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             \author[1]{Rizaldy Taslim  Pinzon}

             \author[2]{Rosa De Lima Renita  Sanyasi}

             \author[3]{Esdras Ardi  Pramudita}

             \author[4]{Septian  Dewi  Periska}

             \affil[1]{  Duta Wacana Christian University School of Medicine, Panti Rapih Hospital, Bethesda Hospital}

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\date{\small \em Received: 16 December 2018 Accepted: 2 January 2019 Published: 15 January 2019}

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\begin{abstract}
        


Background: Chronic pain is the major complaint in subjects with osteoarthritis (OA). Nonsteroid anti-inflammatory drug (NSAID) is still the drug of choice in Indonesia to treat OA patients. The prolonged consumption of NSAID may lead to many adverse events (AE). Some previous studies showed the extract of Curcuma longa and Boswellia serrata is a promising potential as therapeutic interventions against OA.Objective: This study aimed to evaluate the effectiveness and safety of CB extract to relieve symptoms in patients with OA.Study Design: This was a randomized controlled trial (RCT) in OA patients. The treatment used in this trial were CB extract (350 mg of Curcuma longa and 150 mg Boswellia serrata) and NSAID (400 mg ibuprofen or 50 mg diclofenac sodium). Subjects were randomized to 3 different groups (Group 1: CB extract and NSAID; group 2: CB extract; group 3: NSAID). Each medication was taken two times per day for four weeks. Paracetamol tablet 500 mg gave to each subject as a rescue medication.

