EFFICACY AND ABSORPTION OF HYALURONIC ACID AND N-ACETYL D-
GLUCOSAMINE FOT THE TREATMET OF OSETOARTHRITIS: A REVIEW.
Vera Mason1, Andrea Fratter1, Marzia Pellizzato2
1Innovation Technology, Labomar Research , Istrana, Treviso, Italy
2Nutraceutical Formulation Department, Labomar Research , Istrana, Treviso, Italy
Address correspondence to: Vera Mason, Labomar Research, via Filzi 33, 31036 Istrana (TV),
Italy. Email firstname.lastname@example.org
Osteo-articular diseases involve a large part of elderly people producing as
effect a worsening of the quality of life and a remarkable effect on health public
expense. Osteoarthritis, inflammatory articular diseases and cartilage disruption
associated diseases are the most frequently diagnosed.
Beside the remarkable role played by the Non-steroidal anti-inflammatory drugs,
glucocorticoids and physiotherapy it is growing up the use, even under clinical
prescription, of specific nutraceutical products containing chondral-protective
and osteotropic substances able, at certain conditions, of improving signs and
symptoms of such these kind of diseases. In particular, hyaluronic acid,
chondroitin sulfate and glucosamine-derived salts and derivatives are the most
commonly prescribed and used. Despite the large diffusion of these products
which is the real absorption and efficacy of these substances in humans? The
absorption of hyaluronans, since their high molecular weight are questionable
under the enteric physiology point of view and quite the same is for chondroitin
sulfate. On the other side, many clinical published papers refer about a
significant improving of symptoms and articular functionality in patients
suffering from the aforementioned diseases, after assumption of adequate
dosages of these compounds. These paper attempts to clarify the apparent
dichotomy between absorption and efficacy and compare the clinical evidences
between hyaluronic acid and its precursor N-Acetyl glucosamine under the light
of bioavailability considerations.
Keywords:hyaluronic acid, N-acetyl-D-glucosamine, osteoarthritis,
Osteoarthritis (OA) is a degenerative joint disease which occurs when the
cartilage or cushion between joint disrupts. It is the most prevalent form of
arthropathic disease and it appears mostly among old people [1, 2], leading to
pain, stiffness and limited mobility. OA displays reduction of hyaluronic acid
(HA) concentration , together with cartilage disruption , local
inflammation of tendon and synovial fluid [5, 4], osteophyte formation and
muscle weakness .
The etiology of OA is complex and multifactorial, involving different
biochemical pathways and cellular changes . Disease initiation and
progression have not been clearly understood.
Pharmacologic treatments of OA include acetaminophen , non steroidal anti-
inflammatory drugs (NSAIDs)  and corticosteroids (CS) . Beside this mild
stone, in recent years increasing interest has been focused on nutraceutical
preparations, which include the administration of hyaluronic acid (HA) [9, 10],
its precursors N-acetyl-D-glucosamine (NAG) [11, 10] and chondroitin sulphate
(CS). Investigations demonstrate their supportive role and efficacy in
counteracting signs and symptoms of OA , but questionable data are available
regarding their mechanism of action and extent of absorption after oral
administration. The aim of this paper is to focus on clinical investigations
related to HA and its precursor NAG in order to elucidate the current state of the
art about this topic.
First discovered in 1934 by Meyer et al , HA is a non-sulphated
glycosaminoglycan, which occurs naturally in a number of body tissues. HA is a
polysaccharide composed of linear repeating disaccharides of D-glucuronic acid
and N-acetyl-D-glucosamine linked by a glucuronidic β (1→3) bond . HA
molecular weight can be very wide, ranging from 20 to 4,000 kDa  and
polymers can adopt different configuration shape according to their molecular
weight, salt concentration, pH, and associated cations . At physiological pH,
HA occurs in the salt form, hyaluronate, generally sodium hyaluronate . HA
is a major component of extracellular matrix (ECM) and peri-cellular matrix and
represents the main molecule of the gel-like structure composing soft connective
tissues including skin, umbilical cord, synovial fluid, vitreous humor, as well as
in brain, heart valves and lungs .
