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The Open Conference Proceedings Journal, 2010, 1, 69-74 69
2210-2892/10 2010 Bentham Open
Open Access
Potassium Humate Reduces Inflammation and Clinically Improves the
Outcomes of Patients with Osteoarthritis of the Knee
Constance E.J. Van Rensburg*, Breggie E. Badenhorst, Justin J. Gandy and Jacques R. Snyman
Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
Abstract: A pilot study was done to determine if potassium humate, a natural substance derived from brown coal, with
known anti-inflammatory properties, is safe and effective in reducing pain and inflammation in osteoarthritis of the knee.
This was conducted as a randomized, double-blind, placebo-controlled, single centre, cross-over. Participants were
enrolled for a total of 14 weeks, starting with an initial 1-week washout period, after which they were randomly assigned
to either potassium humate or lactose, administered orally for 6 weeks at a dosage of 600mg three times daily. Following
another 1-week washout period, participants were crossed over to the other treatment for another 6 weeks. Participants
were not permitted the use of anti-inflammatory medications. Paracetamol was allowed as rescue medication for the
duration of the trial. The primary efficacy variable were the WOMAC™ scores (visual analogue version) for pain,
stiffness, physical function and total score and health related issues using the RAND 36 levels, rescue medication use,
adverse effects and tolerability.
28 participants were enrolled and 21 participants successfully completed the protocol. A carry-over effect in the stiffness
subscale was observed. There was a significantly greater clinical benefit with potassium humate over placebo with
reduction in all the WOMAC subscale scores for pain. After adjusting for baseline, potassium humate showed a greater
reduction in hs-CRP levels when compared to placebo. Tolerability was good for all groups. Safety parameters remained
unchanged, except for an increase in the GGT-levels (n=4 in potassium humate group, n=2 in the placebo group). Levels
of GGT returned to baseline within 2 weeks of discontinuation of therapy. In conclusion, potassium humate showed
possible benefit over placebo in patients with OA of the knee, with a statistically significant reduction in hs-CRP levels.
The small sample size and the carry-over effect limited further interpretation of data.
Keywords: Potassium humate, inflammation, osteoarthritis of the knee.
INTRODUCTION
Osteoarthritis is one of the most common forms of
arthritis, and is a progressive, debilitating disease that affects
mainly elderly people [1]. It remains a difficult disorder to
treat as there is no cure, and current regimes to treat pain and
maintain joint function, all have long-term risks for the
patients. Paracetamol is not an anti-inflammatory drug, but is
however regarded as a safe and effective analgesic with a
favourable side effect profile, as it causes less
gastrointestinal and renal side effects than NSAIDs (non-
steroidal anti-inflammatory drugs). It has however
demonstrated less symptomatic efficacy than NSAIDs in
some clinical trials [2] whereas NSAIDs provide relief of
pain and inflammation in osteoarthritis. Both paracetamol
and NSAIDs are also associated with adverse effects, such as
gastrointestinal toxicity, renal function impairment [3] and
increased cardiovascular risk [4, 5].
Inflammation is increasingly recognized as a factor
contributing to the symptoms and progression of
osteoarthritis (OA), even in the absence of acute inflam-
matory flares [2]. Inflammatory infiltrates can be found in
the synovial membrane of osteoarthritic joints, and there is
*Address correspondence to this author at the Department of Pharmacology,
Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa;
Tel: +27826552095; Fax: +27123192411; E-mail: connie.medlen@up.ac.za
serological and histological evidence of synovitis, even
though osteoarthritis is not associated with specific immune
markers [6].
High sensitivity C reactive protein (hs CRP) is a sensitive
marker of low grade systemic inflammation and serum levels
of CRP correlates well with CRP levels in the synovial fluid
of patients with osteoarthritis and rheumatoid arthritis.
Increased synovial turnover markers are associated with
increased WOMAC™ scores as well as increased serum
CRP [7].
