Journal of Manipulative and Physiological Therapeutics
Volume 20, Number 6, July/August, 1997
This excerpt reprinted with permission of publisher,
Williams and Wilkins ©1997

JMPT-REVIEWS OF THE LITERATURE

Conservative Management of Spinal Osteoarthritis with Glucosamine Sulfate and Chiropractic Treatment
Marc S. Gottlieb. D.C.

Objective: To evaluate the rationale behind the most commonly used treatments of osteoarthritis, including nonsteroidal anti-inflammatory drugs (NSAIDs), and to assess more effective conservative treatment options.

Summary of Background Data: This review includes a description of the pathophysiology and prevalence of osteoarthritis, joint physiology and NSAID treatment of osteoarthritis, as well as side effects on joints, the gastrointestinal tract, kidneys and liver. Several studies of conservative treatment, consisting of supplementation of glucosamine sulfate (which occurs naturally in the human body), exercise and the use of chiropractic treatment for maintaining joint function and preventing further destruction, are reviewed.

Data Sources: A computerized search of Medline using the key indexing terms osteoarthritis, degenerative joint disease, nonsteroidal anti-inflammatory drugs, glucosamine sulfate, chiropractic and manipulation.

Results: Numerous studies were obtained under each subheading and reviewed by category. Human and animal-model studies are described.

Conclusion: The rationales for using NSAIDs in the treatment of osteoarthritis is controversial and openly contested. Given the detrimental effects of NSAIDs on joints and other organs, their use should bediscouraged and their classification as a first choice conservative treatment should be abolished. A truly effective and conservative approach to the treatment of osteoarthritis should include chiropractic manipulation, essential nutrient supplementation, exogenous administration of glucosamine sulfate and rehabilitative stretches and exercises to maintain joint function. Because there is no correlation between pain levels and the extent of degeneration detected by radiographic or physical examination, conservative treatment should be initiated and sustained based on functional, objective findings and not strictly on how the patient feels. The use of NSAIDs should be limited to the treatment of gross inflammation and analgesics should only be used in the short-term when absolutely necessary for pain palliation. The present conservative approach could lead not only to a better quality of life but also to the saving of health care dollars by reducing the iatrogenic morbidity and mortality associated with NSAID use.(J Manipulative Physiol Ther 1997; 20:400-14).

Key Indexing Terms: Osteoarthritis; Degenerative Joint Disease; Nonsteroidal Anti-inflammatory Drugs; Glucosamine Sulfate; Chiropractic; Alternative and Complementary Medicine

Osteoarthritis is rarely appreciated as one of the greatest problems affecting man. This form of arthropathy is so universal that it is often regarded as a normal part of aging. Osteoarthritis is usually progressive and often deforming and disabling. The prevalence in the U.S. for adults aged 25-74 are 32.5% for the hands (42.4 million persons), 22.2% for the feet (29.0 million), 3.8% for the knees (5.0 million) and 1.3% for the hips (men only, 765,000) (1). Complicating the study of osteoarthritis of the spine is the fact there is little data on its incidence, occurrence and prevalence. This information is not readily available from the Centers for Disease Control, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, American College of Rheumatology or the Arthritis Foundation. Silman and Hochberg (2) cited Van Sasse et al. (3) in an effort to demonstrate prevalence of spinal osteoarthritis. Van Sasse noted that the prevalence of osteoarthritis was age-, site- and gender-specific and was comparable among 10 population surveys. In the study, the prevalence of osteoarthritis determined by radiographic changes demonstrated trends of higher prevalence of cervical and lumbar spine osteoarthritis compared with that of the hand, knee and hip.

A review of current indexed literature investigating the most commonly used treatments of osteoarthritis was undertaken using Medline. The articles retrieved led to further sources of information within the reference sections, which were reviewed individually.

There are many synonyms or acronyms for osteoarthritis. The name used most commonly is degenerative joint disease (DJD). For more than semantic reasons, this name is actually misleading; the words do not accurately describe the pathophysiological phenomena that are involved. The classification of osteoarthritis as a disease has even been questioned by some authors, who prefer to redefine it as "an ancient Paleozoic mechanism of repair of dense tissues" (4). Although the term osteoarthritis literally means inflammation of a bony joint, the term is usually applied to the processes involved in DJD understood as a noninflammatory process that primarily involves breakdown of joint cartilage. However, there are inflammatory and erosive types of osteoarthritis that might be viewed as intermediate points between rheumatoid arthritis and osteoarthritis (5). This extremely common arthropathy can cause severe pain and disability, leading to loss of work and independence in the aged population.

