Osteoarthritis and Alternative Treatment

Glucosamine Gel by PhytoMe
Research in the field of osteoarthritis concentrates on hyaline cartilage as an important part of the joint as a functional unit (hyaline cartilage, subchondral bone, synovia, joint capsules, ligaments and muscles). To withstand biomechanical stress, hyaline cartilage contains a highly organized network of tissue-specific collagens, which is filled with proteoglycans and several noncollagenous matrix proteins. The various components intensively interact with each other and with the chondrocytes, the cellular element of the cartilage(1). 

One of the most prominent alterations that characterizes osteoarthritic cartilage damage is a reduction of proteoglycan content, reflecting an imbalance between synthesis and release of proteoglycans. Both synthesis and release depend on the activity of cartilage cells, chondrocytes, in the upper layer of osteoarthritic human knee cartilage which appear to be phenotypically altered, leading to diminished proteoglycan synthesis (2). 

The double biochemical nature of proteoglycans allows them to combine in the same macromolecule both a proteic (the core protein) and a saccharidic (glycosaminoglycan chains). Through this structural diversity, proteoglycans are highly interactive macromolecules and thus participate in a broad range of matricial and cellular actions. Changes in the metabolism of proteoglycans affects drastically the cartilage and leads to osteoarthritis(3) 
Osteoarthritis consists of the progressive loss of articular cartilage that begins with fraying or fibrillation of the articular surface and progresses to exposure of subchondral bone. Attempted repair of the cartilage, remodeling of subchondral bone, and, formation of osteophytes, accompany the degeneration of the articular cartilage (4,5,6).

Once degeneration of the joint begins, it usually progresses inexorably, causing increasing pain and loss of mobility despite attempted repair of the articular surface. The limited capacity of articular cartilage for repair or regeneration has led to the widely accepted view that an osteoarthritic joint cannot be restored to normal structure and function (7). Even the most effective current treatments for Osteoarthrosis do not restore the joint (8,9). 

CONVENTIONAL TREATMENT LINES OF OSTEOARTHRITIS:
Non-operative treatments, including modifications of lifestyle, exercise programs, steroidal and non-steroidal anti-inflammatory drugs, and physical therapy, can decrease symptoms and improve mobility, but they do not detectably alter the course of the disease for most patients. Arthrodesis of degenerated joints relieves pain but sacrifices mobility. Osteotomies of the hip and knee can decrease pain and, in some patients, can lead to formation of a new articular surface but the results vary considerably among patients (10). Resection of degenerated joints and replacement of these joints with implants fabricated from polyethylene, metal, or another synthetic material predictably relieves pain and improves function. However, these procedures have important limitations, especially for young, active patients, primarily because they do not restore an articular surface with the mechanical properties and durability of articular cartilage. Moreover, synthetic materials must be fixed to the bone of the patient. Thus, the wear of the implant surfaces limits the life span of the implant. Within this life span, the bond between the implant and the bone may fail. 
However, recent reports of methods that promote the formation of new articular surfaces in localized cartilage defects have created a great interest among scientists and physicians in the possibilities for restoration of osteoarthritic joints (11). For all of these reasons, treatments that restore the structure and function of osteoarthrotic joints would be appropriately heralded as breakthroughs and could benefit many patients.

Patients who have Osteoarthritis, always, seek treatments that would repair or regenerate the articular cartilage rather than replace the joints. Successful restoration of osteoarthritic joints requires a detailed analysis of the structural and functional abnormalities of the involved joint followed by application of a treatment plan. This plan may include use of medications that help to maintain or restore articular cartilage.

PHYTOME'S GLUCOSAMINE GEL ALTERNATIVE NATURAL TREATMENT THAT HELPS MAINTAIN AND RESTORE ARTICULAR CARTILAGE

Glucosamine sulfate and Chondroitin sulfate
Chondroprotection is a somewhat new field in the therapy of osteoarthritis, which is designed to improve cartilage repair as well as enhance joint remodeling. It clearly results from both laboratory models as well as from studies on human osteoarthritis, that cartilage contains biological resources to meet the repair of degenerative injuries and inflammation. The Glucosamine sulfate and chondroitin sulfate represent the main biological resources for such repair. Since osteoarthritis results from progressive catabolic loss of cartilage proteoglycans, owing to an imbalance between synthesis and degradation. Standard drug therapy is only of palliative benefit and may exacerbate loss of cartilage. Glucosamine is an intermediate in proteoglycans synthesis, and its availability in cartilage tissue culture can be rate-limiting for proteoglycan production.
Since 1980 and perhaps before, osteoarthritis-modifying drugs were clinically tested with two main aims: not only stopping or reducing the cartilage degenerative process after a long-term treatment, but also controlling the symptoms of the disease within a few days or weeks, thus avoiding or diminishing the use of symptomatic medications. Due to the difficulties of implementing the first aim, the latter aim was more often investigated.
A number of double-blind studies dating from the early 1980s demonstrate that oral Glucosamine decreases pain and improves mobility in osteoarthritis, without side effects. Nevertheless, medical researchers and physicians have totally ignored this rational and safe therapeutic strategy. These and other safe nutritional measures supporting proteoglycan synthesis, may offer a practical means of preventing or postponing the onset of osteoarthritis in older people or athletes (12).

