Background

Collagens are major structural proteins in numerous body tissues, including tendons, ligaments, cartilage, skin, blood vessels, muscles, gut tissue, and dentin.^[1] They are the most abundant proteins in the body, comprising 30 percent of the total protein mass. The human body continuously manufactures collagens to maintain tissue structural integrity. However, aging drives a progressive decrease in protein synthesis and reduced capacity to produce new collagen.^[2]

Collagens are also highly versatile biomaterials with wide applications and usage across medical, dental, and pharmacological fields.^[3] In 2018, financial experts estimated that the collagen market accounted for nearly $3.5 billion and will likely reach $4.6 billion by 2023, in large part due to the rising demand in the medical and healthcare industries.(Source: MarketsandMarkets)

Collagen types and structure

Collagens are characterized by a triple helix arrangement, forming a sturdy, resilient structure comprising approximately 1,300 to 1,400 amino acids. (See Figure 1.) They serve general tissue assembly and maintenance functions, including tissue scaffolding, morphogenesis, and repair.^[4] Twenty-eight distinct collagen proteins have been identified, designated by Roman numerals (I–XXVIII). These collagens differ in their interactions with other proteins, cellular components, and location within the body.^[5]

Collagens I, II, and III are the most abundant collagen types and are considered fibril collagens – bundles of individual collagen proteins that provide tissue support and strength. Collagens I, II, and III have different amino acid sequences and differ in their locations within the body. Type I collagen is found in the connective tissue of tendons, ligaments, corneas, bones, and skin. Type III collagen typically co-locates with collagen I in the skin and blood vessels, while type II collagen is within cartilage.^[4] The amino acids glycine, proline, and hydroxyproline account for more than 50 percent of the amino acids that comprise collagen.^{[6] [7]}

The most common three-amino acid sequence (a tripeptide) in collagens is glycine-proline-hydroxyproline.^[8] However, collagen type III contains more hydroxyproline than type I and II. The two-amino acid sequence proline-hydroxyproline (a dipeptide) is more abundant in type I versus type III.

Hydrolyzed collagen

Collagens type I, II, and III are typically hydrolyzed and used as oral supplements, which have demonstrated promise in improving skin health, decreasing joint pain due to arthritis or athletic injury, and ameliorating hypertension. Hydrolyzed collagen, also referred to as collagen peptides or collagen hydrolysate, is derived by denaturing, or breaking down, collagen into smaller amino acid chains (called peptides) by thermal or enzymatic means. For example, exposure to heat (as in cooking) denatures collagen's structure, reducing it to shorter peptide chains and causing it to form gelatin. The peptides in gelatin are larger than those of hydrolyzed collagen, which typically average 30 to 60 amino acids in length.^[9] The amino acids glycine, proline, and hydroxyproline are hydrolyzed collagen's most abundant amino acids. While oral hydrolyzed collagen supplementation demonstrates some therapeutic effects, it should not be used as a protein replacement as it lacks the essential amino acid tryptophan.

Hydrolyzed collagen sources

Collagen can be derived from numerous sources, including bovine animals (primarily cows), pigs, chickens, and marine animals. After the extraction of collagen from the bones, tendons, lungs, or connective tissue of these animals, hydrolyzed collagen is produced by thermal and enzymatic cleavage.^[9] Collagen types I, II, and III are all from the same fibril collagen family but differ in their amino acid sequence. Although collagens I, II, and III each primarily contain the amino acids glycine, proline, and hydroxyproline, these collagens may have different quantities and types of peptide sequences that the human body distinguishes. Studies comparing potential differences between the hydrolyzed sources and forms of collagen I, II, and III are lacking.

Bovine versus marine collagen sources

Marine and bovine sources may differ in their predominant collagen types and risk profiles. Marine collagens are associated with a lower pathological risk of disease transmission since marine animals do not transmit bovine spongiform encephalopathy (commonly known as "mad cow disease") or avian and swine influenza. ^[10] However, to date, the clinical trials that have used oral hydrolyzed collagen from bovine sources as well as from marine, pig, and chicken sources have found the products to be safe and well-tolerated. Future studies may uncover whether differences exist between the various sources of hydrolyzed collagen. However, no standard therapeutic dose has been established, so studies are needed to determine appropriate doses for specific uses such as skin care or joint health and to distinguish any differences between the collagen sources.

