Chondroitin sulfate is a glycosaminoglycan (often shortened to the abbreviation GAG) which, is one of a group of compounds that makes up cartilage, connective tissue, bone, and skin. It helps extend the life and activity of cartilage-producing cells called chondrocytes, reduces inflammation, and strengthens the load-bearing bones in the joints that sit just under the cartilage, called “subchondral” bone. Often used in combination with glucosamine, chondroitin can help relieve pain by stopping joint damage, and in many cases, restoring mobility. And even used alone, chondroitin has been shown to reduce pain sensation on MRI brain scans of patients in a clinical study.

Study Results Summary – Joint Support Nutrients: Chondroitin Sulfate, Glucosamine Hydrochloride, Hyaluronic acid/Polysaccharides/Collagen

Chondroitin Sulfate – Clinical Trials

1. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus Celecoxib versus Placebo Trial (CONCEPT). OBJECTIVES: Chondroitin sulfate 800 mg/day (CS) pharmaceutical-grade in the management of symptomatic knee osteoarthritis consistent with the European Medicines Agency guideline. METHODS: A prospective, randomised, 6-month, 3-arm, double-blind, double-dummy, placebo and celecoxib (200 mg/day)-controlled trial assessing changes in pain on a Visual Analogue Scale (VAS) and in the Lequesne Index (LI) as coprimary endpoints. Minimal-Clinically Important Improvement (MCII), Patient-Acceptable Symptoms State (PASS) were used as secondary endpoints. RESULTS: 604 patients (knee osteoarthritis) diagnosed according to American College of Rheumalogy (ACR) criteria, recruited in five European countries and followed for 182 days. CS and celecoxib showed a greater significant reduction in pain and LI than placebo. In the intention-to-treat (ITT) population, pain reduction in VAS at day 182 in the CS group (-42.6 mm) and in celecoxib group (- 39.5 mm) was significantly greater than the placebo group (-33.3 mm) (p=0.001 for CS and p=0.009 for celecoxib), while no difference observed between CS and celecoxib. Similar trend for the LI, as reduction in this metric in the CS group (-4.7) and celecoxib group (-4.6) was significantly greater than the placebo group (-3.7) (p=0.023 for CS and p=0.015 for celecoxib), no difference was observed between CS and celecoxib. Both secondary endpoints (MCII and PASS) at day 182 improved significantly in the CS and celecoxib groups. All treatments demonstrated excellent safety profiles. CONCLUSION: A 800 mg/day pharmaceutical-grade CS is superior to placebo and similar to celecoxib in reducing pain and improving function over 6 months in symptomatic knee osteoarthritis (OA) patients. This formulation of CS should be considered a first-line treatment in the medical management of knee OA. [Reginster JY, Dudler J, Blicharski T, Pavelka K. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus Celecoxib versus Placebo Trial (CONCEPT). Ann Rheum Dis. 2017 Sep;76(9):1537-1543.

2. Effects of chondroitin sulphate on synovitis of knee osteoarthritis patients. OBJECTIVE: To evaluate by ultrasonography the effect of chondroitin sulfate (CS) on synovitis in patients with knee osteoarthritis (KOA). To collaborate in the understanding of the biochemical mechanisms involved in the synovial inflammation process. METHODS: Randomized, single-blind, controlled trial involving 70 patients with primary KOA treated for 6 months with CS or acetaminophen (ACT). Evaluation of KOA status at baseline, 6 weeks, 3 and 6 months included: ultrasonography to assess synovitis (following the OMERACT expertise group definition), visual analogue scale and Lequesne index to measure pain and function, and ELISA to quantify inflammatory 7/18/2019 mediators in serum and synovial fluid. RESULTS: Synovitis presence was reduced by 50% in the CS group while a 123% increase was observed in ACT group. Conversely, patients without initial synovitis and treated with ACT reached 85.71% synovitis onset, but only 25% in CS group. Both therapies improved articular function, but only CS resulted in significant pain improvement at the end of the treatment. Changes in RANTES and UCN synovial fluid concentration were associated with CS treatment. CONCLUSIONS: Treatment with CS had a sustained beneficial effect, preventing synovitis onset or reducing its presence as well as reducing KOA symptoms. ACT ameliorated clinical symptoms but had no effect on inflammation. The CS antiinflammatory effect could be related to the observed changes in RANTES and UCN concentration. [Tio L, et al. Effect of chondroitin sulphate on synovitis of knee osteoarthritic patients. Med Clin (Barc). 2017 Jul 7;149(10:9-16.)

3. Effects of chondroitin sulfate on brain response to painful stimulation in knee osteoarthritis patients. A randomized, double-blind, placebo-controlled functional magnetic resonance imaging study. INTRODUCTION: Knee osteoarthritis is causing pain and functional disability. One of the inherent problems with efficacy assessment of pain medication was the lack of objective pain measurements, but functional magnetic resonance imaging (fMRI) has emerged as a useful means to objectify brain response to painful stimulation. We have investigated the effect of chondroitin sulfate (CS) on brain response to knee painful stimulation in patients with knee osteoarthritis using fMRI. METHODS: Twenty-two patients received CS (800mg/day) and 27 patients placebo, and were assessed at baseline and after 4 months of treatment. Two fMRI tests were conducted in each session by applying painful pressure on the knee interline and on the patella surface. The outcome measurement was attenuation of the response evoked by knee painful stimulation in the brain. RESULTS: fMRI of patella pain showed significantly greater activation reduction under CS compared with placebo in the region of the mesencephalic periaquecductal gray. The CS group, additionally showed pre/post-treatment activation reduction in the cortical representation of the leg. No effects of CS were detected using the interline pressure test. CONCLUSIONS: fMRI was sensitive to objectify CS effects on brain response to painful pressure on patellofemoral cartilage, which is consistent with the known CS action on chondrocyte regeneration. The current work yields further support to the utility of fMRI to objectify treatment effects on osteoarthritis pain. [Monfort J, et al. Effects of chondroitin sulfate on brain response to painful stimulation in knee osteoarthritis patients. A randomized, double-blind, placebo-controlled functional magnetic resonance imaging study. Med Clin (Barc). 2017 Jun 21;148(12):539-547.]

