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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 37  |  Issue : 3  |  Page : 152-160

Role of bioactive collagen peptide in the management of monoidoacetate induced osteoarthritis and its comparison with diacerein in rat model: An experimental study


1 Department of Orthopaedics, SN Medical College, Agra, India
2 Department of Pathology, KD Medical College, Uttar Pradesh, India
3 Department of Orthopaedics, LLRM Medical College, Meerut, Uttar Pradesh, India
4 IG ESI Hospital, Delhi, India

Date of Submission11-Oct-2022
Date of Acceptance24-Nov-2022
Date of Web Publication15-Dec-2022

Correspondence Address:
Ravi Kant
Department of Orthopaedics, S N Medical College, Agra, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jbjd.jbjd_32_22

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  Abstract 

Osteoarthritis is the most common joint disorder. Currently, there are no stabilized pharmacological agents capable of retarding the progression or preventing OA. This is a fundamental and important area of current research. Therefore, the present study was to investigate the action of Bioactive Collagen peptide against Monosodium Iodoacetate induced Osteoarthritis in rat models and its comparison with Diacerein. Nine experimental groups were taken. Osteoarthritis was induced by intraarticular injection of Monosodium Iodoacetate (MIA) in knee joints. Bioactive Collagen peptide was given to groups 7, 8 and 9 for 1, 2 and 3 months respectively, then histopathological examination was done. Diacerein was given to groups 4, 5 and 6 for 1, 2 and 3 months respectively followed by histopathological scoring. Significant (P < 0.05) chondroprotection was observed after treatment of Bioactive Collagen peptide when compared with MIA control group as well as Placebo treated group. Significant improvement was also observed when compared with Diacerein treated groups for 1 and 2 monthsIt was concluded that both Bioactive Collagen Peptide and Diacerein are potent chondroprotective agent, but Collagen peptide is far better than Diacerein.

Keywords: Bioactive Collagen peptide, Chondroprotection, Diacerein, Monosodium Iodoacetate, Osteoarthritis


How to cite this article:
Kant R, Rao P, Tank G, Gupta R. Role of bioactive collagen peptide in the management of monoidoacetate induced osteoarthritis and its comparison with diacerein in rat model: An experimental study. J Bone Joint Dis 2022;37:152-60

How to cite this URL:
Kant R, Rao P, Tank G, Gupta R. Role of bioactive collagen peptide in the management of monoidoacetate induced osteoarthritis and its comparison with diacerein in rat model: An experimental study. J Bone Joint Dis [serial online] 2022 [cited 2023 Feb 6];37:152-60. Available from: http://www.jbjd.in/text.asp?2022/37/3/152/363854




  Introduction Top


Osteoarthritis (OA), a degenerative joint disease is characterized by destruction of articular cartilage and formation of osteophytes at the joint surfaces. Osteoarthritis affects the synovial joints such as knees, hips, hands etc. Articular cartilage alters progressively with age. Small fragments detaches, releasing foreign bodies within the joint that become sources of inflammation. OA leads to pain, discomfort, stiffness and swelling in the affected joints.[1]

Conventional drug treatments of Osteoarthritis, such as non-steroidal anti-inflammatory drugs, attenuate symptoms but do not affect the underlying pathology of the disease. Surgical treatment of osteoarthritis can minimize disability. More recent approaches to the treatment of OA have focused on the deceleration of cartilage deterioration and structural modification.[2]

Therefore, there is a continuous need for a pharmacological agent that can maintain joint comfort, function and mobility and could modify structure of degenerated cartilage. Some substances such as glucosamine, chondroitin sulphate, diacerein are already used and have been shown to help to relieve joint discomfort and, in some cases, to modify structural changes.[3]

Bioactive Collagen Peptide, an active form of collagen is a food ingredient that has the potential to improve joint comfort and function. Collagen itself is a natural component of the diet, found in animal products such as meat and fish. However, the absorption of orally ingested collagen that has not been hydrolyzed is poor. Collagen contains unique amino acid sequences found in no other protein (glycine- proline- hydroxyproline). The use of Collagen therefore provides amino acids specific to the collagen network, which could help to maintain the structure and function of joint cartilage, thus improving joint comfort in a safe and efficacious manner.[4],[5] This study was planned to analyze the histopathological evidences and effect of collagen peptide in MIA induced OA in rat modles.


