ArticlePDF Available

Green-lipped mussel (Perna canaliculus) extract efficacy in knee osteoarthritis and improvement in gastrointestinal dysfunction: A pilot study

  • Medlab Clinical Ltd

Abstract and Figures

Clinical data demonstrating efficacy for nutraceutical compounds marketed for the symptom relief of osteoarthritis (OA) have been largely contentious. Furthermore, no association has been linked between clinical trial inconsistencies and gastrointestinal (GI) dysfunction. The aim of this study was to primarily investigate the efficacy of a high-dose New Zealand green-lipped mussel (GLM) extract in patients diagnosed with OA of the knee and concurrently assess GLM impact on GI function. An open label, single group allocation study was conducted, that administered 3,000 mg/day of GLM extract over 8 weeks to 21 subjects diagnosed with knee OA. Outcome measures were scored using the WOMAC, the Lequesne algofunctional index, and the Gastrointestinal Symptom Rating Scale (GSRS) tools. An intention-to-treat analysis was employed and subject data collected at T₀, T₄ and T₈ weeks. Paired t tests showed significant improvement for the Lequesne, WOMAC (p < 0.001) and GSRS (p = 0.005) scores. A repeated measures ANOVA analysis showed significant improvement in scores for the Lequesne (F = 20.317, p < 0.001), WOMAC (F = 28.383, p < 0.001) and the GSRS (F = 9.221, p = 0.002). Green-lipped mussel significantly improved knee joint pain, stiffness and mobility. We report for the first time that the administration of GLM extract also significantly improved GI symptoms by 49% in OA patients. Given that GI dysfunction is linked to analgesic medication use, we further conclude that the therapeutic efficacy of the GLM extract used was possibly correlated to its effects on GI function by improving GSRS scores from baseline. Results from this trial highlight the requisite for further clinical investigations of gastrointestinal tract function in OA patients.
Content may be subject to copyright.
Green-lipped mussel (Perna canaliculus) extract efficacy in knee
osteoarthritis and improvement in gastrointestinal dysfunction:
a pilot study
Samantha Coulson Phillip Vecchio
Helen Gramotnev Luis Vitetta
Received: 2 January 2012 / Accepted: 8 February 2012 / Published online: 26 February 2012
ÓSpringer Basel AG 2012
Objective Clinical data demonstrating efficacy for
nutraceutical compounds marketed for the symptom relief
of osteoarthritis (OA) have been largely contentious. Fur-
thermore, no association has been linked between clinical
trial inconsistencies and gastrointestinal (GI) dysfunction.
The aim of this study was to primarily investigate the
efficacy of a high-dose New Zealand green-lipped mussel
(GLM) extract in patients diagnosed with OA of the knee
and concurrently assess GLM impact on GI function.
Methods An open label, single group allocation study
was conducted, that administered 3,000 mg/day of GLM
extract over 8 weeks to 21 subjects diagnosed with knee
OA. Outcome measures were scored using the WOMAC,
the Lequesne algofunctional index, and the Gastrointestinal
Symptom Rating Scale (GSRS) tools. An intention-to-treat
analysis was employed and subject data collected at T
and T
Results Paired ttests showed significant improvement
for the Lequesne, WOMAC (p\0.001) and GSRS (p=
0.005) scores. A repeated measures ANOVA analysis
showed significant improvement in scores for the Lequesne
(F=20.317, p\0.001), WOMAC (F=28.383, p\
0.001) and the GSRS (F=9.221, p=0.002).
Conclusion Green-lipped mussel significantly improved
knee joint pain, stiffness and mobility. We report for the
first time that the administration of GLM extract also sig-
nificantly improved GI symptoms by 49% in OA patients.
Given that GI dysfunction is linked to analgesic medication
use, we further conclude that the therapeutic efficacy of the
GLM extract used was possibly correlated to its effects on
GI function by improving GSRS scores from baseline.
Results from this trial highlight the requisite for further
clinical investigations of gastrointestinal tract function in
OA patients.
Key words Green-lipped muscle extract Osteoarthritis
Gastrointestinal function
Osteoarthritis (OA) is the most prevalent form of arthritis
and commonly targets the joints of the knee and less fre-
quently joints of the hip, shoulder, spine (most commonly
zygapophyseal, apophyseal, or facet joints of the spine,
especially in the mid and lower cervical spine, and in the
lower lumbar spine, L3 to L5) hands and toes (Buchanan
and Kean 2002a,b; Wieland et al. 2005). With no known
cure or proven disease-modifying therapy, the first-choice
recommended pharmacological treatment for mild to
moderate pain of the knee or hip is acetaminophen, with a
maximum dose of up to 4 g/day (Buchanan and Kean
2002c). In the absence of a beneficial response, or pain and
inflammatory sequelae, alternate therapy with an NSAID is
indicated. Gastrointestinal (GI) safety however, may be
compromised with long-term intake of these medications
as they are associated with gastric or peptic ulcers (Garcia-
Rodriguez et al. 1998; Roderiguez and Hernandez-Diaz
S. Coulson H. Gramotnev L. Vitetta (&)
Centre for Integrative Clinical and Molecular Medicine,
School of Medicine, The University of Queensland and
The Princess Alexandra Hospital,
Brisbane, QLD, Australia
P. Vecchio
The Princess Alexandra Hospital, Rheumatology Department,
199 Ipswich Road, Woolloongabba,
Brisbane, QLD 4102, Australia
Inflammopharmacol (2012) 20:71–76
DOI 10.1007/s10787-012-0128-6 Inflammopharmacology
2001), irritable bowel syndrome (IBS) (Locke et al. 2000)
including dyspepsia (indigestion as discomfort experienced
in the upper abdomen) (Rahme et al. 2002), chronic con-
stipation (Chang et al. 2007), diarrhoea (Etienney et al.
2003) and morphological changes such as intestinal
ulceration and increased GI inflammation and permeability
(Scarpignato and Hunt 2010; Roderiguez and Hernandez-
Diaz 2001).