Humic acids are formed during the decomposition of
organic matter and can therefore be found in practically all
natural environments in which organic materials and micro-
organisms are, or have been present [8]. Peat extracts have
been used in therapeutic baths for the treatment of rheumatic
conditions during the 19th century [9]. It was shown in two
recent studies that potassium humate, derived from brown
coal, suppresses (i) ear swelling in a contact hypersensitivity
animal model, (ii) an increase in paw volume of
carrageenan-induced oedema in rats and (iii) a graft-versus-
host reaction induced in normal and immune incompetent
rats [10, 11]. It was also found that this product had no
effects on the safety parameters tested at 1000mg/kg body
weight per day when administered to rats by gavage for one
month, nor did 500mg/kg body weight have any effect on
pups after oral administration of the product to pregnant
female rats, indicating the safety profile of this compound.
70 The Open Conference Proceedings Journal, 2010, Volume 1 Van Rensburg et al.
The aim of this research was to establish the safety and
efficacy (using clinical and laboratory markers) of potassium
humate in a pilot study in patients suffering from
osteoarthritis of the knee.
MATERIALS AND METHODS
Study Design
In this randomized, double-blind, placebo-controlled,
cross-over single-centre clinical trial (Fig. (1)), volunteers
were enrolled, after signing an informed consent, for a 14
week study period. This study was reviewed and approved
by the Research Ethics Committee of the Faculty of Health
Sciences, University of Pretoria. The study started with a 7-
day washout period of all anti-inflammatory agents, followed
by treatment with either potassium humate or placebo, in a
randomized order in two successive treatment periods of six
weeks each, separated by another 7-day washout period.
Participants were not permitted the use of anti-inflammatory
medications such as NSAIDs, cartilage supplements,
steroids, or any other agents that may affect the outcomes of
the study other than the rescue medication. Any medication
taken by the subjects for two months prior to the inclusion of
the study, and whose intake was stabilized, was permitted
and monitored. The dosing of these medications was not
changed for the duration of the investigation.
Paracetamol and tramadol were provided as rescue
medication in the first washout period, and paracetamol for
the rest of the duration of the trial. Participants completed
medication diaries to indicate the use of all concomitant and
rescue medication.
Screening included clinical assessment, radiographic
assessment, laboratory tests and the disease-specific
questionnaire, WOMAC™ (Western Ontario and McMaster
Universities Osteoarthritis Index questionnaire) [12] as well
as the RAND 36-Item Health Survey [13]. Clinical
assessment consisted of an interview and examination by a
clinician, and the supervised self-administration of the
questionnaire, and a visual analogue scale (VAS) for pain to
ensure that patients scored at least 40mm on a 100mm scale
for pain. Radiographic assessment was performed in patients
who have not had X-rays previous to the trial. It was done
using standard antero-posterior weight-bearing X-ray films
of the knees to determine the presence of osteophytes.
Study Procedure
After the initial screening visit, the participants had 4
scheduled visits to the investigator (randomization visit, after
first 6-week treatment period, after second washout period,
when the treatments were crossed over and after the second
6-week treatment period). Identical maroon capsules
contained 600mg of either potassium humate or lactose was
supplied by Unique Health Trust. All subjects took one
capsule of either potassium humate or lactose, three times
daily, and were allowed paracetamol 2 tablets 4 times daily
(a total maximum of 8 tablets daily) as rescue medication.
Compliance was assessed by a pill count at each study visit.
The primary efficacy outcome measure were the
WOMAC™ that measured pain stiffness and function as
well as the RAND 36-Item Health Survey measured on a
100mm scale which was completed at baseline and at the end
of each 6-week treatment period. The study was designed to
detect a MClD (minimal clinically important difference) of a
reduction of -9.1mm to -7.9mm in the 100mm visual
analogue scale of the WOMAC™ subscale scores.
Secondary efficacy outcome measures included serum hs-
CRP (high sensitivity C-reactive protein) assays, tolerability,
compliance, reduced use of rescue medication and adverse
event reporting. The hs-CRP values were determined at
baseline (after both wash-out periods) and repeated after
each 6-week treatment period.
