Table 2.

Literature overview of UC-II practice in the human and animals for osteoarthritis (OA).

No	Objective	Model	Dose and Duration	Core Findings	Conclusion	Safety	Ref.
1	Demonstrating the UC-II ability, whether it reduces joint pain and swelling in RA subjects.	Human	UC-II (10 mg/day) for 42 days in five female subjects (58–78 years) suffering from severe joint pain.	Reduction of pain including the stiffness was observed.	UC-II found to serve as a novel therapeutic tool in joint inflammatory conditions and symptoms of both OA and RA.	No Adverse events	[49]
2	Evaluating the clinical effectiveness and safety of UC-II in obese-arthritic dogs.	Dogs	Fifteen dogs in three groups received either UC-II (0 mg/day), (1 mg/day), or (10 mg/day) for 90 days, plus 30 days withdrawal.	Both UC-II receiving groups showed significant reductions in overall pain as well as pain during limb manipulation and lameness after physical exertion, also 10 mg showed better improvement. Additionally, no adverse effects and no major alterations were noted in the serum chemistry, suggesting that UC-II was well tolerated.	Daily treatment of arthritic dogs with UC-II, shown to ameliorate the signs and symptoms of arthritis. Relapse of pain was observed during the withdrawal period.	No Adverse events	[20]
3	Determining the therapeutic efficacy and safety of glycosylated active UC-II alone or in combination with hydroxycitric acid (HA) and chromium niacinate (CN).	Dogs	Five groups (n = 5) of 25 arthritic dogs received daily treatments; group I (Placebo control), group II (10 mg active UC-II), group III (1800 mg HA), group IV (1800 mg HA+100 lg CN), and group V (1800 mg HA+100 lg CN+ 10 mg active UC-II). The treatments were given for 120 days and followed up by a 30 days withdrawal period.	The dogs received the active UC-II alone (group II) or in combination (group V) for 90 days exhibited a noticeable decrease in overall, pain upon limb manipulation and exercise-related lameness. Maximum pain decrease was seen in groups II and V after 120 days of treatment. A relapse of pain was exhibited in all the dogs after 30 days of the withdrawal period.	Active UC-II was found to ameliorate the arthritic dogs alone or in combination with HA and CN. The supplements were found to be well tolerated and no adverse effects were noted.	No Adverse events	[68]
4	Determining the therapeutic efficacy and safety of glycosylated active UC-II alone or in combination with glucosamine-HCl and chondroitin sulfate.	Dogs	Dogs were allocated into four groups (n = 5), and orally treated daily for 120 days. Treatments were Group I (placebo control), Group II (10 mg UC-II), Group III (2000 mg glucosamine)+(1600 mg chondroitin sulfate), Group IV, UC-II (10 mg) + 2000 mg glucosamine + 1600 mg chondroitin sulfate, followed by a 30-day withdrawal period.	UC-II alone received dogs showed substantial reductions in overall pain within the first quarter of the study. Maximum decreases in pain were noted after 120 days of treatment. Glucosamine and chondroitin alleviated some pain, but in combination with UC-II (Group IV) significant decreases were provided in overall pain, pain upon limb manipulation and exercise-associated lameness. Following the withdrawal of supplements, all of the animals experienced a relapse of pain.	UC-II alone or in combination with glucosamine and chondroitin significantly alleviated the arthritis pain with daily treatment to the arthritic dogs, and these supplements were found to be well tolerated without any side effects.	No Adverse events	[69]
5	Evaluating the efficiency of pain lessening and safety of UC-II in arthritic horses.	Horses	Six groups of arthritic horses (n = 5–6). G. I (placebo control), G. II (UC-II 20 mg/day), G. III (UC-II 40 mg/day), G. IV (UC-II 80 mg/day), G. V (UC-II 120 mg/day), G. VI (UC-II 160 mg/day). A period of 150 days.	Groups IV, V, and VI of the horses exhibited significant improvements in the arthritic signs. Reduction in overall pain was at 79%, in pain upon limb manipulation was at 71%, and in pain, after physical exertion was at 68%. Horses receiving a higher dose of 120 and 160 mg of UC-II/day showed very little or no signs of arthritis.	UC-II at higher doses (80–160 mg/day) in the horses ameliorated the signs and symptoms of arthritis, which was also well-tolerated.	No Adverse events	[70]