Approximately 40% of the OA patients will self-medi-
cate with dietary supplements, often using them exclusively
(22%) or in combination (16%) with pharmaceutical med-
ications i.e. analgesics (Armstrong et al. 2011). Clinical
efficacy of nutraceuticals for the treatment of OA however
remains collectively inconsistent, impacting the recom-
mendation of their routine use. Popular supplements
marketed towards OA include glucosamine, chondroitin
and green-lipped mussel (GLM) extract (Perna canalicu-
lus), and although clinical trial results variably support their
use in OA, methodological flaws and inconsistent results
preclude the recommendation of such compounds as an
alternative treatment option (Brien et al. 2008; Wandel et al.
2010). In addition to analgesic use, GI function and integ-
rity may possibly be compounded further by the presence of
inflammation (Peuhkuri et al. 2010) and by the underlying
rheumatic disease (Chong and Wang 2008).
The aim of this study was to investigate the therapeutic
effect of a New Zealand GLM extract (GlycOmega
PLUS) in patients diagnosed with OA of the knee(s) in
relation to knee pain, stiffness and function. Furthermore,
we examined GI symptoms and analgesic medication
intake, and the interaction these may have on the therapeutic
outcome of the GLM. It is therefore plausible to hypothesise
that clinical efficacy of GLM in the treatment of knee OA
may be associated with improved GI integrity and function.
Understanding factors that impact digestion, absorption,
metabolism and the health response process is crucial for the
proper interpretation of biological responses, or the lack
thereof, in clinical research (Possemiers et al. 2011).
Patients and methods
The study group comprised 23 patients with knee OA (9
males, 14 females) who satisfied the inclusion and exclu-
sion criteria. Patients were recruited if their knee OA was
confirmed by a Rheumatologist and they were not taking
any form of herbal/multivitamin/nutritional supplements
4 weeks prior to recruitment. Patients were excluded if
they had uncontrolled systemic disease, were pregnant or
breast feeding, or had allergies/intolerances to shellfish.
Participants were recruited from the Rheumatology Clinic
at the Princess Alexandra Hospital, Brisbane from July
2010 to March 2011.
All 23 patients recruited satisfied the decision tree for-
mat of the ACR classification criteria for idiopathic clinical
OA of the knee (Altman et al. 1986). The ACR clinical
criteria for knee OA were fulfilled by the uniform presence
of knee pain and at least 3 of the following 6 criteria: C
50 years of age, morning stiffness lasting B30 min, crep-
itus on movement, bony tenderness, bony enlargement and
no palpable warmth of synovium.
Each patient received written and verbal explanations
regarding their involvement in the study before signing
informed consent. The study protocol was in compliance
with the Helsinki Declaration and was approved by the
Human Research Ethics Committees of The University of
Queensland and The Princess Alexandra Hospital.
Patient demographic data and medical history were
obtained at baseline (T
). Anthropometric measurements,
blood pressure and outcome measures were performed at
and T
weeks, and blood samples for safety measures
were collected at T
and T
Anthropometric measurements
Height was measured with the subject standing barefoot
using a body meter measuring tape with wall stop. Body
mass was measured using calibrated scales and body mass
index (BMI) was calculated using the formula—mass
divided by height squared (kg/m
); waist hip ratios were
calculated by dividing the waist circumference (cm) by the
hip circumference (cm).
Outcome measures
The Western Ontario McMaster Universities Arthritis Index
(WOMAC) (Bellamy 2002) and the Lequesne algofunc-
tional index (Lequesne et al. 1987; Lequesne and Maheu
2003) were designated the primary outcome measures and
were administered via interview format by the clinical
researcher at each participant’s visit (T
and T
). The
WOMAC is a validated questionnaire designed for the
assessment of lower extremity pain and function in OA of
the knee or hip by assessing severity of knee pain (5
questions), stiffness (2 questions) and limitation of physical
function (17 questions) (Bellamy 2002). Maximum scores
of severity for each subscale are 20, 8 and 68, respectively.
The maximum total score of severity for the WOMAC is 96.
The Lequesne algofunctional index includes the measure-
ment of pain (five questions), walking distance (one
question), and activities of daily living (four questions),
72 S. Coulson et al.
with versions available for the hip and knee (Lequesne et al.
1987; Lequesne and Maheu 2003). Scores for each question
are added together to provide a combined disease severity
score. Scores of 1–4 are classified as mild OA, 5–7 mod-
erate, 8–10 severe, 11–13 very severe, and 14 as extremely
severe OA. Secondary outcome measures utilised the Gas-
trointestinal Symptom Rating Score (GSRS) questionnaire
(Svedlund et al. 1988) and the SF-12v2
health survey
(Tucker et al. 2010) via interview format. GI function was
assessed using the validated GSRS questionnaire which
contains 15 items designed to evaluate abdominal pain,
gastro-oesophageal reflux, indigestion, diarrhoea and con-
stipation. Each question is rated 0 to 3 in regards to
intensity, frequency, duration, request for relief and impact
on social performance. General quality of life was assessed
using the SF-12 that includes 12 questions with results
expressed in terms of 2 meta-scores: the physical compo-
nent summary (PCS) and the mental component summary
(MCS) (Ware et al. 1996; Tucker et al. 2010).
Assessment of safety
Blood pathology was performed to assess safety (full blood
count, electrolytes and liver function tests). The inflam-
matory markers, C-reactive protein (CRP) and erythrocyte
sedimentation rate (ESR) were also included. Adverse
events were documented by patients in diaries provided
and events were recorded.
Patients were allocated to 3,000 mg/day (3 9500 mg
b.i.d) of a proprietary blend of freeze-dried greenshell
mussel meat (Perna canaliculus), GlycOmega
(Aroma NZ Ltd), which was dispensed in opaque white
bottles for the 8-week duration. Compliance was monitored
from participant recordings of daily intake of GLM in
diaries provided.
Daily pain and rescue medication recordings
Participants were asked to complete two diaries that
recorded daily intake of GLM, daily knee pain experienced
on a 5 point Likert scale (T
and T
) and daily
rescue medication intake for knee pain.
