with arthritis worldwide, and arthritis has become the world's number one disabling disease. In China, as of 2015, there were 120 million people with arthritis in mainland China, with an incidence rate of about 13%, of which the number of people suffering from OA is the largest [4]. The management of patients with knee OA is mainly based on individualized and gradient treatment for the condition and severity of arthritis [5][6][7]. Among them, the drugs for OA pain are mainly non-steroidal antiinflammatory drugs (NSAID) and specific (COX-2) cyclooxygenase II inhibitors [8]. However, these drugs may be expensive or cause stomach bleeding, and cannot repair cartilage and treat subchondral damage [8][9][10]. Therefore, due to the high incidence of NSAID-related adverse events, there is an urgent need for a safer and effective alternative to OA.
Boswellic acid is the active ingredient in Boswellia serrata; it has shown significant pharmacological activity in the treatment of inflammatory diseases such as rheumatoid arthritis, chronic bronchitis, asthma and chronic inflammatory bowel diseases (ulcerative colitis and Crohn's disease) [11,12]. Current research showed that 3-O-Acetyl-11-keto-beta-boswellic acid (AKBA) is the one boswellic acid with strong pharmacological activity; for example, AKBA has a powerful inhibitory effect on 5-lipoxygenase (5-LOX) [13,14]. Clinical studies have shown that Boswellia serrata extract not only has anti-inflammatory and anti-arthritis properties, but also improves pain and physical function [15][16][17][18]; in vitro experiments also show that Boswellia serrata extract can inhibit the expression of inflammatory factors such as adhesion molecules [19][20][21][22][23]. With regard to the safety of Boswellia serrata, studies showed that Boswellia serrata extract (such as 5-Loxin and Aflapin) does not have toxic side effects at higher doses [23][24][25]. These indicate that the active compound of Boswellia extract (AKBA) is safe based on current evidence [23,25].
As potential anti-inflammatory drugs for OA, the efficacy of Boswellia and Boswellia Extract have been reported in a lot of clinical trials [14-17, 24, 26]. Since 2003 [15], many trials have explored the feasibility of Boswellia and its extracts for the treatment of OA. In the meantime, the latest randomized controlled trials (RCTs) have assessed the benefits and adverse events of Boswellia and its extract for OA. To the best of our knowledge, this is the first systematic review and meta-analysis estimating the effectiveness and safety of Boswellia and its extracts for OA. Therefore, we hope that the results of this systematic review and meta-analysis will provide better evidence for the clinical application of Boswellia and its extract in the treatment of OA.
Why it is important to do the review Boswellia and its extract have theoretical benefits for cultured cells in vitro and experimental animals [19, 21-23, 25, 27]; although several meta-analyses have widely analyzed the effect of herb or dietary supplements on OA [28,29], to our knowledge, there is no systematic review and metaanalysis focused on assessing the efficacy of Boswellia and its extract on OA. For example, Liu et al. [28] conducted a systematic review about dietary supplements for patients with osteoarthritis; Of the studies it included, only three RCTs were about Boswellia and its extract. Meanwhile, its conclusions about Boswellia and its extract on OA failed to provide valuable reference information for clinical decision making. Another systematic review [29] only analyzed the RCTs before 2013. In 5 years, more RCTs about Boswellia and its extract on OA have been completed, which means that relevant conclusions need to be updated or confirmed. Therefore, this systematic review and meta-analysis focus on and summarizes available evidence from RCTs about the role of Boswellia and its extract in OA.

Materials and methods
Protocol Systematic reviews and meta-analysis are carried out strictly in accordance with the protocol (CRD42018086785) and the PRISMA-guidelines (see Supplementary Materials) [30].

Selection criteria Participants
Human with specified diagnosis criteria of OA.

Intervention methods
Boswellia or its extract.

Comparison methods
Other treatments for OA, such as placebo or conventional medicine;

Information retrieval and data extraction method
Three researchers (Ganpeng Yu, Liuting Zeng and Kailin Yang) independently screened the literature based on protocol (CRD42018086785). The discrepancies between the three researchers would be resolved through discussion of all researchers. Literature retrieval is carried out according to the search strategy, the search strategy of Pubmed is shown in Table 1.
After literature retrieval, three researchers (Ganpeng Yu, Liuting Zeng and Kailin Yang) extracted data from the included literature according to a pre-designed table (including author, year of publication, number of cases, inclusion and exclusion criteria of patients, duration of intervention, etc.). The discrepancies between the three researchers would be resolved through discussion of all researchers. The missing data in the literature would be obtained by contacting the author. If the author cannot be contacted, it would be estimated by the method provided by Cochrane Handbook 5.1.0 [31].

Literature quality evaluation methods
The Cochrane collaboration's tool for assessing risk of bias provided by Cochrane Handbook 5.1.0 was used to evaluate the quality of the RCTs [32]. The evaluation content includes random sequence generation, allocation result concealment, blind method, incomplete result data, selective report and other biases. Four researchers (Ganpeng Yu, Wang Xiang, Tianqing Zhang, Liuting Zeng and Kailin Yang) independently assessed the quality of the literature. The discrepancies between the three researchers would be resolved through discussion of all researchers.