\end{abstract}


\keywords{curcuma longa, boswellia serrata, osteoarthritis, WOMAC.}

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\let\tabcellsep& 	 	 		 \par
Abstract-Background: Chronic pain is the major complaint in subjects with osteoarthritis (OA). Non-steroid antiinflammatory drug (NSAID) is still the drug of choice in Indonesia to treat OA patients. The prolonged consumption of NSAID may lead to many adverse events (AE). Some previous studies showed the extract of Curcuma longa and Boswellia serrata is a promising potential as therapeutic interventions against OA.\par
Objective: This study aimed to evaluate the effectiveness and safety of CB extract to relieve symptoms in patients with OA.\par
Study Design: This was a randomized controlled trial (RCT) in OA patients. The treatment used in this trial were CB extract (350 mg of Curcuma longa and 150 mg Boswellia serrata) and NSAID (400 mg ibuprofen or 50 mg diclofenac sodium). Subjects were randomized to 3 different groups (Group 1: CB extract and NSAID; group 2: CB extract; group 3: NSAID). Each medication was taken two times per day for four weeks.\par
Paracetamol tablet 500 mg gave to each subject as a rescue medication. Each subject would be followed up three times: baseline (visit I), two weeks after baseline (visit II), and four weeks after baseline (visit III). The measurement was using WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index).\par
Results: There were 105 subjects at the beginning of the study dominated by a female with mean aged 63 years and have osteoarthritis with KL grade II. Seven subjects were lost to follow up, and three subjects excluded from the study due to adverse event.  \hyperref[b10]{(Lespasio et al., 2017;}\hyperref[b16]{Neogi, 2013)}. It affects not only the knees but also in the hands, feet, and hips \hyperref[b11]{(Litwic et al., 2013)}. The target of OA management is to reduce pain, optimize function, and also modify the process of joint damage \hyperref[b19]{(Sofat and Kuttapitiya, 2014)}. Chronic pain is the most common complaint in subjects with OA \hyperref[b4]{(Cedraschi et al., 2013;}\hyperref[b12]{Lluch et al., 2014)}. Therefore, patients with OA often depend on analgetic, such as non-steroid anti-inflammatory drug (NSAID). Prolonged consumption of NSAID may lead to many adverse events such as gastrointestinal tract bleeding and cardiovascular problems \hyperref[b20]{(Sostres et al., 2013)}.\par
Curcumin is the yellow pigment isolated from the rhizomes of Curcuma longa (CL). CL is also known as turmeric \hyperref[b8]{(Henrotin et al., 2013)}. Many type of research have been published for CL potency as an anti-inflammatory and analgesic properties \hyperref[b7]{(Henrotin et al. 2010}). Curcumin has also demonstrated antiapoptotic activity in chondrocytes \hyperref[b0]{(Akhtar and Haqqi, 2012)}. Boswellia serrata (BS) is a common ingredient in Ayurvedic medicine. It also has an anti-inflammatory effect and beneficial to treat a chronic inflammatory disease \hyperref[b18]{(Siddiqui, 2011)}.\par
The OA process is involved in various interleukins and cytokines such as IL-1? and TNF? and proteases degrading enzymes such as MMP-3, MMP-9, and MMP-13 \hyperref[b1]{(Akuri et al., 2017)}. The anti-arthritic potential of curcumin shows its' capability to downregulate the catabolic and degradative effects in cartilage explants, or chondrocytes stimulated with IL-1?, and TNF? and inhibited the production of MMP-3, MMP-9, and MMP-13 \hyperref[b0]{(Akhtar and Haqqi, 2012}). An oral administration of BS extract also resulted in significantly reduced levels of inflammatory mediators (IL-1?, IL-6, TNF-?, IFN-?, and PGE2) \hyperref[b21]{(Umar et al., 2014)}.\par
NSAID is still the drug of choice in Indonesia to treat OA patients (Indonesian Rheumatology Association, 2014). Many previous studies showed the extract of CL and BS is a promising potential as therapeutic interventions against OA. The administration of CL extract, BS extract, or its combination is expected to reduce the amount of consumption of NSAID and reduce the adverse events due to the chronic administration of NSAID. The research of the combination of CL extract and BS extract (CB extract) in OA patients in Indonesia is very limited. The main objective of this study was to evaluate the effectiveness of CB extract to relieve symptoms in patients with OA. This study also identify the safety of the administration of CB extract in patients with OA. 
\section[{II.}]{II.} 
\section[{Materials and Methods}]{Materials and Methods}\par