Statistical analysis
The data in this clinical trial were treated according to an
intention-to-treat analysis. Participants were included in the
analysis if they had returned at least one diary (e.g. visit 2).
Paired samples ttests were conducted for significant or
marginally significant interactions. These were performed
to investigate the difference in pre- and post-supplemen-
tation scores. Repeated measures analysis of variance
(ANOVA) was conducted to investigate the changes
between the time periods. The significance level was set at
p\0.05. Normality tests were performed for all the
scoring variables to confirm the assumption of normality,
justifying the use of ttests and analysis of variance tests.
Patient characteristics
Three patients withdrew from the trial with 1 patient pro-
viding their first diary, resulting in a total of 21 participants
(8 males and 13 females) with an age range from 41 to
87 years (mean ±SD, 61.1 ±12.2 years) that provided
data for an evaluable analysis. Weight and BMI did not
change significantly between time points (mean ±SD,
=96.9 ±27.1 kg; T
=96.7 ±27.5 kg) and (mean ±
=34.0 ±9.0 kg/m
=34.5 ±9.2 kg/m
), res-
pectively. Waist to hip ratio remained unchanged between
and T
(mean ±SD, 0.9 ±0.1). Current medications
were allowed to continue being taken through the trial
period and included anti-cholesterol agents (n=6), anti-
diabetic agents (n=2), diuretic (n=1), calcium channel
blockers (n=3), beta-blockers (n=1), angiotensin II
receptor agonists (n=3), ACE inhibitor (n=3), anti-
inflammatory medications (n=8), proton pump inhibitors
(n=7), anti-depressant medications (n=9), thyroid
medications (n=3), anti-histamine medication (n=2),
anti-coagulant medications (n=1), gout medication
(n=1) and herpes medication (n=1). Recent intake of
antibiotics was reported by 7 patients, while 12 patients
reported influenza vaccinations.
There were 3 dropouts in total from the original 23 patients
recruited, 2 males and 1 female. These participants were
lost to follow-up due to adverse events (2 males) and lack
of interest in the trial (1 female). One of the male dropouts
did return his first diary and data were included for analysis
as intention-to-treat.
Outcome measures
Paired ttests were performed on the Lequesne, WOMAC
(total and subscores), GSRS, and SF-12 (PCS and MCS
scores) between T
and T
and T
, and T
and T
Lequesne and WOMAC (total) showed significant changes
between all intervals (p\0.001) with WOMAC subscores
of pain (p\0.001), stiffness (p=0.002) and physical
Green-lipped mussel extract for knee osteoarthritis 73
function (p\0.001) indices all statistically significant;
GSRS showed significant changes from T
to T
0.004) and from T
to T
(p=0.005). MCS scores signifi-
cantly changed from T
to T
(p=0.012) only and PCS
scores were not significant. The percentage change in scores
demonstrated significant efficacy on all outcome measures
(Table 1). A repeated measures ANOVA that was per-
formed over the three time points gave significant results for
all scores except PCS (F=0.364, p=0.649). Lequesne
and WOMAC score differences were particularly strong
(p\0.001) as was the GSRS (p=0.002) (Table 1).
Rescue medication
Rescue medication for knee pain associated with OA was
allowed and recorded daily by the participants. Of the 21
patients, 7 did not use any rescue medication over the
8-week trial period, while 14 did and this included panadol
(paracetamol dose 500 mg), panadol osteo (paracetamol
665 mg), panadeine forte (paracetamol 500 mg ?codeine
phosphate 30 mg), prednisone and various NSAIDs (aspi-
rin 100 mg; indomethacin 25 mg; diclofenac sodium
50 mg; ibuprofen 200 mg].
Safety and adverse events
All blood parameters remained normal throughout the trial.
CRP and ESR values did not significantly change over the
8-week period (mean ±SD T
=4.08 ±3.49 mg/L; T
3.31 ±2.69 mg/L) and (mean ±SD T
=14.59 ±8.61
mm/h; T
=14.21 ±7.66 mm/h), respectively. Blood
pressure remained stable throughout duration of the trial
(mean ±SD T
=systolic 130.4 ±18.3 mm Hg and
diastolic 80.8 ±11.8 mm Hg; T
=systolic 125.8 ±
17.3 mmHg and diastolic 76.0 ±11.3 mm Hg). Adverse
events included reflux (n=1); abdominal pain, reflux and
diarrhoea (n=1) and gout (n=2).
We confirm that a standardized high dose (3,000 mg/day)
GLM preparation used in this study was efficacious in
treating OA symptoms of the knee. The improvement in
symptom management from baseline was robustly signifi-
cant for knee pain, stiffness and mobility.
A credible biological anti-inflammatory mechanism of
action is reported for GLM in arthritic animal models,
which have also demonstrated gastro-protective effects
against NSAIDs-induced GI damage (Rainsford and
Whitehouse 1980). A GLM-induced gastro-protective
mechanism was noted in our sample group. Despite plau-
sible mechanisms for the treatment of OA as an inhibitor of
the lipoxygenase and cyclo-oxygenase pathways, a recent
systematic review calls for further methodical investiga-
tions to provide clear evidence of efficacy, particularly
Table 1 Change in primary and secondary outcome measures from baseline (T
) to week 4 (T
) and from baseline to week 8 (T
Outcome Time Mean ±SD ES-Cohen’s d(correlation) tvalue 95% CI pvalue
Lequesne Index T
13.16 5.16
10.30 6.04 1.021 (0.875) 3.94 1.21, 3.94 0.001
9.13 5.79 1.413 (0.864) 5.72 2.38, 5.12 \0.001
WOMAC (total) T
41.63 19.75
30.0 17.30 1.074 (0.829) 4.10 5.08, 15.72 0.001
22.80 17.57 1.957 (0.867) 7.78 12.87, 22.33 \0.001
WOMAC (pain) T
8.64 3.99
4.90 3.34 1.745 (0.829) 5.34 2.13, 4.87 \0.001
3.20 3.21 1.805 (0.649) 7.33 3.72, 6.68 \0.001
WOMAC (stiffness) T
3.82 1.74
2.85 1.69 0.669 (0.643) 3.01 0.30, 1.70 0.007
2.35 1.63 0.816 (0.428) 3.63 0.63, 2.37 0.002
WOMAC (physical) T
29.18 14.96
22.25 12.91 0.879 (0.840) 3.20 2.04, 9.76 0.005
17.25 13.70 1.877 (0.901) 7.38 7.81, 13.99 \0.001
7.41 6.57
3.15 3.92 0.795 (0.478) 3.28 1.39, 6.31 0.004
3.45 3.14 0.843 (0.532) 3.21 1.23, 5.87 0.005
GSRS gastrointestinal symptom rating score, ES effect size (Cohen’s d), Paired ttests between T
and T
scores and T
and T
scores and 95% CI
for the differences
74 S. Coulson et al.
optimal dosing (Brien et al. 2008; Whitehouse et al. 1997).
