Curcumagalactomannoside/Glucosamine Combination Improved Joint Health Among Osteoarthritic Subjects as Compared to Chondroitin Sulfate/Glucosamine: Double-Blinded,Randomized Controlled Study

Abstract

Objective:

A combination of curcumagalactomannosides (CGM) (400 mg) with glucosamine hydrochloride (GLN) (500 mg) was evaluated against a standard dietary supplement combination chondroitin sulfate (CHN) (415 mg)/GLN (500 mg) for their effectiveness in alleviating the pain and symptoms among osteoarthritic subjects.

Design:

Randomized, double-blinded and active-controlled study.

Settings/Location:

The study was conducted in a hospital-based research center in Vadodara, Gujarat, India.

Subjects:

Eighty subjects (38 males and 42 females), with confirmed osteoarthritis (OA) (Class I–III), were randomized into two parallel groups designated as Group I (CGM-GLN) and Group II (CHN-GLN).

Interventions:

All the study subjects were supplemented with their corresponding intervention capsules (ether CGM along with GLN or CHN along with GLN), as a single oral dose twice a day, once in the morning 10–15 min before breakfast and again in the evening before dinner, for 84 days.

Outcome measures:

A validated treadmill uphill walking protocol was used for the study, and the efficiency of supplementation was evaluated using visual analogue scale (VAS) score, Karnofsky Performance Scale (KPS) score, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire at the baseline, 28th, and 84th day following the treatment. Mechanism of action of CGM-GLN combination was analyzed by measuring the levels of serum inflammatory markers interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and soluble vascular cell adhesion molecule-1 (sVCAM) at the baseline and 84th day.

Results:

CGM-GLN was found to offer significant beneficial effects to pain, stiffness, and physical function of OA subjects compared with CHN-GLN, which was evident from the improvement in walking performance, VAS score, KPS score, and WOMAC score. The efficiency of CGM-GLN was almost double compared with the CHN-GLN by the end of the study (84th day). A significant reduction of inflammatory serum marker levels was observed among CGM-GLN subjects compared with CHN-GLN subjects. Compared with the baseline, CGM-GLN produced 54.52%, 59.08%, and 22.03% reduction in IL-1β, IL-6, and sVCAM levels, respectively. Whereas CHN-GLN group of subjects expressed only 23.17%, 21.38%, and 6.82% reduction in IL-1β, IL-6, and sVCAM levels, respectively.

Conclusions:

In conclusion, the present study demonstrated the potential benefits of CGM-GLN supplements in alleviating the symptoms and function of OA subjects compared with the standard CHN-GLN treatment. The augmented efficacy of CGM-GLN combination could be attributed to the enhanced anti-inflammatory effect of CGM.

Introduction

Osteoarthritis (OA) is a degenerative joint disease that commonly affects older people, causing pain, stiffness, and swelling leading to limited mobility. Approximately 50% of the world's elderly population older than 65 years were found to be affected by OA, which covers ∼15% of all musculoskeletal disorders.¹ India displays a higher prevalence of OA, with 22%–39% of the general population being affected, and the frequency increases dramatically with age.^2,3

Analgesics, COX-2 inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) are currently being used as effective pharmaceutical interventions in OA treatment.^4,5 However, the incidence of adverse events, especially gastrointestinal injuries, is a major concern that restricts the long-term or frequent use of these therapeutic agents.⁶ Although various herbal medications and physiotherapy were practiced in traditional medicine systems, their availability, regulatory restrictions, and lack of globally accepted standardisation methods limit their applicability. Dietary supplements and herbal formulations have recently been developed as a crucial part of therapeutic research and clinical practice in rheumatology and orthopedics, owing to their clinical efficacy, reduced toxicity, and adverse effects.^7,8

