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
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
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
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.
NSAID Effect on Joints
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).
Glucosamine Sulfate in the Treatment of Arthritis
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.
Studies Comparing Glucosamine Sulfate and Ibuprofen
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).
Glucosamine Sulfate Compared with Indomethacin
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).
Glucosamine Sulfate Compared with Placebo
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
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
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