In that review, doses in the range of 1,050–1,150 mg/day
were reported. In this study, we report that a high dose of
3,000 mg/day was efficacious and attenuated pain, stiffness
and joint mobility. Efficacy was already established at
4 weeks of supplementation with significant reductions in
pain scores and was maintained when assessed at week 8
(Table 1). The high dose of the GLM employed in this
pilot trial may provide additional information for future
controlled phase IIb dosing studies.
We acknowledge that a weakness of this study is the lack
of a placebo comparator (Zhang et al. 2008). However, as a
preliminary study, it provides additional clinical evidence to
support the efficacy of GLM and to formulate a hypothesis
that has not yet been previously investigated, namely GI
dysfunction in OA. GI dysfunction in clinical trials inves-
tigating nutraceutical efficacy can be a significant limiting
factor. Prescribed analgesic medications can disrupt GI
function (Wolfe et al. 1999; Chang et al. 2007; Etienney
et al. 2003; Scarpignato and Hunt 2010; Roderiguez and
Hernandez-Diaz 2001) and hence this may significantly
affect nutraceutical metabolism, absorption and efficacy.
We have demonstrated that GLM was efficacious in
improving OA symptoms and function, and that it may
have important GI sequelae that assist with GLM utiliza-
tion and hence efficacy. GI dysfunction was significantly
improved with study progress in all subjects.
Ethical approval and clinical trial registration
Approval for this prospective study was obtained from the
Ethics Committee of The University of Queensland and
Princess Alexandra Hospital Human Research Ethics
Committees. The clinical trial was registered with the
Australian and New Zealand Clinical Trail Registry
(ANZCTRN: 12611000517976).
Acknowledgments We thank Shoshannah Beck and Janet Schloss
from The University of Queensland for reading the manuscript and
assisting with data entry and subject recruitment.
Conflicts of interest Funding and study medication for the project
was received from the clinical trial sponsor Aroma New Zealand Ltd.
The sponsor had no involvement in the collection, analysis or inter-
pretation of the data; writing the report; or the decision to submit the
paper for publication.
Altman R, Asch E, Bloch D et al (1986) Development of criteria for
the classification and reporting of osteoarthritis. Classification of
osteoarthritis of the knee. Diagnostic and Therapeutic Criteria
Committee of the American Rheumatism Association. Arthritis
Rheum 29(8):1039–1049
Armstrong AR, Thie
´baut SP, Brown LJ (2011) Australian adults use
complementary and alternative medicine in the treatment of
chronic illness: a national study. Aust NZ J Public Health
Bellamy N (2002) WOMAC: a 20-year experiential review of a
patient-centered self-reported health status questionnaire. J Rheu-
matol 29(12):2473–2476
Brien S, Prescott P, Coghlan B et al (2008) Systematic review of the
nutritional supplement Perna canaliculus (green-lipped mussel)
in the treatment of osteoarthritis. QJM 101:167–179
Buchanan WW, Kean WF (2002a) Osteoarthritis: II: pathology and
pathogenesis. Inflammopharmacol 10:19–48
Buchanan WW, Kean WF (2002b) Osteoarthritis: III: radiological and
clinical definition. Inflammopharmacol 10:53–78
Buchanan WW, Kean WF (2002c) Osteoarthritis IV: clinical thera-
peutic trials and treatment. Inflammopharmacol 10:75–149
Chang J, Locke GR, Schleck CD et al (2007) Risk factors for chronic
constipation and a possible role of analgesics. Neurogastroen-
terol Motil 19:905–911
Chong VH, Wang CL (2008) Higher prevalence of gastrointestinal
symptoms among patients with rheumatic disorders. Singapore
Med J 49:419–424
Etienney I, Beaugerie L, Viboud C et al (2003) Non-steroidal anti-
inflammatory drugs as a risk factor for acute diarrhoea: a case
crossover study. Gut 52:260–263
Garcia-Rodriguez LA, Cattaruzzi C et al (1998) Risk of hospitaliza-
tion for upper gastrointestinal tract bleeding associated with
ketorolac, other nonsteroidal anti-inflammatory drugs, calcium
antagonists, and other antihypertensive drugs. Arch Intern Med
Lequesne MG, Maheu E (2003) Clinical and radiological evaluation
of hip, knee and hand osteoarthritis. Aging Clin Exp Res
Lequesne MG, Mery C, Samson M et al (1987) Indexes of severity for
osteoarthritis of the hip and knee. Validation value in comparison
with other assessment tests. Scand J Rheumatol Suppl 65:85–89
Locke GR, Zinsmeister AR, Talley NJ et al (2000) Risk factors for
irritable bowel syndrome: role of analgesics and food sensitiv-
ities. Am J Gastroenterol 95:905–911
Peuhkuri K, Vapaatalo H, Korpela R (2010) Even low-grade
inflammation impacts on small intestinal function. World J
Gastroenterol 16:1057–1062
Possemiers S, Bolca S, Verstraete W et al (2011) The intestinal
microbiome: a separate organ inside the body with the metabolic
potential to influence the bioactivity of botanicals. Fitoterapia
Rahme E, Pettitt D, LeLorier J (2002) Determinants and sequelae
associated with utilization of acetaminophen versus traditional
nonsteroidal antiinflammatory drugs in an elderly population.
