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European Journal of Applied Sciences – Vol. 11, No. 1
Publication Date: January 25, 2023
DOI:10.14738/aivp.111.13884. Robinson, J. L., Nemzer, B., Reyes-Izquierdo, T., Pietrzkowski, Z., & Hunter, J. M. (2023). Impact of Calcium Fructoborate on
WOMAC and McGill Subscales and Individual WOMAC Questions: Post-Hoc Analyses of Data from a Previously Published 90-Day
Randomized Clinical Trial. European Journal of Applied Sciences, Vol - 11(1). 319-340.
Services for Science and Education – United Kingdom
Impact of Calcium Fructoborate on WOMAC and McGill
Subscales and Individual WOMAC Questions: Post-Hoc Analyses of
Data from a Previously Published 90-Day Randomized Clinical Trial
Jennifer L. Robinson, Ph.D.
Auburn University,
Department of Psychological Sciences, Auburn, AL 36849, United States.
Boris Nemzer, Ph.D.
VDF FutureCeuticals, Inc., Momence, IL 60954, United States
Tania Reyes-Izquierdo, Ph.D.
VDF FutureCeuticals, Inc., Irvine, CA 92606, United States
Zbigniew Pietrzkowski, Ph.D.
VDF FutureCeuticals, Inc., Irvine, CA 92606, United States
John M. Hunter
VDF FutureCeuticals, Inc., Momence, IL 60954, United States
ABSTRACT
Calcium fructoborate (CFB) has been shown to reduce overall joint discomfort on
the Western Ontario and McMaster University Arthritis Index (WOMAC) and the
McGill Pain Questionnaire (MPQ). No study has addressed the impact of CFB on the
subscales of these measures, nor on individual questions. Here, we re-examined
data from a previously peer reviewed and published 90-day, double-blind,
randomized, placebo-controlled study on CFB to determine whether there were
subscale or individual questions differences. In the original study participants were
randomized into three groups: 1) placebo, 2) a morning dose of 216mg of CFB and
evening dose of placebo (CFB1), or 3) a morning and evening dose of 108mg of CFB
(CFB2). Our new analyses indicated that by day 30, both CFB groups were
distinguishable from placebo on the WOMAC Pain and WOMAC Activities of Daily
Living subscales. Furthermore, they were distinguishable from the WOMAC
Stiffness subscale by days 60 and 90 (CFB1, CFB2, respectively). Importantly,
analyses of individual WOMAC questions revealed differences in at little as 14 days.
For the McGill pain subscale, differences emerged by day 7 and 14 between placebo
and CFB1/CFB2 groups, respectively, while the affective dimension was different
from CFB groups by day 60. For the miscellaneous dimension, placebo was
differentiable by day 60 and 90 (CFB1/CFB2, respectively). These data provide
greater visibility into CFB’s joint health benefits and suggest that CFB’s effects
support real improvements in practical aspects of daily physical activity.
Keywords: cfb, calcium fructoborate, Fruite X-B, WOMAC, McGill, osteoarthritis, knee
discomfort, knee pain
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European Journal of Applied Sciences (EJAS) Vol. 11, Issue 1, January-2023
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INTRODUCTION
Knee pain is a highly prevalent condition [1-3], and one that represents a significant global
health burden. In a landmark meta-analysis, Cui, Li, Wang, Zhong, Chen and Lu (2020) pooled
studies examining knee osteoarthritis in population-based observational studies.
Encompassing over 10 million participants, they found prevalence rates of knee osteoarthritis
to be 16% in individuals over 15 years of age, with rates hovering above 22% for those over 40
years of age. Given that the last three decades have been marked by a tremendous increase in
the prevalence rates of knee pain, inclusive of knee osteoarthritis and independent of factors
such as age and body mass index (BMI) [1,2], it is critical to identify sustainable, accessible, and
affordable treatment options for pain management. A promising therapeutic avenue is the use
of naturally derived over the counter (OTC) supplements, such as calcium fructoborate (CFB).
Dietary supplements may offer significant advantages over non-steroidal anti-inflammatory
drugs (NSAIDS) given that they are typically associated with fewer side effects.
CFB is a generally-recognized-as-safe (GRAS) [4], water-soluble material that has
demonstrated pain mitigation properties through anti-inflammatory mechanisms [5-15].
Originally found in small amounts in nuts, dried fruits, herbs, and wine [16], it is industrially
manufactured via a proprietary process. It has been theorized that CFB works on oxidative
metabolic pathways and has been reported to have an influence on cell apoptosis. In addition
to the remarkably consistent effects on knee discomfort, it has been suggested that CFB may
have a protective effect against DNA damage caused by oxidation in rats [17]. Furthermore, it
may serve as an inhibitor against the proliferation of certain types of cancer cells through
overexpression of apoptosis-related proteins [18, 19]. In all cases, however, the
pathophysiological mechanism subserving the effects of CFB on health outcomes appears to be
its anti-inflammatory properties.