6	Assessing the safety and efficacy of UC-II as compared to a combination of glucosamine and chondroitin (G + C) in the treatment of OA of the knee.	Human	A total of 52 subjects, half of them (n = 26) took a daily dose of 40 mg UC-II containing 10 mg of bioactive undenatured type II collagen via 2 capsules. Another half of the subjects (n = 26) took a daily dose of 1500 mg glucosamine and 1200 mg chondroitin via 4 capsules.	UC-II treatment found to be more effective when decreasing all the assessments from the baseline at 90 days. In the G + C treatment group, this effect was not observed. Specifically, although both treatments reduced the Western Ontario McMaster Osteoarthritis Index (WOMAC) score was two folds better reduced by UC-II, than the G + C treated group after 90 days.	UC-II treatment to the subjects exhibited noteworthy enhancement in daily activities, which suggested improvements for their life quality.	No Adverse events	[71]
7	Evaluating the arthritic pain reduction in the horses and comparison of its efficacy with the glucosamine and chondroitin	Horses	Five groups of moderate severity arthritic horses (n = 5–7); Group-I placebo, Group-II 320 mg UC-II, Group-III 480 mg UC-II, Group-IV 640 mg UC-II, Group-V glucosamine + chondroitin	The placebo group showed no change in arthritic conditions, whereas those receiving 320, 480, and 640 mg UC-II showed significant reductions in arthritic pain.	All supplements were tolerated well. Generally, results from this study demonstrated UC-II to be significantly more effective than the glucosamine and chondroitin supplements in arthritic horses.	No Adverse events	[72]
8	Assessing the safety and therapeutic effectiveness of UC-II in arthritic dogs	Dogs	Dogs were daily treated with either placebo or UC-II (10 mg active UC-II) for 120 days.	Substantial decreases (77%) were found in the overall pain of the dogs after the study period, inconsistent with pain reduction (83%) after limb manipulation and pain reduction after physical exercise (84%). Subchronic toxicity and primary dermal and eye irritation studies showed no adverse effects and UC-II did not induce mutagenic effects.	Study results demonstrated that UC-II significantly reduces arthritic pain and is safe.	No Adverse events	[73]
9	Determining the tolerability and safety of the therapeutic efficacy of type II collagen (UC-II) alone or in combination with glucosamine hydrochloride (GLU) and chondroitin sulphate (CHO).	Dogs	4 groups (n = 7–10), were treated daily with; placebo (Group-I), 10 mg active UC-II (Group-II), 2000 mg GLU + 1600 mg CHO (Group-III), and UC-II + GLU + CHO (Group-IV), for 150 days.	A significant reduction in pain was noted in Groups II, III, and IV of dogs. Significant increases in peak vertical force (N/kg body wt) and impulse area (N/kg body wt), indicative of a decrease in arthritis-associated pain, were observed in Group-II (10 mg active UC-II) dogs only. None of the dogs in any group showed changes in physical, hepatic, or renal functions.	When moderately arthritic dogs treated with UC-II (10 mg), a marked reduction in arthritic pain with maximum improvement occurred by day 150.	No Adverse events	[74]
10	Assessing the efficacy and tolerability of UC-II in the moderation of the joint function/pain due to strenuous exercise in healthy subjects.	Human	55 subjects who reported knee joint pain after joining in a standardized step mill performance test were randomized to take placebo (n = 28) or the UC-II (40 mg daily, n = 27) product for 120 days.	Subjects in the UC-II group showed significant improvements in average knee extension compared to placebo and to baseline. The UC-II cohort also revealed a significant change in average knee extension at day 90 versus baseline.	Daily supplementation with 40 mg of UC-II found to be well tolerated and led to improved knee joint extension. UC-II also showed the potential of increasing the period of pain-free strenuous exertion and lessen the joint pain from that.	No Adverse events	[75]
11	Evaluating the efficacy and safety of 150 mg of n-enriched THIAA+10 mg of UC-II in each tablet	Human	Participants took 2 tablets of nTHIAA + UC-II 2 ×/d with meals for 12 weeks.	All participants reported significant improvements in pain. The studied supplement was well tolerated, and no serious side effects occurred.	nTHIAA and UC-II were found to be safe and efficacious in participants having chronic joint pain.	No Adverse events	[50]
