[Effect of nerve growth factor on elderly degenerative knee osteoarthritis pain].

OBJECTIVE: To explore effect of nerve growth factor (NGF) antibody on knee osteoarthritis (KOA) pain model was evaluated by in vitro model. METHODS: Thirty male SPF rats aged 28-week-old were divided into blank group (10 rats with anesthesia only). The other 20 rats were with monoiodoacetate (MIA) on the right knee joint to establish pain model of OA, and were randomly divided into control group (injected intraperitoneal injection of normal saline) and treatment group (injected anti-NGF) intraperitoneal after successful modeling, and 10 rats in each group. All rats were received retrograde injection of fluorogold (FG) into the right knee joint. Gait was assessed using catwalk gait analysis system before treatment, 1 and 2 weeks after treatment. Three weeks after treatment, right dorsal root ganglia (DRG) were excised on L4-L6 level, immunostained for calcitonin gene-related peptide (CGRP), and the number of DRGS was counted. RESULTS: In terms of gait analysis using cat track system, duty cycle, swing speed and print area ratio in control and treatment group were significantly reduced compared with blank group (P<0.05). Compared with control group, duty cycle and swing speed of treatment group were significantly improved (P<0.05), and there was no significant difference in print area ratio between treatment group and blank group (P>0.05). The number of FG-labeled DRG neurons in control group was significantly higher than that in treatment group and blank group (P<0.05). The expression of CGRP in control group was up-regulated, and differences were statistically significant compared with treatment group (P<0.05). CONCLUSION: Intraperitoneal injection of anti-NGF antibody inhibited gait injury and upregulation of CGRP in DRG neurons. The results suggest that anti-nerve growth factor therapy may be of value in treating knee pain. NGF may be an important target for the treatment of knee OA pain.

Tuina Intervention in Sodium Monoiodoacetate Injection-Induced Rat Model of Knee Osteoarthritis.

Knee osteoarthritis (KOA), a common degenerative joint disorder, is characterized by chronic pain and disability, which can progress to irreparable structural damage of the joint. Investigations into the link between articular cartilage, muscles, synovium, and other tissues surrounding the knee joint in KOA are of great importance. Currently, managing KOA includes lifestyle modifications, exercise, medication, and surgical interventions; however, the elucidation of the intricate mechanisms underlying KOA-related pain is still lacking. Consequently, KOA pain remains a key clinical challenge and a therapeutic priority. Tuina has been found to have a regulatory effect on the motor, immune, and endocrine systems, prompting the exploration of whether Tuina could alleviate KOA symptoms, caused by the upregulation of inflammatory factors, and further, if the inflammatory factors in skeletal muscle can augment the progression of KOA. We randomized 32 male Sprague Dawley (SD) rats (180-220 g) into four groups of eight animals each: antiPD-L1+Tuina (group A), model (group B), Tuina (group C), and sham surgery (group D). For groups A, B, and C, we injected 25 µL of sodium monoiodoacetate (MIA) solution (4 mg MIA diluted in 25 µL of sterile saline solution) into the right knee joint cavity, and for group D, the same amount of sterile physiological saline was injected. All the groups were evaluated using the least to most stressful tests (paw mechanical withdrawal threshold, paw withdrawal thermal latency, swelling of the right knee joint, Lequesne MG score, skin temperature) before injection and 2, 9, and 16 days after injection.

Is higher body mass index associated with secondary osteoarthritis in patients treated with bone cement for benign aggressive bone tumors? Long-term evaluation of 43 patients.

