GLUCOSAMINE AND CHONDROITIN constitute the major GAGs in the joint cartilage: glycosaminoglycans serve as major components of articular cartilage. Glycosaminoglycans function by decreasing the presence of harmful pro-inflammatory prostaglandins and other inflammatory enzymes that degrade the cartilage matrix. This results in reduced pain and inflammation, decreased enzymatic destruction of the cartilage, and stimulation of anabolic (cartilage-building) pathways. The GAGs also appear to increase the synthesis of proteoglycans, hyaluronic acid (which acts as a joint lubricant), and collagen.

One novel product called Adequan contains glycosaminoglycans extracted for bovine cartilage and is available in an injectable form. The recommended regimen is a series of eight injections, two each week for four weeks. If the pet has responded favorably during the 4-week trial, the pet is then given an injection as needed (usually one injection every one to 12 months). This injectable product can be used with oral chondroprotective supplements as well. The injectable product can be used to get a faster response than the oral supplements. Further injections are given as needed, or pets can be maintained on oral supplements according to the response seen and the convenience of the pet owner. This product has also shown effectiveness when flushed into joints during joint surgery, allowing faster and smoother recovery.

Side effects with GAGs are extremely rare but are reported to include a dose-dependent inhibition of blood clotting. Concerned owners may want to have their pets' doctors regularly monitor blood coagulation parameters and use homeopathic remedies to help increase blood-clotting factors.

The following points concerning chondroprotective therapy are important to maximize success when using these supplements:

Safety. They are extremely safe and equally effective when compared to NSAIDs.

Cost. This may be an issue for some pet owners. The typical daily cost of using a glucosamine-chondroitin supplement is approximately $1.50/day for a 50-pound dog. This cost can decrease as the dosage of the supplement is lowered to allow the owner to use the least amount to maintain pain relief. The comparable cost of the most popular NSAIDs is approximately $2 to $3 a day for a 50-pound dog making the supplements less expensive, equally effective, and without potentially serious side effects.

Early Diagnosis. Since these supplements work by acting on living cartilage cells, they are most effective when used early in the course of the disease. This requires adequate and early diagnosis.

Response Time. Because they are not drugs but nutritional supplements, the response may not be seen for four to eight weeks. During the four to eight weeks, an increased "induction" dose is used and then the dose is lowered as improvement is seen. Additional short-term therapy (with NSAIDs, acupuncture, or other therapy) can be used during the induction phase.

Effectiveness. The supplements can also be used effectively when no clinical signs are present but yet disease exists. In many practices, a number of dogs are diagnosed via screening radiographs with hip dysplasia and started on the supplements pending a decision on the owner's part for surgical correction or until clinical signs occur.

Product Purity. The purity of products is an important factor. There are many generic knock-off products that sell for much less than patented products produced by reputable manufacturers. Studies have been done showing the effectiveness of these compounds that have used pure grades of products. Products of lesser purity, while often costing less, may also be less effective. Unlike traditional drugs, these compounds are not regulated and labeling can be inaccurate or misleading; manufacturers are not required to analyze their products regarding purity, uniformity, or content. Purchase only quality products from reputable manufacturers as recommended by your doctor.

Recommended Reevaluation. Because the chondroprotective supplements are so effective after four to eight weeks in improving signs seen in arthritic pets, the diagnosis should be reevaluted after this period of time if improvement is not seen.

Shark Cartilage
There is a reported link between blood vessel growth and the development of osteoarthritis as well. The synovial (joint) fluid of arthritic pets includes an increasing amount of a chemical called endothelial cell-stimulating angiogenic factor. This chemical encourages the growth of new blood vessels in the arthritic joint. It is theorized that by inhibiting angiogenesis, further degeneration of cartilage might be prevented.

In the laboratory, shark cartilage has been shown to contain chemicals that inhibit blood vessel formation. Arthritic pets and people taking shark cartilage supplements often experience increased mobility and decreased pain. In one study, eight of ten dogs showed improvement when treated at a dosage of 750 mg/5 kg of body weight for three weeks. When treatment was temporarily discontinued, pain and lameness returned. Administering additional shark cartilage at 50 percent of the original dose resulted in improvement. The relief from pain and inflammation was theorized to occur as a result of decreased blood vessel formation.