The rapid symptomatic response to high-dose Glucosamine in osteoarthritis is explained by (13,14):
 

1. Glucosamine promotes synthesis of cartilage proteoglycans.

2. Glucosamine stimulates synovial production of hyaluronic acid (HA) which is primarily responsible for the lubricating and shock-absorbing properties of synovial fluid. 

Many clinical and veterinary studies have shown that intra-articular injections of high molecular weight HA produce rapid pain relief and improved mobility in osteoarthritis.

The importance of Hyaluronic acid (H.A) is due to:
 

1. HA has an anti-inflammatory and analgesic properties.

2. It promotes anabolic behavior in chondrocytes.

3. As the concentration and molecular weight of synovial fluid HA are decreased in osteoarthritis, reversing this abnormality though giving high-dose Glucosamine may provide rapid symptomatic benefit, and in the longer term aid the repair of damaged cartilage.

4. The visco-elasticity of the synovial fluid is entirely due to its HA content.

5. HA forms an integral part of the proteoglycans of articular cartilage.

6. HA may influence the disease by interacting with components of the synovial fluid and synovial cavity. 

Studies done on Chondroitin sulfate, a sulfated glycosaminoglycans, has also proved that it has a significant chondroprotective function (15). Chondroitin sulfate proteoglycans are synthesized by different tissues and cell types (16). Thus Glucosamine and chondroitin sulfates may help the production of key elements of the cartilage matrix, and then protect them. They may actually help body repair damaged or eroded cartilage. In other words, glucosamine and chondroitin sulfates strengthen the body's natural repair mechanisms. They can replace what the body fails to make i.e. they are important for maintaining the cartilage in good condition. Since they are substances we already consume and produce in very small quantities in our bodies, glucosamine and chondroitin sulphate have no known significant side effects. This amazing fact stands in stark contrast to painkillers such as non-steroidal anti-inflammatories and cortisone. Glucosamine sulfate is an amino acid derivative of glucose that plays an essential role in the formation of connective tissue. Sustained release forms of glucosamine and chondroitin sulfate may provide prolonged and higher serum levels of these important nutrients. The addition of chondroitin sulfate potentiates the effects of glucosamine sulfate. 

Clinical trials testing the efficacy and tolerance of preparations of pure glucosamine sulfate have started approximately 20 years ago. In 1980 the efficacy and tolerance of oral glucosamine sulfate were tested against placebo in a prospective double-blind trial in 20 out-patients with established osteoarthritis. Two capsules of either glucosamine sulfate (250 mg) or placebo were administered 3-times daily over a period of 6 to 8 weeks. Articular pain, joint tenderness and restricted movement were semi-quantitatively scored 1 to 4 every 3 days, and individually averaged over the treatment period. Possible side-reactions were similarly scored upon positive questioning of the patients. Haematology, erythrocyte sedimentation rate, urine analysis and X-rays were recorded before and after treatment. Significant alleviation of symptoms was associated with the use of the active drug at the prescribed dose. Patients given glucosamine sulfate experienced earlier alleviation of symptoms compared with those who had placebo. No adverse reactions were reported by the patients treated with glucosamine, and no variation in laboratory tests was recorded (17). 

In 1981 injectable and oral form of glucosamine sulfate, were investigated in 30 patients with osteoarthrosis. Two groups of in-patients with chronic degenerative articular disorders received daily for 7 days either 400 mg glucosamine sulfate or a piperazine/chlorbutanol combination by intravenous or intramuscular injection. During the 2 following weeks, the patients receiving glucosamine had oral glucosamine capsules (6 x 250 mg daily); the other group had placebo. Efficacy was tested by semi-quantitative scoring of pain at rest and during active and passive movements, as well as limitation of articular function, before and after 7 and 21 days of treatment. Patients were positively questioned daily for possible intolerance symptoms. Haematology, circulatory data and urine analysis were tested before and after treatment. During both initial parenteral treatments, each symptom significantly improved, but to a faster and greater extent in the group treated with glucosamine. During the maintenance period, a further improvement was recorded in the patients treated with glucosamine, whereas in those on placebo the symptom scores increased almost to the pre-treatment level. Clinical and biological tolerance were excellent with both treatments (injectable and oral forms), and no definitely drug-related complaints were recorded. It was suggested that parenteral and/or oral treatment with pure glucosamine sulfate should be considered as basic therapy for the management of primary or secondary degenerative osteoarthrosis disorders (18). 