"A study found that the key amino acids glycine, proline, and hydroxyproline were significantly lower in various bone broth preparations compared to a reference 20-gram collagen supplement. The amino acid content of the broths varied considerably according to preparation techniques" Click To Tweet

Bone broth as a source of hydrolyzed collagen

Bone broth is a dietary collagen source that has received numerous medical claims, from aiding digestion to supporting bone and joint health. The broth is made by simmering bone and connective tissue of various animals in a liquid such as water for extended periods to extract collagen and additional amino acids, minerals, and bone marrow. Unlike hydrolyzed collagen, however, the evidence regarding the health effects of bone broth consumption is limited. Additionally, bone broth may provide unreliable hydrolyzed collagen concentrations compared to supplemental hydrolyzed collagen forms. A study found that the amino acids glycine, proline, and hydroxyproline were significantly lower in various bone broth preparations compared to a reference 20-gram collagen supplement. The amino acid content of the broths varied considerably according to preparation techniques.^[11] While bone broth is not necessarily harmful to consume in terms of nutritional quality, wide variation in amino acid content due to differences in preparation techniques raises concerns over reliability and, ultimately, therapeutic value. In this regard, commercially prepared, therapeutically-dosed collagen supplements may be more reliable sources.

Hydrolyzed collagen absorption

Proteins can comprise thousands to tens of thousands of linked amino acids that must be denatured into individual amino acids or short peptide sequences of two to three amino acids in length to facilitate their absorption by the body.^[12] Because hydrolyzed proteins are smaller in length than undenatured proteins, they are generally absorbed more readily.^[13] Therefore, hydrolyzed collagen may be absorbed faster and more efficiently than undenatured collagen.

A study involving 10 healthy men between the ages of 18 and 35 found that hydrolyzed collagen enhanced the post-meal absorption rate of amino acids better than undenatured collagen. The study used a crossover design in which the men consumed one of three products on non-consecutive days: a placebo, 35 grams of hydrolyzed collagen, or 35 grams of undenatured collagen, each dissolved in 250 milliliters of water. Both the hydrolyzed and undenatured collagen supplements were from a commercial product derived from beef bone, which contains primarily type I collagen. After the study participants consumed the product or placebo, the authors sampled their plasma every 20 minutes for up to 240 minutes. Compared to the placebo, there was a significant increase in the total amino acid concentration in the plasma after ingesting either collagen supplement, but there was no significant difference between the collagen-supplemented groups. All amino acid concentrations peaked faster after hydrolyzed collagen intake than undenatured collagen. Over the course of 240 minutes, the average concentrations of the individual amino acids glycine, proline, and hydroxyproline in the plasma were significantly higher after hydrolyzed collagen consumption than undenatured collagen.^[14] Thus, ingesting hydrolyzed collagen may lead to substantially higher glycine, proline, and hydroxyproline plasma concentrations than undenatured collagen.

Incorporation of hydrolyzed collagen into connective tissue

Studies in vivo showed that after oral consumption of hydrolyzed collagen, the collagen peptides may accumulate in tissues such as cartilage and skin. A study in mice demonstrated that after feeding mice radiolabeled gelatin hydrolysate, some collagen peptides broke down into amino acids, but others were absorbed intact, likely as two- to three-amino acid peptides. Peptides from gelatin hydrolysate preferentially accumulated (more than twice as much) in the cartilage compared to proline only.^[15]

A separate study found that rats fed either a radiolabeled three-amino acid collagen peptide (glycine-proline-hydroxyproline) or radiolabeled proline alone experienced a rapid increase of radioactivity in the plasma from the portal vein, abdominal aorta, and tail vein in both groups, indicating that the collagen tripeptide can be absorbed undenatured. The glycine-proline-hydroxyproline peptide exhibited no cartilage-specific accumulation, but the peptide was present in the skin 14 days after feeding.^[16] These rodent studies indicate that peptides from hydrolyzed collagen may directly deposit in various tissues, aiding tissue growth or repair.

These studies indicate that ingesting hydrolyzed collagen may directly fuel connective tissue-building processes instead of being broken down and utilized as energy or components for other proteins. More studies are needed in humans to determine how much peptides from hydrolyzed collagen accumulate in tissues.

