s40520 022 02151 7

Aging Clinical and Experimental Research (2022) 34:1613–1625
https://doi.org/10.1007/s40520-022-02151-7
ORIGINAL ARTICLE
Prescription‑grade crystalline glucosamine sulfate as an add‑on

therapy to conventional treatments in erosive osteoarthritis
of the hand: results from a 6‑month observational retrospective study
Sara Tenti1 · Nicola Veronese2 · Sara Cheleschi1 · Iole Seccafico1 · Olivier Bruyère3 · Jean‑Yves Reginster3 ·
Antonella Fioravanti1
Received: 23 February 2022 / Accepted: 2 May 2022 / Published online: 30 May 2022
© The Author(s) 2022
Abstract
Objective To evaluate the efficacy of prescription-grade Crystalline Glucosamine Sulfate (pCGS) as an add-on treatment to
conventional therapy, compared to usual therapy alone, in patients with erosive osteoarthritis of the hand (EHOA).
Methods This 6-month retrospective case–control study included patients with concomitant knee osteoarthritis and symp-
tomatic EHOA. Participants were stratified into two groups based on whether or not pCGS (1500 mg/day) was added to the
conventional therapy (education and training in ergonomic principles, exercise and use on-demand of symptomatic drugs)
for hand osteoarthritis. Patients were evaluated at baseline, after 3 and 6 months. Primary outcomes were the change from
baseline to month 6 in Visual Analogue Scale (VAS) hand pain and in Functional Index for Hand Osteoarthritis (FIHOA)
score. A set of secondary parameters was also evaluated.
Results 123 patients were included as follows: 67 treated with pCGS in addition to conventional therapy (pCGS Group) and
56 with conventional therapy alone (Control Group). After 6 months a significant difference in VAS and in FIHOA score
(p < 0.01 and p < 0.001, respectively) was observed in favor of pCGS Group. Similar results were found for morning stiffness
duration (p < 0.05), health assessment questionnaire (p < 0.01) and physical and mental component score of 36-item short
form (p < 0.05 and p < 0.001, respectively). A significant reduction of symptomatic drug consumption at 3 and 6 months was
reported in the pCGS Group (p < 0.001). No serious adverse event was recorded in both groups.
Conclusions Despite all the limitations inherent to an observational study, our results suggest the potential effectiveness of
pCGS, when used in combination with conventional therapy in EHOA. Further randomized placebo-controlled trials are
needed to confirm these positive findings.
Trial Registration ClinicalTrials.gov, http://www.clinicaltrials.gov, date of registration: February2, 2022, NCT05237596.
The present trial was retrospectively registered.
Keywords Prescription-grade crystalline glucosamine sulfate · Hand osteoarthritis · Erosive hand osteoarthritis ·
Symptomatic slow-acting drugs for osteoarthritis · Retrospective study · Pain
* Antonella Fioravanti Introduction