When zeroing in on knee pain, CFB has consistently demonstrated reductions in discomfort. In
clinical trials, CFB’s effectiveness emerges in as little as 7 days [5], and persists throughout 90
days [6]. In a randomized, placebo-controlled clinical trial Pietrzkowski et al. (2018)
demonstrated that CFB reduced scores in both the McGill Pain Questionnaire (MPQ) and the
Western Ontario and McMaster University Arthritis Index (WOMAC). Study participants were
assessed at baseline and then at days 7, 14, 30, 60, and 90. Data demonstrated that CFB groups
differentiated from placebo in as little as 7 days and persisted throughout the entire study.
However, due to the fact that the scores for MPQ and WOMAC are presented as a single number,
it remained unclear from these initial analyses whether CFB may have been preferentially
impacting certain dimensions of joint discomfort: flexibility, stiffness or pain, whether when in
motion, or at rest. Consequently, it was our intent to conduct a deeper, targeted examination of
these data. Here, we reanalyze the data from the earlier study [6] to determine whether CFB
preferentially affected certain subscales. Specifically, we hypothesized that the CFB groups
would outperform placebo such that subscale scores would decrease significantly over time for
CFB groups, while placebo scores would not. Furthermore, and perhaps most importantly, we
conducted exploratory analyses on individual questions of the WOMAC in order to better
understand and articulate the possible real-world daily-activity impacts of CFB.
MATERIALS & METHODS
The original published study was a double-blind, placebo-controlled study [6]. CFB was
provided by VDF FutureCeuticals, Inc. (Momence, IL, USA). Placebo capsules were composed of
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Robinson, J. L., Nemzer, B., Reyes-Izquierdo, T., Pietrzkowski, Z., & Hunter, J. M. (2023). Impact of Calcium Fructoborate on WOMAC and McGill
Subscales and Individual WOMAC Questions: Post-Hoc Analyses of Data from a Previously Published 90-Day Randomized Clinical Trial. European
Journal of Applied Sciences, Vol - 11(1). 319-340.
URL: http://dx.doi.org/10.14738/aivp.111.13884
silica oxide (50mg) and fructose (80mg) from Sigma Chemical Company (St. Louis, MO, USA).
Participants between the ages of 35 and 65 were recruited for the study (M ± SD = 52.80 ± 8.19
years). Participants were randomized into three groups: 1) placebo, 2) a single dose of 216mg
CFB (CFB1), or 3) morning and evening doses of 108mg CFB (CFB2). Importantly, all groups
took 1 capsule in the morning, and 1 capsule in the evening (thus, for placebo, they took a
placebo capsule in the morning, and a placebo capsule in the evening; for CFB1, the 216mg CFB
was ingested in the morning capsule followed by a placebo capsule in the evening; for CFB2,
both morning and evening capsules contained 108mg CFB). The study lasted 90 days with
assessments at baseline (day 0), day 7, day 14, day 30, day 60, and day 90. The full details of the
original study design are outlined in the published manuscript [6]. In short, groups did not
differ with regard to age, sex or body-mass index (BMI) [6]. Participants were excluded if 1)
their body mass index was < 21 or > 30, 2) they were pregnant, nursing, or planning to get
pregnant, or if they had 3) cardiovascular disease, 4) a knee injury or osteoarthritis, 5) diabetes,
6) a respiratory infection, or 7) were enrolled in another study. Furthermore, participants were
advised not to take any anti-inflammatory medications, supplements, steroid-containing
prescriptions, non-prescription medications, or vitamin D for 30 days prior to the start of the
trial and had to refrain from these materials for 2 weeks prior to enrolling in the study. All study
participants were generally healthy and reported knee discomfort, defined by McGill scores >50
but <65, for more than 4 weeks prior to study enrollment. An a priori power analysis indicated
a total sample size of N = 120 would be necessary to achieve 90% power with an effect size of f
= 0.25. A final sample of 121 participants were allocated into the three (3) study groups (nplacebo
= 40, nCFB1 = 40, nCFB2 = 41). A simple randomization consisting of tokens generated by the
researchers containing either a number “1”, “2” or “3” was implemented within male and female
groups to ensure each study condition (i.e., placebo, CFB1, and CFB2) was matched on sex. Both
researchers and participants were blind to study condition assignment. The primary outcome
measures for the study were the WOMAC and McGill assessments conducted at baseline (day
0), day 7, 14, 30, 60, and 90.
This earlier study was conducted according to the guidelines set forth in the Declaration of
Helsinki, and all procedures were approved by the Institutional Review Board (Comité de Ética
en Investigación Biomédica para el Desarrollo de Fármacos, S.A. de C.V., Av. Sebastian Bach No.