  Material and Methods Top


The present study was conducted in department of orthopaedics, LLRM Medical College Meerut from May 2015 to April 2016. This study has been approved by the Institutional Animal Ethical Committee, LLRM Medical College, Meerut.

Test compound

  1. Bioactive Collagen peptide in the form of powder was procured from Sanofi India Limited Andheri (E) Mumbai.


  2. Diacerein in the form of capsule was taken from Macleods Pharmaceutical Pvt. Limited Andheri (E) Mumbai.


  3. Mono Iodo acetate was obtained from Sigma Aldrich corporation.


Determination of LD50

After taking permission from Animal Ethics Committee (), LD50 of Bioactive Collagen peptide was determined on albino mice.[6] Mice of both sex and weighing 25-30g were divided into four groups of 10 mice each. The animal groups were fed orally the test compound in doses of 1, 2, 4, 6 g/100g/day respectively. During the study, the animals were observed continuously for the initial two hours and then every half hourly for further four hours. Any abnormal behavior or mortality was recorded.

Study design

Albino rats (Wistar strain) of either sex, age range from 8 to 16 weeks and weighing 150–250 grams were obtained from Central animal house (L L R M Medical College Meerut Uttar Pradesh). The animals were housed in cages under controlled conditions of temperature (25°C) and alternating 12 hour cycle of light and darkness. The animals had free access to standard rat pellet diet (Lipton India Ltd.) and tap water ad lib. After one week of acclimatization, the animals were considered suitable for study.

After Approval from Animal Ethical Committee, all animal experiments were conducted according to the guidelines of CPCSEA.

Induction of osteoarthritis

A pilot study was undertaken to induce osteoarthritis with monosodium iodoacetate (MIA). On day 0, rats were anaesthetized with ketamine hydrochloride (50 mg/kg body weight) and xylazine (10 mg/kg body weight) and the both knees were shaved and disinfected with isopropyl alcohol 70% v/v (sprit) followed by povidone-iodide. A single injection of 50 μl sterile normal saline containing 3 mg monosodium iodoacetate (Crystal Powder M=185.96 g/mol, Germany, Sigma) was injected into each knee joint through infrapatellar ligament using a 300 μl syringe fitted with a 29 G needle.,[7] as described by Vermeirsch et al. On day 8th post MIA administration, the knee joints were examined histopathologically and cartilage was stained with hematoxylin and eosin for accessing whether osteoarthritis was produced or not.[8]

After establishing MIA-induced osteoarthritis in pilot study, nine experimental groups 1, 2, 3, 4, 5, 6, 7, 8 and 9 each consisting of six rats were taken. Rats of groups 1 and 2 were naive control and vehicle control, respectively

Group-1 (Naïve control)

On day 0 rats of this group were injected a single dose of 50 μl of normal saline in each knee joint. After 7 days, all six rats were sacrificed using a lethal dose of intraperitoneal injection of Ketamine (75 mg/kg) and Diazepam (10 mg/kg) anaesthesia.[9] The both knees of the rats were resected and placed in 10% formaldehyde solution, then sent for histological analysis to the pathology department of LLRM Medical College Meerut, since it would be expected that in the normal knees, there will not be any apparent change in the cartilage within the short time frame of testing.

Group 2, 3, 4, 5, 6, 7, 8 and 9

On day 0 all rats of these groups were subjected to intra-articular injection of monosodium-iodoacetate (MIA) to induce osteoarthritis as described above. After 7 days of intra-articular injection of MIA, rats of group-2 were sacrificed; both knees were removed and placed in 10% formaldehyde solution, then sent for histological analysis to evaluate the osteoarthritis.

Group 3

After one week of intra-articular injection of MIA all six rats of this group were given normal saline (Placebo) orally, up to 3 months and sacrificed after that to resect both knees and sent for histopathological examination to evaluate any spontaneous healing or regeneration of the damaged cartilage.

Group 4, 5 and 6

After 7 days of MIA injection, rats of these groups received Diacerein, 100 mg/kg/day per orally. Diacerein was given to group-4 for 1 month, group-5 for 2 months and group-6 for 3 months of duration followed by resection of knees and subjected to histopathological examination at 1, 2, and 3 month respectively.