[email protected]
1
Clinic for the Diagnosis and Management of Hand Hand Osteoarthritis (HOA) is a very common condition and
Osteoarthritis, Rheumatology Unit, Department of Medicine, one of the main leading causes of disability. The prevalence
Surgery and Neuroscience, Azienda Ospedaliera of symptomatic HOA ranges from 13 to 26% in women older
Universitaria Senese, Policlinico Le Scotte, Viale Bracci 1, than 70 years with an estimated lifetime risk of 40% [1, 2].
53100 Siena, Italy
2
Erosive osteoarthritis (EHOA) is a peculiar variant of HOA,
Geriatric Unit, Department of Internal Medicine featured by prominent signs of inflammation, high severity
and Geriatrics, University of Palermo, Palermo, Italy
3
progression and typical radiographic changes, as character-
Division of Public Health, Epidemiology and Health, istic central erosions with collapse of the subchondral bone
Economics, WHO Collaborating Centre for Public Health,
Aspects of Musculo-Skeletal Health and Ageing, University and a ‘gull-wing’ or ‘saw-tooth’ deformity [3–6]. It is still
of Liege, Liege, Belgium highly debated if EHOA represents an advanced stage of
13
Vol.:(0123456789)
1614 Aging Clinical and Experimental Research (2022) 34:1613–1625
the classical HOA or rather a separate entity with inflamma- conventional therapy for HOA, in comparison to conven-
tory features [7, 8]. EHOA poses a significant clinical chal- tional therapy alone, in patients with concomitant EHOA
lenge, considering the substantial disability and the negative and knee OA. The conventional regimen consisted in edu-
impact on quality of life (QoL), the paucity of symptomatic cation and training in ergonomic principles, exercise pro-
effective treatments and the lack of disease modifying anti- gram for HOA and acetaminophen or oral NSAIDs, used
rheumatic drugs (DMARDs) [9–20]. on-demand.
Specific guidelines for EHOA management have not
yet been provided, so they are actually extrapolated by the
2018 update of the European League against Rheumatism Patients and methods
(EULAR) recommendations for the treatment of HOA.
These suggest an individualized and multidisciplinary Study design
approach, including a combination of non-pharmacological
and pharmacological strategies. Among the first ones, edu- The current study was an observational cohort study with
cation and training in ergonomic principles, use of assistive retrospective review of medical records, conducted at the
devices, exercise to improve function and muscle strength Center for the diagnosis and the management of Hand Oste-
and to reduce pain should be offered to every patient [21]. oarthritis, Rheumatology Unit of the Azienda Ospedaliera
Among the pharmacological options, topical non-steroidal Universitaria Senese (Italy).
anti-inflammatory drugs (NSAIDs), oral analgesics and In accordance with national regulations on the conduction
intra-articular injection of glucocorticoids in case of painful of observational analysis [36], the local Ethics Committee
interphalangeal (IP) joints are recommended [21]. Chondroi- was notified of the current retrospective observational study.
tin sulfate (CS) is the only symptomatic slow-acting drug According to our routinary care, all patients were
for osteoarthritis (SYSADOAs) included in the EULAR informed that their demographical and medical data could
recommendations update, considering the randomized con- be used in a scientific study and provided their written con-
trolled trial (RCT) demonstrating its efficacy in relief pain sent for the collection and publication of anonymous data.
and improving functionality in HOA patients [21, 22]. Also, The study was registered on http://www.clinicaltrials.gov
in EHOA, CS showed some promising results [23]. Finally, with number NCT05237596.
EULAR recommends against the use of conventional or bio-
logical DMARDs, as hydroxychloroquine, different Tumor Participants
Necrosis Factor (TNF)-inhibitors and anti-interleukin (IL)-1
and IL-6 antibodies [11–18]. We analyzed the records, collected since October 2016 to
Glucosamine is a natural component of the glycosami- October 2021 in the departmental archives, of all the outpa-
noglycans found in the cartilage matrix and synovial fluid; tients affected by concomitant mono-or bilateral knee OA,
when administered exogenously, it affects the cartilage and diagnosed according to the American College of Rheuma-
chondrocytes metabolism, mainly leading to the reverse of tology (ACR) criteria [37], and EHOA, defined as the pres-
the pro-inflammatory and joint-degenerating effects of IL-1 ence of the classical central erosion in at least two IP joints
[24, 25]. The prescription-grade crystalline glucosamine [3, 38], and who have been treated with prescription-grade
sulfate (pCGS) formulation is widely used for the treatment crystalline glucosamine sulfate (Dona®), in addition to the
of knee OA thanks to its well-demonstrated effectiveness in conventional therapy for HOA or with conventional therapy
improving pain and function [26–31]. Furthermore, pCGS alone.
and CS are recommended as chronic background therapy We included in our analysis the records of patients of
by European Society for Clinical and Economic Aspects of both sexes, aged between 48 and 87 years who had clinical
Osteoporosis, Osteoarthritis and Musculoskeletal Diseases symptoms of HOA for at least 3 months, defined as global
(ESCEO) algorithm for knee OA [32–34]. hand pain score in the previous 48 h superior to 40 mm on a
No randomized placebo-controlled trials evaluating the 0–100 Visual Analogue Scale (VAS) and a functional index
possible symptomatic effects of GS in patients with HOA for hand osteoarthritis (FIHOA) score of at least 6. Fur-
have been performed. Some positive and promising results thermore, to be included in our analysis, patients have had
were derived from our previous 6-months’ retrospective plain radiography of both hands performed within the past
study, demonstrating the efficacy of pCGS (1500 mg/day) 6 months before the first visit at our clinic. Radiographic
added to conventional therapy, on hand pain and functional- disease severity was determined based on the Kellgren/
ity [35]. However, to the best of our knowledge, no data are Lawrence scoring system and was performed by an expert
available in EHOA. rheumatologist (A.F.). All individual distal interphalangeal
For these reasons, we decided to retrospectively evaluate (DIP), proximal interphalangeal (PIP) and carpometacar-
the possible efficacy of pCGS, as an add-on treatment to pal (CMC) joints were scored according to Kellgren and
13
Aging Clinical and Experimental Research (2022) 34:1613–1625 1615
Lawrence grading [39]. The final score was determined by provided to all patients through the use of a 11-page educa-
the joint with the highest grade [16]. tional booklet (Supplementary material 1). Training in ergo-
Patients with a history of any inflammatory joint disease, nomic principles and pacing of activity (formerly known as
septic arthritis, previous articular fracture of the concerned “joint protection”) were offered to all patients trough two
joints, or the presence of any other rheumatic diseases that individual face-to-face sessions with a physiotherapist.
could cause secondary OA, such as hemochromatosis, rep- Concerning exercise, in our routinary care, we refer to
resented exclusion criteria. Further, patients who underwent the program, described by Østerås et al. [40, 41] in order
therapy with SYSADOAs, other than pCGS, steroids by any to maintain or increase the flexibility of the metacarpal
route of administration and intra-articular injection of any (MCP), DIP and PIP joints, to strengthen the mm. extensors
joint with hyaluronic acid during the previous 6 months and abductors pollicis and to potentiate grip strength. Four
were excluded. Also patients treated with intra-muscular or weekly face-to-face sessions with a trained physiotherapist
intra-venous bisphosphonates in the previous 6 months were were offered to all patients, and then they were instructed to
not considered. Other obvious exclusion criteria, consider- perform three home sessions for week.
ing that in none of these conditions, we prescribe pCGS According to the Italian Society for Rheumatology clini-
therapy according to our routinary care, were a known his- cal practice guidelines [42], acetaminophen was prescribed
tory of allergy to pCGS, to any of the other ingredients of up to a maximum of 1000 mg for 3 times/day and oral non-
this medicine or to shellfish, as glucosamine is produced selective or COX-2 selective NSAIDs for a limited period
from shellfish, significant comorbidities, as diabetes or of time, taking into account all patients’ comorbidities,
impaired glucose tolerance, severe cardiovascular, liver or contraindications and special warnings. Particularly, the
kidney diseases, asthma, phenylketonuria, pregnancy and treatment with NSAIDs includes diclofenac (single daily
breast-feeding. dose ≤ 150 mg) or piroxicam (single daily dose ≤ 20 mg) or
naproxen (maximum 500 mg for 2 times/day) or aceclofenac
Treatments (maximum 100 mg for 2 times/day) or ibuprofen (maxi-
mum 400 mg for 3 times/day) or celecoxib (single daily
The participants were stratified into two groups based on dose ≤ 200 mg) or etoricoxib (single daily dose ≤ 60 mg).
whether or not pCGS treatment was added to the conven-
tional therapy for EHOA. Thus, pCGS-exposed Group
included patients treated with pCGS (Dona®, VIATRIS), Data collection
in sachets of powder for oral solution, at the dose of 1500 mg
glucosamine sulfate once daily, for a total period of 6 con- Data from routine clinical practice of eligible patients were
secutive months according to the approved indication for collected by completion of case report forms during each
knee OA, in addition to conventional therapy for HOA, visit. In particular, the following data were extracted from
while pCGS-unexposed Group included patients treated the chart review and aggregated into a Microsoft Excel®
with conventional therapy alone for 6 consecutive months. spreadsheet database: demographic and anthropometric
The treatment with pCGS is prescribed in our routi- measures such as age, gender, and body mass index (BMI),
nary care, as background therapy, in patients with knee clinical data, as patient’s history, comorbidities and related
OA, according to the algorithm recommended by ESCEO treatments. This information was self-reported by the
[14–16]. Thus, the decision by the physician to not prescribe patients and checked by evaluation of the referred clinical
pCGS depends exclusively on patients' contraindications or documentation. Data about HOA characteristics, includ-
co-morbidities, as reported above (known history of allergy ing disease duration, radiological score, pain severity and
to pCGS, to any of the other ingredients of this medicine algo-functional indexes, and features of other frequently
or to shellfish, as glucosamine is produced from shellfish, affected joints, as knee and hip, as well as QoL tests were
significant comorbidities, as diabetes or impaired glucose also collected.
tolerance, severe cardiovascular, liver or kidney diseases,
asthma, phenylketonuria, pregnancy and breast-feeding).
Furthermore, in some cases, patients decided to not take Outcomes
pCGS because they cannot afford the cost of this drug since
it is not covered by our National Health Service (NHS), The study parameters were collected during the visits at the
opposite to NSAIDs and acetaminophen. out-patient clinic specialized for the diagnosis and manage-
The conventional treatment for HOA consisted of edu- ment of HOA of our institution, which are scheduled every
cation and training in ergonomic principles, exercise pro- 3 months for each patient. In case of impossibility for the
gram for HOA and acetaminophen or oral NSAIDs, used patients to come to the center for follow-up visits, we usually
on-demand. Education and information about HOA were reach them by phone.
13
In the present study, we considered only data regarding evaluating possible differences between pCGS and controls
HOA, which is the focus of this paper and we did not report at baseline.
any assessments about knee OA. Mean changes from baseline in the outcomes of interest,
The primary outcome criteria were the change from base- i.e., VAS pain, VAS rigidity, FIHOA, HAQ, SF-36 physi-
line to month 6 in the patient’s assessment of global spon- cal component score (PCS) and mental component score
taneous hand pain, perceived in the previous 48 h, by VAS (MCS), were compared using a generalized linear model
(0–100 mm), with 0 representing the absence of pain and (GLM) with repeated measures, calculating the differences
100 the maximum imaginable pain, and in hand function between exposed and unexposed, over time. The same was
by FIHOA score. due to for the weekly consumption of symptomatic drugs.
The FIHOA score represents a quantitative measure of For all analyses, a p value of less than 0.05 was consid-
functional disability of the hands; it contains 10 items and ered as statistically significant, applying the Bonferroni’s
is an investigator-administered questionnaire. Patients are correction in the sensitivity analysis.
asked to answer each item using a four-point Likert scale: All analyses were performed using the SPSS 20.0 for
0 = possible without difficulty, 1 = possible with slight dif- Windows (SPSS Inc., Chicago, Illinois).
ficulty, 2 = possible with considerable difficulty, 3 = impos-
sible. The range of scores is 0–30 and the highest values Data entry and management
indicate the worst functionality. The validated Italian version
of FIHOA was used [43, 44]. Data were collected through the prespecified case report
Among secondary outcomes we evaluated the change forms we usually fill during our ambulatory care. Paper-
in the duration of morning stiffness, measured in minutes based data were stored in locked cabinets with restricted
and based on the self-report of patients. Further second- access to the rheumatologists of the Center for the diagnosis
ary endpoints were the Italian version of the Health Assess- and the management of Hand Osteoarthritis, Rheumatology
ment Questionnaire (HAQ), the medical outcomes study Unit of the Azienda Ospedaliera Universitaria Senese (Italy).
36-item short form (SF-36), symptomatic drug consump- Electronic data were stored in a password-protected database
tion from baseline to month 6 of follow-up and the percent- with secured and restricted access. Patients were identified
age of treatment responders at 3 and 6 months, according by study ID with other information potentially identifying
to the Outcome Measures in Rheumatology (OMERACT) individuals removed.
and Osteoarthritis Research Society International (OARSI)
criteria [45–49].
For both primary and secondary outcomes, the target Results
hand was defined as the patient’s most symptomatic hand
or, when patients referred both hands as equally painful, Participants
their dominant hand. The acetaminophen and NSAIDs con-
sumption was calculated asking the patients at each visit the We revised the medical charts of 436 patients with con-
number of tablets taken weekly. comitant EHOA and knee OA. Of these, 200 patients were
Furthermore, we evaluated all adverse events, whether excluded because of the unavailability of recent hand radio-
reported spontaneously by the patients or observed by the graphs to confirm the diagnosis of EHOA and 78 for the
physician, were recorded, describing the severity and any concomitant treatment with intra-muscular bisphospho-
possible relationship with the treatment. nates. Furthermore, we excluded other 35 patients, because
they did not meet other inclusion criteria or fulfilled other
Statistical analysis exclusion criteria. Only 10 patients presented a poor compli-
ance to the combination program prescribed and were not
A sample size of at least 50 patients per group was adequate included. Finally, a total of 123 patients with complete data
for evidencing a difference between the two groups of at were included in our analysis as follows: 67 in the pCGS-
least 10 mm in the change in global hand pain score between exposed Group and 56 in the pCGS-unexposed Group
baseline and the 6-month end-point, hypothesizing a stand- (Fig. 1).
ard deviation (SD) of 15 mm, with a power of 80% and an Baseline demographic and clinical characteristics of the
alpha error of 0.05. study population are reported in Table 1. The two groups
Continuous variables were evaluated in term of means were comparable, except for the percentage of acetami-
and standard deviation (SD), after checking their normal- nophen users that was greater in the pCGS-unexposed Group
ity. For categorical relative frequencies (%) were reported. (p < 0.05); participants were mainly women with a mean
Parametric univariate tests (p-values were referred to Fisher age (SD) of 66.6 (9.6) years and a disease duration of 3.7
Exact for frequencies and t-test for means) were used for (1.7) years.
13
Fig. 1 Flow diagram of the