4. Chondroitin sulfate efficacy versus celecoxib on knee osteoarthritis structural changes using magnetic resonance imaging: a 2-year multicentre exploratory study. BACKGROUND: In osteoarthritis (OA) treatment, although chondroitin sulfate (CS) was found in a number of studies using radiography to have a structure-modifying effect, to date CS use is still under debate. A clinical study using quantitative magnetic resonance imaging (qMRI) is therefore of the utmost importance. Here we report data from a 24- month, randomised, double-blind, double-dummy, controlled, comparative exploratory 7/18/2019 study of knee OA. The primary endpoint was to determine the effect of CS 1200 mg/day versus celecoxib 200 mg/day on cartilage volume loss (CVL) in the lateral compartment over time as measured by qMRI. Secondary endpoints included assessment of the OA structural changes and signs and symptoms of OA. METHODS: qMRI was performed at baseline and at 12 and 24 months. CVL, bone marrow lesion size, and synovial thickness were evaluated using qMRI. The primary statistical analysis was carried out on the modified intention-to-treat (mITT) population (n = 138) using chi-squared, Fisher’s exact, Wilcoxon Mann-Whitney, and Student’s t tests and analysis of covariance. Analyses were also conducted on the according-to-protocol (ATP; n = 120) population. RESULTS: In the adjusted mITT analysis, compared with celecoxib treatment, patients treated with CS had a significant reduced CVL at 24 months in the medial compartment (celecoxib -8.1 % ± 4.2, CS -6.3 % ± 3.2; p = 0.018) and medial condyle (-7.7 % ± 4.7, -5.5 % ± 3.9; p = 0.008); no significant effect was seen in the lateral compartment. In the ATP population, CS reduced CVL in the medial compartment at 12 months (celecoxib -5.6 % ± 3.0, CS -4.5 % ± 2.6; p = 0.049) and 24 months (celecoxib -8.4 % ± 4.2, CS -6.6 % ± 3.3; p = 0.021), and in the medial condyle at 24 months (celocoxib -8.1 % ± 4.7, CS – 5.7 % ± 4.0; p = 0.010). A trend towards a statistically reduced synovial thickness (celecoxib +17.96 ± 33.73 mm, CS -0.66 ± 22.72 mm; p = 0.076) in the medial suprapatellar bursa was observed in CS patients. Both groups experienced a marked reduction in the incidence of patients with joint swelling/effusion and in symptoms over time. Data showed similar good safety profiles including cardiovascular adverse events for both drugs. CONCLUSION: This study demonstrated, for the first time in a 2-year randomised controlled trial using qMRI, the superiority of CS over celecoxib at reducing CVL in knee OA patients. [Pelletier JP, et al. Chondroitin sulfate efficacy versus celecoxib on knee osteoarthritis structural changes using magnetic resonance imaging: a 2-year multicentre exploratory study. Arthritis Res Ther. 2016 Nov3;18(1):256.

5. Total Knee Replacement as a Knee Osteoarthritis Outcome: Predictors Derived from a 4-Year Long-Term Observation following a Randomized Clinical Trial Using Chondroitin Sulfate. OBJECTIVE: To predict, using clinical and qMRI data, the incidence of total knee replacement (TKR) during the long-term follow-up of knee osteoarthritis (OA) patients who formerly received chondroitin sulfate (CS) or placebo treatment. DESIGN: A post hoc intention-to-treat analysis to evaluate the incidence of TKR was done on knee OA patients who had participated in a 12-month trial evaluating the impact of CS (800 mg/d) versus placebo for 6 months, followed by a 6-month openphase in which all patients received CS. Additionally, the clinical and qMRI predictors of TKR were determined. RESULTS: Thirteen TKRs were performed in the population after a 4-year follow-up. More TKRs were performed in the placebo group than in the CS group (69% vs. 31%, P = 0.150, logistic regression). The statistically significant predictors of TKRs were, at baseline, higher WOMAC pain and function scores, presence of bone marrow lesions (BMLs), and higher C-reactive protein levels. Loss of medial cartilage volume and increase in WOMAC pain and function at one-year were also predictors of TKR. Multivariate analyses revealed that baseline presence of BML and higher WOMAC pain score were independent predictors. Time to occurrence of the TKR 7/18/2019 also favored the CS group versus placebo (log-rank, P = 0.094). CONCLUSION: Symptoms such as knee pain and function, presence of BML, and cartilage volume loss predict the long-term occurrence of a “hard” outcome such as TKR. [Raynauld JP, et al. Total Knee Replacement as a Knee Osteoarthritis Outcome: Predictors Derived from a 4- Year Long-Term Observation following a Randomized Clinical Trial Using Chondroitin Sulfate. Cartilage. 2013 Jul;4(3):219-226.] 6. Equivalence of a single dose (1200 mg) compared to a three-time a day dose (400 mg) of chondroitin 4&6 sulfate in patients with knee osteoarthritis. Results of a randomized double blind placebo controlled study. OBJECTIVE: Evaluation of the efficacy and safety of a single oral dose of a 1200 mg sachet of chondroitin 4&6 sulfate (CS 1200) vs three daily capsules of chondroitin 4&6 sulfate 400 mg (CS 3*400) (equivalence study) and vs placebo (superiority study) during 3 months, in patients with knee osteoarthritis (OA). DESIGN: Comparative, double-blind, randomized, multicenter study, including 353 patients of both genders over 45 years with knee OA. Minimum inclusion criteria were a Lequesne index (LI) ≥ 7 and pain ≥ 40 mm on a visual analogue scale (VAS). LI and VAS were assessed at baseline and after 1-3 months. Equivalence between CS was tested using the per-protocol procedure and superiority of CS vs placebo was tested using an intent-to-treat procedure. RESULTS: After 3 months of follow-up, no significant difference was demonstrated between the oral daily single dose of CS 1200 formulation and the three daily capsules of CS 400. Patients treated with CS 1200 or CS 3*400 were significantly improved compared to placebo after 3 months of follow-up in terms of LI (<0.001) and VAS (P < 0.01). No significant difference in terms of security and tolerability was observed between the three groups. CONCLUSION: This study suggests that a daily administration of an oral sachet of 1200 mg of chondroitin 4&6 sulfate allows a significant clinical improvement compared to a placebo, and a similar improvement when compared to a regimen of three daily capsules of 400 mg of the same active ingredient. [Zegels B, Crozes P, Uebelhart D, Bruyere O, Reginster JY. Equivalence of a single dose (1200 mg) compared to a three-time a day dose (400 mg) of chondroitin 4&6 sulfate in patients with knee osteoarthritis. Results of a randomized double blind placebo controlled study. Osteoarthritis Cartilage. 2013 Jan;21(1):22-27.

7. Symptomatic effects of chondroitin 4 and chondroitin 6 sulfate on hand osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial at a single center. OBJECTIVE: To evaluate the symptomatic effects of highly purified chondroitin 4 and chondroitin 6 sulfate (CS) therapy in patients with osteoarthritis (OA) of the hand. METHODS: This investigator-initiated, single-center, randomized, doubleblind, placebo-controlled clinical trial included 162 symptomatic patients with radiographic evidence of hand OA (American College of Rheumatology criteria). Inclusion criteria included patient’s assessment of global spontaneous hand pain of at least 40 mm on a 0-100-mm visual analog scale (VAS) and functional impairment of at least 6 (0-30 scale) on the Functional Index for Hand OA (FIHOA) in the most symptomatic hand. Patients received either 800 mg of CS (n = 80 patients) or placebo (n = 82 patients) once daily for 6 months and were analyzed in an intent-to-treat approach. The two primary outcomes were the change in the patient’s assessment of global 7/18/2019 spontaneous hand pain and in hand function (by FIHOA score) from baseline to month 6. Secondary outcomes were improvement in grip strength, duration of morning stiffness, acetaminophen consumption, and the investigator’s global impression of treatment efficacy. RESULTS: There was a significantly more pronounced decrease in the patient’s global assessment of hand pain in the CS group than in the placebo group (difference VAS scores -8.7 mm; P = 0.016). Hand function improved significantly more in the CS group than in the placebo group (difference in FIHOA scores -2.14; P = 0.008). There was a statistically significant between-group difference in favor of CS for the duration of morning stiffness and for the investigator’s global impression of treatment efficacy. Changes in grip strength, acetaminophen consumption, and safety end points were not significantly different between the two groups. CONCLUSION: This study demonstrates that CS improves hand pain and function in patients with symptomatic OA of the hand and shows a good safety profile. [Gabay C, Medinger-Sadowski C, Gascon D, Kolo F, Finckh A. Symptomatic effects of chondroitin 4 and chondroitin 6 sulfate on hand osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial at a single center. Arthritis Rheum. 2011 Nov;63(11):3383-3391.

8. Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis patients starting as early as 6 months after initiation of therapy: a randomized, double-blind, placebo-controlled pilot study using MRI. OBJECTIVE: To determine the effect of chondroitin sulphate (CS) treatment on cartilage volume loss, subchondral bone marrow lesions (BML), synovitis and disease symptoms in patients with knee osteoarthritis (OA). METHODS: In this pilot multicentre, randomised, double-blind, controlled trial in primary knee OA, 69 patients with clinical signs of synovitis were randomised to receive CS 800 mg or placebo once daily for 6 months followed by an open-label phase of 6 months in which patients in both groups received CS 800 mg once daily. Cartilage volume and BML were assessed by MRI at baseline and at 6 and 12 months; synovial membrane thickness was assessed at baseline and at 6 months. RESULTS: The CS group showed significantly less cartilage volume loss than the placebo group as early as 6 months for the global knee (p=0.030), lateral compartment (p=0.015) and tibial plateaus (p=0.002), with significance persisting at 12 months. Significantly lower BML scores were found for the CS group at 12 months in the lateral compartment (p=0.035) and the lateral femoral condyle (p=0.044). Disease symptoms were similar between the two groups. CONCLUSION: CS treatment significantly reduced the cartilage volume loss in knee OA starting at 6 months of treatment, and BML at 12 months. These findings suggest a joint structure protective effect of CS and provide new in vivo information on its mode of action in knee OA. [Wildi LM, et al. Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis patients starting as early as 6 months after initiation of therapy: a randomized, double-blind, placebo-controlled pilot study using MRI. Ann Rheum Dis. 2011 Jun;70(6):982-989.

9. Effectiveness of chondroitin sulphate in patients with concomitant knee osteoarthritis and psoriasis: a randomized, double-blind, placebo-controlled study. OBJECTIVE: The aim of the trial was to assess the efficacy of chondroitin sulphate (CS) 7/18/2019 on symptomatic knee osteoarthritis (OA) associated to psoriasis. METHODS: In this randomized, double-blind, placebo (PBO)-controlled clinical trial 129 patients with symptomatic knee OA and concomitant psoriasis were randomized into two groups receiving 800 mg daily of CS or PBO for 3 months. The primary efficacy outcome for knee OA was the Huskisson’s visual analogue scale (VAS) and for psoriasis was the Psoriasis Area and Severity Index (PASI). Additionally, other secondary efficacy criteria for both conditions were assessed. RESULTS: After 3 months of treatment, CS was more effective than PBO, relieving pain VAS (CS -26.9+/-24.8 vs PBO -14.23+/-20.8mm, P<0.01), decreasing the Lequesne index (CS -4.8+/-3.4 vs PBO -3.3+/-3.5, P<0.05) and reducing the number of patients using acetaminophen as rescue medication (CS 43% vs PBO 64%, P<0.05). Regarding PASI, Overall Lesion Severity Scale and Physician’s Global Assessment of Change no statistically significant changes were detected in front of PBO. However, CS improved plantar psoriasis compared to PBO (CS 87% vs PBO 27%, P<0.05). Quality of life improved significantly in CS-treated patients according to the Short Form-36 health survey and the Dermatology Life Quality Index (DLQI). CS tolerability was excellent. Adverse events were infrequent and evenly distributed among groups. The incidence of psoriatic flares did not increase after treatments. CONCLUSIONS: This study confirms the efficacy and safety of CS as a symptomatic slow-acting drug in patients with knee OA and shows that CS improves plantar psoriasis. The use of CS could represent a special benefit in patients with both pathologies since non-steroidal anti-inflammatory drugs have been reported to induce or exacerbate psoriasis. [Moller I, et al. Effectiveness of chondroitin sulphate in patients with concomitant knee osteoarthritis and psoriasis: a randomized, double-blind, placebo controlled trial. Osteoarthritis Cartilage. 2010 Jun;18 Suppl 1:S32-40.

10. Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trials. OBJECTIVE: To assess the long-term effects of chondroitins 4 and 6 sulfate (CS) on the radiographic progression of, and symptom changes associated with, knee osteoarthritis (OA). METHODS: We performed an international, randomized, double-blind, placebo-controlled trial in which 622 patients with knee OA were randomly assigned to receive either 800 mg CS (n = 309 patients) or placebo (n = 313 patients) once daily for 2 years. Radiographs of the target knee, using the Lyon schuss view, were obtained at the time of enrollment and at 12, 18, and 24 months. The minimum joint space width (JSW) of the medial compartment of the tibiofemoral joint was assessed by digital image analysis. The primary outcome was the loss in minimum JSW over 2 years. RESULTS: The intent-to-treat analysis demonstrated a significant reduction (P < 0.0001) in minimum JSW loss in the CS group (mean +/- SEM -0.07 +/- 0.03 mm) as compared with the placebo group (-0.31 +/- 0.04 mm). The percentage of patients with radiographic progression > or =0.25 mm was significantly reduced in the CS group compared with the placebo group (28% versus 41% [P < 0.0005]; relative risk reduction 33% [95% confidence interval 16-46%]). The number of patients needed to treat was 8 (95% confidence interval 5-17). Pain improved significantly faster in the CS group than in the placebo group (P < 0.01). There were no differences in safety between groups. 7/18/2019 CONCLUSION: The long-term combined structure-modifying and symptom-modifying. [Kahan A, Uebelhart D, De Vathaire F, Delmas PD, Reginster JY. Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2009 Feb;60(2):524-533.

11. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. OBJECTIVE: To determine whether chondroitin sulfate (CS) is effective in inhibiting cartilage loss in knee osteoarthritis (OA). METHODS: In this randomized, double-blind, placebo-controlled trial, 300 patients with knee OA were recruited from an outpatient clinic, from private practices, and through advertisements. Study patients were randomly assigned to receive either 800 mg CS or placebo once daily for 2 years. The primary outcome was joint space loss over 2 years as assessed by a posteroanterior radiograph of the knee in flexion; secondary outcomes included pain and function. RESULTS: Of 341 patients screened, 300 entered the study and were included in the intent-to-treat analysis. The 150 patients receiving placebo had progressive joint space narrowing, with a mean +/- SD joint space loss of 0.14 +/- 0.61 mm after 2 years (P = 0.001 compared with baseline). In contrast, there was no change in mean joint space width for the 150 patients receiving CS (0.00 +/- 0.53 mm; P not significant compared with baseline). Similar results were found for minimum joint space narrowing. The differences in loss of joint space between the two groups were significant for mean joint space width (0.14 +/- 0.57 mm; P = 0.04) and for minimum joint space width (0.12 +/- 0.52 mm; P = 0.05). CS was well tolerated, with no significant differences in rates of adverse events between the two groups. CONCLUSION: While there was no significant symptomatic effect in this study, long-term treatment with CS may retard radiographic progression in patients with OA of the knee. However, the clinical relevance of the observed structural results has to be further evaluated, and further studies are needed to confirm the structural effects of CS. [Michel BA, et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis Rheum. 2005 Mar;52(3):779-786.

12. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a oneyear, randomized, double-blind, multicenter study versus placebo. OBJE-CTIVE: To investigate the efficacy and tolerability of a 3-month duration, twice a-year, intermittent treatment with oral chondroitin sulfate (CS) in knee osteoarthritis (OA) patients. DESIGN: A total of 120 patients with symptomatic knee OA were randomized into two groups receiving either 800mg CS or placebo (PBO) per day for two periods of 3 months during 1 year. Primary efficacy outcome was Lequesne’s algo-functional index (AFI); secondary outcome parameters included VAS, walking time, global judgment, and paracetamol consumption. Radiological progression was assessed by automatic measurement of medial femoro-tibial joint space width on weight-bearing X-rays of both knees. Clinical and biological tolerability was assessed. RESULTS: One hundred and ten of 120 patients were included in the ITT analysis. AFI decreased significantly by 36% in the CS group after 1 year as compared to 23% in the PBO group. Similar results were found for the secondary outcomes parameters. Radiological progression at month 12 7/18/2019 showed significantly decreased joint space width in the PBO group with no change in the CS group. Tolerability was good with only minor adverse events identically observed in both groups. CONCLUSION: This study provides evidences that oral CS decreased pain and improved knee function. The 3-month intermittent administration of 800mg/day of oral CS twice a year does support the prolonged effect known with symptom-modifying agents for OA. The inhibitory effect of CS on the radiological progression of the medial femoro-tibial joint space narrowing could suggest further evidence of its structuremodifying properties in knee OA. [Uebelhart D, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage. 2004 Apr;12(4):269-279.

13. Systems to assess the progression of finger joint osteoarthritis and the effects of disease modifying osteoarthritis drugs. Our objective was to assess the progression of osteoarthritis (OA) using scoring systems based on the anatomical changes recorded in the finger joints on standard radiographs and to test how far these scoring systems could be used to evaluate the effects of candidate “disease modifying osteoarthritis drugs” (DMOAD). The appearance and growth of osteophytes, narrowing of the joint space and subchondral bone changes allowed the classic OA-associated anatomical lesions to be used to score the progression of finger joint OA. Progression of OA in the finger joints was also assessed by the their evolution through previously described and predictable anatomical phases on standard X-rays. These phases were characterised by complete loss of the joint space preceding or coinciding with the appearance of subchondral cysts eroding the entire subchondral plate, and have been described in “inflammatory” or “erosive” OA. The erosive episodes were followed by processes of remodelling. In order to interfere with the progression of osteoarthritis, two chondroitin sulphates with possible DMOAD effects were used in two series of patients with OA of the finger joints. The patients were included in two separate randomised, double-blind placebo-controlled trials: 46 of them received chondroitin polysulphate and 34 received chondroitin sulphate. Eighty-five patients were kept on placebo medication and were used as controls. All 165 patients were followed for 3 years. Posteroanterior X-rays of the metacarpophalangeal and interphalangeal (IP) finger joints were obtained at the start of this prospective study and at yearly intervals thereafter. Almost 80% of the distal IP and 50% of the proximal IP were affected at study entry. In approximately 40% of the patients the classic picture of OA of the IP joints was complicated by manifest erosive OA changes. The two systems to score the progression of OA (Anatomical Lesion and Anatomical Phase Progression Score System) showed definite progression within 3 years of follow-up, especially in the IP joints. When compared with the placebo controls, none of the chondroitin sulphates prevented OA from occurring in previously normal finger joints. However, when the classic OA-associated anatomical lesions were considered, OA was less progressive in both active treatment groups. Furthermore, fewer patients from both chondroitin sulphate- and chondroitin polysulphate-treated groups developed “erosive” osteoarthritis. In conclusion, conventional radiographs can be used to assess the morbidity and progression of hand OA. The systemsused to score the progression of finger joint OA allowed the DMOAD effects of both chondroitin sulphates to be evaluated. The data 7/18/2019 recorded during these pilot studies should help investigators to design future long-term clinical experiments. [Verbruggen G, Goemaere S, Veys EM. Systems to assess the progression of finger joint osteoarthritis and the effects of diseases modifying osteoarthritis drugs. Clin Rheumatol. 2002 Jun;21(3):231-243.

14. Anti-inflammatory activity of chondroitin sulfate. The pharmacokinetics of chondroitin sulfate (CS, Condrosulf, IBSA, Lugano, Switzerland) were investigated in rats and in healthy volunteers using CS tritiated at the reducing end and CS labeled with 131I or 99mTc respectively. A rapid absorption of orally administered CS is observed in rats and in humans when the drug is dissolved in water. Lower and delayed absorption is observed when CS is administered in gastroresistant capsules. The absolute bioavailability is 15 and 12% for rats and humans respectively. The CS shows a tropism for cartilagineous tissues in rats and for knee tissues in humans as demonstrated by scintigraphic analysis with 99mTc-CS. Monomers, oligo and polysaccharides produced by enzymatic hydrolysis of CS appear in the blood and tissues together with native CS. The effects of partially depolymerized (m.m. 3 to 15 kD) and desulfated fractions on human leukocytes were investigated. CS and its fractions inhibit the directional chemotaxis induced by zymosan-activated serum, are able to decrease the phagocytosis and the release of lysozyme induced by zymosan and to protect the plasma membrane from oxygen reactive species. In rats the oral administration of CS significantly decreases granuloma formation due to sponge implants and cell migration and lysosomal enzyme release in carrageenan pleurisy. Compared with nonsteroidal anti-inflammatory drugs (indomethacin, ibuprofen), CS appears to be more effective on cellular events of inflammation than on edema formation. It is noteworthy that CS is devoid of dangerous effects on the stomach, platelets and kidneys. In synovial fluid of patients requiring joint aspiration, treated orally for 10 days with CS (800 mg/day) the hyaluronate concentration and the intrinsic viscosity significantly increased, while collagenolytic activity, phospholipase A2 and N-acetylglucosaminidase (NAG) decreased. These results give an insight into the mechanism of the anti-inflammatory and chondroprotective actions demonstrated by this drug in a number of clinical trials in patients with osteoarthritis. [Ronca F, Palmieri L, Panicucci P, Ronca G. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage. 1998 May;6 Suppl A:14-21.]