Improvement may also result from a relief from pain due to a large number of mucopolysaccharides contained in the cartilage, which can help nourish and heal the cartilage. As a result of studies such as this one, many vets feel it is prudent to prescribe shark cartilage as it can substitute for therapy with medications like non-steroidal drugs that have potential side effects. The main problem with using shark cartilage is the large dosage required. This suggested dosage would require giving a large number of capsules to the pet daily. And since it is among our more expensive supplements, the dosage of shark cartilage needed for medium to large breed arthritic dogs would be unaffordable for most pet owners.

Shark cartilage should not be used in people who have recently suffered a heart attack, in pregnant women, and those who have or are recently recovering from deep surgery. Similar precautions probably apply to pets.

Because of the potential for impure product, owners should consult with their doctors before using shark cartilage.

Several products on the market supply a much lower dosage than that listed in the reported studies. This lower dosage has proved beneficial in some dogs. Because shark cartilage is very expensive to use in larger dogs ($40 to $50 for 2-week supply) some owners are tempted to give less than the recommended dosage. This can be useful after a one to two month stabilization period. Work with your doctor to determine the most effective dose. As is often the case with nutritional supplements, we don't know the best or most effective dose for shark cartilage. Therefore, we must use the products currently available and adapt the dosage to the individual pet's needs.

Perna
Perna canaliculus, the green-lipped mussel, is a shellfish that is a natural source of highly concentrated glycosaminoglycans (GAGs), including chondroitin, as well as a number of other nutrients, including complex proteins, amino acids, nucleic acids, naturally chelated minerals, and an inhibitor of prostaglandin syntheses, which makes it effective as an anti-inflammatory supplement.

Several studies in people have confirmed improvement in patients with osteoarthritis and rheumatoid arthritis. Ongoing studies, as well as anecdotal evidence, show the benefit of Perna in dogs with osteoarthritis. (Benefits in cats are scant, as arthritis is quite rare in cats when compared to dogs. However, veterinarians are using many dog products safely in cats.)

Stabilized powder (Seatone, MacFarlane Laboratories, Surrey Hills, Victoria, Australia) and the lipid extract (Lyprinol, MacFarlane Laboratories, Surrey Hills, Victoria, Australia) showed similar results in people with rheumatoid and osteoarthritis. The lipid extract is a 20-fold concentrate of the originally dried mussel. As is true with the powder form, the lipid extract is believed to be a potent but slow-acting antiinflammatory that inhibits cyclooxygenase and5-lipooxygenase. This is probably via the omega-3 fatty acid content of the mussels. In a laboratory experiment in rats, the dosage of Lyprinol was 20 mg/kg. In studies in people, a dosage of 300 mg twice daily for the first 30 days followed by a dosage of 150 mg twice daily showed positive results. Check with your vet for dog and cat dosages of these products.

Perna is inexpensive and readily accepted by most dogs. A product showing favorable results in pets is called Glyco-Flex Plus; it combines benefits of Perna with MSM.

Sea Cucumber
The sea cucumber, cucumaria frondosa, also known by the names, trepang and beche demer, is a marine animal related to urchins. It is believed these organisms inhibit harmful prostaglandins involved in causing pain and arthritis. They are also rich in nutrients needed by cartilage. One popular product supplies the sea cucumber in a unique jerky-type treat (Sea Jerky-R), which dogs find quite palatable. Other compounds in this product include sea kelp, natural vitamin E, lecithin, garlic, omega-3, and glucosamine hydrochloride. Each treat provides 1200 mg of chondroitin.

In testing by independent laboratories the product showed excellent anti-inflammatory activity in rats. The anti-inflammatory response was superior to that of Rimadyl and phenylbutazone. This study also showed that Sea Jerky-R had higher activity than a product made from Perna mussels and a glucosamine/chondroitin supplement, indicating this product might be preferred if a dog fails to respond to another supplement.

The recommended dosage for this product is one piece of jerky per day for a 60 to 70-pound dog. While it was assumed the active ingredient in the product was chondroitin, further research showed that while the sea cucumber contains chondroitin, another substance called InflaStatin appears to be the active ingredient.