Paents with knee and hand OA who were prescribed pCGS therapy in addion to
study population. OA osteoar-
thritis, pCGS prescription-grade convenonal therapy or convenonal therapy alone from October 2016 to
crystalline glucosamine sulfate; October 2021
DMARDs disease modifying n=436
anti-rheumatic drug
Excluded (n=278)
• X-Ray not available to confirm diagnosis (n=200)
• Concomitant treatment with bisphosphonates (n=78)
Assessed for eligibility

n=158
Excluded (n= 35)

• Treatment duraon less than 6 months (n=10)
• Other inclusion criteria not met or exclusion criteria

fulfilled (n=25)
Analyzed
n=123
pCGS-exposed Group pCGS-unexposed Group

n=67 n=56
Primary and secondary clinical outcomes baseline for HAQ was −0.28 [SD 0.59] in pCGS-exposed
Group and 0.01 [SD 0.46] in pCGS-unexposed Group with
Figure 2a shows the changes in the patient’s assessment a mean between-group difference of −0.29 (p < 0.01). The
of global hand pain, calculated by VAS (0–100 mm), after difference between groups in VAS stiffness became statisti-
3 and 6 months of treatment. The mean change between cally significant at 3 months and remained unchanged at
baseline and month 6 in VAS pain in pCGS-exposed Group 6 months (p < 0.05), while for HAQ the statistical signifi-
was greater than in pCGS-unexposed Group (mean −21.79 cance between groups was reached at the end of follow-
[SD 22.18] versus −10.33 [SD 19.99] mm; mean between- up (Fig. 3a, b). SF-36 significantly improved through the
group difference −11.46 [p < 0.01]) (Fig. 2a). The difference follow-up in the pCGS-exposed Group with a mean change
between groups was slightly significant after 3 months of between basal time and the end of follow-up in PCS of
treatment (p < 0.05) and became more evident at 6 months 3.98 [SD 9.21] versus −0.12 [SD 6.39] in the pCGS-unex-
(p < 0.01) (Fig. 2a). posed Group with a mean between-group difference of 4.1
The changes in FIHOA scores at 3 and 6 months were (p < 0.05) (Fig. 3c). Also, the mean change between baseline
reported in Fig. 2b. Similarly, to VAS pain, the mean change and month 6 in SF-36 MCS was greater in pCGS-exposed
from baseline and month 6 in FIHOA was more pronounced Group compared to pCGS-unexposed Group (mean 5.77
in patients treated with pCGS than in unexposed ones (mean [SD 13.3] versus −1.67 [SD 9.51]; mean between-group
−4.16 [SD 4.63] versus −1.57 [SD 2.37]; mean between- difference 7.44 [p < 0.001] (Fig. 3d).
group difference −2.59 [p < 0.001]). The statistical signifi- In Table 2 we reported the values of primary and second-
cance between groups was reached already at 3 months and ary outcomes expressed as mean and standard deviation in
maintained until 6 months (p < 0.001) (Fig. 2b). the two studied groups through the follow-up period.
The results about the secondary outcomes are shown in Concerning the use of symptomatic drugs, at baseline
Fig. 3a–d. The mean change between basal time and the end there was a significant major consumption of acetami-
of follow-up in VAS stiffness was higher in patients treated nophen in pCGS-unexposed Group than in pCGS-exposed
with pCGS than in unexposed (mean −5.11 [SD 7.54] ver- Group. It remained stable over time in pCGS-unexposed
sus −1.96 [SD 8.70] minutes; mean between-group differ- Group, while significantly decreased in the pCGS-exposed
ence −3.15 [p < 0.05]). At six months the mean change from Group (p < 0.001). The difference between groups became
13
Table 1 Demographic and pCGS-exposed pCGS-unexposed p-value

clinical characteristics of the Group (n = 67) Group (n = 56)
study population
Age (years) 66.5 (9.5) 66.8 (9.9) 0.88a
Sex males/females, n 5/62 3/53 0.63b
Education, n (%)
Primary school 16 (24) 13 (23) 0.93b
Middle school 18 (27) 18 (32) 0.52b
High school 26 (39) 23 (41) 0.52b
University 7 (10) 2 (4) 0.14b
BMI (kg/m2) 25.1 (3.4) 24.0 (3.6) 0.09a
Disease duration (years) 3.7 (1.7) 3.7 (1.7) 0.93c
Radiographic Score (K/L grade), n (%) (°)
II 26 (39) 21 (37) 0.88b
III 41 (61) 35 (63) 0.88b
Swollen IP joints
Right hand 0.9 (1.4) 1.2 (1.9) 0.25c
Left hand 0.8 (1.5) 1.2 (1.8) 0.26c
Patients with concomitant TMC OA, n (%) 56 (83.6) 44 (79) 0.50b
Current smokers, n (%) 5 (7) 9 (16) 0.13b
CV disease, n (%) 11 (16) 11 (20) 0.63b
Hypertension, n (%) 30 (45) 26 (46) 0.86b
Autoimmune thyroiditis, n (%) 22 (33) 14 (25) 0.43b
Hypercholesterolemia n (%) 42 (63) 32 (57) 0.53b
Hypertriglyceridemia, n (%) 8 (12) 2 (4) 0.09b
ESR (mm/h) 22.5 (14.0) 18.6 (11.8) 0.05a
CRP (mg/dl) 0.24 (0.19) 0.42 (1.33) 0.27a
VAS pain (0–100 mm) 66.8 (18.5) 66 (17.5) 0.80a
VAS stiffness (min) 10.8 (10) 13.5 (13.8) 0.21a
FIHOA (0–30) 10.8 (4.8) 11.1 (4.7) 0.74a
HAQ (0–3) 0.75 (0.5) 0.77 (0.5) 0.81a
SF-36 PCS 40.6 (11.1) 41.4 (10.2) 0.69a
SF-36 MCS 36.7 (16.6) 37.2 (15.9) 0.84a
Acetaminophen users, n (%) 32 (48) 37 (66) 0.04b
NSAIDs users, n (%) 41 (61) 29 (52) 0.29b
Except where indicated otherwise, values are expressed as mean ± SD