Group 7, 8 and 9

After 7 days of intra-articular injection of monosodium-iodoacetate all the rats of these groups were received Bioactive Collagen peptide for 1, 2 and 3 months respectively per orally in the dose of 10 g/kg/day and then rats were sacrificed to take biopsy from the knee and sent for histopathological examination to the pathology department to evaluate the status of osteoarthritis.

The test compounds (Bioactive Collagen peptide) and Diacerein was administered by gavage method with rats fasted 3–4 hours prior and 1 hour after administration to ensure proper absorption of the drugs.

Histopathological analysis

After giving lethal dose of intraperitoneal injection of Ketamine (75 mg/kg) and Diazepam (10 mg/kg) anaesthesia[9] both knees of rats were removed and placed in 10% formaldehyde solution, then sent for histological analysis. The knees were kept in this solution for one day and further demineralization was done in 7.5% nitric acid for three days and embedded in paraffin wax. Longitudinal slides of the distal femur and proximal tibia were prepared (5 micrometer in thickness) and stained with hematoxylin and eosin (HandE) for routine histological evaluation. Cartilage damage was evaluated according modified Mankin scoring system.[10] The pathologist was blinded to the groups under analysis.


  Observations and Results Top


The four rats died before the scheduled sacrifice date, one in group 2 and one each in groups 3, group 5 and 7. Therefore total numbers of four rats were excluded from the study. Bioactive Collagen peptide was found to be safe even in the maximum tried dose of 6g/100g/day in mice during the LD50 study.

Histopathological findings

Microscopic examination of serial sections prepared from the knee joints of group 1 (naive control group) revealed smooth articular cartilage surface overlying a uniformly distributed layer of normal flattened chondrocytes in the tangential zone. Chondrocytes were distributed in parallel rows in the transitional and radial zones of the non-calcified part of the articular cartilage. The intercellular matrix was homogenous and uniformly stained with HandE stain. The total average pathology score was 0.0 ± 0.0 [Table 1] [Figures 1]A and B.
Table 1: Effect of collagen peptide II (10 g/kg/day) and diacerein (100 mg/kg/day) for different durations, on mono-iodoacetate (MIA) induced osteoarthritis (mean ± SD) (n = 12)

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Figure 1: Microscopic features of the knee joint of control group. Showing smooth articular caiiilage surface overlying a uniformly distributed layer of normal flattened chondrocytes in the tangential zone. Chondrocytes are distributed in parallel rows in the transitional and radial zones of the non-calcified part of the articular cartilage. A: H & E Stain 10X view. B: H & E Stain 40X view

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Photomicrograph of knees of monosodium-iodoacetate (MIA) control group (group 2) revealed the surface irregularity with fibrillation and cracking. Surface is eroded with disorganization and hypertrophy of chondrocytes exhibiting formation of duos and clones. At some places there was decrease in colour with increased spacing between chondrocytes due to hypocellularity. The score of histopathology showed significant increase from 0.0 ± 0.0 in naive control group to 26.17 ± 2.03 (P < 0.05), [Figures 2]A and B.
Figure 2: Microscopic features of the knee joint of MIA group. Showing surface inegularity with fibrillation and cracking. Surface is eroded with disorganization and hypertrophy of chondrocytes. At some places decrease in colour with increased spacing between chondrocytes seendue tohypocellularity. MIA - Mono Sodium Iodo Acetate. A: H & E Stain 10X view, B: H & E Stain 40X view

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Like MIA control group histology of placebo treated group (group 3) for three months showed the surface irregularity with fibrillation and cracking. Surface is eroded with disorganization and hypertrophy of chondrocytes exhibiting formation of duos and clones. At some places there was decrease in colour with increased spacing between chondrocytes due to hypocellularity with histological mankin score of 24.67 ± 1.79 which was noticed highly significant when compared with negative control group (0.0 ± 0.0), (p value <0.05), Diacerein treated (3 months) group (3.5 ± 1.12) and Bioactive Collagen peptide treated (3 months) group (3 ± 0.82). It was also found significant when compared with other groups of Diacerein and Collagen peptide, [Figure 3]A and B.
Figure 3: Microscopic features of the knee joint of Placebo group. Showing surface irregularity with fibrillation and cracking. Surface is eroded with disorganization and hypertrophy of chondrocytes. At some places decrease in colour with increased spacing between chondrocytes dueto hypocellularity. A: H & E Stain 10X view. B: H & E Stain 40X view