Turmeric (Curcuma longa L.) is a traditional drug well recognized for its wide range of pharmacologic activities, including anticancer, anti-inflammatory, neuroprotective, antioxidant, antimicrobial, cardioprotective, hypolipidemic, and antimutagenic properties.⁹ Different combinations and formulations of curcuminoids, the bioactive molecules in turmeric, have been demonstrated to be highly beneficial in improving the quality of life of OA patients.^10,11 Natural curcumin is a mixture of three significant curcuminoids (72%–78% curcumin, 12%–14% demethoxycurcumin, and 3%–5% bisdemethoxycurcumin), and its biological activities are vastly influenced by its poor solubility, low absorption, rapid metabolism, and quick systemic elimination.^12,13

Various formulations of curcumin with improved oral bioavailability of conjugated curcumin metabolites such as glucuronides and sulfates have been reported and are commercially available as “bioavailable” curcumin supplements.^14,15 Recently, curcumin glucuronides, the primary metabolites of curcumin, have been shown to exhibit weak antioxidant, anti-inflammatory, and antiproliferative effects when compared with their native unconjugated (free) form.^16,17 A water dispersible formulation of curcumin with soluble fenugreek dietary fiber (galactomannans), designated as curcumagalactomannosides (CGM), was demonstrated to have high free curcuminoids bioavailability in human subjects.¹⁸ It has also been shown to be safe and possess enhanced blood–brain barrier permeability and tissue distribution in rats when administered orally.^19,20 CGM was found to be highly beneficial in multiple sclerosis,²¹ improving cognition,²² ameliorating neurotoxicity,²³ reducing arterial stiffness,^24,25 modulating hepatic injury,^26,27 and relieving stress and anxiety.²⁸

Chondroprotectives such as chondroitin sulfate (CHN) and glucosamine hydrochloride (GLN) are broadly recommended by physicians for the treatment of knee OA.^29,30 The present study hypothesized that a combination of GLN with CGM would provide the better anti-arthritic effect than the standard combination of CHN-GLN because of its enhanced bioavailability and anti-inflammatory effect. In the present study, a combination of CGM with GLN (CGM-GLN) was compared with CHN-GLN combination (CHN-GLN) in subjects with Class I–III OA, and the efficacy was followed by standard questionnaires and analysis of serum inflammatory marker levels (interleukin 1 beta [IL-1β], interleukin 6 [IL-6], and soluble vascular cell adhesion molecule-1 [sVCAM]).

Materials and Methods

Materials

The intervention consisted of identical gelatin capsules filled with CGM, GLN, or CHN, provided by Akay Natural Ingredients, Cochin, India. The isolation of fenugreek soluble fiber and the preparation of CGM were performed as per the method of Krishnakumar et al.³¹ CGM capsule were composed of curcuminoid formulation with fenugreek fiber in a 35:65 (w/w) ratio, which consisted of 126.2 mg curcumin, 23.6 mg demethoxycurcumin, and 4.3 mg bisdemethoxycurcumin with a total curcuminoids content of 154.2 mg/400 mg.³¹ Each GLN capsule contained 500 mg GLN, and the CHN capsule encompassed 415 mg of CHN.

Study design and participants

The present randomized, double-blinded, parallel control study was conducted in a hospital-based research center in Vadodara, Gujarat, India. The duration of the study was 84 days. The study was performed in strict accordance with the Government of India's clinical research guidelines and was registered in the clinical trial registry of India (CTRI/2019/03/017954 dated March 7, 2019). The study protocol was approved by the registered ethical committee (Ref. ID. LCBS-OA-January 31, 2019), and written informed consent was obtained from all the study participants in agreement with the Declaration of Helsinki principles.

Subjects were requested to visit their designated study site on four different occasions, namely visit 1, screening and enrolment; visit 2, baseline/randomization (day 1); visit 3, follow-up visit (day 28); and visit 4, end of the study (day 84) (Fig. 1). The power used to calculate sample size is 80% and got a minimum sample size of 40 per arm required for the study. At visit 1, 104 subjects (aged 40–70 years), who were identified to have Class I–III OA based on Kellgren and Lawrence system,³² were screened for the study. Vital signs were assessed, and basic laboratory investigations were performed. All the subjects enrolled in the study were capable of performing the treadmill walking test and were able to understand the queries in the questionnaires.