The significance of bold value is p < 0.05
pCGS prescription-grade crystalline glucosamine sulfate, BMI body mass index, K–L grade Kellgren–
Lawrence grade, IP interphalangeal, TMC OA trapeziometacarpal osteoarthritis, CV cardiovascular, ESR
erythrocyte sedimentation rate, CRP C-reactive protein, VAS Visual Analogue Scale, FIHOA Functional
Index for Hand Osteoarthritis, HAQ Health Assessment Questionnaire, SF-36 PCS medical outcome study
36-item short form physical component summary, SF-36 MCS medical outcome study 36-item short form
mental component summary, NSAIDs non-steroidal anti-inflammatory drugs
°Determined by the joint with the highest grade
a
Unpaired t test
b
Chi square test
c
Mann–Whitney test
more significant (p < 0.001) after 3 and 6 months (Table 3). baseline, the results did not change (p < 0.0001 for the
After adjusting our analyses for the differences between comparison at 3 and 6 months). Non-selective or COX-2
the two groups in the weekly use of acetaminophen at selective NSAIDs consumption resulted significantly
13
Fig. 2 Means with standard

error changes in the Visual Ana-
logue Scale (VAS) (0–100 mm)
(a), and in the Functional
Index for Hand Osteoarthritis
(FIHOA) score (0–30) (b), after
3 and 6 months in prescription-
grade Crystalline Glucosamine
sulfate (pCGS)-exposed Group
and pCGS-unexposed Group.
pCGS-exposed Group vs pCGS-
unexposed Group: *p < 0.05;
**p < 0.01; ***p < 0.001
reduced at 3 and 6 months (p < 0.001) in the pCGS- the disorder, while dyspepsia and nausea resolved spontane-
exposed Group, while the unexposed patients experienced ously after few days. 21% of the patients in the pCGS-unex-
a slight, but not significant decrease of NSAIDs use during posed Group experienced several adverse events, mainly
the follow-up. The differences between the groups were epigastralgia and increase of systemic blood pressure. The
significant (p < 0.01) at the end of the follow-up (Table 3). five patients suffering of epigastralgia needed a brief course
The pCGS-exposed Group had a greater rate of respond- of oral pump inhibitor therapy. Fortunately, the increase of
ers, according to OMERACT-OARSI criteria, compared systemic blood disease was only transient and did not need
to pCGS-unexposed Group both at 3 (23.8 versus 3.5%, any specific treatment (Table 4).
between-group difference = 0.001) and 6 months (50.7 ver-
sus 19.6%, between-group difference < 0.001).
Discussion
Safety
This observational retrospective study demonstrates the abil-
With regard to the safety analysis, pCGS treatment resulted ity of the prescription-grade crystalline glucosamine sulfate
safe and well tolerated. Only a minority of the patients of improving pain and function, when used in combination
treated with pCGS (13%) reported side effects, all transient to conventional therapy, in patients with erosive osteoarthri-
and of light intensity that no one had to interrupt the ther- tis of the hand. The improvement of both parameters was
apy. The more frequent side effects in this group were diar- already significant after 3 months of therapy, but became
rhea reported in four patients and dyspepsia/nausea in three more evident after 6 months. In agreement with previ-
patients. Three of the four patients suffering from diarrhea ous results, the effects on hand functionality, measured by
received 1 week therapy with probiotics with resolution of
13
Fig. 3 Means with standard error changes in morning stiffness, meas- Mental Component Score (MCS) of SF-36 (d), after 3 and 6 months
ured by Visual Analogue Scale (VAS) (minutes) (a), in the Health in prescription-grade Crystalline Glucosamine Sulfate (pCGS)-
Assessment Questionnaire (HAQ) (0–3) (b), in the Physical Compo- exposed Group and pCGS-unexposed Group. pCGS-exposed Group
nent Score (PCS) of the Short-Form Survey 36 (SF-36) (c), and in the vs pCGS-unexposed Group: *p < 0.05; **p < 0.001; ***p < 0.001
Table 2 Mean ± standard deviation (SD) of primary and secondary outcomes at each evaluation time
Parameter pCGS-exposed Group (n = 67) pCGS-unexposed Group (n = 56)

Baseline 3-months 6-months Baseline 3-months 6-months
(T0) (T1) (T2) (T0) (T1) (T2)
VAS pain (mm) 66.8 ± 18.5 53.5 ± 21.31*** 45 ± 24.01*** 66 ± 17.4 58.7 ± 19.2** 55.7 ± 22.2**
FIHOA score 10.8 ± 4.8 7.8 ± 4.6*** 6.7 ± 4.6*** 11.1 ± 4.7 10.2 ± 5.1 9.5 ± 5.1*
VAS stiffness (min) 10.8 ± 10 7.5 ± 7.5** 5.7 ± 5.5*** 13.5 ± 13.8 12.5 ± 12.8 11.6 ± 11
HAQ 0.7 ± 0.5 0.5 ± 0.4** 0.4 ± 0.3*** 0.7 ± 0.5 0.7 ± 0.5 0.7 ± 0.5
SF-36 PCS 40.6 ± 11.1 42.9 ± 10.2 44.7 ± 10.2** 41.4 ± 10.2 41.3 ± 11.1 41.3 ± 11.1
SF-36 MCS 36.7 ± 16.6 40.4 ± 14.4 42.4 ± 14.5** 37.2 ± 15.9 35.5 ± 16.3 35.5 ± 16.3
pCGS prescription-grade Crystalline Glucosamine Sulfate, VAS Visual Analogue Scale, FIHOA Functional Index for Hand Osteoarthritis, HAQ
Health Assessment Questionnaire, SF-36 PCS medical outcome study 36-item short form physical component summary, SF-36 MCS medical
outcome study 36-item short form mental component summary
* p < 0.05 T2 vs T0; ** p < 0.01 T1, T2 vs T0; *** p < 0.001 T1, T2 vs T0
FIHOA, resulted more pronounced than those on VAS pain symptomatic drugs intake. Particularly, we observed a sig-
[22, 35]. nificant reduction in acetaminophen and selective or non-
Furthermore, a significant difference in the change of selective NSAIDs use, after 3 and 6 months, with a signifi-
duration of morning stiffness, HAQ and SF-36 was observed cant difference between the studied groups. These findings
between the two studied groups. In our opinion, the sig- suggest an overall better control of the disease symptoms
nificant increase of PCS and MCS of SF-36 at 6 months with pCGS therapy in agreement with previous studies [52,
(p < 0.001) is noteworthy, considering that EHOA is known 53]. In particular, the Pharmaco-Epidemiology of GonAr-
to be associated with a high impact on quality of life [9, 50, trhoSis (PEGASus) study reported that, among the analyzed
51]. SYSADOAs (pCGS, glucosamine hydrochloride, pCS, avo-
In line with the above-reported beneficial effects, the cado soybean unsaponifiables and diacerein), only pCGS
treatment with pCGS resulted in a relevant decrease in
13
Table 3 Symptomatic drugs consumption at each evaluation time

Parameter pCGS-exposed Group (n = 67) pCGS-unexposed Group (n = 56)
Baseline 3-months (T1) 6-months Baseline 3-months 6-months
(T0) (T2) (T0) (T1) (T2)
Acetaminophen consumption (n 1.9 (2.7) 1.1 (2.2)°°° 0.9 (1.8)°°° 3.1 (3.7)* 3.2 (3.7)*** 3.2 (3.3)***
of 500 mg-tablets/week)
NSAIDs consumption 2.3 (2.3) 1.3 (1.5)°°° 0.6 (1.7)°°° 2.1 (2.5) 1.5 (2.0) 1.4 (2.1)**
(n of tablets/week)
Data are reported as mean ± SD