These treats are perfect for the dog that is hard to medicate.

The jerky treats can also be used in conjunction with other similar pill supplements, as it is unlikely to overdose a pet on glucosamine or chondroitin. For those pets with arthritis, most owners and doctors like the idea of giving them a daily treat that is good for them.

Bone broths are highly valued for their benefits, especially for joints and the digestive tract. Name almost any major cuisine in the world and broths and stocks are essential components. In pre-late 20th Century households, these liquids provided the foundation for sauces, soups, stews and numerous other products of the kitchen. However, they went beyond this to provide the bases for nutrient rich tonic foods considered to be good for the bones, joints, digestive system, immune system and general vigor.

The traditional expectations of bone broths are given in numerous books and articles on the topic, but are unlikely to find substantiation as such on PubMed because modern medical research focuses on pure compounds and on items that can be patented. Bone broth benefits from the broths themselves generally are observations from history, not from the scientific literature. For those who are interested, a full history of gelatins and similar usage and science focusing on knowledge and use up to the end of the 19th Century can be found in Gotthoffer, NR, Gelatin in Nutrition and Medicine(Graylake IL, Grayslake Gelatin Company, 1945), which can be purchased as a Kindle edition on amazon. Another book on the topic worth reading is Nourishing Broth: An Old-Fashioned Remedy for the Modern World by Sally Fallon Morell and Kaayla T. Daniel. More history, but also modern science focusing on individual broth components is wonderfully reviewed in "Traditional Bone Broth in Modern Health and Disease," by Allison Siebecker in the Townsend Letter for Doctors and Patients (2005).¹

The benefits of traditional bone broth reflect an emphasis on the building blocks for tissues as the sources of repair. The idea is not to substitute for the body’s own mechanisms, but instead to assist the body in making its repairs. In line with this approach, collagen and gelatin components, such as chondroitin sulfate, found in bone broth support the tissues in the body that themselves are constructed or repaired from these components, for example, the joints and their cartilage, the skin, and connective tissues in general. Similarly, minerals from bone broth support or even stimulate the repair of various tissues. Keep in mind that bone broths traditionally were foods, which are to say, consumed in considerable quantity in gram amounts, not milligram amounts. Efficacy in milligrams only is important for tablets and capsules and often focuses only on the narrowest of ranges of benefits. Total Health has touched on this issue before in terms of the entourage effect (September 2015). This issue has been examined in medical circles, for instance, "Whole Food versus Supplement: Comparing the Clinical Evidence of Tomato Intake and Lycopene Supplementation on Cardiovascular Risk Factors."²

Bone Broth Nutrition Basics
Before examining one bone broth component–chondroitin sulfate–in depth, below is a short listing of the a few of the nutrients found in bone broths.

Amino Acids
Bone broths throughout history have been associated with healing, whether of the gut, the joints, or more generally in response to illness. Part of the reason for this involves immune-supporting amino acids. Depending on the broth, these include arginine, cysteine, glycine and proline. These are found in beef and chicken bones, marrow, etc. Fish broths offer different nutrient mixtures from those found in land-based animal broths. For those interested in the roles of proline and glycine in digestive health, the Weston Price Foundation has published "Why Broth is Beautiful/Essential Roles for Proline, Glycine and Gelatin."³

Collagen and Chondroitin
More specific nutrition factors include bioactive Type I and Type II collagen peptides and cartilage chondroitin sulfate. Collagen is the most abundant protein in humans, representing about 25-30 percent of total protein in the body. It is the main component of skin, cartilage, ligaments, tendons and bones. Glucosamine, chondroitin sulfate and hyaluronic acid (a component of Collagen Type II) are the chief components of the extracellular matrix.

Collagen Type I is associated with the preservation of bone mineral density; in conjunction with hydroxyapatite, it accelerates osteogenesis. There is a further association with the health of the immune system known as oral tolerance that may be important for joint health.

Collagen Type II is a low molecular weight, water-soluble glycosaminoglycan complex that supports joint health and skin hydration.