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Histological slides of Diacerein treated group for the duration of one month (group 4) showed irregularity of surface with few cracking effects hypocellular area with haphazard distribution of chondrocytes, few duos and clones present with decreased colour at some places. Total average pathological mankin score was 20.25 ± 1.74 which showed significant change from the MIA control group (26.17 ± 2.03) and with naive control group to 0.0 ± 0.0 (P < 0.05) [Figure 4]A and B.
Figure 4: Microscopic features of the knee joint of DC 1M group. Showing irregularity of surface with few cracking effects hypocellular area with haphazard distribution of chondrocytes, with decreased colour at some places. DC lM - Diacerein 1month. A: H & E Stain 10X view. B: H & E Stain 40X view

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Treatment of rats of group 5 with Diacerein for the duration of 2 months significantly improved the damage of articular cartilage to 9.5 ± 0.87 (P < 0.05) with articular surface comparatively smoother i.e. without erosion and fibrillations but areas of hypocellularity and decreased colour still present and occasional duos seen. It was also found significant in comparison to placebo treated group (24.67 ± 1.79) (P < 0.05) [Figures 5]A and B.
Figure 5: Microscopic features of the knee joint of DC 2M group. Showing articular surface comparatively smoother i.e. without erosion and fibrillations but areas ofhypocellularity and decreased colour seen. DC 2M - Diacerein 2 months. A: H & E Stain 10X view. B: H & E Stain 40X view

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Histology of Diacerein treated group for three months (group 6) showed smooth surface with normal distribution and number of chondrocytes with only occasional duos, a significant decrease in pathological score (3.5 ± 1.12) was detected which represent a marked improvement in the histopathological finding and was significant (P < 0.05) when comparison to MIA control group (26.17 ± 2.03) and placebo group (24.67 ± 1.79) [Figure 6]A and 6B.
Figure 6: Microscopic features of the knee joint of DC 3M group. Showing smooth surfacewith normal distribution and number of chondrocytes. DC 3M - Diacerein 3 months. A: H & E Stain 10X view. B: H & E Stain 40X view

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Photomicrograph of histology of knees of the rats of group 7 (Bioactive Collagen peptide treated group for one month) revealed that surface of cartilages eroded with area of fibrillations, hypocellularity and decreased colour with disorganized and variably distributed chondrocytes, few chondrocytes showed hypertrophy, duos and clones formation. Histopathological scoring was 14.75 ± 2.65 (P < 0.05) [Figures 7]A and B which was found significant when compared with MIA control group and negative control group and placebo treated group.
Figure 7: Microscopic features of the knee joint of CP 1M Group. Showing surface of cartilages eroded with area of fibrillations,hypocellularity and decreased colour with disorganized and variably distributed chondrocytes, few chondrocytesshowinghypertrophy. CP 1M - Bio Active Collagen Peptied for 1month. A: H & E Stain 10X view. B :H & E Stain 40X view

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Treatment of rats of group 8 with Bioactive Collagen peptide for 2 months duration significantly improved the damage of articular cartilage after MIA administration to 7.25 ± 1.16 (P < 0.01) with surface comparatively regular, cellularity slightly increased with organized distribution of chondrocytes, only occasional areas showed decreased colouration. It was also found significant (P < 0.01) when compared with placebo group [Figure 8]A and B.
Figure 8: Microscopic features of the knee joint of CP 2M Group. Showing surface comparatively regular, cellularity slightly increased with organized distribution of chondrocytes, only occasional areas showing decreased colouration. CP 2M - Bio Active Collagen Peptied for 2 months. A: H & E Stain 10X view. B: H & E Stain 40X view

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Microscopic examination of serial sections prepared from the knee joints of group 9 (Bioactive Collagen peptide treated group for 3 months) revealed smooth regular surface with normal number, distribution and morphology of chondrocytes. Significant drop in the pathological score was noticed (3 ± 0.82) and found highly significant when compared with MIA control group (26.17 ± 2.03), placebo group (24.67 ± 1.79), Diacerein treated group for one month (20.25 ± 1.74) and two months (9.5 ± 0.87) and Collagen peptide treated group for one month (14.75 ± 2.65) (P < 0.05) [Figure 9]A and B.
Figure 9: Microscopic features of the knee joint of CP 3M Group. Showing smooth regular surface with normal number, distribution and morphology of chondrocytes. CP 3M - Bio Active Collagen Peptied for 3 months. A: H & E Stain 10X view. B: H & E Stain 40X view