Use of rescue medication, i.e. paracetamol, was
documented as a measure of both pain management and
efficacy. The amount of rescue medication was only
assessed in terms of total use at the conclusion of the study
period. Rescue medication use was assessed sequentially
along with other variables. Safety outcome measures
included the recording of vital signs at each visit and
laboratory tests (full blood count, sedimentation rate,
creatinine and liver function tests, i.e. ALT and GGT, which
Fig. (1). The trial was done in a cross-over fashion. Participants were enrolled for 14 weeks, starting with a 7-day washout period of all anti-
inflammatory agents, followed by treatment with either potassium humate or placebo, in two successive treatment periods of six weeks each,
separated by another 7-day washout period.
Potassium Humate Reduces Inflammation and Clinically Improves The Open Conference Proceedings Journal, 2010, Volume 1 71
were done at screening and repeated at the end of each 6-
week treatment period.
Patients
Patients, aged over 45 years of both male and female
gender, with unilaterally symptomatic idiopathic OA of the
knee were recruited. To be considered for the study, patients
had to meet clinical and radiographic enrolment criteria.
The clinical criteria included the American College of
Rheumatologist (ACR) Classification Criteria for Idiopathic
Osteoarthritis of the Knee [14] and the presence of pre-
enrolment ambulatory pain (defined as a score of at least
40units on a 100unit mm visual analogue scale (VAS) for
pain. The radiographic criteria consisted of the presence of
radiographic OA (Kellgren-Lawrence grade 2 or 3) [15, 16].
Participants were selected according to standardized
inclusion and exclusion criteria. Except for OA of the knee
patients had to be otherwise healthy. Recent use of non
steroidal anti-inflammatory drugs (NSAIDS) and systemic
corticosteroids required a 3 month washout period.
Treatments
Potassium humate (Zymate™) was supplied by Unique
Health Trust, Milnerton, South Africa. The product is
marketed as a food supplement. Lactose was used as the
placebo.
All treatment capsules were uniform in size, colour,
bottle filling, labelling, and packaging. Treatments were
packaged in maroon gelatine capsules (size 0) containing
600mg of potassium humate or lactose and packed in wide
mouthed white opaque plastic bottles with screw caps in a
clean room.
Statistical Methods
In this study the RAND 36-Item Health Survey as
described by Garratt et al. [13], as well as the WOMAC
score [15] were used as primary outcome.
Differences in WOMAC scores and health survey
parameters were used in treatment groups at baseline, 7
weeks, and 14 weeks, and group wise changes between
baseline, 7 weeks and 14 weeks. Outcome scores were
analyzed for variation in effect for Sequence, Treatment,
Period and Carryover. Results for the WOMAC score were
analysed using an ANOVA and the health survey results
were analysed using the Wilcoxon test for paired values. A p
value of <0.05 was regarded as significant.
Bonferoni test for multiple comparisons was used to
compare differences in hs-CRP values, measured at the onset
as well as at the end of each treatment period (week 2 and
week 7; week 8 and week 15). Statistical significance was
taken at the 95% level (p < 0.05). Results are expressed as
the mean ± SD.
All participants lost to follow-up had been accounted for.
RESULTS
Subject Characteristics and Study Flow
Of the 55 patients screened, 28 patients met the clinical
and radiographic criteria at enrolment and were randomized.
The characteristics of the subjects at enrolment and
randomization are given in Table 1. 21 Participants
successfully completed the protocol. A summary of patient
disposition can be seen in Fig. (2).
Table 1. Baseline Characteristics of Patients on Trial
Age (mean in years) 63.46
±
9.48
Body Mass Index (BMI) (kg/m2) (mean) 31±5.13
Gender: Female n=21
Male n=7
Knee affected: Right n=16
Left n=12
Duration of OA: 1-5 years n=12
5-10 years n=10
>10 years n=6
Pre-study pain medication: Paracetamol n=1
NSAID/ high dose aspirin n=7
NSAID & paracetamol n=5
None n=15
Fig. (2). Patient disposition in the double blind cross-over trial.
1One patient withdrawn due to lack of efficacy and two patients due
to adverse effects.
2One patient withdrawn due to an unrelated adverse event and one
patient due to an unrelated reason.