Arthritis Rheum 46:3046–3054
Rainsford KD, Whitehouse MW (1980) Gastroprotective and anti-
inflammatory properties of green lipped mussel (Perna canalic-
ulus) preparation. Arzneimittelforschung 30:2128–2132
Roderiguez GL, Hernandez-Diaz S (2001) Risk of upper gastrointes-
tinal complications among users of acetaminophen and non-
steroidal anti-inflammatory drugs. Epidemiology 12:570–576
Scarpignato C, Hunt RH (2010) Nonsteroidal antiinflammatory drug-
related injury to the gastrointestinal tract: clinical picture,
pathogenesis and prevention. Gastroenterol Clin N Am
Svedlund J, Sjodin I, Dotevall G (1988) GSRS: a clinical rating scale
for gastrointestinal symptoms in patients with irritable bowel
syndrome and peptic ulcer disease. Dig Dis Sci 33:129–134
Tucker G, Adams R, Wilson D (2010) New Australian population
scoring coefficients for the old version of the SF-36 and SF-12
health status questionnaires. Qual Life Res 19:1069–1076
Green-lipped mussel extract for knee osteoarthritis 75
Wandel S, Juni P, Tendal B et al (2010) Effects of glucosamine,
chondroitin, or placebo in patients with osteoarthritis of hip or
knee: network meta-analysis. BMJ 341:c4675
Ware JE, Kosinski M, Keller SD (1996) A 12-Item Short-Form
Health Survey: construction of scales and preliminary tests of
reliability and validity. Med Care 34(3):220–233
Whitehouse MW, Macrides TA, Kalafatis N et al (1997) Anti-
inflammatory activity of a lipid fraction (lyprinol) from the NZ
green-lipped mussel. Inflammopharmacology 5:237–246
Wieland HA, Michaelis M, Kirschbaum BJ et al (2005) Osteoarthri-
tis—an untreatable disease? Nat Rev Drug Discov 4:331–344
Wolfe MM, Lichtenstein DR, Singh G (1999) Gastrointestinal
toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med
Zhang W, Moskowitz RW, Nuki G et al (2008) The placebo effect
and its determinants in osteoarthritis: meta-analysis of random-
ised controlled trials. Ann Rheum Dis 67:1716–1723
76 S. Coulson et al.
... Across the studies, the average age of subjects ranged from 52.8 to 69.6 years. Four studies investigated only patients with knee OA (Coulson et al. 2012(Coulson et al. , 2013Gibson and Gibson 1998;Lau et al. 2004). Three studies included patients with knee and/or hip OA (Cho et al. 2003;Stebbings et al. 2017;Zawadzki et al. 2013). ...
... preparations and different dosages were evaluated. GSM was used in the form of a whole extract powder in four studies, with doses ranging from 1050 to 3000 mg/day (Audeval and Bouchacourt 1986;Coulson et al. 2012Coulson et al. , 2013Gibson et al. 1980). Four studies used a lipid extract in doses ranging 210 and 1200 mg/day (Cho et al. 2003;Lau et al. 2004;Stebbings et al. 2017;Zawadzki et al. 2013). ...
... A single study compared a GSM lipid extract versus a whole GSM powder (Gibson and Gibson 1998). The included studies used olive oil (Lau et al. 2004), glucosamine sulphate (Coulson et al. 2013), corn oil (Stebbings et al. 2017), whole fish powder (Gibson et al. 1980), or fish oil (Zawadzki et al. 2013) as controls; one study used a non-specified placebo (Audeval and Bouchacourt 1986) and two studies lacked a comparator group (Cho et al. 2003;Coulson et al. 2012). Seven of the nine included trials were parallel and randomized-controlled trials (Audeval and Bouchacourt 1986;Coulson et al. 2013;Gibson and Gibson 1998;Gibson et al. 1980;Lau et al. 2004;Stebbings et al. 2017;Zawadzki et al. 2013), and the remaining two were one-arm open-label trials (Cho et al. 2003;Coulson et al. 2012). ...
Full-text available
Objectives Intervention studies using New Zealand green-lipped or greenshell™ mussel (GSM) ( Perna canaliculus ) extract in osteoarthritis (OA) patients have shown effective pain relief. This systematic review summarises the efficacy of GSM extracts in the treatment of OA. Methods A literature search of the three databases EMBASE, MEDLINE, and Scopus was performed to identify relevant articles published up to March 2020. Inclusion criteria were clinical trials published in English measuring the effect of supplementation of whole or a lipid extract from GSM on pain and mobility outcomes in OA patients. Results A total of nine clinical trials were included in systematic review, from which five studies were considered appropriate for inclusion in a forest plot. Pooled results showed that GSM extracts (lipid extract or whole powder) provide moderate and clinically significant treatment effects on a visual analogue scale (VAS) pain score (effect size: − 0.46; 95% CI − 0.82 to − 0.10; p = 0.01). The whole GSM extract improved gastrointestinal symptoms in OA patients taking anti-inflammatory medications. The GSM extract was considered to be generally well tolerated in most of the studies. Conclusion The overall analysis showed that GSM provided moderate and clinically meaningful treatment effects on OA pain. However, the current evidence is limited by the number and quality of studies, and further larger and high-quality studies are needed to confirm the effectiveness and to identify the optimal GSM format. Nevertheless, it is worth considering using GSM extracts especially for patients seeking alternative pain relief treatments with fewer side effects compared to conventional treatment.
... GSM contains high amounts of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (20:5 n-3 EPA) and docosahexaenoic (22:6 n-3 DHA), and several other bioactive compounds [12]. With potent antiinflammatory properties, GSM oil extracts have been shown to alleviate the arthritic symptoms [13]. ...
... The current study aims to address several gaps in the current scientific evidence for GSM interventions. Firstly, until now there have been a limited number of studies which investigated the effectiveness of whole GSM extract interventions on clinical symptoms of OA in individuals with diseased state [13,22]. The current study will include biomarkers of cartilage turnover and inflammation to address the paucity of evidence on cartilage-protective effectiveness of GSM intervention in healthy individuals without OA. ...