pCGS prescription-grade Crystalline Glucosamine Sulfate, NSAIDs non-steroidal anti-inflammatory drugs
*
p < 0.05 pCGS-exposed Group vs pCGS-unexposed Group; **p < 0.01 pCGS-exposed Group vs pCGS-unexposed Group; ***p < 0.001 pCGS-
exposed Group vs pCGS-unexposed Group; °°°p < 0.001 T1, T2 vs T0
Table 4 Number (%) of patients with treatment-related adverse events subcutaneously every 2 weeks or placebo in a double-blind
in the study population RCT [11]. In addition, other two double-blind RCTs failed
pCGS-exposed pCGS-unexposed to demonstrate significant improvement of pain and other
Group (n = 67) Group (n = 56) outcomes after adalimumab therapy versus placebo [12, 13].
Also, etanercept resulted not superior to placebo in reducing
Epigastralgia 2 (2.9%) 5 (8.9%)
VAS pain after 24 weeks in a 1-year double-blind RCT [15].
Dyspepsia/nausea 3 (4.4%) 2 (3.5%)
Conversely, in a single-blind study, monthly intra-articular
Diarrhea 4 (5.9%) 1 (1.7%)
injections of infliximab into the affected joints led to a sig-
Increased blood pressure 0 (0%) 4 (7%)
nificant improvement of pain after 12 months compared to
Total n of patients with 9 (13.2%) 12 (21.1%)
adverse event intra-articular injections of saline [54]. Also, the data about
targeting IL-1 and IL-6 are not very encouraging. Indeed,
pCGS prescription-grade Crystalline Glucosamine Sulfate a recent placebo-controlled randomized study did not show
significant improvement of pain after 24 weeks of therapy
was able to induce a reduction of 36% of NSAIDs intake with lutikizumab 200 mg subcutaneously every 2 weeks
(OR 0.64; 95% CI 0.45–0.92) [53]. [17]; similarly, two infusions, 4 weeks apart, of tocilizumab
Furthermore, in the present study, we observed a lower resulted no more effective than placebo in inducing pain
amount of side effects, especially of the gastric ones, in the relief at week 4, 6, 8 or 12 [18]. In agreement with these
pCGS Group, probably due to the overall decrease of symp- clinical trials on biologics, a recent study on HOA patients
tomatic drugs consumption. showed poorly detectable IL-1β concentrations and minimal
To the best of our knowledge, this is the first study evalu- inflammasome activity in the peripheral blood mononuclear
ating the effectiveness of pCGS, as an add-on therapy to cells of both erosive and non-erosive HOA patients [55].
conventional treatments in patients with EHOA, a very Furthermore, the results derived from trials assessing the
complex disease which is actually lacking of effective thera- efficacy of the classical DMARDs, as hydroxychloroquine,
pies. It is still debated if EHOA represents a more advanced methotrexate and colchicine, were not more positive [14,
phase of the classical HOA or rather a separate and more 16, 19, 20, 56]. Conversely, intravenous and intra-muscular
severe entity; its pathogenetic mechanisms are still poorly clodronate, a first-generation bisphosphonate, currently reg-
known [7, 8]. For decades, an important role in the underly- istered in Europe for the treatment of postmenopausal osteo-
ing processes of EHOA was attributed to inflammation, but porosis, was demonstrated as effective in reducing pain and
the disappointing and contrasting results derived from trials disability in patients with EHOA [57, 58].
evaluating the treatment with the classical and biological Altogether, these data might question the pivotal role of
anti-rheumatic drugs in this pathology induces an impor- pro-inflammatory cytokines in the complex pathogenetic
tant reflection about the need for a better understanding of processes involved in HOA and suggest that the treatments
the basic disease mechanisms and the potential therapeutic targeting a single mechanism of action may be insufficient
targets [5]. Indeed, several clinical trials assessing the effi- [59].
cacy of anti-TNF agents and other anti-cytokine inhibitors It is likely that the positive results obtained in the current
in EHOA failed to reach the primary outcomes. Particularly, study can beneficiate of a multimodal approach rather than a
no differences in erosive progression were reported after single pharmacological agent. According to EULAR guide-
12 months between patients treated with adalimumab 40 mg lines for HOA [21], our study population was treated with
13
a combination of non-pharmacological (education, training evaluated the effects of pCGS in addition to conventional
in ergonomic principles and exercise) and pharmacological therapy compared to usual therapy alone in 108 patients
interventions (acetaminophen or NSAIDs on-demand) and affected by non-erosive HOA. The treatment with pCGS
some patients received also pCGS for the concomitant knee resulted associated to a more significant improvement of
OA, as chronic background therapy [32–34]. The compli- pain and function, as well as to a reduction of concomi-
ance to this multimodal therapeutic program was good; this tant symptomatic drugs intake [35]. The present study
was probably due to the education about the nature of the shows similar results in erosive osteoarthritis of the hand,
disease and the therapeutic objectives, offered to all patients. suggesting a promising and potential role of pCGS as
Indeed, it is recognized that these measures have minimal add-on therapy to conventional treatment in this patho-
effect on OA symptoms, but they are essential for treatment logic condition.
adherence [32]. The main limitation of the present analysis consists in
Glucosamine is a natural compound of glycosaminogly- its observational retrospective design with all the limita-
cans in the cartilage matrix and synovial fluid. It is com- tions inherent to a not randomized, not blinded and not
mercially available as glucosamine hydrochloride, derived placebo-controlled trial. In particular, the lack of a placebo
from an extraction process and often used as a nutraceutical arm could have led to overestimate the positive results
or over-the-counter (OTC) product or glucosamine sulfate, in pCGS Group, considering that HOA patients are very
a more complex compound, obtained only by a proprietary susceptible to placebo effects [70, 71]. In addition, the
semi-synthetic route and stabilization process, responsible small sample size did not allow us to perform any sub-
for the production of the pCGS [60–63]. pCGS, adminis- group analysis or to adjust our analysis according to con-
tered as once-daily dose of 1500 mg, is the only glucosamine founder factors, such as comorbidities. Then, demographic
formulation highly bioavailable and able to reach therapeutic and clinical characteristics of the two studied groups were
concentrations at the site of action [64–67]. comparable at baseline, except for the percentage of aceta-
pCGS is widely used for the treatment of knee OA for minophen users which was higher in the pCGS-unexposed
its symptomatic and disease-modifying effects, explained Group. Thus, although this difference was only minor, it
through several different mechanisms. Pre-clinical studies could have affected our results. Furthermore, although we
demonstrated the ability of pCGS to inhibit superoxide-rad- selected as primary outcomes VAS pain and FIHOA score,
ical production, inducible nitric oxide synthesis, the COX-2 according to the Osteoarthritis Research Society Interna-
and prostaglandin E2 (PGE2) generation, probably respon- tional (OARSI) and ESCEO recommendations for the con-
sible for the relatively fast onset of symptomatic action dem- duct of pharmacological clinical trials in HOA [72, 73],
onstrated in previous clinical trials. Furthermore, in vitro we are aware that FIHOA includes some items culturally
studies on OA chondrocyte cultures demonstrated that the challenging or outdated and thus, it was rejected as a core
above-described mechanism of action is mediated by the outcome measure for HOA trials [74]. Other limitations
inhibition of the nuclear factor kappa B (NF-kB) pathway, were represented by the duration of 6 months of the fol-
activated by IL-1 during the inflammatory process [24, 25, low-up and by the lack of any standardization for NSAIDs
66]. consumption. Further, this study was performed in a single
The effectiveness of pCGS has been well demonstrated center and included only EHOA with certain inclusion
in knee OA in three high-quality trials which showed a criteria (e.g. VAS pain > 40 mm and FIHOA > 6), so the
mild–moderate effect on WOMAC pain ( effect size of 0.27) results may not be generalisable to every setting.
and, WOMAC function subscales (effect size 0.33) and on In conclusion, this observational retrospective study
Lequesne algo-functional index [26, 27, 29]. A network showed that oral pCGS, at the dosage of 1500 mg once
meta-analysis by Gregori et al. [68], who analyzed published daily, used as an add-on therapy to conventional treatments
long-term (12 months) RCTs in knee OA, demonstrated that, was more effective than usual care alone in improving
when studies at high risk of bias were excluded, pCGS was hand pain and functionality in patients with EHOA. This
the only analyzed drug able to induce a significant improve- symptomatic effect was evident already after 3 months of
ment of pain and physical function. Similar results were therapy and persisted until 6 months. These findings can
reported in a recent systematic review and network meta- be promising; however, they should be considered with
analysis with a 6-month time horizon [69]. caution, and confirmed in future RCTs.
Unfortunately, the treatment with pCGS in patients
with HOA has never been evaluated in RCTs; for this Supplementary Information The online version contains supplemen-
tary material available at https://d oi.o rg/1 0.1 007/s 40520-0 22-0 2151-7.
reason, this drug is not included in the update of the 2018
EULAR recommendations for the management of HOA. Funding Open access funding provided by Università degli Studi di
In a previous retrospective study, for the first time, we Siena within the CRUI-CARE Agreement.
13
Declarations 11. Verbruggen G, Wittoek R, Vander Cruyssen B et al (2012)