15. Comparison of the anti-inflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. OBJECTIVE: To assess the clinical efficacy of chondroitin sulfate (CS) in comparison with the nonsteroidal antiinflammatory drug (NSAID) diclofenac sodium (DS) in a medium/longterm clinical study in patients with knee osteoarthritis (OA). METHODS: This was a randomized, multicenter, double blind, double dummy study. 146 patients with knee OA were recruited into 2 groups. During the first month, patients in the NSAID group were treated with 3 x 50 mg DS tablets/day and 3 x 400 mg placebo (for CS) sachets; from Month 2 to Month 3, patients were given placebo sachets alone. In the CS group, patients were treated with 3 x 50 mg placebo (for diclofenac) tablets/day and 3 x 400 mg CS sachets/day during the first month; from Month 2 to Month 3, these patients received only CS sachets. Both groups were treated with 3 x 400 mg placebo sachets from Month 7/18/2019 4 to Month 6. Clinical efficacy was evaluated by assessing the Lequesne Index, spontaneous pain (using the Huskisson visual analog scale), pain on load (using a 4 point ordinal scale), and paracetamol consumption. RESULTS: Patients treated with the NSAID showed prompt and plain reduction of clinical symptoms, which, however, reappeared after the end of treatment; in the CS group, the therapeutic response appeared later in time but lasted for up to 3 months after the end of treatment. CONCLUSION: CS seems to have slow but gradually increasing clinical activity in OA; these benefits last for a long period after the end of treatment. [Morreale P, et al. Comparison of the antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol. 1996 Aug;23(8):1385-1391.]

16. Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3 x 400mg/day vs placebo. This multicenter randomized, double-blind, controlled study was performed to compare the efficacy and tolerability of chondroitin sulfate (CS, Condrosulf, IBSA, Lugano, CH) 1200mg/day oral gel vs CS 3 x 400 mg/day capsules vs placebo, in patients with mono or bilateral knee osteoarthritis (Kellgren and Lawrence radiographic score grade I to III). A total of 127 patients, 40 of whom were treated with CS 1200 mg/day, 43 with CS 3 x 400 mg/day and 44 with placebo, were included in the statistical analysis of this 3-month treatment study. In the CS groups, Lequesne’s Index and spontaneous joint pain (VAS) showed a significant reduction of clinical symptoms (P < 0.01 for both parameters), while only a slight reduction was observed in the placebo group (P = ns for Lequesne’s Index and P < 0.05 for VAS). The physician’s and patient’s overall efficacy assessments were significantly in favour of the CS groups (P < 0.01). The treatment carried out with the three formulations was very well tolerated. In conclusion, these results indicate that CS favours the improvement of the subjective symptoms, improving the joint mobility. An additional consideration is that the efficacy of 1200 mg CS as a single daily dose does not differ from that of 3 x 400 mg daily doses of CS for all the clinical parameters taken into consideration. [Bourgeois P, et al. Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3 x 400 mg/day vs placebo. Osteoarthritis Cartilage. 1998 May;6 Suppl A:25-30.]

17. Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. Patients with osteoarthritis (OA) of the knee were treated with chondroitin sulfate (CS, Condrosulf, IBSA, Lugano, CH) in a randomized, double-blind, placebo-controlled study, performed in two centres. The efficacy and tolerability of oral CS capsules 2 x 400 mg/day vs placebo was assessed in a 6-month study period. Patients with idiopathic or clinically symptomatic knee OA, with Kellgren and Lawrence radiological scores I-III, were included in this trial. Clinical controls were performed at months 0, 1, 3 and 6. Eighty patients completed the 6-month treatment period. Lequesne’s Index and spontaneous joint pain (VAS) decreased constantly in the CS group; on the contrary, slight variations of the scores were reported in the placebo group. The walking time, defined as the minimum time to perform a 20-meter walk, showed a statistically significant constant reduction only in the CS group. ANOVA with repeated measures 7/18/2019 showed a statistically significant difference in favor of the CS group for these three parameters. During the study, patients belonging to the placebo group reported a higher paracetamol consumption, but this consumption was not statistically different between the two treatment groups. Efficacy judgements were significant in favor of the CS group. Both treatments were very well tolerated. All these results strongly suggest that chondroitin sulfate acts as a symptomatic slow-acting drug in knee OA. [Busci L, Poor G. Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. Osteoarthritis Cartilage. 1998 May;6 Suppl A: 31-36.

18. Effects of oral chondroitin sulfate of the progression of knee osteoarthritis: a pilot study. The aim of this study was to assess the clinical, radiological and biological efficacy and tolerability of the SYSADOA, chondroitin 4- and 6-sulfate (CS, Condrosulf, IBSA, Lugano, Switzerland), in patients suffering from knee osteoarthritis. This was a 1- year, randomized, double-blind, controlled pilot study which included 42 patients of both sexes, aged 35-78 years with symptomatic knee OA. Patients were treated orally with 800 mg chondroitin sulfate (CS) per day or with a placebo (PBO) administered in identical sachets. The main outcome criteria were the degree of spontaneous joint pain and the overall mobility capacity. Secondary outcome criteria included the actual joint space measurement and the levels of biochemical markers of bone and joint metabolism. This limited study confirmed that chondroitin sulfate was well-tolerated and both significantly reduced pain and increased overall mobility capacity. Treatment with CS was also associated in a limited group of patients with a stabilization of the medial femoro-tibial joint width, measured with a digitized automatic image analyzer, whereas joint space narrowing did occur in placebo-treated patients. In addition, the metabolism of bone and joint assessed by various biochemical markers also stabilized in the CS patients whereas it was still abnormal in the PBO patients. These results confirm that oral chondroitin 4- and 6-sulfate is an effective and safe symptomatic slow-acting drug for the treatment of knee OA. In addition, CS might be able to stabilize the joint space width and to modulate bone and joint metabolism. This is the first preliminary demonstration that a SYSADOA might influence the natural course of OA in humans. [Uebelhart D, Thonar EJ, Delmas PD, Chantraine A, Vignon E. Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study. Osteoarthritis Cartilage. 1998 May;6 Suppl A:39-46.

19. Double-blind, dose-effect study of oral CS 4&6 1200 mg, 800 mg, 200 mg and placebo in the treatment of knee osteoarthritis. [Pavelka K, et al. Double-blind, doseeffect study of oral CS 4&6 1200 mg, 800 mg, 200 mg and placebo in the treatment of knee osteoarthritis. Litera Rheumatologica. 1998;24:21-30.

Chondroitin Sulfate Combination Research- Clinical Trials

1. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a mulicentre, randomized, double-blind, non-inferiority trial versus celecoxib. OBJECTIVES: To compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH) versus celecoxib in patients with knee osteoarthritis and severe pain. METHODS: Double-blind Multicentre Osteoarthritis interVEntion trial 7/18/2019 with SYSADOA (MOVES) conducted in France, Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with Kellgren and Lawrence grades 2-3 knee osteoarthritis and moderate-to-severe pain (Western Ontario and McMaster osteoarthritis index (WOMAC) score ≥301; 0-500 scale). Patients were randomised to receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D. RESULTS: The adjusted mean change (95% CI) in WOMAC pain was – 185.7 (-200.3 to -171.1) (50.1% decrease) with CS+GH and -186.8 (-201.7 to -171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin of -40: -1.11 (-22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6 months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a similar reduction was seen for effusion. No differences were observed for the other secondary outcomes. Adverse events were low and similarly distributed between groups. CONCLUSIONS: CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile. [Hochberg MC, et al. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre-, randomized, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis. 2016 Jan;75(1):37-44.