Chondroitin Sulfate acts like a biological version of a "liquid magnet," attracting fluid into proteoglycans, protein chains that form the basis of cartilage and the extracellular matrix. This fluid acts as a shock absorber and also brings nutrients with it into the cartilage. Perhaps of greater significance than its fluid-enhancing properties, chondroitin protects existing cartilage through its modulatory effects on enzymes that degrade cartilage. Furthermore, chondroitin stimulates the production of proteoglycans and collagen that are needed for healthy new cartilage.

Natural Cartilage Components Heal The Joints
A just released study in the Annals of the Rheumatic Diseases (May 2017) shows that a relatively small quantity of the supplement chondroitin sulfate is effective in improving the symptoms of osteoarthritis.⁴ Pitted against either the prescription drug celecoxib (Celebrex) or placebo in a blinded trial, 800 mg chondroitin sulfate per day led to improvements in pain and joint function that were significantly greater after six months (chondroitin sulfate) and three months (celecoxib). Joint function improved more quickly in patients taking celecoxib, but there were no overall differences in the effectiveness and the benefit-risk profile strongly favored the chondroitin sulfate treatment. These results should be viewed in light of a 2016 study that demonstrated in a 2-year randomized controlled trial that treatment with 1,200 mg per day chondroitin sulfate was superior to celecoxib in preventing cartilage volume loss.⁵

Such results offer the promise of help to large numbers of individuals. Joint pain and connective tissue injuries are amongst the most common complaints of older individuals and affect 15 percent or more Americans whom exhibit some form of arthritis. Not just the elderly, but even young and fit athletes through overuse can exceed the repair capacity of the joints. Non-steroidal anti-inflammatories (NSAIDS) can relieve pain and initially help with joint inflammation and swelling, yet at the cost of slowing healing and for some individuals causing irritation and bleeding of the stomach. This has led to a search for alternatives. The idea that natural compounds such as glucosamine and/or chondroitin sulfate might have therapeutic effects in treating osteoarthritis by providing the substrates for the repair of cartilage has been around since the mid-1950s. Major issues have included determining which forms and how much of such supplements are necessary for benefits. For instance, confirming earlier studies, research published in 2005 involving approximately 1,500 osteoarthritis patients demonstrated that a daily dose of 1,500 mg glucosamine hydrochloride in combination with 1,200 mg chondroitin sulfate was equally as effective with fewer side effects than 200 mg of prescription celecoxib in treating moderate to severe knee pain, albeit relief took longer to appear. At the same forum, it was reported that 1,500 mg glucosamine sulfate was superior to acetaminophen in relief. Both of these studies involved quite large dosages of supplements leaving open the question of whether such large amounts are necessary. The 2017 study demonstrated efficacy with a dose of chondroitin sulfate that was less than half of that which had been tested previously and shown to be effective.

Study Summary
Chondroitin sulfate is a sulfated glycosami¬noglycan composed of chains of alternating D-glu¬curonic acid and N-acetyl-Dgalactosamine.⁶ It is a major component of cartilage, a tissue in which it exists attached to proteoglycans. Proteoglycans are commonly described as looking like tree trunks with many branches to which are connected bottle brush-like bristles. Chondroitin sulfate is especially important in joint synovial fluid and for the fluid-retaining qualities of the proteoglycans.⁷ In the 2017 study, the primary issue was whether chondroitin sulfate could be effectively used for long-term treatment of osteoarthritis, in particular in an aging population.

For study purposes, 604 patients diagnosed with symptomatic knee osteoarthritis were randomly assigned to one of three daily treatments in what is known as a double-blind, double-dummy design. In the chondroitin sulfate group, 199 patients were given 800 mg chondroitin sulfate; the second group made up of 200 patients received 200 mg celecoxib; the third group consisting of 205 patients received dummy tablets. Pain, joint function, and overall patient acceptability were assessed using validated scoring systems on days 30, 91 and 182. Improvements in pain and joint function were significantly greater after six months (chondroitin sulfate) and three months (celecoxib). Joint function improved more quickly in patients taking celecoxib, but there were no overall differences in the effectiveness. The benefit-risk profile favored the chondroitin sulfate treatment, meaning benefits fewer or no side effects.