Tumour necrosis factor blockade for the treatment of erosive
osteoarthritis of the interphalangeal finger joints: a double
Conflict of interest On behalf of all authors, the corresponding author
blind, randomised trial on structure modification. Ann Rheum
states that there is no conflict of interest.
Dis 71:891–898. https://doi.org/10.1136/ard.2011.149849
12. Chevalier X, Ravaud P, Maheu E, et al.; French Section of Osteo-
Ethical approval For this type of study, ethics approval is not required.
arthritis (2015) Adalimumab in patients with hand osteoarthritis
refractory to analgesics and NSAIDs: a randomised, multicentre,
Informed consent Informed consent was obtained from all individual
double-blind, placebo-controlled trial. Ann Rheum Dis 74:1697–
participants included in the study.
1705. https://doi.org/10.1136/annrheumdis-2014-205348
13. Aitken D, Laslett LL, Pan F et al (2018) A randomised double-
Open Access This article is licensed under a Creative Commons Attri- blind placebo-controlled crossover trial of HUMira (adalimumab)
bution 4.0 International License, which permits use, sharing, adapta- for erosive hand OsteoaRthritis - the HUMOR trial. Osteoarthr
tion, distribution and reproduction in any medium or format, as long Cartil 26:880–887. https://doi.org/10.1016/j.joca.2018.02.899
as you give appropriate credit to the original author(s) and the source, 14. Kingsbury SR, Tharmanathan P, Keding A et al (2018) Hydrox-
provide a link to the Creative Commons licence, and indicate if changes ychloroquine effectiveness in reducing symptoms of hand oste-
were made. The images or other third party material in this article are oarthritis: a randomized trial. Ann Intern Med 168:385–395.
included in the article's Creative Commons licence, unless indicated https://doi.org/10.7326/M17-1430
otherwise in a credit line to the material. If material is not included in 15. Kloppenburg M, Ramonda R, Bobacz K et al (2018) Etanercept
the article's Creative Commons licence and your intended use is not in patients with inflammatory hand osteoarthritis (EHOA): a
permitted by statutory regulation or exceeds the permitted use, you will multicentre, randomised, double-blind, placebo-controlled trial.
need to obtain permission directly from the copyright holder. To view a Ann Rheum Dis 77:1757–1764. https://doi.org/10.1136/annrh
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. eumdis-2018-213202
16. Lee W, Ruijgrok L, Boxma-de Klerk B et al (2018) Efficacy of
hydroxychloroquine in hand osteoarthritis: a randomized, dou-
ble-blind, placebo-controlled trial. Arthritis Care Res (Hobo-
References ken) 70:1320–1325. https://doi.org/10.1002/acr.23471
17. Kloppenburg M, Peterfy C, Haugen IK et al (2019) Phase IIa,
1. Qin J, Barbour KE, Murphy LB et al (2017) Lifetime Risk of placebo-controlled, randomised study of lutikizumab, an anti-
Symptomatic Hand Osteoarthritis: The Johnston County Osteo- interleukin-1α and anti-interleukin-1β dual variable domain
arthritis Project. Arthritis Rheumatol 69:1204–1212. https://doi. immunoglobulin, in patients with erosive hand osteoarthritis.
org/10.1002/art.40097 Ann Rheum Dis 78:413–420. https://d oi.o rg/1 0.1 136/a nnrh
2. Arthritis Foundation (2019) Osteoarthritis of the Hands. eumdis-2018-213336
https:// w ww. a rthr i tis. o rg/ d isea s es/ m ore- a bout/ o steo a rthr 18. Richette P, Latourte A, Sellam J et al (2020) Efficacy of toci-
itis-of-the-hands lizumab in patients with hand osteoarthritis: double blind, ran-
3. Addimanda O, Mancarella L, Dolzani P et al (2012) Clinical and domised, placebo-controlled, multicentre trial. Ann Rheum Dis.
radiographic distribution of structural damage in erosive and https://doi.org/10.1136/annrheumdis-2020-218547
nonerosive hand osteoarthritis. Arthritis Care Res (Hoboken) 19. Ferrero S, Wittoek R, Allado E et al (2021) Methotrexate treat-
64:1046–1053. https://doi.org/10.1002/acr.21658 ment in hand osteoarthritis refractory to usual treatments: a ran-
4. Gazeley DJ, Yeturi S, Patel PJ et al (2017) Erosive osteoarthri- domised, double-blind, placebo-controlled trial. Semin Arthritis
tis: A systematic analysis of definitions used in the literature. Rheum 51:831–838. https://d oi.o rg/1 0.1 016/j.s emart hrit.2 021.0 4.
Semin Arthritis Rheum 46:395–403. https://doi.org/10.1016/j. 016
semarthrit.2016.08.013 20. Kedor C, Detert J, Rau R et al (2021) Hydroxychloroquine in
5. Marshall M, Watt FE, Vincent TL et al (2018) Hand osteoar- patients with inflammatory and erosive osteoarthritis of the hands:
thritis: clinical phenotypes, molecular mechanisms and disease results of the OA-TREAT study-a randomised, double-blind, pla-
management. Nat Rev Rheumatol 14:641–656. https://doi.org/ cebo-controlled, multicentre, investigator-initiated trial. RMD
10.1038/s41584-018-0095-4 Open 7:e001660. https://doi.org/10.1136/rmdopen-2021-001660
6. Favero M, Belluzzi E, Ortolan A et al (2022) Erosive hand 21. Kloppenburg M, Kroon FP, Blanco FJ et al (2019) 2018 update
osteoarthritis: latest findings and outlook. Nat Rev Rheumatol. of the EULAR recommendations for the management of hand
https://doi.org/10.1038/s41584-021-00747-3 osteoarthritis. Ann Rheum Dis 78:16–24. https://d oi.o rg/1 0.1 136/
7. Marshall M, Nicholls E, Kwok WY et al (2015) Erosive osteo- annrheumdis-2018-213826
arthritis: a more severe form of radiographic hand osteoarthri- 22. Gabay C, Medinger-Sadowski C, Gascon D et al (2011) Sympto-
tis rather than a distinct entity? Ann Rheum Dis 74:136–141. matic effects of chondroitin 4 and chondroitin 6 sulfate on hand
https://doi.org/10.1136/annrheumdis-2013-203948 osteoarthritis: a randomized, double-blind, placebo-controlled
8. Poletto E, Tinazzi I, Marchetta A et al (2021) Hand erosive clinical trial at a single center. Arthritis Rheum 63:3383–3391.
osteoarthritis and distal interphalangeal involvement in psoriatic https://doi.org/10.1002/art.30574
arthritis: the place of conservative therapy. J Clin Med 10:2630. 23. Rovetta G, Monteforte P, Molfetta G et al (2004) A two-year study
https://doi.org/10.3390/jcm10122630 of chondroitin sulfate in erosive osteoarthritis of the hands: behav-
9. Tenti S, Ferretti F, Gusinu R et al (2020) Impact of thumb osteo- ior of erosions, osteophytes, pain and hand dysfunction. Drugs
arthritis on pain, function, and quality of life: a comparative study Exp Clin Res 30:11–16
between erosive and non-erosive hand osteoarthritis. Clin Rheu- 24. Largo R, Alvarez-Soria MA, Díez-Ortego I et al (2003) Glucosa-
matol 39:2195–2206. https://d oi.o rg/1 0.1 007/s 10067-0 20-0 4982-z mine inhibits IL-1beta-induced NFkappaB activation in human
10. McAlindon TE, Driban JB, Roberts MB et al (2021) Erosive osteoarthritic chondrocytes. Osteoarthr Cartil 11:290–298. https://
hand osteoarthritis: incidence and predictive characteristics doi.org/10.1016/s1063-4584(03)00028-1
among participants in the osteoarthritis initiative. Arthritis 25. Cheleschi S, Tenti S, Giannotti S et al (2021) A combination of