2. Combined glucosamine and chondroitin sulfate, once or three times daily, provides clinically relevant analgesia in knee osteoarthritis. We compared the analgesic efficacy and safety of glucosamine sulfate (GS) and chondroitin sulfate (CS) capsules or sachet preparations with glucosamine hydrochloride (GH) and CS capsules in knee osteoarthritis (OA) patients. 1,120 subjects with radiographic knee OA (Kellgren/Lawrence 2-3) were randomized (1:1:1) at 16 centers to receive GS 500 mg/CS 400 mg three times daily capsules (GI) or once daily sachet (GII) or GH 500 mg/CS 400 mg threetimes daily (GIII) for a 16-week trial. Primary outcome, intention-to-treat (ITT) was change from baseline of patient reported pain intensity (0-100 mm visual analogue scale) in the affected knee and variation of Lequesne’s index (LI). Monthly secondary outcomes were changes from baseline in patient reported pain and LI, patient and physician global assessments of disease activity, acetaminophen consumption, and adherence. ITT population comprised 302, 301, and 306 patients in GI, GII, and GIII. Pain significantly decreased (GI = -30.9 ± 1.5; GII = -28.7 ± 1.5; GIII = -29.7 ± 1.5 mm) in all groups (P < 0.001) as well as LI (GI = -3.8 ± 0.2; GII = -3.7 ± 0.2; GIII = -3.9 ± 0.2; P < 0.001). All secondary outcomes improved (P < 0.005) for all groups. Patients that did not complete the study were 77 (44.8 %) for lack of adherence, 16 (9.3 %) consent withdrawal, 11 (6.4 %) adverse events, eight (4.7 %) lost to follow-up, and 17 (9.9 %) for other causes. Non-inferiority analysis found no differences among groups. This is a large 7/18/2019 study showing that GS/CS and GH/CS provide clinically meaningful and sustained analgesia in knee OA regardless of dose fractionation and capsule or sachet formulations. [Provenza JR, Shinjo SK, Silva JM, Peron CR, Rocha FA. Combined glucosamine and chondroitin sulfate, once or three times daily, provides clinically relevant analgesia in knee osteoarthritis. Clin Rheumatol. 2015 Aug;34(8):1455-1462.]

3. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. BACKGROUND: Knee osteoarthritis (OA) is a major cause of pain and functional limitation in older adults, yet longer-term studies of medical treatment of OA are limited. OBJECTIVE: To evaluate the efficacy and safety of glucosamine and chondroitin sulphate (CS), alone or in combination, as well as celecoxib and placebo on painful knee OA over 2 years. METHODS: A 24-month, double-blind, placebocontrolled study, conducted at nine sites in the US ancillary to the Glucosamine/chondroitin Arthritis Intervention Trial, enrolled 662 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomised treatment: glucosamine 500 mg three times daily, CS 400 mg three times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The primary outcome was a 20% reduction in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain over 24 months. Secondary outcomes included an Outcome Measures in Rheumatology/Osteoarthritis Research Society International response and change from baseline in WOMAC pain and function. RESULTS: Compared with placebo, the odds of achieving a 20% reduction in WOMAC pain were celecoxib: 1.21, glucosamine: 1.16, combination glucosamine/CS: 0.83 and CS alone: 0.69, and were not statistically significant. CONCLUSIONS: Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo. However, glucosamine and celecoxib showed beneficial but not significant trends. Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments. [Sawitzke AD, et al. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann Rheum Dis. 2010 Aug;69(8):1459-1464.

4. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. BACKGROUND: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. METHODS: We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. RESULTS: The mean age of the patients was 59 years, and 64 percent were 7/18/2019 women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. CONCLUSIONS: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.). [Clegg DO, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knees osteoarthritis. N Engl J Med. 2006 Feb 23;354(8):795-808.

5. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. OBJECTIVES: The objective of this study was to evaluate the oral combination of glucosamine HCl, sodium chondroitin sulfate and manganese ascorbate for the treatment of osteoarthritis (OA) of the knee. DESIGN: A randomized placebo-controlled study design was implemented. We recruited 93 patients with OA of the knee from a single center. The intervention group received 1000 mg FCHG49 glucosamine HCl, 800 mg TRH122 low molecular weight sodium chondroitin sulfate and 152 mg manganese ascorbate twice daily (Cosamin DS). Patients were evaluated initially and then every 2 months for 6 months. The primary outcome was the Lesquene Index of severity of osteoarthritis of the knee (ISK). RESULTS: Patients with radiographically mild or moderate OA (N=72) in the intervention group showed significant improvement in the ISK at 4 and 6 months (P=0.003 and P=0.04, respectively). The response rate to the medication was 52% vs a 28% response rate to placebo. Patients with radiographically severe osteoarthritis (N=21) did not show significant improvements in the ISK. There was a 17% incidence of adverse events in the intervention group and 19% in the placebo group. CONCLUSIONS: The studied combination of glucosamine HCl, sodium chondroitin sulfate and manganese ascorbate was found to be effective for the treatment of radiographically mild to moderate OA of the knee as measured by the ISK. This is the first U.S. study of these agents. [Das A Jr, Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage. 2000 Sep;8(5):343-350.]

Hyaluronic acid/Polysaccharides/Collagen – Clinical Trials

1. Effectiveness of a low-fat yoghurt supplemented with rooster comb extract on muscle strength in adults with mild knee pain and mechanisms of action on muscle regeneration. PURPOSE: To determine the effects of the intake of low-fat yoghurt supplemented with rooster comb extract (RCE) on muscle strength. METHODS AND RESULTS: 148 subjects, with mild knee pain, participated in a randomized, placebo-controlled, double-blind, and parallel study. Muscle strength, knee effusion, and pain perception were measured. C2C12 myoblasts were used to elucidate the mechanisms of action involved. RCE improved total work and mean power in men, and also peak torque in extension by 10%. RCE reduced synovial effusion by 11.8% and pain perception by 24.6%. Both RCE and HA increased myoblast proliferation by 29%, while RCE reduced myoblast differentiation by 36.2%, suggesting a beneficial role of RCE in muscle regeneration. CONCLUSIONS: Low-fat yoghurt supplemented with RCE improved muscle strength. This effect is partially explained by muscle regeneration enhancement, reduced synovial effusion, and reduced pain perception, which could exert a beneficial clinical impact on men affected by mild knee pain. [Moriña D, et al. Effectiveness of a low-fat yogurt supplemented with rooster comb extract on muscle strength in adults with mild knee pain and mechanisms of action on muscle regeneration. Food Funct. 2018 Jun 20;9(6):3244-3253.]