The authors of the study concluded that a daily dose of 800 mg of pharmaceutical-grade chondroitin sulfate was better than a dummy product and as good as celecoxib in reducing pain and improving joint function in symptomatic knee osteoarthritis. However, the researchers advised care in selecting the form of chondroitin sulfate utilized: "Chondroitin sulfate is available as pharmaceutical-grade and nutraceutical-grade products, the latter exhibiting striking variations in preparation, composition, purity as well as clinical effects." In other words, the quality of the vendor should be the guide to choosing a product.

Chondroitin Sulfate Heals More Than The Joints
Chondroitin sulfate has many roles in the body other than in contributing to the health of the joints. Connective tissues which depend upon chondroitin sulfate are widely dispersed, which is to say that they are found not only as cartilage, but also as bone, tendon, skin, blood vessel walls, and mucous membranes. Any one or all of these tissues may benefit from supplementation with chondroitin sulfate.

Atherosclerosis (hardening of the arteries) is a case in point. Over a six-year period in a study involving one hundred and twenty subjects already suffering from diagnosed atherosclerosis and undergoing medical treatment, the group which supplemented daily with 1,500 mg of chondroitin sulfate fared strikingly better. The supplemented group had only one third as many deaths (4 versus 13) and one seventh the number of total cardiovascular incidents of types (6 versus 42). Inasmuch as this study lasted for six years, the safety of a large daily ingestion of chondroitin sulfate also was shown.

Chondroitin sulfate has a number of effects that have been demonstrated, but not always clearly explained. For instance, mucopolysaccharides in some tests have proven to be interesting immunomodulators that increased immune activity when it was too low and helped to turn it down when it was too high, such as in autoimmune conditions. Chondroitin sulfate has anti-inflammatory benefits and wound healing benefits. Some tests have indicated that chondroitin sulfate can help to regulate normal cell division. The range of benefits becomes clearer when it is realized that the following items all contain forms of chondroitin: bone broths, bovine cartilage extracts, shark cartilage extracts, extracts from sea cucumber and the green-lipped mussel.

Conclusions
Bone broths no doubt date back to prehistoric times and are staples in a number of established medical systems, such as Traditional Chinese Medicine. The principles remain the same today as in centuries past. Mineral and protein-rich broths containing the building blocks of the digestive system and connective tissues are surprisingly versatile in helping the body to heal itself. Although modern medical research typically does not examine complex food such as bone broths, research into the benefits of individual components often yields impressive results. Chondroitin sulfate is a case in point. Properly made, even seemingly small amounts can yield joint health benefits equal to those found with modern drugs along with other benefits, such as for the cardiovascular system. But why depend on pills when you can brew bone broth yourself?

References:

1. http://www.townsendletter.com/FebMarch2005/broth0205.htm
2. Burton-Freeman B, Sesso HD. Whole food versus supplement: comparing the clinical evidence of tomato intake and lycopene supplementation on cardiovascular risk factors. Adv Nutr. 2014 Sep;5(5):457–85.
3. https://www.westonaprice.org/health-topics/why-broth-is-beautifulessential-roles-for-proline-glycine-and-gelatin/
4. Reginster JY, Dudler J, Blicharski T, Pavelka K. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT). Ann Rheum Dis. 2017 May 22. pii: annrheumdis-2016–210860. doi: 10.1136/annrheumdis-2016–210860. [Epub ahead of print]
5. Pelletier JP, Raynauld JP, Beaulieu AD, Bessette L, Morin F, de Brum-Fernandes AJ, Delorme P, Dorais M, Paiement P, Abram F, Martel-Pelletier J. Chondroitin sulfate efficacy versus celecoxib on knee osteoarthritis structural changes using magnetic resonance imaging: a 2-year multicentre exploratory study. Arthritis Res Ther. 2016 Nov 3;18(1):256.
6. Martel-Pelletier J, Farran A, Montell E, et al. Discrepancies in composition and biological effects of different formulations of chondroitin sulfate. Molecules2015;20:4277–89.
7. Crolle G, D’Este E. Glucosamine sulphate for the management of arthrosis: a controlled clinical investigation. Curr Med Res Opin. 1980;7(2):104–9.