BACKGROUND: This study was designed to investigate the secondary osteoarthritis rate in patients with benign aggressive bone tumors treated with curettage and cementing at long-term follow up. METHODS: Patients diagnosed with benign aggressive bone tumor (giant cell or aneurysmal bone cyst), treated with extended curettage and cementation with polymethylmethacrylate, who had a minimum of 60 months of follow up after surgery were included in this study. After definitive diagnoses were confirmed by a histopathologist, we decided to perform standard surgical management. Osteoarthritis was staged radiologically using the Kellgren-Lawrence scoring system, and the contralateral knees of the patients were used as the control group. Based on the Kellgren-Lawrence classification system, stages 3 and 4 were accepted as the existence of osteoarthritis. Body mass index, the distance to the subchondral joint line, tumor mass volume, the location of the tumor (i.e., femur, tibia, medial condyle, or lateral condyle), age, and sex were also investigated, all of which are factors that can affect the occurrence of osteoarthritis. RESULTS: Forty-three patients, 24 male (56%) and 19 female (44%), were included in the study. The mean age of the patients was 29.5 ± 10 years, and mean follow up duration was 128.7 months. Tumor localization was the distal femur in 20 patients (46.5%) and the proximal tibia in 23 patients (53.5%). The mean tumor mass volume was 77.84 cm3 and the distance to the knee joint subchondral line was 3.2 ± 2 mm. According to this scoring system, 14 patients were at stage 0, 10 patients were at stage 1, 10 patients were at stage 2, four patients were at stage 3, and five patients were at stage 4. When we compared osteoarthritis development, the affected knee had a significantly higher rate of osteoarthritis development than the contralateral knee. A univariate analysis demonstrated that age (P = 0.002) and body mass index (P = 0.045) were associated with secondary osteoarthritis. Moreover, multivariate analysis demonstrated that none of the variables were independently associated with secondary osteoarthritis. CONCLUSION: Patients with contralateral osteoarthritis had bilateral knee osteoarthritis, indicating that primary osteoarthritis progressed in both knees. Seven of the 43 patients (16.2%) showed secondary osteoarthritis. Although age and body mass index were associated with secondary osteoarthritis in univariate analysis, none of the variables were independently associated with secondary osteoarthritis in the multivariate analysis.

Specification, validation, and adherence of quality indicators to optimize the safe use of nonsteroidal anti-inflammatory drugs for knee osteoarthritis pain in the primary care setting.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) used for osteoarthritis (OA) in primary care may cause gastrointestinal or renal injury. This study estimated adherence to two quality indicators (QIs) to optimize NSAID safety: add proton pump inhibitors (PPI) to NSAIDs for patients with gastrointestinal (GI) risk (QI #1 NSAID-PPI) and avoid oral NSAIDs in chronic kidney disease (CKD) stage G4 or G5 (QI #2 NSAID-CKD). METHODS: This retrospective study included index primary care clinic visits for knee OA at our health system in 2019. The validation cohort consisted of a random sample of 60 patients. The remainder were included in the expanded cohort. Analysis of structured data extracts was validated against chart review of clinic visit notes (validation cohort) and estimated QI adherence (expanded cohort). RESULTS: Among 60 patients in the validation cohort, analysis of data extracts was validated against chart review for QI #1 NSAID-PPI (100% sensitivity and 91% specificity) and QI #2 NSAID-CKD (100% accuracy). Among 335 patients in the expanded cohort, 44% used NSAIDs, 27% used PPIs, 73% had elevated GI risk, and only 2% had CKD stage 4 or 5. Twenty-one percent used NSAIDs and had elevated GI risk but were not using PPIs. Therefore, adherence to QI #1 NSAID-PPI was 79% (95% CI, 74-83%). No patients with CKD stage 4 or 5 used NSAIDs. Therefore, adherence to QI #2 NSAID-CKD was 100%. CONCLUSION: A substantial proportion of knee OA patients with GI risk factors did not receive PPI with NSAID therapy during primary care visits.

