Collagen is a vital component of structural matrix throughout most tissues and organs in the human body. It is concentrated in cartilage, where it plays a significant role in the integrity of joint-related connective tissues. The important role played by collagen in joints is vividly shown by the severe generalized arthritis associated with collagen gene mutations [78,79].
The amount of collagen in the diet can be increased by consuming specific foods, such as meats with gristle or connective tissue still intact. Collagen also can be found in foods containing gelatin. Dietary supplements also can be used to increase the amount of collagen contributed by the diet. An example of such a supplement is collagen hydrolysate, which is prepared by enzymatic hydrolysis of collagenous tissue, such as bone, hide, and hide split from pigs and cows. Collagen hydrolysate is soluble in cold water and is composed of proteins with a molecular weight of 3 to 6 kD.
Collagen hydrolysate provides high levels of amino acids. Among these are glycine and proline, two amino acids that are essential for the stability and regeneration of cartilage. To synthesize a single picogram of collagen type II, more than 1 billion glycine molecules and 620 million proline molecules are required. In the absence of these amino acids, the anabolic phase of cartilage metabolism can be impaired.
In studies of rats and humans, concentrations of the amino acids proline, hy-droxyproline, and glycine after administration of collagen hydrolysate (10 g in humans) increased significantly compared with placebo . In a single-blind, randomized, and placebo-controlled study of 60 male sports students, the amino acid concentrations in peripheral blood after a daily intake of 10 g of collagen hydrolysate for 4.5 months were measured. It was found that levels of the amino acids glycine, proline, and hydroxyproline were significantly higher in the treated group than in the control group. The concentrations of alanine, asparagine, glutamic acid, and tryptophan also were higher.
It has been shown that about 90% of orally administered collagen hydrolysate is resorbed within 6 hours from the gastrointestinal tract . It also has been found that collagen hydrolysate has a special affinity for cartilage, and that this affinity to cartilage has a stimulating effect on the synthesis of chondrocytes (Fig. 3) .
Collagen hydrolysate has been studied for the management of joint pain in four open-label and three double-blind studies [82-88]. The earliest of these, by Krug , studied the clinical effect of collagen hydrolysate on degenerative joint disease in patients with knee osteoarthritis with tibial, femoral, or retropatellar involvement or with degenerative disc disease of specific parts of the spine. Patients received 5 to 7 g of collagen hydrolysate by mouth for 1 to 6 months. The author reported results on 56 patients: 10 (24%) had very good success, 18 (44%) had noticeable improvement, and 13 (32%) reported no improvement. The author did not report the statistical significance of the findings .
In 1982, Gotz  reported the results of a study in which 60 juvenile patients diagnosed with retropatellar osteoarthritis received collagen hydrolysate treatment (one 7-g sachet per day by mouth) for 3 months. The sachet also included 24,000 U of vitamin A and 120 mg of the sulfur-containing amino acid L-cysteine. Gotz  reported that after treatment, 75% of patients showed improvement: 45% of patients were symptom-free, and 30% had clearly improved symptoms; the remainder of the patients did not improve. No P values were provided in this report.
An open-label study of 154 patients with osteoarthritis provided additional evidence of the clinical efficacy of collagen hydrolysate . Patients with diagnosed osteoarthritis of the knee, hip, or lower spine were randomized among three treatment groups: therapeutic exercises; therapeutic exercises plus collagen hydrolysate with vitamin A and L-cysteine; or collagen hydrolysate, vitamin A, and L-cysteine without therapeutic exercise. The collagen hydroly-sate, vitamin A, and L-cysteine were given as one sachet per day by mouth. After 3 months of treatment, the percentage of patients with a very good response was 26% for the supplement-only group, 20% for the supplement plus exercise group, and 6% for the exercise-only group . Similar results were found for good response (supplement only, 43%; supplement plus exercise, 36%; and exercise only, 14%), whereas the opposite results were found for patients who were considered unchanged (supplement only, 6%; supplement plus exercise, 14%; and exercise only, 43%).
Collagen hydrolysate has been studied in populations other than patients diagnosed with osteoarthritis. An observational study investigated the effects of collagen hydrolysate in athletes who had joint pain, but who did not have osteoarthritis. In this study, 100 participants with hip, knee, or shoulder pain resulting from intense physical activity were treated with orally administered collagen hydrolysate (10 g/d) for 12 weeks . Of the 88 patients who could be evaluated in the study, 78% of patients achieved pain reduction after taking collagen hydrolysate for 12 weeks (68 patients improved, 19 patients were unchanged or worsened, and 1 patient was incompletely documented for pain on movement) .
In addition to these open-label trials, collagen hydrolysate has been studied in a prospective, randomized, double-blind, placebo-controlled clinical trial conducted by Adam . Researchers recruited 81 patients with osteoarthritis of the knee or hip and used a complex crossover design to compare four different nutritional supplements that included collagen hydrolysate (10 g in the form of 20 capsules, each 500 mg, by mouth). They found that 81% of patients taking collagen hydrolysate achieved meaningful pain reduction compared with 23% of patients taking a control substance (egg albumin). In addition, 69% of patients taking collagen hydrolysate had a 50% or greater decrease in the consumption of analgesics compared with 35% of the patients taking egg albumin . The author noted that the results from treatment with all nutritional supplements, including collagen hydrolysate, were significantly different from egg albumin, but he did not define statistical significance .
Another study of collagen hydrolysate by Moskowitz  was a prospective, randomized, double-blind, placebo-controlled clinical trial. The study included sites in Germany, the United Kingdom, and the United States and recruited 389 patients with knee osteoarthritis. Patients were randomly assigned to receive 10 g of collagen hydrolysate per day or placebo, by mouth, for 24 weeks. The primary outcome measures were the WOMAC pain score, function score, and patient global assessment. After 24 weeks of treatment, there were no statistically significant differences for the total study group for differences of mean score for pain. Moskowitz  reported, however, that one group of patients (the German patients, n = 112) experienced a statistically significant benefit from collagen hydrolysate in terms of pain reduction (P = .016) and functional improvement (P = .007), but not patient global evaluation (P = .074).
The benefits of collagen hydrolysate for patients with mild symptoms of os-teoarthritis were examined in a randomized, placebo-controlled, double-blind study with 250 adults diagnosed with mild symptoms of osteoarthritis of the knee. A total of 190 patients completed the study (88 treatment and 102 placebo patients). Treatment consisted of oral administration of collagen hydroly-sate (10 g/d) or placebo for 14 weeks. Isokinetic and isometric leg strength was assessed using a Biodex Multi-Joint System B2000 . A 6-minute walk test and a 50-foot walk test were used to assess functional mobility, and joint pain, stiffness, and perceived functional mobility were assessed using the WOMAC Index, the Lequesne Index, and the Knee Pain Scale.
After 14 weeks of treatment, there were no statistically significant differences between the treatment groups for measures of pain, stiffness, mobility, or flexibility measurements. The collagen hydrolysate-treated group showed statistically significant improvement, however, in three out of six isokinetic leg strength measures (peak torque/body weight for extension at 60°/sec , peak torque/body weight for flexion at 60°/sec-1, and total work/body weight for extension at 60°/sec-1; P < .05 compared with placebo for all three tests) . The investigators stated the findings suggest that collagen hydrolysate may contribute to early changes in knee cartilage (M. Carpenter, personal communication, 2006), which is consistent with animal data .
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