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  Discussion Top


The result of the present work has shown that significant increase in Mankin pathological scoring (26.17 ± 2.03) has been detected predominantly after one week of osteoarthritis induction in the both knee joints of all rats of group-2 when compared (P < 0.05) to control group-1 (00 ± 00). The findings were in accordance with the findings described in previous studies by Al-saffar et al.[11],[12] who used monosodium iodoacetate to induce osteoarthritis in rat models [Table 1] [Figure 2]A and B

In the present study it was also observed, that Diacerein, significantly decreased the pathological score after one (20.25 ± 1.74), two (9.5 ± 0.87), and three (3.5 ± 1.12) months of treatment in group 4, group 5 and Group 6 respectively, which represent a marked improvement in the histopathological finding in a duration dependent fashion i.e. more improvement was seen after three months of treatment than two months and one month. Therefore it can be said that chondroprotective effect of diacerein was duration dependent that is gradual improvement seen after treatment of one, two and three months respectively [[Figures 4]A and B, [5] A and B, [6] A and B].

The results of our study were in accordance with in vivo studies done on different OA animal models, as well as, in vitro studies done on human articular cartilage, using different indices of cartilage degradation. Brandt KD et al. found that, diacerein decreased the collagenase level in the cartilage of dogs and rabbits,[13 while Moore et al.[14] stated that diacerein also reduced the loss of hydroxyproline and proteoglycans in mouse cartilage, and decreased the inducible NO synthase (iNOS) in dog cartilage, Pelletier et al.[15] and Tamura et al.[16] found that rhein which is the active metabolite of diacerein, down regulates the gene expression and production of matrix metalloproteinases and up-regulates the production of tissue inhibitors of metalloproteinase-1 in rabbit articular chondrocytes. Hwa et al.[17] described a reduction in subchondral bone remodeling in sheep with diacerein treatment. Another study done by Rezende et al.[18] also found that diacerein lowered the degree of articular stiffness in experimentally induced osteoarthritis model in rats with reduction in the histopathological score. While Legendre et al.[19] found that, rhein inhibits proliferation of synoviocytes, suggesting that the drug may decrease the development of the inflammatory synovial tissue that accompanies joint pathologies. Its action as anticatabolic on chondrocytes and anti-proliferative on synoviocytes may explain its beneficial effect in the treatment of joint diseases.

The collagen peptide is a principal molecular component of mammalian cartilages.[20] The present work is focused on the study of this fibrous protein as preventive of MIA-induced articular damage. A daily dose of 10 g/kg/day of bioactive collagen peptide per oral were given to group-7, 8 and 9 for the durations of one, two and three months respectively starting from the 8th day of post MIA injection. This dose was chosen on the bases of the efficacy demonstrated by Park KS et al. in rheumatoid arthritis models.[21]

Orally administrated bioactive collagen peptide, reduced the Mankin pathological score significantly (P < 0.05) after one (14.75 ± 2.65), two (7.25 ± 1.16) and three (3 ± 0.82) months in the respected groups. This was reflected in histopathology that smooth regular surface with normal number, distribution and morphology of chondrocytes. Marked drop in the pathological score were noticed and found highly significant (P < 0.05) when compared with MIA control group (2) (26.17 ± 2.03) and placebo treated group (3) (24.67 ± 1.79). However, rats receiving placebo (group-3) did not show any improvement in arthritic condition. The results of collagen peptide treated group for three month (3 ± 0.82) were found to be comparable and in close association with the scores of naive control group (P > 0.05) [Figure 7]A and B, [Figure 8] A and B, [Figure 9] A and B.