Full-text available
Background New Zealand Greenshell™ mussels (GSM; Perna canaliculus ) have recently been shown to decrease cartilage degradation in a rat model of induced metabolic osteoarthritis (MetOA). However, this effect has not been investigated in human subjects. This study aims to determine the effect of GSM powder on biomarkers of cartilage metabolism, bone resorption, and inflammation in New Zealand healthy overweight/obese postmenopausal women who are at early stage or at high risk of OA. Method Fifty overweight or obese (BMI 25–35 kg/m ² ) postmenopausal women (aged 55–75 years) will be recruited by advertisement. Participants will be randomized based on a double-blind randomization schedule and stratified randomization based on BMI and age distribution. The participant will be assigned with a 1:1 allocation ratio to receive 3 g/d whole meat GSM powder or placebo (sunflower seed protein) for 12 weeks. Data on socio-demographics, physical activity, and dietary intake will be collected for each subject. Cartilage turnover biomarkers [(C-telopeptide of type II collagen (CTX-II), C-propeptide of type II procollagen (CPII), Cartilage oligomeric matrix protein (COMP)], and bone resorption marker (CTX-I) will be measured in blood and urine samples. Inflammatory status (hs-CRP and cytokine panel) will be assessed and iron status will be measured. Body composition including fat mass (FM), lean mass (LM), and fat percentage will be measured using dual-energy X-ray absorptiometry (DXA). Joint pain and knee function will be assessed using a 100-mm visual analog scale (VAS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, respectively. Discussion This trial will be the first to explore the effects of whole meat GSM powder on cartilage turnover, bone resorption, and inflammation biomarkers in overweight/obese postmenopausal women. The results from this trial will provide evidence on the efficacy of GSM in the prevention of OA. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000413921p . Registration on 27 March 2020.
... All trials showed some degree of improvement with use of GLM, although specific outcome measures varied. 28,[30][31][32][33] Of special interest are the trials by Coulson et al., which assessed GI dysfunction in addition to OA symptomatology. 30,31 In Coulson's 2012 pilot study, for example, 49% of participants had significantly improved GI symptoms. ...
... 28,[30][31][32][33] Of special interest are the trials by Coulson et al., which assessed GI dysfunction in addition to OA symptomatology. 30,31 In Coulson's 2012 pilot study, for example, 49% of participants had significantly improved GI symptoms. Because NSAID use is widespread in people with OA, likely contributing to GI upset, providing a therapeutic option that not only helps joint symptoms, but also improves GI function, is an attractive possibility. ...
... Marine organisms are a major source of food, which are gaining a lot of interest from the scientific community for their nutritional value, and potential role in the functional food and nutraceuticals industry. The health-promoting effects of many products isolated from marine organisms have been established after successful clinical trials (Coulson, Butt, Vecchio, Gramotnev, & Vitetta, 2013;Coulson, Vecchio, Gramotnev, & Vitetta, 2012;Kean et al., 2013;Stebbings, Gray, Schneiders, & Sansom, 2017). ...
... Another over-the-counter anti-inflammatory drug, Cadalmin, owe its origin to P. viridis (Indian green mussel) extract (Chakraborty, 2012). Reports from a couple of clinical trials have advocated effectiveness of P. canaliculus extract in knee osteoarthritis and gastrointestinal dysfunction producing nonsignificant alterations in the gut microbiota (Coulson et al., 2012;Coulson et al., 2013). Similarly, the pain-relieving efficacy of a commercial extract from this mollusk (BioLex) in osteoarthritis has been investigated in a clinical trial, which advocated its effectiveness as a long-term treatment based on observations in the postintervention period (Stebbings et al., 2017). ...
... Green-lipped mussel (Perna canaliculus) or Greenshell TM mussel (GSM) is a commercial marine species endemic to New Zealand (NZ) waters. GSM is a rich source of longchain omega-3 PUFAs [11], which are proven to have potent anti-inflammatory and antiarthritic properties [12]. Our previous study has shown that flash-dried powder from whole GSM could prevent OA induction or slow its progression in a rat model of MetOA. ...
Full-text available
This study aimed to examine the changes in lipid and metabolite profiles of ovariectomized (OVX) rats with diet-induced metabolic syndrome-associated osteoarthritis (MetOA) after supplementation with greenshell mussel (GSM) using an untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach. Ninety-six rats were fed with one of four diets: control, control supplemented with GSM + GSM, high fat/high sugar (HFHS), or high fat/high sugar enriched with GSM (HFHS + GSM). After 8 weeks on experimental diets, half of the rats in each group underwent OVX and the other half were sham operated. After being fed for an additional 28 weeks, blood samples were collected for the metabolomics analysis. Lipid and polar metabolites were extracted from plasma and analysed by LC-MS. We identified 29 lipid species from four lipid subclasses (phosphatidylcholine, lysophosphatidylcholine, diacylglycerol, and triacylglycerol) and a set of eight metabolites involved in amino acid metabolism (serine, threonine, lysine, valine, histidine, pipecolic acid, 3-methylcytidine, and cholic acid) as potential biomarkers for the effect of HFHS diet and GSM supplementation. GSM incorporation more specifically in the control diet generated significant alterations in the levels of several lipids and metabolites. Further studies are required to validate these findings that identify potential biomarkers to follow OA progression and to monitor the impact of GSM supplementation.
... Edible bird's nest extract --Reduces the expression of genes MMP-1, MMP-3, IL-1, IL-6, IL-8, COX-2, PGE2, and iNOS and increases the level of type 2 collagen, aggrecan, and SOX-9 [50] Green-Lipped Mussel Extract -Reducing pain and improving knee mobility [51] Suppresses the synthesis of the pro-inflammatory molecule leukotriene B4 and the production of PGE2 [52] Lactobacillus casei -Decreases TNF-α, IL-6, NF-κB, COX-2, MMP-1, −3, −13 and increases IL-4 and IL-10 ...