This study was a randomized controlled trial (RCT) held at Bethesda Hospital and Panti Rapih Hospital, Yogyakarta, Indonesia. Subject enrollment at the first visit included male or female patients, age >18 years old, and has knee osteoarthritis with Kellgren-Lawrence grade II or III. Subject with a known hypersensitivity to CB extract, ibuprofen, diclofenac sodium and/or paracetamol, participation in other clinical trial in the last 1 month before this study, pregnant or has a pregnancy program, incompetent to give a consent and answer the questionnaire, or receiving other pain treatment in the last 24 hours before this study excluded in this study. The sample size calculation based on the assumption of a 95\% confidence interval and 80\% power of the study. The minimum sample requirement was 25 subjects in each group. A total of 100 subjects enrolled for achieving normal distribution. Subjects divided into three groups randomly. The treatment used in this trial were CB extract (350 mg of Curcuma longa and 150 mg Boswellia serrata) and NSAID (400 mg ibuprofen or 50 mg diclofenac sodium). Group 1 received the CB extract and NSAID, group 2 received CB extract, and group 3 received NSAID. Each medication was taken two times per day for four weeks. Paracetamol tablet 500 mg was given to each subject as a rescue medication. The remaining number of rescue medication at the third visit was calculated at the end of the study. Figure \hyperref[fig_1]{1} shows the schematic study flowchart. Each subject signed an informed consent form. Subjects followed-up three times with interval of two weeks between each visit.  
\section[{Analysis}]{Analysis}\par
Demographic profile including sex, age, occupation, marital status, education background, comorbidity, and the degree of OA. The degree of knee OA was measured using the Kellgren-Lawrence (KL) grading scale. It determined based on the result of knee X-Ray and interpreted by a radiologist. WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) commonly used as a standardized questionnaire to evaluate the condition of patients with osteoarthritis. It consists of three categories of questions, five questions for pain, two questions for stiffness, and 17 questions for physical functioning of the joints. Each question is scored on a scale of 0 to 4 (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = extreme), thus score range for pain, stiffness, and physical functioning are 0-20, 0-8, and 0-68 respectively. The total score for all questions is 96. The higher score indicates the worse OA symptom. Any adverse event (AE) in this trial would be reported and monitored strictly. The assessment of AE based on the type of AE, the degree of AE, the correlation to the administration of CB extract or NSAID, and the action taken to treat the AE. All data obtained from this study is classified. This study verified by Duta Wacana Christian University School of Medicine Ethical Research Committee, Yogyakarta, Indonesia. The number of ethical clearance is 867/C.16/FK/2018.\par
The analysis of this study is the intention to treat based. The demographic profile of subjects mentioned in percentage. After the normality test with Kolmogorov-Smirnov test, numeric variables analyzed using a t-test or Wilcoxon signed-rank test. Based on the result of the homogeneity test, ANOVA or Kruskal Wallis test used to identify the mean differences between the three groups. The significant level was set at p <0.05. 
\section[{III.}]{III.} 
\section[{Results}]{Results}\par
There were 105 subjects at the beginning of the study dominated by a female (80\%) with a mean aged 63 years. About 57.1\% of the subjects have osteoarthritis with KL grade II. The detail of subjects' characteristics seen in Table \hyperref[tab_2]{1}. Figure \hyperref[fig_1]{1} shows the detail of the number of subjects in each group. Seven subjects were lost to follow up and three subjects excluded from the study due to drug's side effect. Ninety-five subjects (36 subjects from group 1, 29 subjects from group 2, 30 subjects from group 3) remained for complete analysis. DM: diabetes mellitus, CVD: cardiovascular disease, GIT: gastrointestinal WOMAC scores tend to be higher of female subjects, single, not working, have a KL grade III, and without any comorbidity. An analysis in these variables proved that age, gender, marital status, occupation, the degree of OA, and the presence of comorbidity were not correlated to the WOMAC score (Table \hyperref[tab_3]{2}).    \hyperref[tab_4]{3} and Figure \hyperref[fig_2]{2}). However, group 1 showed the greatest reduction of WOMAC score after four weeks of treatment (Î?"WOMAC = 12.08 ± 18.6). Group 3 has the least WOMAC score reduction. There was no statistically different Î?"WOMAC score between groups (Table \hyperref[tab_6]{4}). Each subject was given 20 tablets of 500 mg paracetamol as a rescue medication. At the end of the study, the remaining number of paracetamol calculated. The highest consumption of rescue medication was in group 3 (15 tablets of paracetamol), whereas the least consumption was in group 2 (12 tablets of paracetamol), as seen in Table \hyperref[tab_7]{5}. There was no statistical difference of rescue medication consumption between groups (p: 0.346). H Group 3 was the most frequent group with reported AE, whereas group 2 has the least reported treat AE based on the symptoms, and the degree of severity. Three subjects need to discontinue the medication due to the AE, two among them were subjects in group 3 and one among them was subject in group 2. No fatal AE reported in all groups and no subject needed an inpatient treatment due to the AE. After a further investigation, only one case (dizziness) of AE that related to the administration of CB extract and 5 cases (abdominal pain) related to the administration of NSAID. There were no statistically different from the prevalence of AE between groups at the visit II (p: 0.119) and the visit III (p: 0.767). Table \hyperref[tab_7]{5} shows the detail of the AE in each group.  