Hydrolyzed collagen and skin

"By the time a person reaches 80 years old, collagen production in the skin may be decreased by 75 percent compared to young adults." Click To Tweet

Collagen plummets as we age. Collagen comprises roughly 70 percent of the skin's dry weight.^[17] Of the skin's total collagen content, type I collagen comprises 80 percent, and type II comprises 15 percent. After a person reaches the age of 18 years, their skin collagen content decreases by about 1 percent per year.^[17] By the time a person reaches 80 years old, collagen production in the skin may be decreased by 75 percent compared to young adults.^[9]

While some evidence supports ingesting collagen to improve specific parameters of skin health, topical collagen, as in cosmetics, has weaker overall evidence. Collagen is a component of numerous cosmetic formulations because it maintains skin structure and integrity. Undenatured collagen cannot penetrate the skin, but hydrolyzed collagen may penetrate the first layer of the skin to some extent. As a result, undenatured collagen and hydrolyzed collagen creams and lotions will not replace collagen loss in the skin but may aid in skin moisturizing, potentially by promoting cell proliferation or the release of specific molecules from cells.^[18][19] Conversely, ingesting oral hydrolyzed collagen improves signs of skin aging.

Oral intake of hydrolyzed collagen elicited a reversal in the natural decline of skin elasticity in aging women. A randomized placebo-controlled trial in 69 women between the ages of 35 and 55 demonstrated that oral hydrolyzed collagen intake may improve skin elasticity (the ability to resume original shape after being stretched). The women consumed either 2.5 grams of hydrolyzed collagen, 5 grams of hydrolyzed collagen, or 2.5 grams of placebo (maltodextrin) daily for eight weeks. The hydrolyzed collagen was porcine type I collagen. The women had similar baseline measurements of skin elasticity, skin moisture, transepidermal water loss, and skin roughness. Compared to the placebo, both hydrolyzed collagen doses increased skin elasticity by an average of 7 percent after four and eight weeks of intake. There was no statistically significant difference between either dose of hydrolyzed collagen intake. A subgroup analysis showed that an improvement in skin elasticity was more pronounced in women older than 50 years compared to women younger than 50 years, regardless of the dose of hydrolyzed collagen.^[20]

A separate randomized placebo-controlled trial studied the effects of hydrolyzed collagen on skin aging. The study involved 112 women between the ages of 39 and 59 years who were assigned to take a placebo (500 milligrams of cellulose) or a commercial product (containing 300 milligrams of hydrolyzed type II collagen, 100 milligrams of chondroitin sulfate, and 50 milligrams of hyaluronic acid) twice a day for 12 weeks. Chondroitin sulfate is an essential structural component of cartilage, while hyaluronic acid is a structural component of cartilage, connective, epithelial, and neural tissue. The women were required to abstain from all topical skin-treatment products during the study. The objectively measured outcomes included facial lines, wrinkles, crow's feet lines, skin texture, smoothness, skin tone, and erythema or dryness. Both the placebo and commercial product groups had statistically significant improvements in skin dryness, crow's feet, texture, smoothness, and skin tone from baseline to week 12. However, the commercial product significantly outperformed the placebo in improvements of facial lines and wrinkles, with an average percent improvement from baseline for facial lines and wrinkles of 8.35 percent for those who supplemented with the commercial product versus 0.63 percent for those who supplemented with the placebo. Supplementation with the commercial hydrolyzed collagen product was well tolerated, with no allergic reactions reported, and effectively decreased wrinkles.^[21]

Another randomized, placebo-controlled trial studied the effects of hydrolyzed collagen for improving hydration, elasticity, and wrinkling in human skin in women between the ages of 40 and 60 years. The study's authors assigned 64 women to receive 50 milliliters of a liquid supplement containing a placebo or 1,000 milligrams of hydrolyzed collagen with greater than 15 percent of the collagen hydrolyzed into tripeptides once daily for 12 weeks. The liquid supplement also contained 100 milligrams of vitamin C and fruit concentrate mix. Aside from helping maintain healthy skin, vitamin C is a cofactor for enzymes involved in collagen stabilization, and vitamin C has been shown to increase collagen gene expression.^[22] The collagen obtained for the study was derived from the catfish skin; therefore, the collagen was likely type I. The women were permitted to use only topical cosmetics supplied by a specific company (unspecified) for the duration of the study. The hydrolyzed collagen-supplemented group had a 7.23-fold greater improvement in skin hydration at six weeks and a 2.9-fold greater improvement in skin hydration at 12 weeks compared to the women who supplemented with the placebo. The researchers suggested that the improvement seen at 12 weeks in the placebo group might have been due to the placebo effect (vitamin C and fruit concentrate) or the topical cosmetics supplied. Additionally, the visual grade related to wrinkle formation was significantly improved from the baseline to 12 weeks in the collagen-supplemented group, and the improvement in wrinkle visual grade was 10.5-fold greater in the collagen-supplemented compared to placebo. The net elasticity of the skin was significantly higher in the test group than in the placebo group at 12 weeks.^[23]