Statistical analysis
The RevMan5.3 software provided by the Cochrane collaboration network was used for system evaluation and meta-analysis. Enumeration data is represented by risk ratio (RR) and 95% confidence interval (CI), and measurement data is represented by mean deviation (MD) and CI. The heterogeneity between the results of the studies was tested by X 2 . If the heterogeneity of the study is low (P > 0.10, I 2 < 50%), the fixed effect model is used for analysis; otherwise (P < 0.10, I2 > 50%), the source of heterogeneity is analyzed first and then subgroup analysis or random effect model is adopted.

Description of included trials
A total of 7 RCTs with 545 participants were included. Sengupta's RCTs consist of 2 trial groups and 1 control group [24,26]. According to the method of Cochrane Handbook 5.1.0, the control group was divided into two groups, matching the two trial groups (Sengupta 2008a and Sengupta 2008b; Sengupta 2010a and Sengupta 2010b) [31]. The characteristics of the RCTs were shown in Tables 2 and 3.

Risk of Bias in included studies
The summary and graph of risk of bias ware shown in Fig. 2.

Sequence generation
Among the 7 included RCTs, three studies [35][36][37] adopted unclear randomization procedures, we therefore rated it as having an unclear risk of bias.  [37] described the implementation process of blinding. Thus, we gave a low risk of bias for them. The other RCTs were rated as having an unclear risk of bias for they did not describe the blind implementation process.
For blinding of outcome assessment, the statisticians in Sengupta 2010 [24], Sengupta 2008 [26] and Vishal  [35] were rated as having an unclear risk of bias for they did not describe the blind implementation process.

Incomplete outcome data
The missing outcome data of all RCTs balanced in numbers across intervention groups with similar reasons for missing data across groups. We gave them low risks of bias.

Selective reporting
One RCT (Vishal 2011 [33]) failed to provide all outcomes mentioned in its protocols, thus we thought its risk of bias was high. The other RCTs provided their protocols, and all of the study's pre-specified outcomes that are of interest in the review had been reported in the pre-specified way; their risks of bias were low.

Other potential bias
In the RCTs of Sengupta 2010 [24], Sengupta 2008 [26] and Vishal 2011 [33], their protocols noted three primary outcome parameters, which means that when p = 0.05/3 = 0.017, the difference is significant. Strictly speaking, the statistics of this study were not carried out correctly. Hence, their risks of bias were high. Similarly, in Haroyan 2018 [34]'s RCT, the difference is significant when p = 0.05 / 2 = 0.025. Its risk of bias was also high.
Other sources of bias were not observed in other RCTs; therefore, the risks of other bias of them were low.    1. a diagnosis of OA of the knee according to the criteria of the American College of Rheumatology 2. grade 3 Kellgren and Lawrence radiographic staging,16 in which the severity of the arthritis is assessed on a scale in the range of 0-4, hypothesizing a sequential evolution from the manifestation of osteophytes through a reduction in the width of the joint space, to subchondral sclerosis and finally the formation of cysts 3. frequent joint pain (several days a week) for at least 6 months before recruitment 4. pain in the knee, scored at least 4 cm on a 10 centimetric visual analogic scale (VAS) (from moderate to severe pain), where 0 means no pain and 10 is the worst pain possible 5. a score of > 2 on the Lequesne painfunction index (LI). 18 The LI is an OA-specific validated questionnaire that poses a series of questions about pain in the knee (five questions on a scale from 0 to 2, where 0 indicates no pain and 2 intense pain), functional limitation (four questions, using the same scale), and maximum walking distance (one question, with a score from 0 to 6, where 0 indicates the ability to walk for an unlimited distance and 6, the inability to cover 100 m). The maximum worst final score is 24  13 in which the severity of the arthritis is assessed on a scale from 0 to 4, hypothesizing a sequential evolution from the manifestation of osteophytes through a reduction in the width of the joint space, to subchondral sclerosis and fnally the formation of cysts; 4. frequent joint pain (several days a week) for at least 6 months before recruitment; 5. pain in the knee, scored at least 2 cm on a 10 centimetric visual analogic scale (VAS), where 0 means no pain and 10 is the worst pain possible; 6. a score of > 2 on the Lequesne painfunction index (LI).14 The LI is a diseasespecific validated questionnaire that poses a series of questions about pain in the knee (five questions on a scale from 0 to 2, where 0 indicates no pain and 2 intense pain), functional limitation (four questions, using the same scale) and maximum walking distance (one question, with a score from 0 to 6, where 0 indicates the ability to walk for an unlimited distance and 6, the inability to cover 100 m). The maximim worst fnal score was 24.
1. previous surgery of the affected knee; 2. disease processes such as rheumatoid arthritis, autoimmune diseases, systemic diseases, and tumors; 3. obesity (BMI > 30 kg/m2); 4. altered blood chemistry and kidney, liver, and metabolic (diabetes mellitus) function; 5. intra-articular hyaluronic acid/cortisone infiltrations to the affected knee within 3 months before the start of the study; 6. systemic cortisone treatment taken within 3 months before the start of the study; 7. supplements (glucosamine, chondroitin sulfate, bromeline, etc) taken within 3 months before the start of the study (patients were also informed that they were not to be taken for the following 6 months).