\section[{Discussion}]{Discussion}\par
The present study aimed to identify the effectiveness of CB extract compared to the combination of CB extract and NSAID with NSAID alone. Each medication was taken two times per day for four weeks. The measurement was using WOMAC. The WOMAC was the most commonly used in OA patients. It used to measure the severity and frequency of symptoms. The higher scores indicate a higher severity \hyperref[b5]{(Grover and Samson, 2016)}.\par
The result of this study was indicated the administration of both CB extract and NSAID or its combination improve the symptom of OA (Table \hyperref[tab_4]{3}). Group 1 had the greater reduction of WOMAC score after four weeks of treatment, followed by group 2 and group 3 (Table \hyperref[tab_6]{4}). The administration of CB extract alone has a greater reduction in the severity and frequency of OA symptoms than the administration of NSAID alone. This study was similar to many previous studies. An administration of CL extract, BS extract, or its combination was beneficial in OA patients. About 201 subjects were investigated in a three-arm, parallelgroup, randomized, double-blinded, placebo-controlled trial to identify the effects of 333 mg curcuminoids and a combination of 350 mg curcuminoids and 150 mg boswellic acid. The medication was taken orally three times a day for 12 weeks. The administration of a combination of curcumin and boswellic acid had a superior effect size (physical performance tests and the WOMAC joint pain index) than curcuminoid alone \hyperref[b6]{(Haroyan et al., 2018)}.\par
A study by \hyperref[b3]{Bolognesi et al. (2016)} administered standard management of OA combined with oral supplementation in 26 subjects compared with a supplementation containing N-acetyl-D-glucosamine, ginger, and BS extract. Significant improvements in the functional outcomes and pain-free walking distance were observed after 1, 3 and 6 months in OA patients supplemented with a combination of N-acetyl-Dglucosamine, ginger, and BS extract \hyperref[b3]{(Bolognesi et al., 2016)}. Treatment with BS extract showed a statistically significant (p < 0.001) decrease in WOMAC score after 120 days  {\ref (Majeed et al., 2018)} In this current study, the CB extract group had the least consumption of rescue medication. Conversely, the NSAID group had the highest consumption of rescue medication (Table \hyperref[tab_7]{5}). A non-randomized, openlabeled, and non-comparative study by Reddy and Faruqui (2016) was using a combination of curcumin 500 mg and piperine 5 mg twice daily for 12 weeks. It showed that the assessment of the WOMAC score at the end of the 12th week showed a statistically significant change from baseline with a reduction in pain, stiffness, and physical function (p <0.001) and showed a trend of decrease in need of rescue medication \hyperref[b17]{(Reddy and Faruqui, 2016)}.\par
The present study showed that the CB extract group had the least reported AE (Table \hyperref[tab_8]{6}). Nausea and loss of appetite were the most common type of AE in subjects with CB extract medication. No fatal AE was seen in CB extract group. The highest prevalence of AE seen in the NSAID group. NSAID group was also had more excluded subjects due to AE. This result is in concordance with previous studies. The number of AE of abdominal pain/discomfort was significantly higher in the ibuprofen group than that in the Curcuma domestica extracts group (p = 0.046)  {\ref (Kuptniratsaikul et al., 2014)}. A review by Bee and Liew (2010) stated that turmeric and BS are generally well-tolerated. It may cause GIT side effects such as nausea and diarrhea. It was similar to the result of a study by \hyperref[b17]{Reddy and Faruqui (2016)}; three patients reported mild gastrointestinal AE. Supplementation with a combination of N-acetyl-Dglucosamine, ginger, and BS extract are safe, welltolerated, and also showing the beneficial effect \hyperref[b3]{(Bolognesi et al., 2016)}.\par
There is still a very limited study which is investigating CB extract in OA patients in Indonesia. The limitation of this study was unblinded assessment of outcomes and a short length of treatment. This research did not receive any specific grant from funding agencies, in the public, commercial, or not-for-profit sectors.\par
V. 
\section[{Conclusion}]{Conclusion}\par
CL extract in combination with BS extract effective for treatment in OA patients. It also has a great safety profile and well-tolerated compared to NSAID. 
\section[{Conflict of interest}]{Conflict of interest}\par
There are no conflicts of interest to disclose.\begin{figure}[htbp]
\noindent\textbf{1}\includegraphics[]{image-2.png}
\caption{\label{fig_1}Figure 1 :}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{2}\includegraphics[]{image-3.png}
\caption{\label{fig_2}Figure 2 :}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{} \par 
\begin{longtable}{}
\end{longtable} \par
 