3One patient withdrawn due to lack of efficacy and the second
patient due to an unrelated reason.
72 The Open Conference Proceedings Journal, 2010, Volume 1 Van Rensburg et al.
Clinical Response
Primary Efficacy Variable
The primary efficacy variable was a clinically significant
reduction on a 100 mm visual analogue scale (VAS) in the
WOMAC scores for stiffness, global score and mean score in
the group with order placebo cross over to potassium humate
(Table 2). This was not the case in the group with order
potassium humate cross over to placebo (Table 3) or when
grouped together, indicating a carry-over effect. The high SD
values could be due to the differences in individuals’
response to the active ingredient, but overall when the
patients where on the active, they responded significantly
better than when on placebo.
The health survey parameters were tested using a
Wilcoxon Rank test to test for significant variances within
each group. The only significant difference obtained in the
health survey was between the combined placebo groups and
the treatment groups regarding physical functioning, where
an increase of 12.86 on the VAS scale was documented vs
6.52 for the placebo group (Table 4).
Secondary Efficacy Variables
hs-CRP
Potassium humate treated participants, using the
combined placebo groups and the treatment group results,
had a significant reduction (p<0.5) in hs-CRP from a mean
value of 14.4 to 6.6 mg/L (Fig. (3)).
Patient Disposition and Consumption of Rescue
Medication and
There were no significant differences in patient
disposition or the use of paracetamol in both groups.
Tolerability
Tolerability was good for all groups. Pill counts
performed at each study visit demonstrated greater than 90%
compliance in both groups (results not shown).
Safety Measures
Safety parameters remained unchanged, except for an
increase in the GGT-levels (n=4 in potassium humate group,
n=2 in the placebo group). Increased levels of GGT were
still within normal limits and returned to baseline values
within 2 weeks of discontinuation of therapy.
Adverse Events
No serious adverse events were noted. Patients receiving
potassium humate experienced black stools (n=3) and
headache (n=2), while patients on placebo complained of
headache (n=2), nausea (n=2), diarrhoea (n=2), flatulence
(n=1) and loss of libido (n=1). Black stools could be
explained by the black nature of the product.
Table 2. Effect of Potassium Humate vs Placebo on the WOMAC™ Scores with Respect to Baseline with Order Placebo Cross
Over to Potassium Humate
Visual Analogue Scale (min=0, max=100)
Baseline Placebo Potassium Humate
Mean ±SD Mean ±SD Mean ±SD
Pain Dimension 45.667 16.948 30.089 19.781 29.533 26.745
Stiffness Dimension 52.333 16.145 42.611 26.726 *28.611 26.871
Physical Function 42.781 14.677 35.653 25.215 27.134 26.579
Global Score 140.781 39.756 108.353 68.230 *85.279 79.836
Mean Score 46.927 13.252 36.118 22.743
Washout/Cross-over
*28.426 26.612
*Indicating statistical significant difference from baseline (p < 0.05).
Table 3. Effect of Potassium Humate vs Placebo on the WOMAC™ Scores with Order Potassium Humate Cross Over to Placebo
Visual Analogue Scale (min=0, max=100)
Baseline Potassium humate Placebo
Mean ±SD Mean ±SD Mean ±SD
Pain Dimension 46.217 28.480 44.177 20.870 35.358 23.123
Stiffness Dimension 64.000 25.733 64.892 32.479 58.667 31.186
Physical Function 54.001 22.834 48.136 21.153 46.649 27.356
Global Score 161.917 66.660 157.204 64.710 140.674 78.814
Mean Score 53.972 22.220 52.401 21.570
Washout/Cross-over
46.891 26.271
*Indicatin
g
statistical si
g
nificant difference from baseline
(p
< 0.05
)
.
Potassium Humate Reduces Inflammation and Clinically Improves The Open Conference Proceedings Journal, 2010, Volume 1 73
Fig. (3).