5257, Col. La Estancia, C.P. 45030, Zapopan, JAL, Mexico) (IRB: FCE-NCI-16-06-KNN).
Participants provided written, informed consent prior to enrollment. The study was performed
by NutraClinical, Inc. (Irvine, CA, USA).
Western Ontario and McMaster University Arthritis Index (WOMAC)
The WOMAC [20] is a validated questionnaire used to assess the physical function of joints, and
consists of 24 items divided into 3 subscales: 1) the WOMAC Pain Subscale (WOMAC-P) which
consists of 5 items with a score range from 0-20; 2) the WOMAC Stiffness Subscale (WOMAC-S)
which consists of 2 items with scores ranging from 0-8; and 3) the WOMAC Activities of Daily
Living Subscale (WOMAC-ADL; or functional limitations subscale) which consists of 17 items
with a scoring range between 0-68. Although analyses on individual questions have not been
validated in previous research, we did these exploratory analyses to identify any potential real- world clinical outcomes.
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McGill Pain Questionnaire (MPQ)
The McGill Pain Questionnaire (MPQ) is a validated assessment tool to quantify the quality and
intensity of pain [21, 22]. The first twenty (20) questions contain 4 subscales consisting of 78
total words that participants endorse. The words represent sensory, affective, and evaluative
aspects of pain. As such, the subscales are 1) sensory-discriminative pain, consisting of 10 items
with a total scoring range between 0-42 (MPQ-P); 2) the affective-motivational dimension,
consisting of 5 items with a total scoring range between 0-14 (MPQ-A); 3) the miscellaneous
dimension, consisting of 4 items with a total scoring range between 0-17 (MPQ-M); and 4) the
cognitive-evaluative dimension, consisting of 1 item with a total scoring range between 0-5
(MPQ-E). Analyses on individual questions was not performed because MPQ items merely ask
participants to endorse descriptive words, which are not necessarily representative of a Likert
scale.
Original analyses on the total scores of the WOMAC and MPQ were reported in Pietrzkowski,
Roldán Mercado-Sesma, Argumedo, Cervantes, Nemzer and Reyes-Izquierdo (2018) [6]. Our
current manuscript is a re-analysis of the data from the subscales of each of the assessments
and of the individual questions from WOMAC.
RESULTS
WOMAC Results
WOMAC Pain Subscale (WOMAC-P):
A repeated measures ANOVA was conducted for the WOMAC-P subscale. Time-based
measurements (day 0, 7, 14, 30, 60, and 90) were within-participants factors, and group
(placebo, CFB1, and CFB2) was the between-participants factor. There was a significant effect
of time (F (5, 590) = 30.715, p < 0.001, partial h2 = 0.207) as well as a significant group * time
interaction (F(10, 590) = 8.910, p < 0.001, partial h2 = 0.131). There was also a significant main
effect of group (F (2, 118) = 7.122, p = 0.001, partial h2 = 0.108). Follow-up univariate tests
examining the main effect of group at each timepoint indicated that groups were different at
day 30 (F(2, 118) = 9.250, p < 0.001, partial h2 = 0.136), day 60 (F(2, 118) = 8.300, p < 0.001,
partial h2 = 0.123) and day 90 (F(2,118) = 38.228, p < 0.001, partial h2 = 0.393). Post-hoc
pairwise comparisons with Bonferroni correction revealed that there were no significant
differences at baseline (day 0), day 7, or day 14. However, at day 30 and for the remainder of
the study, the placebo group had significantly higher scores than CFB1 (p = 0.001) and CFB2 (p
= 0.002). The CFB groups were indistinguishable from each other. Follow-up multivariate tests
examining the main effect of time within each group indicated a significant effect for all groups
(placebo: F (5,114) = 4.086, p = 0.002, partial h2 = 0.152; CFB1: F (5,114) = 20.865, p < 0.001,
partial h2 = 0.478; CFB2: F(5, 114) = 14.595, p < 0.001, partial h2 = 0.390). Post-hoc pairwise
comparisons with Bonferroni correction revealed that the placebo group WOMAC-P scores
were significantly different between day 60 and 90 (p = 0.024), and that these differences
represented increases in the pain subscale score. In contrast, CFB1 had significant differences
from baseline throughout the entire study and demonstrated further significant decreases
between subsequent measurements. Specifically, there were significant decreases from day 7
to day 30 (p < 0.001), day 60 (p < 0.001) and day 90 (p < 0.001), as well as between day 14 and
days 60 (p = 0.047) and 90 (p < 0.001). CFB2 had significant decreases from baseline
throughout the entire 90-day period – these differences were notable within the first 7 days (p
= 0.007). There were subsequent significant decreases between day 7 and days 30 (p =0.023),