When individual component of Mankin histological score i.e. Depth of damage, Cartilage changes, Cellular abnormality, Matrix staining, Extent of Inflammation, Panus formation, number of Osteoclasts were studied separately within the different groups it was found that bioactive collagen peptide significantly limits the all components of damage. It was observed that collagen peptide treatment for three months showed much more improvement in all components of Mankin scoring system in comparison to one and two months treatment [Figure 7]A and B, [Figure 8] A and B, [Figure 9] A and B, [Figure 10] and [Figure 11].
Figure 10: Effect of bioactive collagen peptide (10 g/kg/day) and diacerein (100 mg/kg/day) for different durations, on monosodium-iodoacetate (MIA) induced Osteoarthritis (Mean ± SD) (n=12)

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Figure 11: Effect of diacerein and bioactive collagen peptide treatment for different durations on different component of Mankin system

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In our study it was also observed that the effect of Bioactive collagen peptide as a chondroprotective agent was much better than the effects of Diacerein and it was found significant (P < 0.05) after one and two months of treatment, while when effect of Bioactive collagen peptide is compared with Diacerein for duration of three months it was found insignificant (P > 0.05).

The results of our study were in accordance with some previous studies such as a non-randomized trial done by Gotz et al, in which they tested the effect of collagen hydrolysate in 60 patients over 3 months. 56% of patients had improved considerably. At the end of the study, 75% of patients had, at minimum, clearly improved joint comfort.[22]

Various studies by Krug et al. (1979); Moskowitz et al. (2000); Zuckley et al. (2004); Carpenter et al. (2005); Banzer et al. (2006); Bello and Oesser et al. (2006) Showed that a daily intake of 10 g Collagen Hydrolysate (CH) for 60 days or longer resulted in pain reduction in patients with OA of the hip or knee This effect is considered to be due to a specific effect of Collagen Hydrolysate on joint tissues, since it is unlikely to have any analgesic or anti- inflammatory effects.[23],[24],[25],[26],[27],[28]

The possible mechanisms of bioactive collagen peptide for regeneration of articular cartilage are that the hydrolyzed collagen accumulates in the cartilage and stimulate production of collagen by the chondrocytes, the cells of cartilage. Several studies have shown that a daily intake of hydrolyzed collagen increases bone mass density. It was suggested by Fujioka M et al. that hydrolyzed collagen peptide stimulate differentiation of osteoblasts activity over that of osteoclsts.[29]

In experimental investigations, it has been demonstrated that orally administered bioactive collagen peptide was found safe even in maximum tried dose of 6 g/100g/day during LD 50 study. These results were similar as shown by previous studies that Collagen products are recognized as safe components of pharmaceuticals and foods by the US Food and Drug Administration (FDA). Beuker and Rosenfeld et al. (1996); Zeijdner et al. (2002) said the fact that collagen is normally present in the diet, and the food ingredient, Collagen hydrolysate, has been shown to be absorbed intestinally[30],[31] especially in fermented dairy products and has been used for many years (as gelatine in foods) and declared safe (European Food Safety Authority 2005), makes collagen hydrolysate an ideal ingredient for a functional food.[31]

It also has been demonstrated by Oesser S et al. that orally administered collagen peptide is thoroughly absorbed by the intestine and circulated in the blood stream, reaching a maximal plasma concentration in 6 hour.[32]

But further pharmacokinetic properties of bioactive collagen peptide are largely unknown. An elaborate investigation to explore the pharmacokinetic profile may lead to better efficacy and potency of bioactive collagen peptide at smaller doses.


  Conclusion Top


In the recent years there have been outstanding advances in management of osteoarthritis including drug treatment as well as surgical modalities, even though the prevalence of osteoarthritis increasing continuously day by day.

It can be concluded from our study that the Bioactive Collagen Peptide is a potent chondroprotective agent. It is also concluded that the effect of Diacerein for the treatment of OA is good, but Collagen peptide is significantly better than Diacerein for initial two months of treatment and also good result at 3 months. Bioactive Collagen Peptide showed overall better results in comparison to Diacerein but only drawback of Collagen Peptide is its high dose.

It is suggestible that the dosage form of Collagen Peptide can be changed from the current form of Bioactive Collagen Peptide to some other form such as collagen peptide II or any other so that further better results could be obtained at reduced doses and at lesser price.

Since the safety profile of Bioactive Collagen Peptide has been very encouraging in this study therefore, it can be used in human being without any risk. The mechanism of action of Bioactive Collagen Peptide is still not very clear so further studies are needed to know better and detailed explanations of mechanisms.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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