Non-weight-bearing exercise attenuates papain-induced knee osteoarthritis in rats via the TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND AND AIM: Knee osteoarthritis (KOA) is characterized by joint wear and degeneration. Unfortunately, the medical community currently lacks effective treatment options for this disease. Suspension exercise therapy is considered an effective form of non-weight-bearing exercise for treating KOA. However, its mechanism of intervention in KOA is unclear. Therefore, this study aimed to evaluate the protective effects of non-weight-bearing exercise on rats with KOA and attempted to explore the underlying mechanisms. METHODS: In this study, a papain-induced KOA model was constructed, and the pathological changes in cartilage tissue were observed by hematoxylin and eosin (H&E) staining and scored according to the Mankin scoring principle. The serum levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay. Reverse transcription-quantitative polymerase chain reaction and Western blotting were used to detect the expression of mRNA and proteins in the TLR4/MyD88/NF-κB signaling pathway. RESULTS: H&E staining and Mankin score data confirmed that non-weight-bearing exercise significantly improved articular cartilage degradation compared with that in the model group. Further, we observed that non-weight-bearing exercise differentially reduced serum levels of IL-1ß, IL-6, and TNF-α. Mechanistically, non-weight-bearing exercise downregulated gene and protein expression of TLR4, MyD88, and NF-κB in cartilage tissue. CONCLUSION: Non-weight-bearing exercise resulted in the progression of KOA by modulating the TLR4/MyD88/NF-κB signaling pathway and decreasing the levels of the inflammatory cytokines IL-1ß, IL-6, and TNF-α to slow down the degeneration of articular cartilage.

Relatively low fluoride in drinking water increases risk of knee osteoarthritis (KOA): a population-based cross-sectional study in China.

Previous studies indicate that fluoride in drinking water has a toxic effect on cartilage and skeleton, which triggers osteoarthritis (OA) of which the most frequent is knee OA (KOA). A cross-sectional study was conducted to assess the association between fluoride exposure and KOA among 1128 subjects. Water fluoride (WF) and urinary fluoride (UF) were chosen as external exposure (internal exposure) of fluoride. Logistic regression analysis showed that an increased fluoride exposure was a risk factor for KOA (WF: OR = 1.318, 95% CI 1.162-1.495, p < 0.001; UF: OR = 1.210, 95% CI 1.119-1.310, p < 0.001). After adjusting for covariates, the risk of KOA in the 4th quartile (Q) of WF was twice that of the 1st Q (OR = 2.079, 95% CI 1.448-2.986, p < 0.001). The risks of KOA in the 2nd Q, 3rd Q and 4th Q of UF were 1.6, 1.5, and 2.9 times higher than in the 1stQ (OR = 1.597, 95% CI 1.066-2.393, p = 0.023; OR = 1.560, 95% CI 1.043-2.333, p = 0.030; OR = 2.897, 95% CI 1.957-4.288, p < 0.001). The population aged < 60 exposed to the 4th Q of WF (or UF) had a higher risk than the population exposed to the 1st Q of WF (or UF) (ORWF = 1.958, 95% CI 1.249-3.070, p = 0.003; ORUF = 2.923, 95% CI 1.814-4.711, p < 0.001). With increasing UF by Q, the male had a risk of KOA. In conclusion, excessive fluoride dose in drinking water could increase the risk of KOA. Especially, the population with aged < 60, male and obesity more likely to having KOA when they exposed to same higher fluoride.

Ameliorative Effects of Prolotherapy on Histomorphology of Tibial Articular Cartilage of Chemically Induced Osteoarthritic Knee Joint in a Rat Model.

OBJECTIVE: To determine the ameliorative effects of prolotherapy on monosodium iodoacetate (MIA) induced and histomorphological changes in the articular cartilage of tibial condyles at rat knee joint. STUDY DESIGN: An experimental study. Place and Duration of the Study: Department of Anatomy, Army Medical College Rawalpindi, NUMS, Rawalpindi, from August to November 2021. METHODOLOGY: Thirty adult male Sprague Dawley rats were divided into three groups, each having 10 rats. Group A was control. Group B was injected with single dose of 1mg MIA intraarticularly in the right knee to induce osteoarthritic changes. Group C was injected with single dose of 1mg MIA intraarticularly, in right knee was followed by 0.1ml Prolotherapy (3ml of 25% dextrose, 2ml of 2% xylocaine, 1ml of injection neurobion, and 1ml of injection methecobal) as intra articular injection at week 2, 6 and 10 in right knee. Rats were sacrificed after one month of the last dose of Prolotherapy. Articular cartilage was collected for gross and histological examination and compared among the groups. RESULTS: Articular cartilage belonging to control group A was normal. While group B showed statistically significant deterioration in gross appearance (p = 0.001**), reduction in number of chondrocytes (p = 0.005*) and thickness of articular cartilage (p = 0.001**) in comparison to group A. In group C due to prolotherapy statistically significant improvement in gross appearance (p = 0.034*), increase in number of chondrocytes (p = 0.003*), and thickness of articular cartilage (p = 0.001**) was observed as compared to group B. CONCLUSION: Prolotherapy significantly ameliorates histomorphology of tibial articular cartilage against MIA induced osteoarthritic changes in rat knee joint. KEY WORDS: Articular cartilage, Knee joint, Monosodium iodoacetate, Osteoarthritis, Prolotherapy.