Rheumatol 73:2015–2024. https://doi.org/10.1002/art.41757 celecoxib and glucosamine sulfate has anti-inflammatory and
13
chondroprotective effects: results from an in vitro study on human 39. Kellgren JH, Lawrence JS (1957) Radiological assessment of
osteoarthritic chondrocytes. Int J Mol Sci 22:8980. https://d oi.o rg/ osteo-arthrosis. Ann Rheum Dis 16:494–502. https://doi.org/10.
10.3390/ijms22168980 1136/ard.16.4.494
26. Reginster JY, Deroisy R, Rovati LC et al (2001) Long-term effects 40. Østerås N, Hagen KB, Grotle M et al (2014) Exercise programme
of glucosamine sulphate on osteoarthritis progression: a ran- with telephone follow-up for people with hand osteoarthritis -
domised, placebo-controlled clinical trial. Lancet 357:251–256. protocol for a randomised controlled trial. BMC Musculoskelet
https://doi.org/10.1016/S0140-6736(00)03610-2 Disord 15:82. https://doi.org/10.1186/1471-2474-15-82
27. Pavelka K, Bruyere O, Rovati LC et al (2003) Relief in mild-to- 41. Østerås N, Kjeken I, Smedslund G et al (2017) Exercise for
moderate pain is not a confounder in joint space narrowing assess- hand osteoarthritis: a cochrane systematic review. J Rheumatol
ment of full extension knee radiographs in recent osteoarthritis 44:1850–1858. https://doi.org/10.3899/jrheum.170424
structure-modifying drug trials. Osteoarthr Cartil 11:730–737. 42. Ariani A, Manara M, Fioravanti A et al (2019) The Italian Society
https://doi.org/10.1016/s1063-4584(03)00166-3 for Rheumatology clinical practice guidelines for the diagnosis
28. Towheed TE, Maxwell L, Anastassiades TP et al (2005) Glucosa- and management of knee, hip and hand osteoarthritis. Reuma-
mine therapy for treating osteoarthritis. Cochrane Database Syst tismo 71:5–21. https://doi.org/10.4081/reumatismo.2019.1188
Rev. https://doi.org/10.1002/14651858.CD002946.pub2 43. Dreiser RL, Maheu E, Guillou GB (2000) Sensitivity to change
29. Herrero-Beaumont G, Ivorra JA, Del Carmen TM et al (2007) of the functional index for hand osteoarthritis. Osteoarthr Cartil
Glucosamine sulfate in the treatment of knee osteoarthritis symp- 8:S25–S28. https://doi.org/10.1053/joca.2000.0332
toms: a randomized, double-blind, placebo-controlled study using 44. Gandini F, Giannitti C, Fattore G et al (2012) Validation of an
acetaminophen as a side comparator. Arthritis Rheum 56:555– Italian version of the functional index for hand osteoarthritis
567. https://doi.org/10.1002/art.22371 (FIHOA). Mod Rheumatol 22:758–765. https://doi.org/10.1007/
30. Giordano N, Fioravanti A, Papakostas P et al (2009) The efficacy s10165-011-0579-4
and tolerability of glucosamine sulfate in the treatment of knee 45. Ranza R, Marchesoni A, Calori G et al (1993) The Italian ver-
osteoarthritis: A randomized, double-blind, placebo-controlled sion of the Functional Disability Index of the Health Assessment
trial. Curr Ther Res Clin Exp 70:185–196. https://doi.org/10. Questionnaire. A reliable instrument for multicenter studies on
1016/j.curtheres.2009.05.004 rheumatoid arthritis. Clin Exp Rheumatol 11:123–128
31. Bruyère O, Reginster JY, Honvo G et al (2019) Cost-effectiveness 46. Bruce B, Fries JF (2003) The Stanford Health Assessment Ques-
evaluation of glucosamine for osteoarthritis based on simulation tionnaire: dimensions and practical applications. Health Qual Life
of individual patient data obtained from aggregated data in pub- Outcomes 1:20. https://doi.org/10.1186/1477-7525-1-20
lished studies. Aging Clin Exp Res 31:881–887. https://doi.org/ 47. Ware JE Jr, Sherbourne CD (1992) The MOS 36-item short-form
10.1007/s40520-019-01138-1 health survey (SF-36). I. Conceptual framework and item selec-
32. Bruyère O, Cooper C, Pelletier JP et al (2014) An algorithm rec- tion. Med Care 30:473–483
ommendation for the management of knee osteoarthritis in Europe 48. Apolone G, Mosconi P (1998) The Italian SF-36 health survey:
and internationally: a report from a task force of the European translation, validation and norming. J Clin Epidemiol 51:1025–
Society for Clinical and Economic Aspects of Osteoporosis and 1036. https://doi.org/10.1016/s0895-4356(98)00094-8
Osteoarthritis (ESCEO). Semin Arthritis Rheum 44:253–263. 49. Pham T, van der Heijde D, Altman RD et al (2004) OMERACT-
https://doi.org/10.1016/j.semarthrit.2014.05.014 OARSI initiative: Osteoarthritis Research Society International
33. Bruyère O, Cooper C, Pelletier JP et al (2016) A consensus set of responder criteria for osteoarthritis clinical trials revisited.
statement on the European Society for Clinical and Economic Osteoarthr Cartil 12:389–399. https://d oi.o rg/1 0.1 016/j.j oca.2 004.
Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm 02.001
for the management of knee osteoarthritis-From evidence-based 50. Bijsterbosch J, Watt I, Meulenbelt I et al (2010) Clinical burden
medicine to the real-life setting. Semin Arthritis Rheum 45:S3-11. of erosive hand osteoarthritis and its relationship to nodes. Ann
https://doi.org/10.1016/j.semarthrit.2015.11.010 Rheum Dis 69:1784–1788. https://doi.org/10.1136/ard.2009.
34. Bruyère O, Honvo G, Veronese N et al (2019) An updated algo- 125435
rithm recommendation for the management of knee osteoarthritis 51. Michon M, Maheu E, Berenbaum F (2011) Assessing health-
from the European Society for Clinical and Economic Aspects related quality of life in hand osteoarthritis: a literature review.
of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases Ann Rheum Dis 70:921–928. https://doi.org/10.1136/ard.2010.
(ESCEO). Semin Arthritis Rheum 49:337–350. https://doi.org/ 131151
10.1016/j.semarthrit.2019.04.008 52. Bruyere O, Pavelka K, Rovati LC et al (2008) Total joint replace-
35. Tenti S, Giordano N, Mondanelli N et al (2020) A retrospective ment after glucosamine sulphate treatment in knee osteoarthritis:
observational study of glucosamine sulfate in addition to conven- results of a mean 8-year observation of patients from two previous
tional therapy in hand osteoarthritis patients compared to conven- 3-year, randomised, placebo-controlled trials. Osteoarthr Cartil
tional treatment alone. Aging Clin Exp Res 32:1161–1172. https:// 16:254–260. https://doi.org/10.1016/j.joca.2007.06.011
doi.org/10.1007/s40520-019-01305-4 53. Rovati LC, Girolami F, D’Amato M et al (2016) Effects of glu-
36. Agenzia Italiana del Farmaco (AIFA). Guideline for the classifi- cosamine sulfate on the use of rescue non-steroidal anti-inflamma-
cation and conduction of the observational studies on medicines. tory drugs in knee osteoarthritis: Results from the Pharmaco-Epi-
http://www.agenziafarmaco.gov.it/allegati/det_20marzo2008.pdf. demiology of GonArthroSis (PEGASus) study. Semin Arthritis
Accessed 30 Mar 2022 Rheum 45:S34-41. https://doi.org/10.1016/j.semarthrit.2015.10.
37. Altman R, Asch E, Bloch D et al (1986) Development of criteria 009
for the classification and reporting of osteoarthritis. Classification 54. Fioravanti A, Fabbroni M, Cerase A et al (2009) Treatment of