The main property of HA concerns its ability to bind water providing a unique
strong tissue hydration . HA is mainly known for conferring joints
lubrication , tissue viscoelasticity  and dermal tissue hydration ; on
the other side it is also involved in immune system responses [22, 23], wound
healing processes  and vessels connective structure formation .
Furthermore HA interacts with a group of matrix proteins, called hyaladherins
(HYA), modulating cellular activities, cell migration, differentiation and
HA is synthetized by bound membrane enzymes, called HA synthases (HAS).
Three different enzymes are involved in HA synthesis, HAS 1, 2 and 3,
according to the HA chain length . Depending on the molecular weight HA
polymers exhibit different activities .
HA is extensively used in cosmetic industry, health care and pharmaceutical
formulations and, because of its physiological role in synovial fluid, HA is
proposed as supplement [9, 29] or alternatively as sterile jellified fluid to be
injected into synovial space to relieve signs and symptoms of OA. It is
speculated that the main activities of HA in the landscape of OA management
include restoration of synovial viscoelasticity, intervention in cartilage
biosynthesis and degradation processes , and an anti-inflammatory and
analgesic effect .
HA oral absorption in humans is still nowadays subject of studies and
investigations. The proper mechanism of intestinal internalization is still to be
elucidated and evidences are controversial. A series of studies using
radiolabelled HA suggest possible kinetics of absorption and distribution in
tissues. It has been demonstrated that in rats oral HA is absorbed and
accumulates in connective tissue of all body persisting for 48 hours . This
result is confirmed in rats by Oe M et al who show that 90% of oral
administered HA is absorbed in the intestine and distributes in the skin .
Conversely Laznicek M et al report that only low level of HA are detected in the
central compartment after oral assumption . A recent study on rats speculates
that HA is previously metabolised in the cecum by bacteria and the formed
oligosaccharides are absorbed and migrate thought the tissues . However
orally administered HA shows limitation due to the high molecular weight and
short half-life  and clear outcomes has not been reached yet. It is suggested
that polymers with different molecular weights show different bioavailability
profiles. Hisada N et al demonstrate that low-molecular weight HA permeates
through Caco-2 cell model  and absorption was inversely correlated to chain
size . Studies indicates that HA modification, such as acetylation  or
complex with phospholipids , could increase HA biovailability [36, 37].
CLINICAL EVIDENCES FOR HYALURONANS
Chondroprotective role of HA and its precursor NAG is well established both in
animal models and in humans [9, 10]. Many randomized, double-blind, placebo-
controlled clinical trials have been carried out in the recent years, mostly related
to knee OA.
In 2008 twenty subjects showing knee OA symptoms from more than 6 months
were enrolled in a randomized double-blind controlled trial. Ten subjects were
administered with 40 mg of HA from a natural extract of chicken combs for 2
months and were compared to control group-taking placebo. After treatment the
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
shows statistically significant improvement in physical functions and overall
symptom scores in the HA group. Moreover quality of life measured by the
Short Form-36 displays higher score in HA group versus baseline in some
markers, such as bodily pain and the physical component summary . This
result is in line with Sato T and Iwaso H placebo controlled double blind trial,
which proves that daily intake of 200 mg of HA results in knee OA-associated
relief after 2 months of assumption. Effectiveness was monitored using the same
WOMAC Index . The same authors examined the impact of oral HA
supplementation using the Japanese Knee Osteoarthritis Measure (JKOM) score.
The conclusion is equivalent: 2 months treatment of 240 mg of HA evidences
improved quality of life .