These studies, along with others that include hydrolyzed collagen in combination with vitamins and minerals, such as vitamins C and E, biotin, and zinc, suggest that the consumption of oral hydrolyzed collagen may be effective at improving skin aging.^[24][25][26] Studies comparing possible differences between the source of collagen as well as the specific type (I, II, and III) – the ratio of which varies between different sources – would shed more light on the effectiveness of hydrolyzed collagen on skin aging.

Hydrolyzed collagen and arthritis

Arthritis is a degenerative disorder of joints that can cause pain and reduced mobility.^[27] Cartilage destruction within the joints can drive arthritis. Collagen, particularly type II, contributes 60 percent of the dry weight of cartilage.^[28] Currently, there is no cure for arthritis, but some treatments include pain and anti-inflammatory medications, exercise, and joint surgery. Hydrolyzed collagen supplementation may reduce pain and disability in people with arthritis and may be an affordable and effective supplement for treating the symptoms associated with arthritis.

Hydrolyzed collagen and osteoarthritis

Osteoarthritis is a degenerative disease of joint cartilage that typically begins in people over the age of 50 years and likely affects more than 32 million people living in the United States. Osteoarthritis differs from rheumatoid arthritis in that it is primarily age- or injury-related rather than autoimmune. Data from multiple studies suggest that oral hydrolyzed collagen supplementation may be effective in managing osteoarthritis symptoms.

A randomized placebo-controlled trial involving 80 men and women investigated the use of a commercially available hydrolyzed collagen product for the symptoms of osteoarthritis. The participants consumed two doses per day of either 1 gram of a placebo containing cellulose or 1 gram of a commercial product (600 milligrams of hydrolyzed chicken type II collagen, 200 milligrams of chondroitin sulfate, 100 milligrams of hyaluronic acid, and 50 milligrams uncharacterized cartilage components). The use of anti-inflammatory drugs, corticosteroids, and drugs causing central nervous system depression was prohibited during the study duration. On the 70th day of treatment, the study's authors assessed the participants' pain levels, determined by a visual analog scale. The placebo and commercial product supplement groups reported significant decreases in acute and chronic pain compared to baseline measurements. However, the commercial product reduced pain scores by 35 percent compared to 14.9 percent with the placebo, which was statistically significant. On the Western Ontario and McMaster Universities Osteoarthritis Index, a clinical tool used to assess pain, stiffness, and physical function in people with osteoarthritis, those who supplemented with the commercial product had a 38 percent decrease in their scores compared to baseline, while the placebo group had a 19.8 percent reduction compared to baseline. The difference between the commercial product and placebo was statistically significant. No severe adverse events were reported, and the commercial product outperformed the placebo in all measures of pain, stiffness, and physical function.^[29]

Although the commercial product used in the study mentioned above contained additional ingredients other than hydrolyzed collagen, a meta-analysis showed that hydrolyzed collagen is effective at improving osteoarthritis symptoms. The analysis reviewed data from five randomized placebo-controlled trials evaluating the effect of orally administered collagen on people with osteoarthritis. Four studies administered 2 to 10 grams of hydrolyzed collagen per day, while one administered 40 milligrams of undenatured type II collagen per day. The duration of the studies was ten to 48 weeks, and the participants were assessed for pain and physical functioning using the Western Ontario and McMaster Universities Osteoarthritis Index and a visual analog scale. Those who took the hydrolyzed collagen supplement experienced decreased pain, stiffness, and functional limitations on both assessments.^[30] These data indicate that hydrolyzed collagen may be a viable option for reducing symptoms associated with osteoarthritis.