\caption{\label{tab_0}}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{1} \par 
\begin{longtable}{P{0.22956204379562042\textwidth}P{0.22335766423357664\textwidth}P{0.3970802919708029\textwidth}}
\multicolumn{2}{l}{Characteristics}\tabcellsep n (\%)\\
Age (mean)\tabcellsep \tabcellsep 63.24 ± 8.77\\
Gender\tabcellsep Male Female\tabcellsep 21 (20\%) 84 (80\%)\\
Marital status\tabcellsep Married\tabcellsep 78 (74.3\%)\\
\tabcellsep Not married\tabcellsep 27 (25.7\%)\\
Occupation\tabcellsep Working Not working\tabcellsep 70 (66.7\%) 35 (33.3\%)\\
KL Grade\tabcellsep Grade II Grade III\tabcellsep 60 (57.1\%) 45 (42.9\%)\\
Comorbidity\tabcellsep Yes No\tabcellsep 79 (75.2\%) 26 (24.8\%)\end{longtable} \par
 
\caption{\label{tab_2}Table 1 :}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{2} \par 
\begin{longtable}{P{0.20784671532846716\textwidth}P{0.22645985401459853\textwidth}P{0.31952554744525546\textwidth}P{0.09616788321167884\textwidth}}
\multicolumn{2}{l}{Characteristics}\tabcellsep WOMAC Score\tabcellsep p\\
Age\tabcellsep \tabcellsep \tabcellsep 0.870\\
Gender\tabcellsep Male Female\tabcellsep 32.5 ± 17 37.8 ± 19\tabcellsep 0.247\\
Marital status\tabcellsep Married Not married\tabcellsep 36.6 ±19 37.2 ± 19\tabcellsep 0.888\\
Occupation\tabcellsep Working Not working\tabcellsep 36.4 ± 20 37.4 ±16\tabcellsep 0.793\\
KL Grade\tabcellsep Grade II Grade III\tabcellsep 35.3 ±18 38.7 ±20\tabcellsep 0.367\\
Comorbidity\tabcellsep Yes No\tabcellsep 36.58 ± 19 37.2 ± 18\tabcellsep 0.880\end{longtable} \par
 
\caption{\label{tab_3}Table 2 :}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{3} \par 
\begin{longtable}{P{0.14468085106382977\textwidth}P{0.2712765957446809\textwidth}P{0.06329787234042553\textwidth}P{0.2622340425531915\textwidth}P{0.10851063829787233\textwidth}}
45\tabcellsep \tabcellsep \tabcellsep \\
\tabcellsep 41.4\tabcellsep \tabcellsep \\
40\tabcellsep 36.7\tabcellsep \tabcellsep \\
35\tabcellsep 34.3\tabcellsep \tabcellsep \\
30\tabcellsep 33 9\tabcellsep \tabcellsep 30.3 27.9\\
\tabcellsep \tabcellsep \tabcellsep \multicolumn{2}{l}{26.7}\\
20\tabcellsep \tabcellsep \tabcellsep \\
15\tabcellsep \tabcellsep \tabcellsep \\
10\tabcellsep \tabcellsep \tabcellsep \\
5\tabcellsep \tabcellsep \tabcellsep \\
0\tabcellsep \tabcellsep \tabcellsep \\
\tabcellsep WOMAC I\tabcellsep \tabcellsep \multicolumn{2}{l}{WOMAC III}\\
\tabcellsep Group 1\tabcellsep Group 2\tabcellsep Group 3\tabcellsep All subjects\end{longtable} \par
 