In 2010 a randomized double-blind placebo-controlled trial showed that 16 week
treatment of 60 mg HA leads to better score in Japanese Orthopaedic
Association response criteria (YOA). 'Pain/walking function', 'pain/step-up and
-down function' and 'aggregate total symptoms' score was improved in the
treated group compared to control subjects . Furthermore, measurement of
collagen metabolism biomarker evidences that collagen synthesis is positively
affected by HA .
Tashiro T et al  studied oral supplementation of HA over a period of 12
months. This trial covers a longer duration and a higher number of recruited
subjects than the studies just mentioned. Sixty patients older than 50 and
suffering from symptomatic knee OA were randomly given 200 mg of HA daily.
The double-blind, placebo-controlled study imposes HA supplementation
together with leg strengthening exercise. Symptoms variations were monitored
using Japanese Knee Osteoarthritis Measure (JKOM) score. HA
supplementation improved OA conditions, but seems to be more effective
among subjects younger than 70. Furthermore, better relief has been recognized
in the early points at the 2nd and 4th months rather than at 6th and 12th months
when the result was not significant .
Martinez-Puig et al evaluated the efficacy of HA administered in a yoghurt
matrix. Forty subjects presenting mild joint pain have been enrolled in a
randomized, double blind, placebo-controlled intervention study. The trial
evaluates muscle strength using an isokinetic dynamometer. Authors concluded
that HA supplementation improves kneed ability to bend and stretch . Sola R
et al who proved that yoghurt supplemented with rooster comb extract rich in
HA taken in for 3 months improves muscle power in individuals affected by
mild knee discomfort  confirmed this result.
In 2015, Nelson FR et al  studied an oral formulation containing 56 mg of
HA over a period of 3 months in forty subjects suffering knee OA. HA impact
was measured using VAS, WOMAC total score, and WOMAC pain score, but
also observing inflammatory cytokine, bradykinin, and leptin levels. Authors
evidenced that oral assumption of HA reduces significantly pain and reduce
cytokine, bradykinin, and leptin release .
Recently a comparative study between intra-articular injections and oral
administration of HA has been published . The two groups of subjects with
early OA were administered three weekly intra-articular injections or tablets,
containing 300 mg of HA plus Boswellia serrata extract 100 mg (first 20 days)
and 150 mg of HA (other 20 days). Results have been evaluated using American
Knee Society Score (AKSS) and visual analogue scale (VAS) and have been
correlated to subject age. It is reported that both groups evidence beneficial
effects, however it is speculated that intra-articular injections are more effective
for people younger than 60, while oral administration is better for subjects older
than 60 .
NAG is a glucose derivative. Chemically NAG is an amino water-soluble
monosaccaride, resulting from the link of glucosamine (GA) and acetic acid and
polymerizes linearly with (1,4)-β-linkages. NAG is largely present in the body
and, as mentioned, it is recognized as the natural precursor of HA, but NAG is
also a component of cartilage matrix and synovial fluid. Because of its
physiological role, GA derivatives find their space as nutraceutical supplements
for chondroprotection. Mechanisms of action are still under investigation and
several studies focus on this point. It has been demonstrate that on synovium
explants glucosamine hydrochloride (GH) increases HA production, conversely
NAG do not exhibit the same effect . Similar result was achieved by
Igarashi M et al who reported that NAG does not promote HA synthesis in
synovial cells and chondrocites . Conversely it is evidenced that NAG
upregulates the hyaluronan synthase-2 in human articular chondrocytes 
andmediate an anti-inflammatory pathways [50, 51], reducing nitric oxide,
cyclooxygenase-2 and IL-6 production . Shikhman AR et al suggested that
NAG could be more efficient than native GA in HA synthesis .