Undenatured collagen supplementation may reduce pain as well. Hydrolyzed collagen has been the subject of much clinical research on the therapeutic value of collagen supplementation due to higher absorption of glycine, proline, and hydroxyproline, which likely elicit many of the beneficial effects. However, undenatured collagen supplements may also provide some therapeutic value.^[31][32] For example, a study in 52 people with osteoarthritis of the knee showed that supplementation with undenatured type II collagen reduced pain, stiffness, and physical limitations compared to a placebo. The study participants received either 40 milligrams of undenatured collagen II or 1.5 grams of glucosamine and 1.2 milligrams of chondroitin (proteins found in the joint) every day for 90 days. Whereas both treatments reduced the participants' pain, stiffness, and physical limitations compared to baseline, treatment with collagen reduced pain by 33 percent, compared to 14 percent in the glucosamine and chondroitin-treated group. Similarly, compared to baseline measurements, collagen treatment reduced pain by 40 percent compared to 15.4 percent in the glucosamine and chondroitin-treated group. These data suggest that undenatured collagen II is more effective than glucosamine and chondroitin at improving the quality of life in people with knee osteoarthritis.^[33]

Hydrolyzed collagen and rheumatoid arthritis

Hydrolyzed collagen may also effectively treat rheumatoid arthritis, an autoimmune disorder that causes joint degradation. Evidence from in vitro studies suggests that type II collagen regulates the balance of pro-inflammatory immune cells and increases anti-inflammatory mediators to improve joint health.^[34][35]

Collagen supplementation elicits greater improvements than some antirheumatic drugs, except in people treated with methotrexate. A pilot study treated 10 people between the ages of eight and 14 years with active rheumatoid arthritis with undenatured type II collagen. The participants received 100 micrograms of type II collagen for the first month and 500 micrograms for two additional months. The participants were required to discontinue treatment with disease-modifying antirheumatic drugs during the study. At the end of the study period, nine participants had responded to the treatment, with an average decrease of 43 percent in the number of swollen joint counts and an average reduction of 51 percent in the number of tender joint counts compared to baseline. The average duration of morning stiffness and 50-foot walking time decreased after three months of treatment compared to baseline. There were no adverse events related to collagen treatment.^[36]

More extensive clinical trials also demonstrated that hydrolyzed collagen improved symptoms related to rheumatoid arthritis. A study of 274 people between the ages of 18 and 80 years with active rheumatoid arthritis found that hydrolyzed collagen reduced pain, stiffness, and disease activity. The study authors randomized participants to receive a placebo or one of four doses (20, 100, 500, or 2,500 micrograms) of hydrolyzed type II chicken collagen in a diluted liquid of acetic acid (an organic compound) daily for 24 weeks. The clinical assessments of pain, stiffness, and disease activity included three criteria: the Paulus criteria, the American College of Rheumatology criteria, and a reduction of greater than 30 percent in both tender and swollen joint counts. The participants were required to discontinue treatment with disease-modifying antirheumatic drugs.

Of the patients who supplemented with 20 micrograms of hydrolyzed collagen, 39 percent had improvements in the cumulative Paulus criteria compared to 19 percent in the placebo group. The study's authors noted improvements in the 20-microgram group, based on the American College of Rheumatology criteria, and a greater than 30 percent reduction in both tender and swollen joint count scores compared to the placebo group. Improvements were also seen with the other doses but were not statistically significant. Additionally, there were no apparent differences in response rates between doses of hydrolyzed collagen used.^[33]

A 24-week randomized controlled trial involving 503 people diagnosed with rheumatoid arthritis found that hydrolyzed collagen is an effective treatment for the condition. The authors of the study assigned participants to receive 100 micrograms of chicken type II collagen once daily or 10 milligrams of methotrexate (a commonly prescribed drug for the treatment of rheumatoid arthritis) once per week. Compared to baseline, both groups had significant decreases in pain, morning stiffness, tender joint count, and swollen joint count assessed by both a physician and the participant at 12 and 24 weeks, but the methotrexate outperformed hydrolyzed collagen in all parameters. Circulating levels of C-reactive protein (a marker of inflammation) decreased by approximately 11 percent at 24 weeks with hydrolyzed collagen supplementation, but the results were not statistically significant. On the other hand, methotrexate significantly decreased C-reactive protein by 31.1 percent at week 12 and 35.1 percent at week 24.^[37] Compared to methotrexate, hydrolyzed collagen is not a superior treatment; however, hydrolyzed collagen supplementation may be partially effective for treating rheumatoid arthritis.