\caption{\label{tab_4}Table 3}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{3} \par 
\begin{longtable}{P{0.13292181069958847\textwidth}P{0.10144032921810699\textwidth}P{0.05596707818930041\textwidth}P{0.15740740740740738\textwidth}P{0.0419753086419753\textwidth}P{0.11893004115226337\textwidth}P{0.15740740740740738\textwidth}P{0.0839506172839506\textwidth}}
\tabcellsep \multicolumn{3}{l}{WOMAC I (n = 105)}\tabcellsep \tabcellsep \multicolumn{2}{l}{WOMAC III (n = 95)}\tabcellsep \\
Group\tabcellsep Min\tabcellsep Max\tabcellsep Mean\tabcellsep Min\tabcellsep Max\tabcellsep Mean\tabcellsep p\\
\tabcellsep Score\tabcellsep Score\tabcellsep Score\tabcellsep Score\tabcellsep Score\tabcellsep Score\tabcellsep \\
All subjects\tabcellsep 3\tabcellsep 73\tabcellsep 39.7 ± 19\tabcellsep 0\tabcellsep 84\tabcellsep 27.9 ± 21\tabcellsep <0.001\\
Group 1\tabcellsep 5\tabcellsep 73\tabcellsep 41.4 ± 19\tabcellsep 2\tabcellsep 84\tabcellsep 30.3 ± 22\tabcellsep <0.001\\
Group 2\tabcellsep 5\tabcellsep 73\tabcellsep 33.9 ± 17\tabcellsep 0\tabcellsep 79\tabcellsep 26.4 ± 20\tabcellsep <0.001\\
Group 3\tabcellsep 3\tabcellsep 69\tabcellsep 34.3 ± 20\tabcellsep 1\tabcellsep 65\tabcellsep 26.7 ± 21\tabcellsep 0.016\end{longtable} \par
 
\caption{\label{tab_5}Table 3 :}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{4} \par 
\begin{longtable}{P{0.4675\textwidth}P{0.3315\textwidth}P{0.051\textwidth}}
Medication\tabcellsep Mean Î?"WOMAC\tabcellsep p\\
Group 1 (n: 36)\tabcellsep 12.08 ± 19\tabcellsep 0.367\\
Group 2 (n: 29)\tabcellsep 7.2 ± 14\tabcellsep \\
Group 3 (n: 30)\tabcellsep 6.9 ± 16\tabcellsep \end{longtable} \par
 
\caption{\label{tab_6}Table 4 :}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{5} \par 
\begin{longtable}{P{0.2992957746478873\textwidth}P{0.5147887323943662\textwidth}P{0.03591549295774648\textwidth}}
Group\tabcellsep The remaining number of rescue medication (mean)\tabcellsep p\\
Group 1 (n: 36)\tabcellsep seven tablets\tabcellsep \\
Group 2 (n: 29)\tabcellsep eight tablets\tabcellsep 0.346\\
Group 3 (n: 30)\tabcellsep five tablets\tabcellsep \end{longtable} \par
 
\caption{\label{tab_7}Table 5 :}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{6} \par 
\begin{longtable}{P{0.3269230769230769\textwidth}P{0.021794871794871794\textwidth}P{0.016346153846153847\textwidth}P{0.4685897435897436\textwidth}P{0.016346153846153847\textwidth}}
Groups\tabcellsep Visit II\tabcellsep p\tabcellsep Visit III\tabcellsep p\\
\multicolumn{2}{l}{Group 1 (n: 5) 1 (mild lip swelling)}\tabcellsep 0.119\tabcellsep 4 (flank pain, constipation, nausea and loss of appetite, malaise, and dizziness)\tabcellsep 0.767\\
\multicolumn{2}{l}{Group 2 (n: 4) 2 (dizziness and urticaria)}\tabcellsep \tabcellsep 2 (nausea and loss of appetite, dizziness)\tabcellsep \\
\multicolumn{2}{l}{Group 3 (n: 7) 5 (abdominal pain)}\tabcellsep \tabcellsep 2 (abdominal pain and muscle pain/spasm)\tabcellsep \\
IV.\tabcellsep \tabcellsep \tabcellsep \tabcellsep \end{longtable} \par
 
\caption{\label{tab_8}Table 6 :}\end{figure}
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