Compared to HA, GA has a lower molecular weight and have an impact on
absorption and bioavailability. Since GA is naturally present in the human body,
pharmacokinetics studies are difficult to be established and carried out. In vitro
and animal studies demonstrate intestinal internalization of GA [52 -54]. In 1972
Tesoriere G et al suggested that NAG is absorbed by a diffusion process . In
rats it has been proved that radiolabeled NAG shows a peak of adsorption 4 h
after the administration and the residual activity is maintained up to 168 h post-
administration . In dogs, GH is absorbed with a bioavailability of about
10%-12% . Persiani S et al  give evidence of human corroboration:
glucosamine sulphate (GS) is quickly internalized after oral administration,
showing linear pharmacokinetics profile with dosage ranging from 750-1500 mg
and an estimated half-life of 15 h. Twelve subjects have been enrolled for the
study and received daily administration . However, most of the
pharmacokinetic investigations are related to GS.
CLINICAL EVIDENCES FOR GLUCOSAMINE
The use of GA derivatives for treating OA is well known; its use in medical
preparations is established from nearly 40 years  however precise indication
related to the mechanism of action and clear impact on OA course and
contextual pain relief have not been defined yet. In the past decades several
meta-analysis have been carried out to assess the effectiveness of GA.
In 2000 McAlindon TE et al  elaborated a systematic quality assessment and
meta-analysis based on trials found in MEDLINE and Cochrane Controlled
Trials Register, to face the controversial outcomes related to the use of GA in
patients with OA. The evaluations of the studies, which fit the inclusion
parameters, suggested that the GA plays a role in relief of OA-associated pain,
but the mentioned effects are magnified .
In 2003 a comprehensive meta-analysis developed by Richy et al assessed the
effectiveness of GA. 15 studies have been evaluated and clinicians concluded
that GA expresses positive outcomes in all the tested parameters, such as joint
space narrowing, Lequesne Index and WOMAC score .
In 2005 a meta-analysis has been published on Cochrane Database regarding GA
use to counteract OA. Authors concluded that: no significant difference appears
between non-Rotta preparations and placebo, Rotta preparations showed
improvement in pain and muscle functionality, while no differences emerged in
stiffness resolution between GA containing preparation and placebo .
More recently Wandel S et al  proved that the effect of GA, chondroitin, or
the two in combination are not significant in reducing pain and joint space
narrowing. The network meta-analysis has been carried out retrieving 10 studies
In 2015 Zeng C et al  investigated the impact of GA plus chondroitin, GA
alone, and celecoxib on knee OA relief. This analysis stems from the assumption
and recommendations given by American College of Rheumatology, American
Academy of Orthopaedic Surgeons and Osteoarthritis Research Society
International which suggested not to use GA, chondroitin or the combination of
two, to counteract pain associateded with OA. The analysis covers 54
studies and it concluded that both GA plus chondroitin and GA alone exhibit
beneficial effects on pain and function improvement .
Treating specifically NAG, in 2006 the assumption of soymilk beverage
enriched with NAG has proved to have healthy outcomes on patients with knee
joints impairment. The beverage contained 1000 mg or more of NAG and was
assumed once a day. The pain has been reduced and range of motion has
improved in 2 months treatment .
In 2016 Tsuji T et al evidenced NAG effectiveness in improving knee function.
The randomized, double-blind, placebo-controlled trial was carried out
recruiting fifty adult people (aged 52-87 years) suffering knee pain. They were
administered 100 mg of NAG and of chondroitin sulphate daily for 6 months
and the effects were evaluated using Japanese Knee Osteoarthritis Measure
(JKOM) score . Beneficial effects on functional knee activityhas been first
noticed at month 3evaluation .
Recently randomized, double-blind, placebo-controlled studies have been
conducted on healthy volunteers to assess the role of NAG and its proper
effective dosage. The trails draw 16 weeks supplementation and subjects aged
20-64 years old. The conclusion is that 500–1,000 mg/day of NAG improve type
II cartilage metabolism, promoting cartilage synthesis and reducing cartilage
degradation [65-67]. The same research group carried out these studies.