The studies mentioned above used a surprisingly low dose of hydrolyzed collagen (in the microgram range compared to the milligram range used in other studies). Some researchers suggest a low dose of type II collagen may act as an antigen to stimulate active immune suppression. Therefore, hydrolyzed type II collagen administration may induce a peripheral immune tolerance to suppress autoimmune responses in rheumatoid arthritis.^[37]

Another study administered higher doses (1 or 10 grams) of undenatured type II collagen daily for 12 weeks in 90 people with rheumatoid arthritis. The authors of the study evaluated participants for improvements in tender and swollen joint counts and assessment of disease activity. While there was a higher prevalence of responders in type II collagen-supplemented groups compared to the placebo, the authors observed no significant differences.^[38]

More studies are needed to determine the extent to which hydrolyzed or undenatured collagen can improve symptoms of rheumatoid arthritis and the appropriate dose that may elicit benefits.

Hydrolyzed collagen and bone health

Bone health may benefit from supplementation, especially in certain clinical disorders. Bone mineral content is the primary contributor to bone stiffness and rigidity, while collagen fibers provide the shape of the tissue by acting as a scaffold for cells and additional macromolecules.^[39] The importance of properly formed collagen for bone integrity and health is illustrated in specific collagen-related genetic disorders. Osteogenesis imperfecta, a genetic disorder caused primarily by mutations in type I collagen, causes improper bone formation, leading to frequent bone fractures.(Source: Genetics Home Reference) Studies demonstrate that bovine hydrolyzed collagen can stimulate the growth of bone cells and increase mineralized bone matrix formation in vitro. In contrast, hydrolyzed casein (a protein commonly found in milk) had limited effects.^[40][41] Additionally, preclinical studies have shown that hydrolyzed collagen can increase bone healing and prevent bone loss.^[39] Currently, only a few clinical studies have investigated the use of hydrolyzed collagen on bone metabolism.

A randomized controlled study found hydrolyzed collagen increased bone mineral density in postmenopausal women. The study, which involved 131 postmenopausal women between the ages of 46 and 80 years who had reduced bone mineral density, investigated the effects of 5 grams of commercially available hydrolyzed collagen or 5 grams of maltodextrin every day for 12 months. The women in the study were encouraged to take 0.5 to 0.8 grams of calcium and 400 to 800 IU of vitamin D daily, depending on their body weight. The authors assessed the women's bone mineral density of the lumbar spine and femoral neck before and after the 12-month study period.

The women who supplemented with hydrolyzed collagen experienced a statistically significant 3 percent increase in the bone mineral density of the spine and a 6.7 percent increase in bone mineral density of the femoral neck compared to baseline measures. In the placebo group, bone mineral density decreased by 1.3 percent in the spine and by 1 percent in the femoral neck compared to baseline. Amino-terminal propeptide of type I collagen, a biomarker of bone formation, significantly increased by approximately 11.6 percent compared to baseline measures in the hydrolyzed collagen supplement group but not in the placebo group. No adverse events were reported from the collagen supplement.^[42]

Another randomized controlled trial determined that hydrolyzed collagen combined with calcium and vitamin D attenuates bone loss in postmenopausal women. The study included 112 postmenopausal women who had not received hormone replacement therapy for at least three months before study initiation. The authors of the study assigned the women to one of two groups to take either a supplement containing 500 milligrams of calcium and 200 IU of vitamin D3 or a supplement containing 5 grams of hydrolyzed collagen, 500 milligrams of calcium, and 200 IU of vitamin D3 every day for 12 months. Bone mineral density in the lumbar vertebrae of the women in the control group decreased by 2.3 percent, and whole-body bone mineral density significantly reduced by 3.9 percent at 12 months compared to baseline. Bone mineral density in the women who took the hydrolyzed collagen supplement decreased slightly, but the results were not statistically significant, indicating that the collagen supplement may have been more effective at preventing bone loss compared to the control supplement.^[43]

However, a separate randomized placebo-controlled study in postmenopausal women with osteopenia, characterized by low bone mass, found that hydrolyzed collagen alone did not affect bone health. The study involved 71 women (average age, 57 years) who received either a placebo or 10 grams of hydrolyzed collagen daily for 24 weeks. Collagen supplementation did not affect markers of bone resorption and formation compared to the placebo. However, the investigators did not measure bone mineral density as in the previous studies.^[44] Additionally, most women had inadequate calcium intake and were considered overweight. Calcium is the primary mineral of the bone, conferring bone strength and structure.^[45] Conversely, excess body fat can adversely affect bone health.^[46]

Hydrolyzed collagen in combination with calcium and vitamin D may be beneficial in slowing bone loss in postmenopausal women, but more studies are needed to determine the role of hydrolyzed collagen in bone metabolism.