FIG. 1.

CONSORT flow diagram of the study.

Subjects were assessed for Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire score after performing a 6-min treadmill walking test, and a cutoff point for the WOMAC score (total score ≥60) was enforced in subject recruitment, as a means of standardizing the extent of pain and immobility. Physical examination of the target knee was carried out, and the radiographic (X-ray) image of the target knee was acquired to measure the severity of the damage. Of the 104 individuals screened, a total of 80 subjects (38 males and 42 females) with confirmed OA (Class I–III) and satisfied all the other inclusion and exclusion criteria (Table 1) were enrolled for the study.

Table 1.

Inclusion and Exclusion Criteria for the Study

Inclusion criteria	Exclusion criteria
Male and female subjects, aged between 40 and 70 years, who understand the study procedures and are willing to comply and provide signed ICF	Subjects with any critical concomitant illness in the previous 6 months such as malignancies, hepatic injury, severe metabolic disorders including diabetes mellitus, nephropathy, gastrointestinal disorders, and history of cardiovascular, cerebrovascular, or autoimmune diseases
Subjects who have been newly diagnosed with mild-to-moderate primary knee OA (Class I–III) according to Kellgren–Lawrence Scale and confirmed by X-ray and are not currently taking any analgesics or anti-inflammatory medications	Subjects with any history of fracture involving the study joint or with any other type of arthritis or OA secondary to a known disorder such as rheumatoid arthritis, seronegative spondyloarthropathy, mixed connective tissue disease, collagen vascular disease, and psoriasis
Subjects who were capable of performing the treadmill walking test and were able to understand the questions provided in WOMAC questionnaire	Subjects who have been administered hyaluronic acid injections, glucosamine, and/or chondroitin-containing compounds within 7 days before the screening or those were on antibiotic, corticosteroids, or NSAIDs therapy for the past 6 months
Females of child-bearing age agree to use approved birth control methods during the study and confirm negative UPT at the screening	Individuals who had undergone surgery or arthroscopy within 3 months period before the inclusion and those with severe bone or joint deformation or conditions other than OA making the patient unable to walk
	Subjects who were known or suspected to be allergic to curcumin or any herbal products, smokers, alcoholics, and pregnant and lactating women

ICF, informed consent form; NSAIDs, nonsteroidal anti-inflammatory drugs; OA, osteoarthritis; UPT, urine pregnancy test; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

During visit 2, all the enrolled subjects were assigned with a computer-generated unique three-digit randomization code and were randomly distributed into two parallel groups designated as Group I (CGM-GLN) and Group II (CHN-GLN). All the participants were requested to perform a treadmill walking procedure, and the intensity of joint pain, stiffness, and physical function, experienced during the treadmill procedure, was assessed using WOMAC index, visual analogue scale (VAS) score, and Karnofsky Performance Scale (KPS) score at the baseline. Immediately after the baseline pain intensity scores were recorded, all the participants were provided with two intervention capsule bottles, one containing either CGM or CHN, and another containing GLN. The subjects were requested to consume one capsule from each bottle as a single oral dose, twice a day, once in the morning 10–15 min before breakfast and again in the evening before dinner. They were recommended to continue the treatment for another 84 days until the end of the study.

During visit 3 and visit 4 (28th and 84th day following the treatment), the participants were examined for the effectiveness of interventions in reducing the symptoms using the WOMAC, VAS, and KPS scores, by repeating the specified treadmill protocol. Fasting blood samples (5 mL) were collected from the peripheral vein of all the subjects at baseline and visit 4, for the analysis of inflammatory markers IL-1 β, IL-6, and sVCAM and safety markers. The inflammatory marker levels were measured using quantitative enzyme-linked immunosorbent assay (ELISA), on the same day of sample collection, maintaining similar experimental conditions for baseline and the end of the study samples. Subjects were also monitored weekly through regular telephonic follow-ups and short message services.