In 1982 another double-blind trial was carried out in 40 out-patients with unilateral osteoarthrosis of the knee to compare the efficacy and tolerance of oral treatment with 1.5 g glucosamine sulfate or 1.2 g ibuprofen daily over a period of 8 weeks. Pain scores decreased faster during the first 2 weeks in the ibuprofen than in the glucosamine treatment group. Although the rate of decrease was slower, the reduction in pain scores was continued throughout the trial period in patients an glucosamine and the difference between the two groups turned significantly in favour of glucosamine at Week 8. No significant differences were observed in swelling or any of the other parameters monitored. Tolerance was satisfactory with both treatments, with only minor complaints being reported by 2 patients on glucosamine compared with 5 patients on ibuprofen (19).

Also in 1982 an open study was carried out by 252 doctors throughout Portugal to assess the effectiveness and tolerability of oral glucosamine sulfate in the treatment of arthrosis (Pharmatherapeutica. 3(3):157-68, 1982). Patients received 1.5 g daily in 3 divided doses over a mean period of 50 +/- 14 days. The results from 1208 patients were analyzed and showed that the symptoms of pain at rest, on standing and on exercise and limited active and passive movements improved steadily through the treatment period. The improvement obtained lasted for a period of 6 to 12 weeks after the end of treatment. Objective therapeutic efficacy was rated by the doctors as 'good' in 59% of patients, and 'sufficient' in a further 36%. These results were significantly better than those obtained with previous treatments (except for injectable glucosamine) in the same patients. Sex, age, localization of arthrosis, concomitant illnesses or concomitant treatments did not influence the frequency of responders to treatment. Oral glucosamine was fully tolerated by 86% of patients, a significantly larger proportion than that reported with other previous treatments and approached only by injectable glucosamine. The onset of possible side-effects was significantly related to pre-existing gastro-intestinal disorders and related treatments, and to concomitant diuretic treatment.

In 1984 a group of 68 patients with mild or moderate gonarthritis were treated with intra-articular injections of glucosamine sulfate or glycosaminoglycan polysulfate over a period of six weeks. The therapy was successful in two thirds of these patients. "Loading" pain was eliminated or improved in about 80%, and signs of synovitis had improved in about 66%. Gait function and mobility were improved. Glucosamine had a superior effect, in particular in mild arthritis, achieving an improvement of pain in 90%, while glycosaminoglycan polysulfate (chondroitin sulfate) was successful in advanced cases. The tolerance of the two substances was 94%. The results and the underlying modes of action of the substances are discussed (20). 

In 1992 Three double-blind, controlled, parallel groups, randomized, 4-6 week trials of glucosamine sulphate versus placebo or the NSAID ibuprofen on a total of 606 out-patients with gonarthrosis. Movement limitation and pain were scored, and the efficacy goals were strictly pre-determined. Access to other medications was not allowed. Glucosamine was significantly more effective than placebo, while no difference was detected in comparison with the NSAID. On the other hand, glucosamine was as well tolerated as placebo, while the percentage of patients suffering adverse drug reactions was higher in the ibuprofen group(21). 

Since 1992 more attention have been derived towards glucosamine sulfate for the treatment of osteoarthritis. In 1998 a broad data analysis of studies has been done on the usefulness of glucosamine sulfate in the treatment of patients with osteoarthritis (22). Pertinent citations were identified via a MEDLINE search (January 1975-March 1997). It has been concluded that osteoarthritis being the most common form of arthritis represents a major cause of morbidity and disability in the elderly. The main symptom of osteoarthritis is pain and most of the commonly prescribed medications (e.g. acetaminophen, nonsteroidal anti-inflammatory drugs) have been targeted at relieving the pain. Some of these medications have serious adverse effects and do not necessarily change the natural course of the disease. Glucosamine sulfate, a nutritional supplement, has recently emerged as an alternative treatment option for patients with OA. The beneficial effects of this chondroprotective agent have been reported to reverse or at least stop the progression of the disease without inducing serious adverse effects. Limited data from short-term human trials suggest that glucosamine sulfate administered orally, intravenously, intramuscularly, and intra-articularly may produce a gradual and progressive reduction in joint pain and tenderness, as well as improved range of motion and walking speed. Results of the trials have also shown that glucosamine has produced consistent benefits (>50% overall improvement in symptom scores) in patients with OA and that, in some cases, it may be equal or superior to ibuprofen in controlling symptoms.