Hydrolyzed collagen and athletic joint pain

The consumption of hydrolyzed collagen may also be beneficial in athletes with activity-related joint pain. A study in athletes with functional knee problems due to sports found that hydrolyzed collagen significantly improved activity-related joint pain. The study involved 160 women and men between 18 and 30 who received either 5 grams of hydrolyzed collagen or a placebo every day for 12 weeks. Participants were excluded if they had a primary knee joint disease, were injured, or had received injections or taken supplements for joints. The participants and a physician assessed knee pain changes during activity by a visual analog scale.

In both the placebo and hydrolyzed collagen-supplemented groups, knee pain was significantly reduced compared to baseline by the sixth week and until the end of the study. However, hydrolyzed collagen significantly outperformed the placebo by reducing pain by 38.4 percent at the end of the study compared to 27.9 percent in the placebo group. Additionally, the need for additional therapies decreased in both study groups after 12 weeks, but the hydrolyzed collagen-supplemented group experienced a 59 percent reduction compared to 40 percent in the placebo-supplemented group.^[47]

A study involving 150 physically active athletes without evidence of joint disease found that hydrolyzed collagen can reduce activity-related joint pain. The study participants were assigned to receive a commercially available 25-milliliter liquid supplement of 10 grams of hydrolyzed collagen or a 25-milliliter liquid supplement of xanthan as a placebo. The subjects and a physician rated pain across multiple joints using a visual analog scale. Across multiple joints, the placebo and hydrolyzed collagen supplement decreased pain; however, the hydrolyzed collagen supplement markedly reduced pain at rest while walking, carrying objects, and lifting after 24 weeks. In a subgroup analysis, the hydrolyzed collagen-supplemented group had pronounced reductions in knee joint pain after 24 weeks in parameters such as walking, running, and changing direction while running.^[48]

These studies suggest hydrolyzed collagen supplementation effectively reduces joint pain from activity-related discomfort.

Hydrolyzed collagen, hypertension, and type 2 diabetes

Hydrolyzed collagen may effectively decrease blood pressure in people with hypertension and improve metabolic function in people with type 2 diabetes.^[49]

Hypertension, also known as high blood pressure, increases the risk of heart disease and stroke, two of the leading causes of death in the United States. Angiotensin-converting enzyme, or ACE, participates in blood pressure regulation, and active ACE can lead to high blood pressure. ACE inhibitors are common antihypertensive drugs used to reduce blood pressure.^[50]

Multiple in vitro and in vivo studies have found that hydrolyzed collagen, primarily from marine sources, exhibits antihypertensive activity.^{[51][52][53][54]} Similarly, in vitro studies demonstrated that hydrolyzed collagen derived from chicken, pig, and bovine sources elicited antihypertensive effects.^[55][56] Certain dipeptides and tripeptides, particularly those containing proline, which is abundant in collagen, exhibit inhibitory activity against ACE.^[57][58][59]. Clinical studies are needed to determine collagen's effectiveness in lowering human blood pressure.

In rodent studies, marine hydrolyzed collagen improves glucose sensitivity and insulin resistance and decreases inflammatory cytokines and oxidative stress.^[60][61] A few clinical studies indicate that hydrolyzed collagen may be effective at improving insulin sensitivity and glucose and lipid metabolism and reducing hypertension in people with type 2 diabetes and hypertension. A study of 100 people with type 2 diabetes and hypertension and 50 healthy people provided participants with either 6.5 grams of marine hydrolyzed collagen or 6.5 grams of carboxymethylcellulose (as a placebo) twice daily for three months. The study participants were permitted to use antidiabetic and antihypertensive drugs as prescribed throughout the study, and both groups received education about diet and exercise.