Treadmill performance, WOMAC, VAS, and KPS scores

For conducting a treadmill walking test, the subjects were requested to perform an initial familiarizing trial with a treadmill. Subjects were directed to walk at a pace of 4 ± 0.5 mph on the treadmill without elevation for 10 min. After this, a 10-min rest was allowed, and then, the subjects were again asked to perform an uphill walking procedure as described by Mangione et al.,³³ which is considered as the most appropriate treadmill protocol to induce knee pain similar to the real-life situations. The performance was evaluated by analyzing the total distance that could be covered without pain. Treadmill performance was noted at the baseline as well as at every subsequent clinical visit during the study.

The VAS score, which is a widely used unidimensional measure of pain intensity,^34,35 was evaluated at every clinical visit after treadmill performance. During the last 30 sec of each treadmill procedure, the subjects were requested to make a mark in the VAS line (mounted on a hard surface), which corresponds to their perceived intensity of knee pain during exercise.³⁶ The VAS score is determined by measuring the distance (mm) on the 10 cm line between the “no pain” anchor and the patient's mark, providing a range of scores from 0 to 100.³⁷ The VAS score was evaluated at every clinical visit after treadmill performance.

WOMAC score,^38
–40 which is the most widely used outcome measure in subjects with knee OA, was assessed at the baseline and the end of the study. A 24-item WOMAC questionnaire⁴¹ focusing on pain, stiffness, and functional limitation was provided, and the corresponding scores were self-marked by the respondent. Based on the total WOMAC score calculated by adding individual response scores, patients were categorized as low risk (score ≤60), moderate risk (score 60–80), and high risk (score ≥81). KPS score that describes the functional status and different levels of performance of the subject, as a comprehensive 11-point scale correlating with percentage values ranging from 100% (no evidence of disease, no symptoms) to 0% (death),^42
–44 was also evaluated at the baseline and the end of the study.

Analysis of inflammatory markers

Serum levels of IL-1β, IL-6, and sVCAM were measured by a quantitative ELISA using specific kits from Invitrogen, Life Technologies, CA, USA. Briefly, prediluted sera (50–100 μL) and serially diluted standard solutions (100 μL) were added to the precoated microtiter wells, followed by biotin-conjugated mouse anti-antibodies and streptavidin conjugated to horseradish peroxidase. Color was developed using 3,3,5,5-tetramethylbenzidine substrate and was measured at 450 nm using a spectrophotometer after the reaction was terminated with 1 M phosphoric acid. The concentrations of IL-1 β/IL-6/sVCAM in the samples were calculated by comparing the optical density of the samples with the standard curve. All the samples were determined in duplicate, and respective mean values were calculated.

Statistical analysis

Statistical analysis was performed using IBM SPSS Version 26 software. Mean and standard deviation for continuous variables and percentages for categorical variables were reported accordingly. Intergroup comparisons were performed using independent sample t-test, and paired fed comparisons within the groups were performed by repeated-measures analysis of variance (ANOVA). The p values <0.05 were considered as statistically significant.

Results

The anthropometric and biochemical parameters analyzed for different study groups at the baseline and on 84th day are given in Table 2. There was no statistically significant difference observed in the baseline anthropometric, demographic, and biochemical parameters among CGM-GLN and CHN-GLN group subjects. However, the body mass index (BMI) measurements of both the groups indicated the overweight status (25–30 kg/m²) as per the recommendations of the World Health Organization. There was a considerable reduction in the BMI of CGM-GLN-treated subjects on 84th day compared with the baseline. BMI reduced from 25.17 ± 1.08 to 24.10 ± 1.15 in the CGM-GLN group, whereas there was not much reduction in the BMI of the CHN-GLN group observed on the 84th day.

Table 2.