2. A low-fat yoghurt supplemented with a rooster comb extract on muscle joint function in adults with mild knee pain: a randomized, double blind, parallel, placebo-controlled, clinical trial of efficacy. Preliminary results suggested that oraladministration of rooster comb extract (RCE) rich in hyaluronic acid (HA) was associated with improved muscle strength. Following these promising results, the objective of the present study was to evaluate the effect of low-fat yoghurt supplemented with RCE rich in HA on muscle function in adults with mild knee pain; a symptom of early osteoarthritis. Participants (n = 40) received low-fat yoghurt (125 mL d(-1)) supplemented with 80 mg d(-1) of RCE and the placebo group (n = 40) consumed the same yoghurt without the RCE, in a randomized, controlled, doubleblind, parallel trial over 12 weeks. Using an isokinetic dynamometer (Biodex System 4), RCE consumption, compared to control, increased the affected knee peak torque, total work and mean power at 180° s(-1), at least 11% in men (p < 0.05) with no differences in women. No dietary differences were noted. These results suggest that long-term consumption of low-fat yoghurt supplemented with RCE could be a dietary tool to improve muscle strength in men, associated with possible clinical significance. However, further studies are needed to elucidate reasons for these sex difference responses observed, and may provide further insight into muscle function. [Sola R, et al. A low-fat yoghurt supplemented with a rooster comb extract on muscle joint function in adults with mild knee pain: a randomized, double blind, parallel, placebocontrolled, clinical trial of efficacy. Food Funct. 2015 Nov;6(11):3531-3539.

3. Blood cells transcriptomics as source of potential biomarkers of articular health improvement: effects of oral intake of a rooster combs extract rich in hyaluronic acid. The aim of the study was to explore peripheral blood gene expression as a 7/18/2019 source of biomarkers of joint health improvement related to glycosaminoglycan (GAG) intake in humans. Healthy individuals with joint discomfort were enrolled in a randomized, double-blind, placebo-controlled intervention study in humans. Subjects ate control yoghurt or yoghurt supplemented with a recently authorized novel food in Europe containing hyaluronic acid (65 %) from rooster comb (Mobilee™ as commercial name) for 90 days. Effects on functional quality-of-life parameters related to joint health were assessed. Whole-genome microarray analysis of peripheral blood samples from a subset of 20 subjects (10 placebo and 10 supplemented) collected pre- and post-intervention was performed. Mobilee™ supplementation reduced articular pain intensity and synovial effusion and improved knee muscular strength indicators as compared to placebo. About 157 coding genes were differentially expressed in blood cells between supplemented and placebo groups post-intervention, but not pre-intervention (p < 0.05; fold change ≥1.2). Among them, a reduced gene expression of glucuronidase-beta (GUSB), matrix metallopeptidase 23B (MMP23B), xylosyltransferase II (XYLT2), and heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) was found in the supplemented group. Correlation analysis indicated a direct relationship between blood cell gene expression of MMP23B, involved in the breakdown of the extracellular matrix, and pain intensity, and an inverse relationship between blood cell gene expression of HS6ST1, responsible for 6-O-sulfation of heparan sulfate, and indicators of knee muscular strength. Expression levels of specific genes in blood cells, in particular genes related to GAG metabolism and extracellular matrix dynamics, are potential biomarkers of beneficial effects on articular health. [Sanchez J, et al. Blood cells transcriptomics as source of potential biomarkers of articular health improvement: effects of oral intake of a rooster combs extract rich in hyaluronic acid. Genes Nutr. 2014 Sep;9(50:417.]

4. Efficacy of oral administration of yoghurt supplemented with a preparation containing hyaluronic acid (Mobilee™) in adults with mild joint discomfort: a randomized, double-blind, placebo-controlled intervention study. A prospective, randomized, double-blind, placebo-controlled study was designed with 40 healthy individuals with joint discomfort. The effect of oral supplementation with a natural product containing hyaluronic acid included in a yoghurt matrix was evaluated in terms of functional and quality-of-life parameters. An isokinetic dynamometer was used to measure maximum muscle strength, total work and mean power. Participants were divided into 2 groups (n = 20) and ate yoghurt that was either supplemented or not supplemented with the hyaluronic acid product daily for a period of 90 days. The increase in the maximum peak torque of the knee extensors compared to baseline values was 7.6 ± 7.6 Nm for the supplemented yoghurt group and 2.5 ± 4.7 Nm for the control group at 180°/s (P = 0.0582), and 6.5 ± 5.8 Nm for the supplemented yoghurt group and −1.0 ± 7.1 Nm for the control group at 240°/s (P < 0.05). The same pattern of response was observed in total work and in mean power (P < 0.05). Differences were less pronounced in the knee flexors. No differences were detected in the Lequesne score and SF-36 survey except for the social functioning subscale at 1 7/18/2019 month follow-up. This prospective placebo-controlled nutritional study confirmed that 3 months of oral administration of a natural product containing HA (Mobilee™) in healthy individuals with joint discomfort of the knee provides improvements in muscle strength. [Martinez-Puig D, Moller I, Fernandez C, Chetrit C. Efficacy of oral administration of yoghurt supplemented with a preparation containing hyaluronic acid (Mobilee™) in adults with mild joint discomfort: a randomized, double-blind, placebo-controlled intervention study. Mediterranean J of Nutr and Metab. 2013 Apr;6(1):63-68.]

5. Oral Administration of a Natural Extract Rich in Hyaluronic Acid for the Treatment of Knee OA with Synovitis: A retrospective Cohort Study. [Moller I, Martinez D, Chetrit C. Oral Administration of a Natural Extract Rich in Hyaluronic Acid for the Treatment of Knee OA with Synovitis: A retrospective Cohort Study. Clinical Nutrition Supplements. 2009 Dec;4(2):171-172.]

6. Effect of a natural extract of chicken combs with a high content of hyaluronic acid (Hyal-Joint®) on pain relief and quality of life in subjects with knee osteoarthritis: a pilot randomized double-blind placebo-controlled trial. BACKGROUND: Intra-articular hyaluronic acid represents a substantive addition to the therapeutic armamentarium in knee osteoarthritis. We examined the effect of dietary supplementation with a natural extract of chicken combs with a high content of hyaluronic acid (60%) (Hyal-Joint) (active test product, AP) on pain and quality of life in subjects with osteoarthritis of the knee. METHODS: Twenty subjects aged > or =40 years with knee osteoarthritis (pain for at least 15 days in the previous month, symptoms present for > or =6 months, Kellgren/Lawrence score > or =2) participated in a randomized double-blind controlled trial. Ten subjects received AP (80 mg/day) and 10 placebo for 8 weeks. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and quality of life by the Short Form-36 (SF-36v2) were administered at baseline and after 4 and 8 weeks of treatment. RESULTS: WOMAC pain (primary efficacy variable) was similar in both study groups (mean [SD]) with 6.6 (4.0) points in the AP group and 6.4 (2.7) in the placebo group (P = 0.943). As compared with baseline, subjects in both groups showed statistically significant improvements in WOMAC pain, stiffness, physical function subscales, and in the aggregate score, but the magnitude of changes was higher in the AP group for WOMAC physical function (-13.1 [12.0] vs. -10.1 [8.6], P = 0.575) and total symptoms (-18.6 [16.8] vs. -15.8 [11.4], P = 0.694). At 4 weeks, statistically significant mean changes compared with baseline were observed in the SF-36v2 scales of role-physical, bodily pain, social functioning and role-emotional among subjects in the AP group, and in physical functioning, bodily pain, and social functioning in the placebo group. At 8 weeks, changes were significant for rolephysical, bodily pain, and physical component summary in the AP group, and for physical functioning and role-emotional in the placebo arm. Changes in bodily pain and social functioning were of greater magnitude in subjects given AP. CONCLUSION: This pilot clinical trial showed that daily supplementation with oral hyaluronic acid from a natural extract of chicken combs (Hyal-Joint) was useful to 7/18/2019 enhance several markers of quality of life in adults with osteoarthritis of the knee. The results warrant further study in larger sample sizes. [Kalman DS, Heimer M, Valdeon A, Schwartz H, Sheldon E. Effect of a natural extract of chicken combs with a high content of hyaluronic acid (Hyal-Joint®) on pain relief and quality of life in subjects with knee osteoarthritis: a pilot randomized double-blind placebo-controlled trial. Nutr J. 2008 Jan 21;7:3.