Treatment with CR500® improves algofunctional scores in patients with knee osteoarthritis: a post-market confirmatory interventional, single arm clinical investigation.

BACKGROUND: Knee osteoarthritis (OA) is a progressive and degenerative condition. Several pharmacological and non-pharmacological treatments are able to improve the OA symptoms and the structural characteristics of the affected joints. Among these, infiltrative therapy with hyaluronic acid (HA) is the most used and consolidated procedure for the pain management. The addition of skin conditioning peptides to HA promotes the cartilage remodeling processes and a better permeation of the HA-based gel containing a peptide mixture, CR500®. Furthermore, the topic route of administration is convenient over the routinely used intra-articular injective procedures. In this study, the effectiveness of CR500® was evaluated in terms of improvement of the algo-functional symptoms related to unilateral knee OA. METHODS: 38 mild and moderate OA patients were enrolled at a screening visit (V-1), treated at baseline visit (V1), and then continued the topical application of CR500® twice a week for 4 weeks, and followed-up for 3 visits (V2-V4) from week 2 to 4. Lequesne Knee Index (LKI) and Knee injury and Osteoarthritis Outcome Score (KOOS) were collected. Synovial fluid was collected and used for the quantification of neoepitope of type II collagen (C2C), C-terminal telopeptide of type II collagen (CTX-II), type II collagen propeptide (CPII), tumor necrosis factor alpha (TNFα) and HA. The expression of CD11c and CD206 was evaluated on cell pellets. RESULTS: Three patients were excluded, thus 35 patients were included in the analysis. The treatment with CR500® was safe and well tolerated, with 7.9% patients had mild adverse events, not related to the device. The LKI total score showed a significant decrease from V1 to V4. KOOS score also showed a significant improvement of patient condition at V2, V3 and V4 in comparison with V1 for all subscales, except for KOOS sport subscale which improved only from V3. At V1 a negative correlation among KOOS pain subscale values and C2C, CPII and TNFα levels was observed, as well as a positive correlation between KOOS pain subscale and CD11c/CD206 ratio. CONCLUSION: CR500® is safe and appear to be effective in improving pain and function in OA patients during the 4 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05661162. This trial was registered on 22/12/2022.

Highlighting the Advantages and Benefits of Non-NSAID Treatment After Total Knee Arthroplasty: A Cross-sectional Study.

BACKGROUND/AIM: Osteoarthritis is one of the most common degenerative conditions that causes pain, stiffness, and decreased functionality. The management of knee osteoarthritis necessitates collaboration among specialists from different disciplines, considering the primary clinical manifestations and functional level of the disease. The aim of this study was to highlight the disparities in postoperative outcomes between knee arthroplasty procedures with and without non-steroidal anti-inflammatory drugs (NSAIDs). The study specifically focuses on the immediate advantages and outcomes observed at the 6-month milestone. PATIENTS AND METHODS: This study followed 713 patients who were randomly divided into two groups: a group that did not receive non-steroidal anti-inflammatory drugs (N-NSAIDs) consisting of 394 patients, and a group that received non-steroidal anti-inflammatory drugs (NSAIDs) comprising 319 patients. The study spanned a duration of 5 years (2018-2022), with patients being followed and evaluated for up to 6 months after the surgery. RESULTS: It was observed that, from a therapeutic standpoint, the use of injectable treatments decreased. Significantly better differences were recorded in the N-NSAIDs group regarding return to pre-osteoarthritis activities at 6 months and reduced or absent night pain at 3 months (p<0.05). CONCLUSION: Statistically significant improvements were observed in the N-NSAIDs group concerning the ability to resume pre-osteoarthritis activities within 6 months, as well as a reduction or absence of nighttime pain within 3 months.