Osteoarthritis commonly affects the hips, knees, hands and spine. Osteoarthritis (OA) can be defined patho-logically as a condition of a synovial joint characterized by focal areas of articular cartilage loss associated with remodeling of subchondral bone and marginal growth of bone and cartilage (chondroosteophite formation) (6). These pathological changes can be seen on radiographs as joint-space narrowing, subchondral bone sclerosis and osteophytosis. Although the radiographic features are distinctive and often pronounced, a great disparity exists between the observed clinical and radiographic findings in any given patient (7). A person with severe degenerative changes apparent on radiographs may have little pain and vice-versa. More than 50 different terms have been applied to OA. The most common terms in-clude osteoarthrosis, degenerative arthritis, degenerative arthrosis and DJD. The difference between the terms arthrosis and arthritis has come from the appreciation that the disease process is not always inflammatory. For this reason, DJD has gained the most universal acceptance in the literature.

Rapid deterioration of joints after long-term NSAID treatment has been called analgesic arthropathy and is thought to be caused by a loss of protective pain sensation, but it seems much more likely that it is a direct effect of the drug on cartilage. Some anti-inflammatory drugs, including indomethacin, are known to have direct effects on cartilage, which could explain these phenomena (53). The effects NSAIDs have on the biosynthesis of hyaluronic acid by synovial fibroblasts has not been previously investigated. Short-term corticosteroid use may provide a chondrop-rotective effect in OA by down-regulating cell metabolism, suppressing cell proliferation and the synthesis of proteinases and inflammatory mediators. Unfortunately, the long-term consequences, such as inhibition of proteoglycan and hyaluronic acid synthesis by chondrocytes and synovial cells, has limited corticosteroid application (54). Not only is there no evidence that NSAIDs favorably modify the progression of joint breakdown in patients with OA, several NSAIDs including acetylsalicylic acid, sodium salicylate, fenoprofen, sodium tolmetin and ibuprofen have demonstrated the inhibition of proteoglycan synthesis by normal cartilage in vitro (55-57). The augmented in vitro synthesis of proteoglycan in osteoarthritic cartilage that represents a repair effort by the chondrocytes is suppressed by salicylate to a much greater extent than in normal cartilage (58). Indomethacin, which had no effect on normal articular cartilage, inhibited proteoglycan synthesis in osteoarthritic cartilage as effectively as salicylate. The difference between the susceptibility of normal and arthritic cartilage to the metabolic effect of NSAIDs is attributable to a greater diffusion of the drug through the abnormally permeable matrix of the osteoarthritic cartilage (59). As demonstrated in animal models, the proteoglycan concentration of cartilage matrix was significantly lower when dogs were fed aspirin than when they were not, and the augmentation of proteoglycan synthesis in the osteoarthritic cartilage (again reflecting repair activity) was virtually eliminated (60). In addition, oral administration of aspirin markedly accelerated the development of OA in C57 black mice, a strain genetically predisposed to the disease (60). As mentioned earlier, joint movement is critical for maintaining the health of cartilage. Incidentally, to create osteoarthritic joints in animal models, limb immobilization was used to induce articular cartilage atrophy (61). Along with the experimental evidence that NSAIDs interfere with the metabolism of articular cartilage and the repair of bone, clinical experience has shown use of these drugs causes acetabular bone destruction, arthropathy and avascular necrosis of the hip (62-66). Even though NSAID-induced arthropathy has been a well-known entity since the 1960s, in a recent survey, 94% of primary care physicians indicated that they would prescribe an NSAID as an initial treatment for an elderly patient with uncomplicated hip OA; in comparison, only 1% would initiate therapy with a simple analgesic such as acetaminophen (35). Despite their associated risks, given this evidence, NSAIDs are likely to remain the integral component of the treatment in OA without more comprehensive knowledge of their side effects. There are no data to support the concept that treatment of OA with an NSAID or analgesic must be maintained indefinitely (67).

As previously noted, one must understand the mechanisms of a disease process before being able to initiate a successful treatment. Part of the problem is that there are so many terms used to describe OA, and that researchers do not concur on whether the disease process is noninflammatory, inflammatory or, periodically, both. With yet another opinion, Pipitone states that DJD is the result of the physiological aging process of cartilaginous tissue that occurs in old age, generally after 65 (68). "Osteoarthritis is a true disease of cartilaginous tissue with specific etiologic and pathogenic characteristics and it strikes in earlier age groups, often occurring around 45-50" (69). With this controversy in mind, chondroprotection will be reviewed in the hope of satisfying both sides of the dichotomy. Chondroprotection is based on the exogenous introduction of glycosaminoglycans (GAGs) to be used by chondrocytes for the synthesis of proteoglycans. Although this is thought to help the physiological processes of a joint, GAGs also have a proven anti-inflammatory effect. Many types of substances have been used for this type of therapy. Among these chondroprotective agents are galactosaminoglycuronoglycan sulfate, chondroitin sulfate, polysulfated glycosaminoglycan, oxaceprol, diacerein, hyaluronic acid and various forms of glucosamine sulfate (17, 53, 54, 68-70)