Naraoka Y et al have evaluated the impact on NAG administration in subject
with knee discomfort, but without diagnosis of knee OA. Nineteen adult people
were enrolled and were given 3 times a day tablet containing 526.5 mg of NAG
and 33.6 mg of proteoglycan over a period of 3 months. Locomotion function
was improved and pain was reduced after the treatment. Authors suggests that
early administration of NAG and proteoglycans (PG) could prevent structural
knee deformation, and thus the onset of OA .
DISCUSSION AND CONCLUSION
OA is a widespread degenerative disorder that dramatically affect quality of life
of patients. OA damages the entire joint, triggering cartilage and juxta-articular
tissues changes and biomechanical stress, which lead to the loss of articular
cartilage, histological abnormalities in the synovia, joint capsule and muscle
weakness. These modifications limit motility, interfere with daily activities,
induce pain and reduce the overall quality of life.
HA and NAG are two characters that can play a significant role along the way of
retarding and counteracting OA progression. In the last two decades, several
studies examined their both efficacy after oral administration, in reducing pain
and stiffness associated with OA, but the overall results are controversial.
Oral HA supplementation exhibits positive, beneficial and accordant outcomes
on OA discomfort. Daily intake of doses ranging from 40 mg to 300 mg of HA
results in alleviation of pain [39, 45] and improved physical functions [38, 41].
Both supplement formulations and yoghurt HA-enriched display convincing
results in pain and muscle strength. Conversely oral administration of HA
natural precursor NAG does not exhibit the same univocal and solid consent
about its oral use. Speaking generally, the application of GA in treatment of OA,
to reducing pain and counteracting structural modifications, have been widely
investigated. However, most of the studies do not consider specifically the
effectiveness of oral administration of NAG, even if it is the natural precursor of
HA. Most of the trials are related to GS or GH. Despite that, NAG is widely
used in food supplements to promote relief of joint discomfort and counteract
knee functional modifications. Many papers have investigated GA activities,
even though few studies give an undisputed opinion on NAG effectiveness.
Meta-analysis concerning GA do not converge to univocal conclusions.
McAlindon TE et al suggest beneficial effects, but claiming that results are
emphasized , Richy et al and Zeng C et al evince health improvement [59,
62], Wandel et al do not find significant evidences while major guidelines have
even discouraged the use of GA in OA . Conversely, the few papers related
specifically to NAG reveal its beneficial role to improve knee function [64-68],
even if its mechanisms of action are still under investigation, and in some cases,
results involving its participation in improving HA synthesis seem to be
discordant [46-49]. In Italy the role of NAG in HA synthesis is further
confirmed and authorized by the Ministry of Health, which allows indicating in
food supplements containing NAG the claim that it “contributes to HA
synthesis”. Summerizing, NAG role in non-pharmacological OA management
needs to be further and better elucidated in comparison with HA outcomes.
To conclude, these observations are unexpected in terms of bioavailability.
Bioavailability and efficacy are tightly connected together since an active
compound must overcome gastrointestinal tract and reach blood circulation in a
unmodified form to exhibit therapeutic effect. NAG is a small monosaccharide
and few pharmacokinetics studies [54, 55] have investigated its absorption since
it is widely present in our body and it has a low molecular weight. Indeed, its
enteric absorption is considered granted. On the other hand, HA bioavailability
is still subject of investigation, even though its beneficial effects are firmly
confirmed by clinical scientific literature, as mentioned. HA high molecular
weight limits intestinal absorption, so if enteric absorption which not permit an
high and reliable bioavailability, which process governs such positive clinical
outcomes? According to the afore mentioned considerations it would be
expected to have higher positive effects with oral administration of NAG instead
of HA, unless specific and still unknown pathways guarantee efficient HA
absorption. Kimura M et al speculated that prior to the absorption HA is cleaved
up into oligomers by the far intestine standing bacteria. To conclude, further
investigations are need to clearly elucidate HA and NAG role in OA non-
pharmacological treatment, but could be HA derivative oligomers the answer to
these controversial outcomes?
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