12	Evaluating the efficacy and safety of UC-II for knee OA pain and affiliated symptoms compared to glucosamine hydrochloride and chondroitin sulfate (GC).	Human	191 volunteers were randomized into three groups receiving a daily dose of UC-II (40 mg), GC (1500 mg G and 1200 mg C), or placebo for 180 days.	UC-II group demonstrated a significant reduction in overall WOMAC score compared to placebo and GC. Supplementation with UC-II also resulted in significant changes for all three WOMAC subscales. Safety outcomes did not differ among the groups.	UC-II improved knee joint symptoms in knee OA subjects and was well-tolerated.	No Adverse events	[76]
13	Assessing the UC-II to prevention against the excessive articular cartilage deterioration in a partial medial meniscectomy tear (PMMT) surgery performed rat model of OA.	Rats	20 male rats were used in this study. 10 rats received the vehicle and another 10 rats received an oral daily dose of UC-II at 0.66 mg/kg for 8 weeks.	PMMT surgery created a moderate OA at the medial tibia plateau. Immediate treatment with the UC-II protected the weight-bearing capacity of the injured leg, preserved the integrity of the cancellous bone at tibial metaphysis and limited the excessive osteophyte formation and deterioration of articular cartilage.	This study demonstrates that a clinically relevant daily dose of UC-II when applied immediately after an injury can improve the mechanical function of the injured knee and prevent excessive deterioration of articular cartilage.	No Adverse events	[17]
14	The palatability and tolerability of UC-II was studied	Cats	33 European Shorthair cats between the ages of 24 to 72 months were given one chewable tablet containing 10 mg of UC-II, daily for 40 days.	No remarkable findings on physical examination before or after the study and no appreciable changes in body weight were noted. The consumption level rose from 58% on day 0 to 73% on day 40. After an initial acquaintance period of 2–3 weeks, the level of consumption within 5 mins rose to over 70%.	10 mg of UC-II found to be very palatable in the cats studied and was well-tolerated based on physical examination.	No Adverse events	[77]
15	Analyzing the efficacy of UC-II alone or combined with cimicoxib, for OA treatment.	Dogs	45 dogs: 13 cimicoxib, 20 UC-II, and 12 cimicoxib + UC-II. Cimicoxib (2 mg/kg die) and UC-II tablet /day. Study lasted for 30 days.	There was a significant reduction in LOAD scores after the study. Treatment of similar magnitude among the three groups (CIMI = 31.8%, p < 0.001; UC-II = 32.7%, p = 0.013; CIM + UC-II = 31.7%, p = 0.009). Preliminary results of the study show similar effectiveness of the 3 treatments in reducing the degree of impairment of mobility in dogs with OA.	UC-II, while not showing a synergistic effect with cimicoxib, provided a comparable clinical efficacy to the NSAIDs itself.	No Adverse events	[78]
16	This study aimed to evaluate the effects of UC-II as compared to robenacoxib in OA suffering dogs.	Dogs	60 client-owned dogs were randomized in the R group (n = 30, robenacoxib 1 mg/kg/day for 30 days) and in the UC-II group (n = 30, UC-II 1 tablet/day for 30 days).	Based on the data obtained from the study, a significant reduction in LOAD and MOBILITY scores was recorded between T0 and T30 with a similar magnitude among the two groups (R = 31.5%, p < 0.001; UC-II = 32.7%, p = 0.013).	This study showed that UC-II and robenacoxib were able to similarly improve mobility of dogs affected by OA.	No Adverse events	[79]
17	Assessing the safety and effectiveness of un-denatured type 2 collagen in the management of OA performed in patients by 18 orthopaedicians	Human	291 patients were enrolled and followed-up at day 30 (visit 2), day 60 (visit 3), and day 90 (visit 4). Efficacy was assessed by and WOMAC and Visual Analogue scale (VAS) on each visit.	226 of 291 patients completed the 90 days study. Treatment with UC-II was related to a significant reduction in WOMAC and VAS scores.	UC-II was safe and efficacious in Indian patients having OA, which could be considered in the early management of OA.	No Adverse events	[80]
18	The purpose of the present study was to asses the outcome of collagen type II IN osteoarthritis of the knee joint.	Human	100 randomly selected patients that received a daily dose of UC-II (40 mg) for 120 days.	UC-II showed a significant reduction in the overall WOMAC score, LFI, and VAS scores in 120 days of observation. The UC-II led to significant changes in the three WOMAC subscales: pain p = 0.0005; stiffness p = 0.004; physical function p = 0.004.	UC-II improved the knee joint function in knee OA.	No Adverse events	[81]