Because glucosamine sulfate occurs naturally in the human body, is almost devoid of toxicity and is thus suitable for long-term therapeutic use, it was chosen for further evaluation. Glucosamine sulfate exhibits chondrometabolic, antireactive and antiarthritic properties, representing a pharmacological rationale for use as a disease-modifying agent in OA. D-glucosamine is the active principle of glucosamine sulfate, which is the salt of D-glucosamine with sulfuric acid. The D-glucosamine molecule is relatively small and diffuses easily through all biological membranes and occurs as a natural component in almost all tissues of the human body (71). Glucosamine has a high affinity for cartilaginous tissue, where it is readily incorporated into the proteoglycan molecules. The leftover sulfate ion is utilized in the biosynthesis of the GAGS, which are esters of sulfuric acid (71). D-Glucosamine is one of the principle building blocks of many GAGS and hyaluronic acid. Exogenous D-glucosamine is a preferred substrate for the biosynthesis of GAGS (72). D-Glucosamine stimulates proteoglycan synthesis in articular cartilage, thus offering protection against the cartilage-damaging effects of NSAIDs as well as the chondrocyte-damaging effects of corticosteroids (73). The anti-reactive effects of D-glucosamine have been studied in several models of inflammatory reactions. The antireactive activity is usually smaller than that of aspirin (acetylsalicylic acid), but it is notable that D-glucosamine, a substance normally present in the body and practically devoid of toxicity, is able to exert similar antireactive effects as aspirin (27). Although glucosamine is effective in inhibiting the release of proteolytic enzymes and lysosomal enzymes, it does not inhibit prostaglandin biosynthesis. This is the fundamental difference between glucosamine and the NSAIDs. For this reason (to distinguish it from the NSAIDs), Setnikar et al. prefer to call glucosamine an "antireactive" agent rather than an "anti-inflammatory" agent (27). Glucosamine sulfate has proven to be effective in the treatment of OA in double-blind, controlled clinical studies, by improving mobility and relieving pain (71). Setnikar et al. report the relief of pain under glucosamine sulfate appears after 2-3 wk of treatment, although under ibuprofen, the pain is relieved in the first week of treatment (71). This finding is consistent with the pharmacological properties of D-glucosamine. The relief of pain under D-glucosamine seems to be caused by an objective improvement of the articular conditions rather than to an analgesic effect. Thus, it is possible that long-term glucosamine sulfate supplementation could reverse some osteoarthritic conditions. The therapeutic effectiveness of glucosamine treatment has been demonstrated in animal-model research as well as in human clinical trials.

A double-blind trial compared 1.5-g glucosamine sulfate treatment with 1.2-g ibuprofen treatment given daily over a period of 8 wk (74). Pain scores decreased faster during the first 2 wk in the ibuprofen group than in the glucosamine group. Although the rate of decrease was slower, the reduction in pain scores continued throughout the trial period in patients on glucosamine; the difference between the two groups turned sig-nificantly in favor of glucosamine during the eighth week of therapy (74). Similar success was found by Rovati (75) in a double-blind, controlled trial of glucosamine sulfate, placebo and ibuprofen. Initial improvement of symptoms seemed to be faster with ibuprofen than glucosamine, but it was not a statisticaily significant difference. There was definitely no difference between the two groups after the second week of treatment. Oral glucosamine sulfate was as effective as ibuprofen in controlling the symptoms of knee arthrosis (gonarthrosis) with clinically evident signs of inflammation. Glucosamine sulfate was also better tolerated than ibuprofen, which caused gastrointestinal reactions. Glucosamine sulfate was also significantly more effective than the placebo in this study (75).

In animal models, indomethacin provokes erosions, hemorrhages and ulcers in the small intestine. In contrast, daily oral doses of glucosamine sulfate up to 2700 mg/per kg of body weight in rats and 2149 mg/kg of body weight in dogs in 1-yr and 6-month experiments, respectively, did not provoke anatomical lesions of the GI tract or other organs. Given the toxicity of indomethacin and the therapeutic margin with regard to prolonged treatments, glucosamine sulfate was found to be 10-30 times more favorable for the prolonged treatment of inflammatory disorders. Glucosamine sulfate can therefore be considered a treatment of choice for prolonged rheumatic disorders (76).