Efficacy of Veronica incana for Treating Osteoarthritis Induced by Monosodium Iodoacetate in Rats.

The aim of this study is to investigate the efficacy and the underlying mechanism of Veronica incana in osteoarthritis (OA) induced by intraarticular injection of monosodium iodoacetate (MIA). The selected major four compounds (A-D) of V. incana were found from fractions 3 and 4. Its structure elucidation was determined by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) data analysis and nuclear magnetic resonance (NMR) data comparison with literature. MIA (50 µL with 80 mg/mL) for the animal experiment was injected into the right knee joint. The V. incana was administered orally every day to rats for 14 days from 7 days after MIA treatment. Finally, we confirmed the four compounds: (A) verproside; (B) catalposide; (C) 6-vanilloylcatapol; and (D) 6-isovanilloylcatapol. When we evaluated the effect of V. incana on the MIA injection-induced knee OA model, there were a noticeable initial decreased in hind paw weight-bearing distribution compared to the Normal group (P < .001), but V. incana supplementation resulted in a significant increase in the weight-bearing distribution to the treated knee (P < .001). Moreover, the V. incana treatment led to a decrease in the levels of liver function enzymes and tissue malondialdehyde (P < .05 and .01). The V. incana significantly suppressed the inflammatory factors through the nuclear factor-kappa B signaling pathway and downregulated the expression of matrix metalloproteinases, which are involved in the degradation of the extracellular matrix (P < .01 and .001). In addition, we confirmed the alleviation of cartilage degeneration through tissue stains. In conclusion, this study confirmed the major four compounds of V. incana and suggested that V. incana could serve as an anti-inflammatory candidate agent for patients with OA.

Potential drug-drug interactions in patients presenting with osteoarthritis to community orthopaedic clinics of Abbottabad, Khyber Pakhtunkhwa: A cross-sectional study.

OBJECTIVES: Osteoarthritis (OA) causes long-term pain and disorders of lower extremities. Paracetamol is the drug of choice; however, NSAIDs, opioids and steroids are frequently employed in the symptomatic relief of OA. The prescribing of multiple analgesics leads to potential drug-drug interactions (pDDIs). The primary objective of this study was to identify the prevalence and predictors of pDDIs in OA. MATERIALS AND METHODS: A total of three hundred and eighty-six patients, either newly diagnosed or with a history of OA, were enrolled for this cross-sectional study. Data regarding patients' demographics, clinical characteristics and prescribed medications were recorded from the prescriptions and examined for the pDDIs using Medscape multidrug interaction checker. RESULTS: Among 386, most patients were females (53.4%). The most prevalent diagnoses were knee OA (39.7%) and unspecified OA (31.3%). Paracetamol and topical NSAIDs were underprescribed whereas an oral NSAID, Diclofenac, was the most frequently used drug in OA. Total of 109 pDDIs were found in 386 prescriptions, of which 63.3% DDIs were categorised as moderate, followed by minor (34.9%) and major (1.8%). CONCLUSIONS: This study finds a prevalence of DDIs and polypharmacy among the OA patients. Collaborative efforts among healthcare providers, pharmacists, and patients themselves are essential to optimize medication regimens and minimize the polypharmacy including the associated risks as well as DDIs.

Within-subject, double-blind, randomized, placebo-controlled evaluation of combining the cannabinoid dronabinol and the opioid hydromorphone in adults with chronic pain.