In 1999 another review about glucosamine sulfate studies was published(23) and the authors concluded that Glucosamine sulfate's role in halting or reversing joint degeneration appears to be directly due to its ability to act as an essential substrate for, and to stimulate the biosynthesis of, the glycosaminoglycans and the hyaluronic acid backbone needed for the formation of the proteoglycans found in the structural matrix of joints. Successful treatment of osteoarthritis must effectively control pain and should slow down or reverse the progression of the degeneration. Biochemical and pharmacological data combined with animal and human studies demonstrate that glucosamine sulfate is capable of satisfying both of these criteria.

PhytoMe Scientists designed a product with very high efficacy for the treatment of osteoarthritis, in the form of gel containing the active ingredients, glucosamine sulfate and chondroitin sulfate, in high concentration. The emulsifier used in the preparation of the gel has been modified to allow the achievement of maximal effect of the active ingredient on dermal application. The new product will help osteoarthritis sufferers get fast, long-term relief from pain, stiffness, and immobility restoring normal functioning articular cartilage without any negative effects one receives from the commonly prescribed drug. The active ingredients have the ability to permeate the skin and the fine capillary wall around the joints to be highly concentrated in the synovial fluid to stimulate the chondrocytes to synthesize the proteoglycans which is the main building block of the articular cartilage. The healthy smooth articular surface helps good range of joint mobility and reduce the pain of osteoarthritis.

REFERENCES

1. Swoboda B [a]. Pullig O. Kladny B. Willauschus W. Molecular aspects in the characterization and early diagnosis of human osteoarthritis. [German] Aktuelle Rheumatologie. 21(1). 1996. 10-16.

2. Hanneke L A M. Van Der Kraan Peter M. Van Den Berg Wim B. Bijlsma Johannes W J. Transforming growth factor-beta predominantly stimulates phenotypically changed chondrocytes, in osteoarthritic human cartilage. Journal of Rheumatology. 24(3). 1997. 536-542. 

3. Praillet Christel. Lortat-Jacob Hughes. Grimaud Jean-Alexis [a]. Proteoglycans and pathology (II). [French] M S-Medicine Sciences. 14(4). April, 1998. 421-428. 

4. Mankin, Henry J. MD; Buckwalter, Joseph A. MD MS Restoration of the Osteoarthrotic Joint. Journal of Bone and Joint Surgery Volume 78-A(1) January 1996 PP 1-2.

5. Mankin, H. J.: The reaction of articular cartilage to injury and osteoarthritis. (First of two parts.) New England J. Med.,291:1285-1292, 1974.

6. Mankin, H. J.; Dorfman, H.; Lippiello, L.; and Zarins, A.: Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J. Bone and Joint Surg., 53-A:523-537, April 1971. 

7. Buckwalter, J. A., and Mow, V. C.: Cartilage repair in osteoarthritis. In Osteoarthritis, Diagnosis and Medical/Surgica Management, edited by R. W. Moskowitz, D. S. Howell, V. M. Goldberg, and H. J. Mankin. Ed. 2, pp. 71-107. Philadelphia, W. B. Saunders, 1992.

8. Buckwalter, J. A., and Lohmander, S.: Current concepts review. Operative treatment of osteoarthritis. Current practice and future development. J. Bone and Joint Surg., 76-A:1405-1418, Sept. 1994.

9. Dieppe, P.: Osteoarthritis: management. In Rheumatology, pp. 8.1-8.8. Edited by J. H. Klippel and P. A. Dieppe. London, Mosby, 1994.

10. Odenbring, S.; Egund, N.; Lindstrand, A.; Lohmander, L. S.; and Willen, H.: Cartilage regeneration after proximal tibial osteotomy for medial gonarthrosis (arthritis secondary to prolonged gonnoccocal infection). An arthroscopic, roentgenographic, and histologic study. Clin. Orthop., 277:210-216, 1992.

11. Goldberg, V. M., and Caplan, A. I.: Cellular repair of articular cartilage. In Osteoarthritic Disorders, pp. 357-363. Edited by K. E. Kuettner and V. M. Goldberg. Rosemont, Illinois, The American Academy of Orthopedic Surgeons, 1995.

12. McCarty M F. The neglect of Glucosamine as a treatment for osteoarthritis: A personal perspective. Medical Hypotheses. 42(5). 1994. 323-327.

13. McCarty M F [a] Enhanced synovial production of hyaluronic acid may explain rapid clinical response to high-dose glucosamine in osteoarthritis. Medical Hypotheses. 50(6). June, 1998. 507-510.

14. Abatangelo G [a]. O'Regan M. Hyaluronan: Biological role and function in articular joints. European Journal of Rheumatology & Inflammation. 15(1). 1995. 9-16. 

15. Paroli E. Glycosaminoglycan chondroprotection: Pharmacological vistas. International Journal of Clinical Pharmacology Research. 13(SUPPL.). 1993.1-9.