Demographic, Anthropometric, and Biochemical Parameters of the Study Groups

Parameter	CGM-GLN		CHN-GLN
Parameter	Baseline	84th day	Baseline	84th day
Age (years)	53.4 ± 6.64	—	51.5 ± 5.95	—
BMI (kg/m²)	25.17 ± 1.08	24.10 ± 1.15^***	25.01 ± 1.57	25.05 ± 1.61
SGOT (U/L)	24.48 ± 5.03	21.79 ± 3.27^**	22.86 ± 5.8	23.80 ± 4.38
SGPT (U/L)	26.86 ± 4.95	24.59 ± 4.09^*	24.4 ± 3.5	25.93 ± 4.81
Serum creatinine (mg/dL)	1.27 ± 0.07	1.26 ± 0.06	1.21 ± 0.11	1.24 ± 0.13
BUN (mg/dL)	16.13 ± 4.7	14.83 ± 1.06	13.87 ± 1.92	15.17 ± 1.4^*
TC (mg/dL)	184.71 ± 22.23	173.51 ± 20.16^*	174.73 ± 18.01	181.7 ± 20.56
TG (mg/dL)	123.96 ± 25.54	124.01 ± 27.55	121.01 ± 21.56	124.49 ± 16.01
LDL cholesterol (mg/dL)	118.69 ± 19.58	107.34 ± 20.23	106.42 ± 17.18	113.82 ± 20.76
HDL cholesterol (mg/dL)	44.10 ± 1.61	44.6 ± 1.28	44.08 ± 2.43	44.66 ± 1.94
VLDL(mg/dL)	24.78 ± 5.09	24.81 ± 5.51	24.20 ± 4.31	24.9 ± 3.20
TLC (cmm)	7575 ± 1291.08	7255 ± 1241.72	7725 ± 1343.58	7658.33 ± 1712.92
RBC (million/cmm)	5.298 ± 0.27	5.25 ± 0.92	4.93 ± 0.37	4.88 ± 0.32
Hb (g/dL)	13.45 ± 0.29	13.49 ± 0.35	13.39 ± 0.68	13.11 ± 0.47
HCT (%)	40.63 ± 1.11	40.17 ± 1.98	39.76 ± 1.47	40.13 ± 1.44
MCV (fL)	76.94 ± 5.20	79.88 ± 4.38	81 ± 5.5	82.4 ± 4.71
MCH (Pg)	25.44 ± 1.13	27.08 ± 1.56^*	27.26 ± 1.78	26.92 ± 1.29
MCHC (%)	33.12 ± 1.21	33.64 ± 1.16	33.68 ± 0.85	32.68 ± 1.15^*
Platelet (count/cmm)	283666.7 ± 26821.43	289750 ± 44217.5	268833.3 ± 48428.35	265083.3 ± 51655.04

p < 0.05, ^** p < 0.01, ^*** p < 0.001, baseline versus 84th day performed using paired sample t-test.

BMI, body mass index; SGOT, serum glutamate-oxaloacetate transaminase; SGPT, serum glutamate-pyruvate transaminase; BUN, blood urea nitrogen; TC, total blood count; TG, triacylglycerol; LDL, low-density lipoproteins (mg/dl); HDL, high-density lipoproteins; VLDL, very low-density lipoproteins; TLC, total leucocyte count; Hb, hemoglobin; HCT, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; CGM-GLN, curcumagalactomannosides with glucosamine hydrochloride; CHN-GLN, chondroitin sulfate-glucosamine hydrochloride.

Treadmill walking score

The variations in the walking performance of both the treatment groups are provided in Figure 2. The total distance covered without pain by the subjects who received CGM-GLN treatment at the baseline was 95.36 ± 14.68 m, and the performance was improved remarkably (mean difference of 301.35 ± 74.46; p < 0.001), covering 396.7 ± 89 m, indicating a fourfold enhancement in the performance by the end of the study period. Whereas CHN-GLN-treated group subjects presented only a minor improvement in the performance with a mean difference of only 89.78 ± 19.25 m (Table 3).

FIG. 2.

Variation in the treadmill performance and pain intensity scores of different treatment groups.

Table 3.