The potential synergistic effects of combining cannabinoids and opioids for analgesia has received considerable attention. No studies to date have evaluated this combination in patients with chronic pain. The present study aimed to evaluate the combined analgesic and drug effects of oral opioid (hydromorphone) and delta-9-tetrahydrocannabinol (dronabinol), as well as their effects on physical and cognitive functioning, and human abuse potential (HAP) outcomes among individuals with knee osteoarthritis (KOA). This was a within-subject, double-blind, randomized, placebo-controlled study. Participants (N = 37; 65% women; mean age = 62) diagnosed with knee osteoarthritis of ≥3/10 average pain intensity were included. Participants received (1) placebo-placebo, (2) hydromorphone (4 mg)-placebo; (3) dronabinol (10 mg)-placebo, and (4) hydromorphone (4 mg)-dronabinol (10 mg). Clinical and experimentally-induced pain, physical and cognitive function, subjective drug effects, HAP, adverse events, and pharmacokinetics were evaluated. No significant analgesic effects were observed for clinical pain severity or physical functioning across all drug conditions. Little enhancement of hydromorphone analgesia by dronabinol was observed on evoked pain indices. While subjective drug effects and some HAP ratings were increased in the combined drug condition, these were not significantly increased over the dronabinol alone condition. No serious adverse events were reported; hydromorphone produced more mild adverse events than placebo, but hydromorphone + dronabinol produced more moderate adverse events than both placebo and hydromorphone alone. Only hydromorphone impaired cognitive performance. Consistent with laboratory studies on healthy adults, the present study shows minimal benefit of combining dronabinol (10 mg) and hydromorphone (4 mg) for analgesia and improving physical functioning in adults with KOA.

No Evidence for Cognitive Impairment in an Experimental Rat Model of Knee Osteoarthritis and Associated Chronic Pain.

Although chronic pain states have been associated with impaired cognitive functions, including memory and cognitive flexibility, the cognitive effects of osteoarthritis (OA) pain remain to be clarified. The aim of this study was to measure cognitive function in the mono-iodoacetate (MIA) rat model of chronic OA-like knee pain. We used young adult male Lister hooded rats, which are well-suited for cognitive testing. Rats received either a unilateral knee injection of MIA (3 mg/50 µL) or saline as control. Joint pain at rest was assessed for up to 12 weeks, using weight-bearing asymmetry, and referred pain at a distal site, using determination of hindpaw withdrawal thresholds. The watermaze delayed-matching-to-place test of rapid place learning, novel object recognition memory assay, and an operant response-shift and -reversal task were used to measure memory and behavioral flexibility. Open-field locomotor activity, startle response, and prepulse inhibition were also measured for comparison. MIA-injected rats showed markedly reduced weight-bearing on the injured limb, as well as pronounced cartilage damage and synovitis, but interestingly no changes in paw withdrawal threshold. Rearing was reduced, but otherwise, locomotor activity was normal and no changes in startle and prepulse inhibition were detected. MIA-injected rats had intact watermaze delayed-matching-to-place performance, suggesting no substantial change in hippocampal function, and there were no changes in novel object recognition memory or performance on the operant task of behavioral flexibility. Our finding that OA-like pain does not alter hippocampal function, unlike other chronic pain conditions, is consistent with human neuroimaging findings. PERSPECTIVE: Young adult rats with OA-like knee pain showed no impairments in hippocampal memory function and behavioral flexibility, suggesting that OA pain impacts cognitive functions less than other chronic pain conditions. In patients, OA pain may interact with other factors (e.g., age, socio-economic factors, and medication) to impair cognition.

Comparative effectiveness of early initiation of oral nonsteroidal anti-inflammatory drug and oral acetaminophen therapies on the time to knee replacement in patients with knee osteoarthritis in Japan.