Hydrolyzed collagen powder decreased HbA1c, a marker indicative of improved diabetic glucose control. The participants who received hydrolyzed collagen had a 19.7 percent decrease in fasting blood glucose after three months of treatment compared to baseline. The placebo group participants had a slight 3 percent increase in fasting blood glucose. Additionally, HbA1c, a long-term measure of blood glucose levels, decreased by 6.8 percent compared to baseline in the participants who supplemented with hydrolyzed collagen. In comparison, the participants who supplemented with the placebo saw a 1.7 percent increase in HbA1c levels compared to baseline. After three months, systolic blood pressure significantly decreased in both groups of participants, but diastolic blood pressure decreased by 5.7 percent compared to baseline, but only in the participants who supplemented with hydrolyzed collagen. Lastly, hydrolyzed collagen significantly reduced plasma triglycerides, cholesterol, low-density lipoprotein, and free fatty acids, while increasing high-density lipoprotein at three months compared to baseline levels.^[62]

Although dietary and exercise interventions likely contributed to the improvement in the measured metabolic parameters, the participants who supplemented with hydrolyzed collagen outperformed those who supplemented with the placebo, indicating that marine hydrolyzed collagen may be an effective supplement for improving metabolic health. The same researchers conducted similar clinical studies that showed marine hydrolyzed collagen improved glucose and lipid metabolism after three months in participants with type 2 diabetes.^[63][64] These effects may be due to signaling mechanisms of collagen peptides acting through adiponectin and glucagon-like peptide-1. These two hormones modulate numerous metabolic processes, such as insulin secretion, glucose regulation, and fatty acid oxidation.^[65][66][67]

Summary of dosages and correspondent effects

Collagen has shown effects at surprisingly broad dosages. A summary of the many dosages mentioned in this article follows.

• 50 milliliters of a liquid supplement containing 1,000 milligrams of hydrolyzed collagen with greater than 15 percent of the collagen hydrolyzed into tripeptides once daily for 12 weeks elicited a 7.23-fold greater improvement in skin hydration at six weeks and a 2.9-fold greater improvement in skin hydration at 12 weeks.^[23]
• 300 milligrams of hydrolyzed type II collagen, 100 milligrams of chondroitin sulfate, and 50 milligrams of hyaluronic acid twice a day for 12 weeks improved skin dryness, crow's feet, texture, smoothness, and skin tone from baseline to week 12 in middle-aged women.^[21]. Editor's note: Low doses may act as an antigen to stimulate active immune suppression.
• 1 gram of a commercial product composed of 600 milligrams of hydrolyzed chicken type II collagen, 200 milligrams of chondroitin sulfate, 100 milligrams of hyaluronic acid, and 50 milligrams of uncharacterized cartilage components twice daily for 70 days promoted significant decreases in acute and chronic pain compared to baseline measurements; the commercial product reduced pain scores by 35 percent and reduced the scores on the Western Ontario and McMaster Universities Osteoarthritis Index by 38 percent in people with osteoarthritis.^[29]
• 2 to 10 grams of hydrolyzed collagen per day for 10 to 48 weeks decreased pain, stiffness, and functional limitations in five randomized placebo-controlled trials in people with osteoarthritis^[30]
• 100 micrograms of chicken type II collagen once daily elicited significant decreases in pain, morning stiffness, tender joint count, and swollen joint count at 12 and 24 weeks in people with rheumatoid arthritis.^[37]
• 5 grams of hydrolyzed collagen, 500 milligrams of calcium, and 200 IU of vitamin D3 taken every day for 12 months partially blunted loss of bone mineral density in postmenopausal women.^[43]
• 25 milliliters of a liquid supplement of 10 grams of hydrolyzed collagen taken for 24 weeks markedly reduced pain at rest while walking, carrying objects, and lifting in athletes with activity-related joint pain.^[48]
• 6.5 grams of marine hydrolyzed collagen taken twice daily for three months promoted a 19.7 percent decrease in fasting blood glucose, a 6.8 percent decrease in HbA1c, and a 5.7 percent decrease in diastolic blood pressure in people with type 2 diabetes and hypertension.^[62]

Conclusion

Collagen is vital for maintaining the structural integrity of every tissue in the body. Aging decreases the body's capacity to synthesize collagen, contributing to skin aging, joint disease, and diminished bone health. Oral hydrolyzed collagen supplementation represents an inexpensive and convenient strategy to offset some of the physiological declines associated with aging. In particular, hydrolyzed collagen supplementation may improve various aspects of skin aging, decrease pain associated with osteoporosis, increase bone mineral density in postmenopausal women, and improve metabolic health in people with type 2 diabetes and hypertension. More studies are needed to distinguish the therapeutic benefits between the types of collagen (types I, II, and III) and the source (marine, bovine, chicken, and pig).