Changes in the Walking Performance and Pain Intensity from the Baseline to 84th Day

Treatment/groups	Group I (CGM-GLN)	Group II (CHN-GLN)	p
Treadmill walking score (m)
Baseline	92.30 ± 13.5	97.92 ± 14.41	0.000
84th Day	377.69 ± 80.48	187.73 ± 30.95
Difference	285.39 ± 67.13	89.81 ± 30.95^***
VAS score
Baseline	7.03 ± 0.5	6.59 ± 0.61	0.000
84th Day	2.80 ± 0.31	5.26 ± 0.45
Difference	4.23 ± 0.61	1.33 ± 0.32^***
KPS score
Baseline	62.31 ± 5.87	60 ± 8.49	0.001
84th Day	86.92 ± 6.18	76.15 ± 6.97
Difference	24.62 ± 6.47	16.15 ± 8.04^***

p Values measured using two-way repeated-measures analysis of variance performed for CGM-GLN versus CHN-GLN; ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001, versus the CGM-GLN group performed using independent sample t-test; p < 0.05 were considered as statistically significant.

KPS, Karnofsky Performance Scale; VAS, visual analogue scale.

VAS score

The difference in the VAS score, from the baseline to 84th day, of both the treatment groups is given in Figure 2. CGM-GLN-treated group subjects showed a significant reduction in VAS scores (60.46% improvement) on 84th day from the baseline (p < 0.001). The average difference in the VAS score of CGM-GLN-treated subjects was 4.27 ± 0.6. Whereas CHN-GLN-treated subjects exhibited only a moderate improvement (21.25%) in the intensity of pain, with an average difference of 1.4 ± 0.4.

KPS score

The change in the KPS scores among various treatment groups from the baseline to 84th day is given in Figure 2. There was a significant (p < 0.001) improvement in the performance of CGM-GLN-treated group subjects compared with CHN-GLN-treated subjects. The mean difference in the KPS score of CGM-GLN-treated subjects was 24.19 ± 6.20. Whereas CHN-GLN-treated subjects showed only moderate progress in the performance score (16.56 ± 7.45) (Table 2).

WOMAC score

In the present study, WOMAC scores for pain, stiffness, and functional performance were assessed individually, and the total score was calculated. The observations are given in Figure 3, and the difference in WOMAC scores from the baseline to 84th day among various treatment groups is presented in Table 4. A significant variation in the total WOMAC (p < 0.001) and pain intensity (p < 0.001) scores was observed in the CGM-GLN-treated group compared with the CHN-GLN-treated group. CGM-GLN was also good at easing the difficulty in physical function (p ≤ 0.001), with the combination being most effective. Stiffness scores were reduced moderately in CGM-GLN (p ≤ 0.05), with activity slightly higher than the standard drug (CHN-GLN).

FIG. 3.

Variation in the WOMAC scores of different treatment groups with days. WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Table 4.

Difference in the Total and Individual Western Ontario and McMaster Universities Osteoarthritis Index Scores from the Baseline to 84th Day

Treatments/groups	Total score	Pain score	Stiffness score	Difficulty score
Group I (CGM-GLN)	34.77 ± 8.33	7.58 ± 1.83	2.31 ± 1.35	24.88 ± 5.32
Group II (CHN-GLN)	18.12 ± 7.6^***	4.73 ± 1.9^***	1.73 ± 1.31^ns	11.65 ± 5.2^***
p	0.000	0.003	0.803	0.000

Effect on inflammatory markers

Figure 4 illustrates the inflammatory marker concentrations in the blood of treated subjects among various groups. The treatments with CGM-GLN have reduced IL-1β and IL-6 levels in the blood of treated subjects. There was a 54.52% reduction in the levels of IL-1β in the CGM-GLN-treated group. Correspondingly, 59.08% reduction in the concentration of IL-6 was also observed in the CGM-GLN-treated group. On the contrary, only a 23.17% and 21.38% reduction was found in the IL-1β and IL-6 marker levels, respectively, in the CHN-GLN-treated group. A similar trend was also detected in the level of sVCAM, another critical biomarker of the inflammatory process. There was a 22.03% and 6.82% reduction in the sVCAM levels identified in the serum of CGM-GLN- and CHN-GLN-treated subjects, respectively.

FIG. 4.

Effect of treatments on inflammatory markers levels in blood.