of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria erosive osteoarthritis of the hands by intra-articular infliximab
Committee of the American Rheumatism Association. Arthritis injections: a pilot study. Rheumatol Int 29:961–965. https://doi.
Rheum 29:1039–1049. https://doi.org/10.1002/art.1780290816 org/10.1007/s00296-009-0872-0
38. Fioravanti A, Cheleschi S, De Palma A et al (2018) Can adi- 55. Fioravanti A, Tenti S, McAllister M et al (2019) Exploring the
pokines serum levels be used as biomarkers of hand osteoarthritis? Involvement of NLRP3 and IL-1β in Osteoarthritis of the Hand:
Biomarkers 23:265–270. https://d oi.o rg/1 0.1 080/1 35475 0X.2 017. Results from a Pilot Study. Mediators Inflamm 2019:2363460.
1401665 https://doi.org/10.1155/2019/2363460
13
56. Davis CR, Ruediger CD, Dyer KA et al (2021) Colchicine is not 67. Bruyère O, Altman RD, Reginster JY (2016) Efficacy and safety of
effective for reducing osteoarthritic hand pain compared to pla- glucosamine sulfate in the management of osteoarthritis: evidence
cebo: a randomised, placebo-controlled trial (COLAH). Osteoar- from real-life setting trials and surveys. Semin Arthritis Rheum
thr Cartil 29:208–214. https://doi.org/10.1016/j.joca.2020.11.002 45:S12-17. https://doi.org/10.1016/j.semarthrit.2015.11.011
57. Saviola G, Abdi-Ali L, Campostrini L et al (2012) Clodronate and 68. Gregori D, Giacovelli G, Minto C et al (2018) Association of
hydroxychloroquine in erosive osteoarthritis: a 24-month open pharmacological treatments with long-term pain control in
randomized pilot study. Mod Rheumatol 22:256–263. https://doi. patients with knee osteoarthritis: a systematic review and meta-
org/10.1007/s10165-011-0506-8 analysis. JAMA 320:2564–2579. https://doi.org/10.1001/jama.
58. Saviola G, Abdi-Ali L, Povino MR et al (2017) Intramuscular 2018.19319
clodronate in erosive osteoarthritis of the hand is effective on 69. Beaudart C, Lengelé L, Leclercq V et al (2020) Symptomatic
pain and reduces serum COMP: a randomized pilot trial-The efficacy of pharmacological treatments for knee osteoarthritis: a
ER.O.D.E. study (ERosive Osteoarthritis and Disodium-clo- systematic review and a network meta-analysis with a 6-month
dronate Evaluation). Clin Rheumatol 36:2343–2350. https://doi. time horizon. Drugs 80:1947–1959. https://doi.org/10.1007/
org/10.1007/s10067-017-3681-y s40265-020-01423-8
59. Felson DT, Neogi T (2018) Emerging treatment models in rheu- 70. Zou K, Wong J, Abdullah N et al (2016) Examination of overall
matology: challenges for osteoarthritis trials. Arthritis Rheumatol treatment effect and the proportion attributable to contextual effect
70:1175–1181. https://doi.org/10.1002/art.40515 in osteoarthritis: meta-analysis of randomised controlled trials.
60. Kucharz EJ, Kovalenko V, Szántó S et al (2016) A review of glu- Ann Rheum Dis 75:1964–1970. https://doi.org/10.1136/annrh
cosamine for knee osteoarthritis: why patented crystalline glu- eumdis-2015-208387
cosamine sulfate should be differentiated from other glucosamines 71. Nakagawa Y, Tatebe M, Yamamoto M et al (2021) Choice of
to maximize clinical outcomes. Curr Med Res Opin 32:997–1004. control group treatments in hand osteoarthritis trials: a systematic
https://doi.org/10.1185/03007995.2016.1154521 review and meta-analysis. Semin Arthritis Rheum 51:775–785.
61. Bruyère O, Cooper C, Al-Daghri NM et al (2018) Inappropri- https://doi.org/10.1016/j.semarthrit.2021.04.006
ate claims from non-equivalent medications in osteoarthritis: a 72. Kloppenburg M, Maheu E, Kraus VB, et al.; OARSI Hand Clini-
position paper endorsed by the European Society for Clinical and cal Trial Recommendations Work Group (2015) OARSI Clinical
Economic Aspects of Osteoporosis, Osteoarthritis and Muscu- Trials Recommendations: design and conduct of clinical trials for
loskeletal Diseases (ESCEO). Aging Clin Exp Res 30:111–117. hand osteoarthritis. Osteoarthr Cartil 23:772–786. https://d oi.o rg/
https://doi.org/10.1007/s40520-017-0861-1 10.1016/j.joca.2015.03.007
62. Reginster JL, Bruyere O, Cooper C (2018) Different glucosamine 73. Reginster JL, Arden NK, Haugen IK et al (2018) Guidelines for
sulfate products generate different outcomes on osteoarthritis the conduct of pharmacological clinical trials in hand osteoarthri-
symptoms. Ann Rheum Dis 77:e39. https://d oi.o rg/1 0.1 136/a nnrh tis: Consensus of a Working Group of the European Society on
eumdis-2017-212251 Clinical and Economic Aspects of Osteoporosis, Osteoarthritis
63. Veronese N, Demurtas J, Smith L, et al.; on behalf on the Euro- and Musculoskeletal Diseases (ESCEO). Semin Arthritis Rheum
pean Geriatric Medicine Society Special Interest Groups in Sys- 48:1–8. https://doi.org/10.1016/j.semarthrit.2017.12.003
tematic Reviews and Meta-Analyses and Arthritis (2020) Glu- 74. Kroon FPB, van der Heijde D, Maxwell LJ et al (2021) Core
cosamine sulphate: an umbrella review of health outcomes. Ther outcome measurement instrument selection for physical function
Adv Musculoskelet Dis 12:1759720X20975927. https://doi.org/ in hand osteoarthritis using the OMERACT Filter 2.1 process.
10.1177/1759720X20975927 Semin Arthritis Rheum 51:1311–1319. https://doi.org/10.1016/j.
64. Persiani S, Roda E, Rovati LC et al (2005) Glucosamine oral bio- semarthrit.2021.08.014
availability and plasma pharmacokinetics after increasing doses
of crystalline glucosamine sulfate in man. Osteoarthr Cartil Publisher's Note Springer Nature remains neutral with regard to
13:1041–1049. https://doi.org/10.1016/j.joca.2005.07.009 jurisdictional claims in published maps and institutional affiliations.
65. Persiani S, Rotini R, Trisolino G et al (2007) Synovial and plasma
glucosamine concentrations in osteoarthritic patients following
oral crystalline glucosamine sulphate at therapeutic dose. Osteo-
arthr Cartil 15:764–772. https://d oi.org/10.1016/j.joca.2007.01.
019
66. Chiusaroli R, Piepoli T, Zanelli T et al (2011) Experimental phar-
macology of glucosamine sulfate. Int J Rheumatol 2011:939265.
https://doi.org/10.1155/2011/939265
13

s40520 022 02151 7

Uploaded by

Copyright:

Available Formats

s40520 022 02151 7

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

s40520 022 02151 7

Uploaded by

Copyright:

Available Formats

Aging Clinical and Experimental Research (2022) 34:1613–1625

Prescription‑grade crystalline glucosamine sulfate as an add‑on

* Antonella Fioravanti Introduction

Fig. 1 Flow diagram of the

• Concomitant treatment with bisphosphonates (n=78)

Assessed for eligibility

Excluded (n= 35)

• Other inclusion criteria not met or exclusion criteria

pCGS-exposed Group pCGS-unexposed Group

Table 1 Demographic and pCGS-exposed pCGS-unexposed p-value

Except where indicated otherwise, values are expressed as mean ± SD

Fig. 2 Means with standard

Parameter pCGS-exposed Group (n = 67) pCGS-unexposed Group (n = 56)

Table 3 Symptomatic drugs consumption at each evaluation time

Data are reported as mean ± SD

Declarations 11. Verbruggen G, Wittoek R, Vander Cruyssen B et al (2012)

You might also like