Full-text available
Osteoarthritis (OA) is a degenerative joint disease and an important cause of incapacitation. There is a lack of drugs and effective treatments that stop or slow the OA progression. Modern pharmacological treatments, such as analgesics, have analgesic effects but do not affect the course of OA. Long-term use of these drugs can lead to serious side effects. Given the OA nature, it is likely that lifelong treatment will be required to stop or slow its progression. Therefore, there is an urgent need for disease-modifying OA treatments that are also safe for clinical use over long periods. Phytonutraceuticals are herbal products that provide a therapeutic effect, including disease prevention, which not only have favorable safety characteristics but may have an alleviating effect on the OA and its symptoms. An estimated 47% of OA patients use alternative drugs, including phytonutraceuticals. The review studies the efficacy and action mechanism of widely used phytonutraceuticals, analyzes the available experimental and clinical data on the effect of some phytonutraceuticals (phytoflavonoids, polyphenols, and bioflavonoids) on OA, and examines the known molecular effect and the possibility of their use for chondroprotection.
... PCSO-524 ® , an extract of the New Zealand green-lipped mussel (Perna canaliculus), is rich in polyunsaturated fatty acids and has strong anti-inflammatory properties [29,30] and, therefore, presented itself as a strong candidate for further investigation. It has received interest as a treatment for arthritis [31,32], but has never been tested for use with neurological conditions of aging, particularly AD. ...
Full-text available
Cell cycle reentry is a unified mechanism shared by several neurodegenerative diseases, including Alzheimer's disease (AD) and Ataxia Telangiectasia (A-T). This phenotype is often related to neuroinflammation in the central nervous system. To mimic brain inflammation in vitro, we adopted the previously established method of using conditioned medium collected from activated THP-1 cells and applied it to both differentiated HT22 cells and primary neurons. Unscheduled cell cycle events were observed in both systems, indicating the potential of this approach as an in vitro model of neurodegenerative disease. We used this assay to measure the neuroprotective effects of New Zealand green-lipped mussel extract, PCSO-524 ® , to protect post-mitotic cells from cell cycle reentry. We found that, both in vitro and in an animal model, PCSO-524 ® displayed promising neuroprotective effects, and thus has potential to postpone or prevent the onset of neurodegenerative disease.
The human gut microbiome can be altered with probiotics, prebiotics, synbiotics, and anti-inflammatory foods and spices as part of an evidence-based strategy that targets inflammation and pain in common orthopedic conditions. Implementing these strategies avoids adverse effects associated with nonsteroidal anti-inflammatory drugs and minimizes the potential for opioid use. This review focuses exclusively on human trials studying the effects of gut microbiome alterations to address pain and inflammatory markers in common orthopedic conditions: osteoarthritis, rheumatoid arthritis, fractures/osteoporosis, and bone pain associated with chemotherapy. Individualized supplementation strategies can be further explored with the information in this review. [Orthopedics. 20XX;XX(X):xx-xx.].
Osteoarthritis is a most widespread chronic degenerative joint disease that causes pain, cartilage deformation, and joint inflammation. Adverse alterations of intestinal microbiota like dysbiosis may lead to metabolic syndrome and inflammation, two important components of osteoarthritis progression. Aim. In this study we investigated the effect of chondroitin sulfate and probiotics on the gut microbiome in monoiodoacetate-induced osteoarthritis model in rats. Methods. The species and quantitative composition of feces were determined using diagnostic media with selective properties. Further identification of isolated microorganisms was carried out according to morphological, tinctorial, physiological and metabolic parameters. The results are presented in the form of lg CFU/g. Results. Induction of osteoarthritis caused significant increasing the number of opportunistic enterobacteria and lactose-negative Escherichia coli against the decreasing of lacto- and bifidobacteria that may indicate a dysbiotic condition. Coadministration of chondroitin sulfate and probiotic bacteria has led to improvement the quantitative composition of the gut microbiota in experimental animals, the numerous of Bifidobacterium, Lactobacillus were increasing against decreasing the quantitative composition of opportunistic microorganisms. Conclusions. Monoiodoacetate-induced osteoarthritis caused dysbiosis of gut in rat. We observed beneficial effect of combined administration of chondroitin sulfate and probiotics on gut microbiota composition in rats with experimental osteoarthritis. Thus, adding of supplements like probiotics to standard treatment of osteoarthritis may have potentials to prevent and treat this disease.
Osteoarthritis (OA) is a leading cause of musculoskeletal disorders that mainly affects the elderly population. Some herbal medicines have the potential to alleviate the pain associated with OA and improve physical activity mostly through anti-inflammatory and anti-oxidative properties. The aim of this study was to investigate the effects of herbal medicines, especially topical types, on osteoarthritis. In this systematic review, the keywords “osteoarthritis”, “herbal compounds”, “herbal medicine”, “topical drug”, “hydrogels”, “cream” and “treatment” were used to search publications published from 2010 to 2019 and indexed in databases including PubMed, SCOPUS, Web of Science and Google Scholar. After screening of titles and abstracts and detection of duplicate publications, 38 eligible articles were included in the main review. We also included herbal formulations in vivo. Bioactive fractions of herbal medicines mostly worked on OA through suppression of interleukin-1β (IL-1β), inducing nuclear factor-κB (NF-κB) activation by inhibition of inhibitor of NF-κB (IκBα) phosphorylation, IκBα degradation, p65 phosphorylation, and p65 nuclear translocation, downregulation of NF-κB targets including COX-2 and MMPs, upregulation of collagen type II, cartilage-specific proteoglycans (CSPGs), β1-integrin, and expression of cartilage-specific transcription factor SOX-9 protein. Noticeably, herbal medicines do not produce desirable effects, thereby using their combinations with other therapeutic agents seem to exert substantial clinical outcomes. Herbal gels have demonstrated robustly significant healing effects on knee pain, stiffness and mobility. It is worth considering that because OA is a chronic disease, longer duration of the studies/trials would even lead to obtaining more reliable judgments regarding topical treatment tolerability, safety and efficacy and clarify local or systemic adverse effects. Stability and standardization of a defined amount or concentrations of herbal gels would give promising effects on OA treatment and pain relief.