Discussion

The conventional mode of treating OA includes the use of NSAIDs, and their long-term use is associated with substantial risks on the cardiovascular and gastrointestinal system.^6,45 Being a chronic degenerative joint disorder, OA necessitates prolonged treatment. Therefore, the identification of safe and efficient natural agents is of great significance. Glucosamine and chondroitin being natural components of the healthy cartilage are believed to have a beneficial effect in alleviating the joint health problems of pain and stiffness and are currently available as an over-the-counter dietary supplement in the market.⁴⁶ However, there are conflicting studies reported on chondroitin and glucosamine; while a few are demonstrating its healing power,^47,48 some others have designating no beneficial effects over the placebo in repairing the cartilage or reducing the pain.^49
–51 Even though these compounds are being randomly used as supplements by OA patients, their therapeutic usage in the clinical setting is still uncertain.⁵² Reports from a double-blind, randomized, placebo-controlled clinical trial with a 2-year follow-up demonstrated that treatment with high doses of glucosamine sulfate (1500 mg/day) and CHN (800 mg/day) either individually or in combination, for 2 years, offered no significant symptomatic benefit over the placebo.⁵³ Moreover, some mild-to-moderate adverse effects such as headache, drowsiness, skin reactions, elevated blood pressure, nausea, and stomach upset have also been reported, mainly due to their high dosage of around 2.5 g/day.^48,51,54 Being manufactured from animal sources, such as shellfish or cow cartilage, GLN and CHN are also not suitable for vegetarians and those who are known to be allergic to shellfish.

The observations in the current study revealed the excellent curative effect of CGM in arthritic subjects when combined with GLN. While comparing with the dietary supplement combination (CHN-GLN), very often recommended by the clinicians for the treatment of OA, the CGM-GLN combination expressed almost threefold enhancement in walking performance and twofold efficacy in the reduction of pain intensity scores. CGM-GLN was also found to be highly effective in reducing knee stiffness and significantly improved physical function. The improvement in the walking performance, physical function, VAS score, KPS score, and total WOMAC scores of subjects was evident on the 28th day itself, and the treatment with CGM-GLN maintained substantial progress until the end of the study (84th day) (Figs. 2 and 3). Hence the combination of CGM and glucosamine, which has established to possess dual potency, can be considered as a safer alternative to the standard CHN-GLN combination.

OA mainly develops due to the damage or break in the cartilage that acts as a cushion between the bones in a joint. Deterioration in the cartilage triggers inflammation causing swelling, pain, and stiffness leading to functional impairment and chronic disability. The imbalance of inflammatory signaling in the chondrocytes and synovial cells, with abnormal activation of cytokine cascade and overproduction of inflammatory mediators, is the characteristic of OA.⁵⁵ IL-1β and IL-6 are the major proinflammatory cytokines involved in the pathophysiology of OA.⁵⁶ The upregulation of these inflammatory cytokines leads to the activation of arthritic-relevant proteases such as ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) and matrix metalloproteinase leading to subsequent deterioration in collagen synthesis.⁵⁷ Inflammatory cytokines can also induce nerve growth factor, which acts as a sensitizer of pain in OA.⁵⁸

Synovitis is another crucial factor to be considered in OA as the symptoms such as pain, aching, or stiffness are vastly heterogeneous.⁵⁹ sVCAM, an inducible cell surface sialoglycoprotein, serves as a critical synovial inflammatory marker associated with joint pain, aching, and stiffness.⁶⁰ sVCAM plays a crucial role in the development of inflammation by mediating the adhesion of monocytes, lymphocytes, basophils, and eosinophils to vascular endothelium⁶¹ and may function as an indicator of a symptomatic inflammatory OA endotype.⁶⁰

In the present study, CGM-GLN intervention could significantly inhibit the production of inflammatory cytokines IL-1β, IL-6, and sVCAM in human subjects, thus preventing the induction of pain and cartilage degradation. The chondroprotective effect of CGM-GLN could be mainly attributed to the anti-inflammatory effect of CGM, which has been shown to be mediated through the regulation of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway, cytokines, and adhesion molecules.⁶² Furthermore, curcumin was proven to inhibit matrix degradation^63,64 and accelerate matrix synthesis by refurbishing type II collagen and glycosaminoglycan synthesis.^65,66