Many double-blind placebo studies have demonstrated positive outcomes with the use of glucosamine sulfate. Most studies reflect no change in laboratory tests of blood or urine but a significant reduction in symptomatology. A reduction in joint pain tenderness, swelling and an increase in mobility are the most common findings. Reichelt et al, utilized 400-mg intra-muscular injections of glucosamine sulfate twice a week for 7 wk. A significant decrease in the index of symptoms was observed for glucosamine compared with the placebo (77). Drovanti et al, found patients treated with glucosamine sulfate experienced a reduction in overall symptoms that was almost twice as large and twice as fast as subjects on placebo. Samples of articular cartilage were examined by electron microscopy. The patients on placebo showed typical established osteo-arthrosis, whereas those on glucosamine sulfate appeared more similar to healthy cartilage. It was concluded that glucosamine sulfate rebuilds damaged cartilage, thus restoring articular function in most chronic arthrosic patients (78). In this study, the subjects were given 500-mg oral doses three times daily. Of incidental note, occult blood in feces disappeared in three of the five patients under the glucosamine sulfate with a positive pretreatment test, which, in comparison to other NSAID therapies, demonstrates the tolerability of glucosamine. Glucosamine sulfate was found to be the treatment of choice for the basic management of patients with osteoarthrosis by Pujalte et al, after performing a placebo-controlled study administering 500 mg of glucosamine sulfate three times daily over a period of 6-8 weeks (79). In a placebo-controlled study, Crolle and D'Este found 400 mg of glucosamine sulfate injected daily, either intramuscularly or intra-articularly, improved symptoms significantly, with a trend for faster and greater recovery with glucosamine, mainly in restricted function. No drug-related complaints were recorded and they concluded that glucosamine sulfate should be considered for the basic therapy of primary or secondary osteoarthrosis, mainly because it restores articular function to a certain extent (80). Glucosamine sulfate was tested for anti-inflammatory activities and has been shown to protect against edema provoked in the rat paw by carrageenin, dextran and formalin, but not against the edema provoked by specific inflam-mation mediators such as bradykinin, serotonin and histamine. Glucosamine sulfate inhibited in vitro superoxide generation and lysosomal enzymes of the liver; notably, toxicity on the gastrointestinal tract was virtually absent (81). With yet another approach, D'Ambrosio et al. administered 400 mg of glucosamine sulfate by intravenous or intramuscular injection daily for 7 days; then, during the ensuing 2 wk, administered oral glucosamine sulfate capsules (250 mg six times daily) and made comparison with a control group receiving placebo. Again, symptoms improved sig-nificantly in both groups, but more quickly and to a greater extent in the group treated with glucosamine versus the placebo. Most importantly, during the maintenance period with oral glucosamine, a further improvement was recorded in the glucosamine patients, whereas those on placebo had a return of symptoms almost to the pretreatment level (84).

Although glucosamine sulfate is prescribed as a drug in some countries it is commonly available in the United States and marketed and sold as a nutritional supplement. Even though dose-related clinical trials have not been completed, an accepted standard dose for glucosamine sulfate has been recommended by manufacturers. Commonly, 1500 mg per day is recom-mended in three 500-mg doses. Also available are 750-mg doses given twice daily. I have found in private clinical practice that, when prescribing the 500-mg capsules three times daily, there is poor patient compliance with taking the mid-day dose. From a practical standpoint, most patients take the first and third doses respectively at breakfast and dinnertime by leaving the bottle conspicuously placed at home. However, many people do not eat lunch at home and therefore forget to take a mid-day dose. Some patients took the three 500 mg doses without fail for periods of approximately 2 months and subsequently stopped taking the "nuisance" mid-day dose. This was initially perceived as a troublesome compliance issue, but this eventually yielded important clinical information. Although purely anecdotal at this point, patients who lowered their dosage after a period of a couple of months seem to maintain the positive results achieved initially with 1500 mg of glucosamine sulfate. This may be early evidence needed to pursue testing lower dosages and/or protocols of higher doses for an initial period followed by a lower "maintenance" dose over time.

Although glucosamine is clearly an effective supplement in maintaining healthy joint cartilage, other nutrients are essential to enable the body to produce glucosamine. Glycosaminoglycan synthesis occurs as a byproduct of glycolysis. Magnesium is essential for the conversion of glucose to glucose-6-phosphate, the conversion of glucose-6-phosphate to fructose-6-phosphate and fructose-6-phosphate or glutamine is then converted to glucosamine-6-phosphate. A number of studies have shown that a large number of patients with OA are ingesting less than the United States recommended daily allowance of vitamins A, C, D, E, pyridoxine, folacin, pantothenic acid and the minerals zinc, magnesium, iron and calcium (83, 84).

Pain is not a good indicator of the treatment that is needed. Because there is no correlation between pain levels and the extent of degeneration detected by radiographic examination, conservative treatment should be initiated and sustained based on functional, objective findings and not strictly on how the patient feels. Chiropractic manipulation and glucosamine sulfate can positively affect the pathophysiology of OA, whereas NSAIDs and other therapies have failed in this respect. The present conservative approach could lead not only to a better quality of life but also to the saving of health care dollars by reducing the iatrogenic morbidity and mortality associated with NSAID use.

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