Full-text available
Regression methods were used to select and score 12 items from the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) to reproduce the Physical Component Summary and Mental Component Summary scales in the general US population (n = 2,333). The resulting 12-item short-form (SF-12) achieved multiple R squares of 0.911 and 0.918 in predictions of the SF-36 Physical Component Summary and SF-36 Mental Component Summary scores, respectively. Scoring algorithms from the general population used to score 12-item versions of the two components (Physical Component Summary and Mental Component Summary) achieved R squares of 0.905 with the SF-36 Physical Component Summary and 0.938 with the SF-36 Mental Component Summary when cross-validated in the Medical Outcomes Study. Test-retest (2-week) correlations of 0.89 and 0.76 were observed for the 12-item Physical Component Summary and the 12-item Mental Component Summary, respectively, in the general US population (n = 232). Twenty cross-sectional and longitudinal tests of empirical validity previously published for the 36-item short-form scales and summary measures were replicated for the 12-item Physical Component Summary and the 12-item Mental Component Summary, including comparisons between patient groups known to differ or to change in terms of the presence and seriousness of physical and mental conditions, acute symptoms, age and aging, self-reported 1-year changes in health, and recovery from depression. In 14 validity tests involving physical criteria, relative validity estimates for the 12-item Physical Component Summary ranged from 0.43 to 0.93 (median = 0.67) in comparison with the best 36-item short-form scale. Relative validity estimates for the 12-item Mental Component Summary in 6 tests involving mental criteria ranged from 0.60 to 1.07 (median = 0.97) in relation to the best 36-item short-form scale. Average scores for the 2 summary measures, and those for most scales in the 8-scale profile based on the 12-item short-form, closely mirrored those for the 36-item short-form, although standard errors were nearly always larger for the 12-item short-form.
Full-text available
Objective To determine the effect of glucosamine, chondroitin, or the two in combination on joint pain and on radiological progression of disease in osteoarthritis of the hip or knee. Design Network meta-analysis. Direct comparisons within trials were combined with indirect evidence from other trials by using a Bayesian model that allowed the synthesis of multiple time points. Main outcome measure Pain intensity. Secondary outcome was change in minimal width of joint space. The minimal clinically important difference between preparations and placebo was prespecified at −0.9 cm on a 10 cm visual analogue scale. Data sources Electronic databases and conference proceedings from inception to June 2009, expert contact, relevant websites. Eligibility criteria for selecting studies Large scale randomised controlled trials in more than 200 patients with osteoarthritis of the knee or hip that compared glucosamine, chondroitin, or their combination with placebo or head to head. Results 10 trials in 3803 patients were included. On a 10 cm visual analogue scale the overall difference in pain intensity compared with placebo was −0.4 cm (95% credible interval −0.7 to −0.1 cm) for glucosamine, −0.3 cm (−0.7 to 0.0 cm) for chondroitin, and −0.5 cm (−0.9 to 0.0 cm) for the combination. For none of the estimates did the 95% credible intervals cross the boundary of the minimal clinically important difference. Industry independent trials showed smaller effects than commercially funded trials (P=0.02 for interaction). The differences in changes in minimal width of joint space were all minute, with 95% credible intervals overlapping zero. Conclusions Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged.
This article discusses the potential usefulness of clinical therapeutic trials and criticises the failure of the value of guidelines in the management of osteoarthritis (OA). We have provided an overview of the benefits and side effects of non steroidal anti-inflammatory drugs (NSAIDs) in OA, including the introduction of the COX-2 selective inhibitors. In addition we have briefly reviewed the use of local NSAIDs, narcotic analgesics, injection methods, disease modifying drugs, gene therapy, surgical treatment, and non pharmacological intervention.
For the purposes of classification, it should be specified whether osteoarthritis (OA) of the knee is of unknown origin (idiopathic, primary) or is related to a known medical condition or event (secondary). Clinical criteria for the classification of idiopathic OA of the knee were developed through a multicenter study group. Comparison diagnoses included rheumatoid arthritis and other painful conditions of the knee, exclusive of referred or paraarticular pain. Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop sets of criteria that serve different investigative purposes. In contrast to prior criteria, these proposed criteria utilize classification trees, or algorithms.
The objectives of this study were to identify the prevalence of the use of vitamin/mineral supplements or natural/herbal remedies, concurrent use of pharmaceutical medication, and to profile those most likely to use these complementary and alternative medicines (CAM) in the treatment of five chronic conditions identified as national health priorities (asthma, diabetes, arthritis, osteoporosis, heart or circulatory condition) within the Australian adult population. Analysis of the Australian National Health Survey database, 2004-05. Approximately 24% (1.3 million) of Australian adults with a chronic condition regularly applied CAM to treatment. CAM was most often used exclusively or in combination with pharmaceutical medicine in the treatment of arthritis and osteoporosis. Fewer than 10% of adults with asthma, diabetes or a heart or circulatory condition used CAM, most preferring pharmaceutical medicine. Regular CAM users were more likely to be aged ≥60, female, have a secondary school education and live in households with lower incomes than non-users. Non-users were more likely to be 30-59 years old and tertiary educated. Arthritis, osteoporosis and, to a lesser extent, heart or circulatory conditions are illnesses for which doctors should advise, and patients need to be most aware about the full effects of CAM and possible interactive effects with prescribed medicine. They are also conditions for which research into the interactive effects of CAM and pharmaceutical medication would seem of most immediate benefit.
Increasing life expectancy in developed countries has led to a growing prevalence of arthritic disorders, which has been accompanied by increasing prescriptions for nonsteroidal antiinflammatory drugs (NSAIDs). These are the most widely used agents for musculoskeletal and arthritic conditions. Although NSAIDs are effective, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular system, skin, and gut. Gastrointestinal (GI) side effects are the most common. The dilemma for the physician prescribing NSAIDs is, therefore, to maintain the antiinflammatory and analgesic benefits, while reducing or preventing GI side effects. The challenge is to develop safer NSAIDs by shifting from a focus on GI toxicity to the increasingly more appreciated cardiovascular toxicity.