DISCUSSION
This is the first study to demonstrate the safety profile of
potassium humate, at a daily dose of 1.8g in humans, which
was consistent with the preclinical results obtained in a study
done in rats [10]. Patients were selected with unilaterally
symptomatic idiopathic OA of the knee. All haematology
and biochemical parameters stayed within normal ranges
during the study. Potassium humate treatment caused a
reduction in inflammation in these patients as seen in a
reduction in hs-CRP levels as well as clinically significant
improvement of patients on the treatment drug compared to
the placebo group.
Mechanistic studies done by Joone et al. on oxihumate, a
water-soluble humate obtained through a wet oxidation of
bituminous coal [17], decreases the expression of
complement receptor 3 (CR3) by phorbol-12-myristate-13-
acetate (PMA) stimulated human neutrophils as well as the
adhesion of these cells to a baby hamster kidney cell line
expressing intracellular adhesion molecule-1 (ICAM-1) [18],
possibly contributing to its anti-inflammatory effects. An in
vitro finding has recently been documented [19] indicating
that brown coal derived potassium humate inhibits the
activation of both the classical and alternative pathways of
complement activation. It was also shown, in the same study,
that potassium humate inhibits the release of the
inflammatory related cytokines TNF-, IL-1 and IL-6 in
vitro. In the case of arthritis complement activation of both
these pathways have been associated with the presence of
auto-antibodies against joint components such as type II
collagen [20]. Controlling complement activation with
monoclonal anti-C5 antibodies has been proven to be
effective in decreasing inflammation in animal models of
experimental lupus erythematosus, rheumatoid arthritis and
septic shock [21]. Regarding the blocking of cytokines, it has
been shown that Anakinra, an interleukin-1 (IL-1) receptor
antagonist, can be used successfully in the treatment of
inflammation and bone destruction in
rheumatoid
arthritis [22]. Similar results were obtained with infliximab,
an anti TNF therapy when combined with methotrexate
[23]. Further studies need to be done to confirm the
mechanism of action of potassium humate plus efficacy
studies in other inflammatory diseases such as rheumatoid
arthritis.
Studies with bigger sample sizes than this one will have
to be done in order to determine whether the results can be
replicated. A washout period of more than one week is also
recommended.
The identification of a naturally occurring compound that
is safe and effective in reducing a serological marker of
inflammation in an autoimmune disease such as OA of the
knee, merits further evaluation in the treatment of patients
suffering from other inflammatory arthropathies such as
rheumatoid arthritis.
ABBREVIATIONS
OA = osteoarthritis
CRP = C-reactive protein
NSAIDs = non-steroidal anti-inflammatory drugs
Table 4. Effect of Potassium Humate vs Placebo on the 8 Divisions of the Health Survey; Combined SF-36 Results
Health Survey (%)
Baseline Placebo Potassium Humate
Division Mean ±SD Mean ±SD Mean ±SD
Physical functioning 39.306 18.726 45.826 22.171 *52.222 26.113
Bodily pain 46.944 17.722 55.625 25.760 60.104 23.135
Role limitations due to physical health problems 48.958 35.341 46.181 44.881 57.292 43.276
Role limitations due to personal or emotional
problems 66.667 42.559 66.667 42.886 64.352 45.097
Emotional well-being 73.875 66.833 75.056 19.441 74.958 19.266
Social functioning 76.042 23.720 75.521 22.165 78.472 15.965
Energy/fatigue 54.236 14.593 60.208 23.941 55.556 17.341
General health 74.514 17.990 70.694 17.141 70.486 19.307
*Indicatin
g
statistical
si
g
nificant
difference
from
baseline
(p
<0.05
)
.
74 The Open Conference Proceedings Journal, 2010, Volume 1 Van Rensburg et al.
WOMAC™ = Western Ontario and McMaster
Universities Osteoarthritis Index
questionnaire)
VAS = visual analogue scale
ICAM-1 = intracellular adhesion molecule-1
MClD = minimal clinically important difference
ACKNOWLEDGEMENTS
This research was financially supported by Unique
Health Trust and a grant from the South African National
Research Foundation (NRF).
The corresponding author, Dr C.E.J. van Rensburg, acts as
consultant for Unique Health Trust.
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Received: April 12, 2010 Revised: July 15, 2010 Accepted: July 16, 2010
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