But, the anti-inflammatory effect of GLN and CHN was reported to be marginal. In an earlier in vitro model of OA, GLN declined the release of inflammatory markers, while CHN did not show any significant effect.⁶⁷ A clinical study to evaluate the impact of GLN-CHN combination (1500 mg GLN and 1200 mg CHN) on synovial fluid IL-1β, IL-6, tumor necrosis factor alpha (TNF-α), and PGE2 levels in internal derangements of temporomandibular joint; the treatment group showed a significant decrease in PGE2 level while there was only a nonsignificant decrease in IL-1β, IL-6, and TNF-α levels.⁶⁸

OA is more prevalent among obese individuals than people with healthy BMI, affecting their quality of life. CGM-GLN-supplemented subjects in the present study showed a decrease in BMI. This observation is fascinating because bodyweight management is considered to be highly advantageous for the reduction of pain and other symptoms in obese arthritis patients.^69,70 Fenugreek dietary fiber used in the formulation of CGM could be a reason for the observed bodyweight reduction. Fenugreek dietary fiber has been proven to have a significant prebiotic effect in regulating the intestinal microbiota leading to a healthier flora and exerts a positive influence on bodyweight, glycemic control, immune responses, and liver beta-oxidation.^71
–73 Fenugreek seed extract inhibited fat accumulation and improved dyslipidemia in high-fat diet-induced obese rats.⁷⁴ It was found to improve high-density lipoprotein (HDL) to low-density lipoprotein (LDL) ratio without disturbing circulating triglycerides, total cholesterol, or glycerol levels in high fat-fed mice.⁷⁵ Fenugreek supplementation was also demonstrated to promote metabolic resiliency via its specified influence on hyperlipidemia, adipose pathology, and glucose regulation.⁷⁵

Conclusions

In summary, CGM can be used as an adjuvant with GLN for the management of Class I–III knee OA instead of NSAIDs. CGM-GLN combination possesses remarkable benefits over the standard dietary supplement chondroitin, in managing of pain and inflammation of OA patients with an added advantage of plausible weight reduction. More studies in a large and diverse osteoarthritic population with longer duration and X-ray analysis of the knee would add more values to the results of the present study. Experiments should also be planned to discover other possible mechanisms of CGM with particular emphasis on different inflammatory and metabolic pathways.

Footnotes

Acknowledgments

The authors thank M/s Akay Natural Ingredients Pvt. Ltd., Cochin, India, for providing the study samples. The authors are grateful to Dr. Ramadasan Kuttan, former Director of Research at Amala Cancer Research Centre, Thrissur, India, for the advice on study and preliminary anti-inflammatory screening of CGM combinations with CHN and GLN.

Author Disclosure Statement

The authors disclose the following conflict of interest. “CurQfen^®” is the registered trademark of M/s Akay Natural Ingredients Pvt. Ltd., Cochin, India, for CGM. S.S.D., T.P.S., B.M., and I.M.K. belong to the company M/s Akay Natural Ingredients Pvt. Ltd. (Cochin, India), who prepared the study drugs, conceived the idea, and approved the protocol. A.K. is the PI who conducted the study. J.V.T. belongs to a contract clinical research organization (Leads Clinical Research & Bio Services Pvt. Ltd., Bangalore, India), which conducted and monitored the present human intervention study as per CTRI norms. A.B.K. belongs to a nonprofit research organization that critically evaluated the data and does not have any conflict of interest. R.M. belongs to a nonprofit research institution and was involved in the protocol designing, data analysis, and evaluation of the article. The sponsoring company has no role in the conduction of the study, data analysis, interpretation of the results, and drafting of the article.

Funding Information

This study was supported by M/s Akay Natural Ingredients Pvt. Ltd., Cochin, India, under Spiceuticals^® development program (AKAY/SB/R&D/02/2017-19).

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