Type II Collagen – Clinical Trial

1. Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial. OBJECTIVE: The aim of this randomized controlled study was to evaluate the efficacy of oral native type II collagen treatment on the symptoms and biological markers of cartilage degradation, when given concomitantly with acetaminophen in patients with knee osteoarthritis. MATERIALS AND METHODS: Thirty-nine patients diagnosed with knee osteoarthritis were included and randomly distributed into two groups: one treated with 1500 mg/day of acetaminophen (group AC; n=19) and the other treated with 1500 mg/day of acetaminophen plus 10 mg/day of native type II collagen (group AC+CII; n=20) for 3 months. Visual Analogue Scale (VAS) at rest and during walking, Western Ontario McMaster (WOMAC) pain, WOMAC function, and Short Form-36 (SF-36) scores, were recorded. Coll2-1, Coll2- 1NO2 and Fibulin-3 levels were quantified in urine as biomarkers of disease progression. ClinicalTrials.gov: NCT02237989. RESULTS: After 3 months of treatment, significant improvements compared to baseline were reported in joint pain (VAS walking), function (WOMAC) and quality of life (SF-36) in the AC+CII group, while only improvements in some subscales of the SF-36 survey and VAS walking were detected in the AC group. Comparisons between the groups revealed a significant difference in VAS walking score in favour of the AC+CII group as compared to AC group. Biochemical markers of cartilage degradation in urine did not significantly improve in any of the groups. CONCLUSION: All in all, these results suggest that native type II collagen treatment combined with acetaminophen is superior to only acetaminophen for symptomatic treatment of patients with knee osteoarthritis. [Bakilan F, et al. Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial. Eurasian J Med. 2016 Jun;48(2):95-101.]

Type II Collagen, Glucosamine, and Chondroitin Sulfate – Studies

1. Biomarkers, type II collagen, glucosamine and chondroitin sulfate in osteoarthritis follow-up: the “Magenta osteoarthritis study”. BACKGROUND: The purpose of the present study was to determine relationship between disease activity, systemic markers of cartilage degradation, urinary C-terminal cross-linking telopeptides of type II collagen (uCTX-II), and bone degradation, urinary C-terminal cross-linking telopeptides of type I collagen (uCTX-I), structural progression of osteoarthritis (OA) and potential therapeutic efficacy of type II collagen (COLLII) in combination with glucosamine and chondroitin sulfate (GC). MATERIALS AND METHODS: An observational retrospective study, 1- year follow-up, on 104 patients with OA (nodular osteoarthritis of the hand, erosive 7/18/2019 osteoarthritis of the hand, EOA, osteoarthritis of the knee or hip) who were treated with GC or glucosamine, chondroitin sulfate and collagen type II (GCC). The following information was collected at entry: demographics, BMI, characteristics of OA, patient global assessment (VAS), C-terminal cross-linking telopeptides of collagen types I (uCTX-I) and II (uCTX-II) and radiographs. After 6 months: VAS, uCTX-I and uCTX-II. After 1 year: VAS, uCTX-I, uCTX-II and radiographs. RESULTS: After 6 months and 1 year of treatment VAS, uCTX-I and uCTX-II mean values were significantly lower than the baseline. 57 were treated with GCC and 47 with GC. The group that received GCC showed a similar VAS mean value after 6 months and 1 year when compared with the group treated with GC. uCTX-I and uCTX-II mean level was lower in the group treated with GCC (P < 0.05). Radiological score (Kellgren and Lawrence summarized score for hands) after 1 year showed a reduced progression compared to the baseline in the hand osteoarthritis group, especially after GCC treatment (P < 0.05). Finally, uCTX-I has better correlation with radiological score and with GC in the EOA subgroup (Pearson index: R = 0.44). CONCLUSIONS: (a) uCTX-I and uCTX-II proved to be useful biomarkers in OA monitoring; (b) uCTX-I is better correlated with hand EOA and could represent a potential further marker to assess the evolution of EOA bone damage; (c) GC slow down OA progression; (d) finally COLLII could represent a further protective factor in OA cartilage. [Scarpellini M, et al. Biomarkers, type II collagen, glucosamine and chondroitin sulfate in osteoarthritis follow-up: the “Magenta osteoarthritis study”. J Orthop Traumatol. 2008 Jun;9(2):81-87.]

Hyaluronic Acid, Glucosamine, and Chondroitin Sulfate – Studies

1. Absorption, distribution and mechanism of action of SYSADOAS. Symptomatic Slow Acting Drugs for Osteoarthritis (SYSADOA), such as hyaluronic acid (HA), chondroitin sulfate (CS) and glucosamine (GlcN) are natural compounds, composed of repeating disaccharides, used to treat patients with osteoarthritis (OA). Many questions about the kinetics and mechanism of action of SYSADOA remain poorly answered. This review examines the data supporting oral absorption and body distribution of SYSADOA, and discusses their mechanism of action. SYSADOA are absorbed in the small intestine with a bioavailability ranging from 5 to 45% and accumulate in articular tissues. The mechanism of action of HA and CS differs in several aspects from that of GlcN. Being large molecules, HA and CS do not penetrate into chondrocytes, synoviocytes, osteoblast, osteoclast and osteocytes, and so elicit the anti-inflammatory effect by engaging membrane receptors, e.g. CD44, TLR4, and ICAM1, with a resulting dual effect: impede the fragments of extracellular matrix engaging these receptors, cause of inflammatory reaction, and block the signal transduction pathways activated by the fragments and so diminish the nuclear translocation of pro-inflammatory transcription factors. GlcN penetrates into cells by means of glucose transporters. The primary effect of GlcN is associated to its ability to O-GlcNAcylate proteins and as a consequence, modulates their activity, e.g. decrease nuclear factor-κB nuclear translocation. GlcN may also affect the transcription of pro-inflammatory cytokines by epigenetic mechanisms. 7/18/2019 The characteristics of the mechanism of action support the use of CS combined with GlcN, and suggest that HA and CS shall be more effective in initial phases of OA. [du Souich P. Absorption, distribution and mechanism of action of SYSADOAS. Pharmacol Ther. 2014 Jun;142(3):362-374.]