Secondary outcomes Pain
Several RCTs reported Pain index (VAS and/or WOMAC pain) at week 4, 8, 12. The details of them were shown in Table 4 and Figure S1~S6 (see Supplementary Materials).

Stiffness
Several RCTs reported Stiffness index (WOMAC stiffness) at week 4, 8, 12. The details of them were shown in Table 5 and Figure S7~S9 (see Supplementary Materials).

Function
Several RCTs reported Function index (WOMAC function) at week 4, 8, 12. The details of them were shown in Table 6 and Figure S10~S12 (see Supplementary  Materials).

Adverse events
Five studies [24,[33][34][35]37] reported AEs. Three of them were excluded because they reported no events in both arms. According to the results, there is also not strong evidence that which one is safer because there was no statistical difference (RR 0.63; 95% CI 0.22, 1.83; P = 0.39) (Fig. 8).

Discussions
This systematic review and meta-analysis including 7 RCTs analyzes the effectiveness and safety of Boswellia and its extract for OA. Compared with the control group, Boswellia and its extract may relieve the pain (VAS and WOMAC pain) and stiffness (WOMAC stiffness), and improve the joint's function (WOMAC function and lequesne index). In particular, since the doses of Boswellia and its extract reported in RCTs used for secondary outcomes analysis are 100-250 mg, based on the current evidence, pain, stiffness and joints' function start to improve after 4 weeks of continuous Boswellia and its extract (at least 100-250 mg) intervention. While this finding seems promising, it should be interpreted with caution mainly due to the unclear risk of bias for selection bias (random sequence generation, allocation concealment) and attrition bias (incomplete outcome data), the high risk of bias for reporting bias (selective reporting), and the small number of participants. Five studies [24,[33][34][35]37] reported AEs. Three of them were excluded because they reported no events in both arms. According to the results, there is also not strong evidence that which one is safer because there was no statistical difference. However, safety studies conducted according to OECD guidelines and extensive acute and dose-dependent subchronic safety experiments on rats demonstrate that Boswellia and its extract does not exhibit toxic manifestations [23,25], which means Boswellia and its extract might be a safety treatment option. But the absence of information on AEs does not mean that the intervention is safe [43]. Thus, although based on current evidences, we consider that Boswellia and its extract is a relatively safe treatment, we cannot assure it. Future clinical trials are required to report AEs with more explanations [44]. Thus, although based on current evidences, we consider that Boswellia and its extract is a relatively safe treatment, we cannot assure it. Future clinical trials are required to report AEs with more explanations [45].
Although there were several meta-analyses that have been widely analyzed the effect of herb or dietary supplements on OA [28,29], as far as we know, this systematic review and meta-analysis is the first one that focused on evaluating the efficacy and safety of Boswellia and its extract for patients with OA. Compared with similar previous works [28,29], we included more RCTs (including [33][34][35][36]) about Boswellia and its extract; thus, our conclusions were more accurate and reliable. In particular, compared with the work of Cameron et al. [29], we not only verified some outcomes (such as WOMAC) but also provide the recommended duration and dosage of Boswellia and its extract and so on. However, there are still some deficiencies in this study. For example, the risk of bias of some RCTs are high; the number of RCTs      and cases included in this study is insufficient; the heterogeneity of some outcomes is high; these all affect the accuracy of the conclusions. The heterogeneity may be related to the discrepancies in the pharmacological effects of different Boswellia preparations. This may result from the different standardization of Boswellia and its extract manufacturing process, dosage, duration of treatment, units of laboratory tests and races of the selected patients or other places. Meanwhile, the recommended duration and dosage of treatment should also be interpreted with caution because the pain, stiffness and function index between week 1 and week 4 and the dosage of Boswellia and its extract outside 100-250 mg were not reported. Additionaly, since the quality of the RCTs is generally medium to low, all results should be interpreted more cautiously. Last but not least, further rigorously designed studies with high quality are needed to confirm the effectiveness and safety of Boswellia and its extract preparations for patients with OA.

Conclusion
This systematic review and meta-analysis showed that Boswellia and its extract may be a novel drug for patient with OA. Based on current evidence, the recommended duration and dosage of treatment with Boswellia and its extract is at least 100-250 mg 4 weeks. However, current RCTs have limitations, including the missing information of pain, stiffness and function index between week 1 and week 4 and small sample sizes. Meanwhile, since the quality of the RCTs is generally medium to low, we should formulate the conclusion more cautiously. More double-blind, large sample size RCTs of Boswellia and its extract for OA that reported pain, stiffness and function index before 4 weeks and the dosage of Boswellia and its extract outside 100-250 mg are needed in the future to confirm or modify the result of this work.