BACKGROUND: Although disease-modifying properties of nonsteroidal anti-inflammatory drugs (NSAIDs) for osteoarthritis (OA) have been reported, the effects of NSAIDs on OA progression remain controversial. The purpose of this study was to investigate the effect of early initiation of oral NSAID therapy on the progression of knee OA. METHODS: In this retrospective cohort study, we extracted data of patients newly diagnosed with knee OA between November 2007 and October 2018 from a Japanese claims database. The primary outcome was the time to knee replacement (KR), and the secondary outcome was the time to composite event including joint lavage and debridement, osteotomy, or arthrodesis in addition to KR. Weighted Cox regression analysis with standardized mortality/morbidity ratio (SMR) weight was performed to compare the outcomes between patients prescribed oral NSAID (NSAID group) and those prescribed oral acetaminophen (APAP) (APAP group) early after a diagnosis of knee OA. Propensity scores were calculated using logistic regression conditioned on potential confounding factors, and SMR weights were calculated using the propensity scores. RESULTS: The study population comprised 14,261 patients, who were divided into two groups as follows: 13,994 in the NSAID group and 267 in the APAP group. The mean ages of patients in the NSAID and APAP groups were 56.9 and 56.1 years, respectively. Furthermore, 62.01% and 68.16% patients in the NSAID and APAP groups, respectively, were female. The NSAID group had a reduced risk of KR compared with the APAP group in the analysis using SMR weighting (SMR-weighted hazard ratio, 0.19; 95% confidence interval, 0.05-0.78). While no statistically significant difference was found for the risk of composite event between the two groups (SMR-weighted hazard ratio, 0.56; 95% confidence interval, 0.16-1.91). CONCLUSIONS: The risk of KR in the NSAID group was significantly lower than that in the APAP group after accounting for residual confounding using SMR weighting. This finding suggests that oral NSAID therapy early after the initial diagnosis is associated with a reduced risk of KR in patients with symptomatic knee OA.

Chondroprotective Effects of Grapefruit (Citrus paradisi Macfad.) Juice in a Complete Freund's Adjuvant Rat Model of Knee Osteoarthritis.

Osteoarthritis (OA) is a common disorder that can affect any joint in the human body. This study aimed to examine the anti-arthritic properties of high and low doses of grapefruit juice (GFJ), as grapefruit appears to contain anti-inflammatory biochemicals. Forty male Sprague-Dawley rats weighing 170-180 g were divided into five groups. These groups comprised the untreated control group and osteoarthritic (Osteo) rats administered intra-articular injections of Freund's complete adjuvant (CFA; 0.5 mL; 1 mg/mL) as follows: OA rats administered low doses of GFJ (Osteo+GFJ (low); 5 mL/kg body weight (BW)); OA rats administered high doses of GFJ (Osteo+GFJ (high); 27 mL/kg BW); and OA rats administered diclofenac sodium (Osteo+Diclo) as a reference drug. Injections of CFA induced OA, as indicated by a significant increase in the serum levels of the inflammatory biomarkers C-reactive protein (CRP), interleukin-1ß (IL-1ß), and (prostaglandin (PGE2), as well as matrix metalloproteinases (MMP-1) and cathepsin K. The synovial levels of glycosaminoglycans (GAGs), tumor necrosis factor (TNF-α), and interleukin 6 (IL-6) also increased, with a concomitant reduction in osteocalcin levels. The administration of either high or low doses of GFJ reduced CRP, IL-1ß, PGE2, MMP-1, cathepsin K, and osteocalcin while increasing the synovial levels of GAGs, TNF-α, and IL-6, slowing cartilage degradation and boosting joint function. The results showed comparable histopathological and biochemical responses. A comparison of the treatments showed that high-dose GFJ had a greater chondroprotective effect than low-dose GFJ.

Eplerenone modulates the inflammatory response in monosodium iodoacetate-induced knee osteoarthritis in rats: Involvement of RANKL/OPG axis.

AIMS: Osteoarthritis (OA) is a multifactorial degenerative disease marked by the progressive deterioration of articular cartilage with inflammation of the synovium. OA's main symptoms include pain and function loss. Monosodium Iodoacetate (MIA) experimental model is widely-used for OS induction since it produces symptoms comparable to those occurring in humans. MATERIALS AND METHODS: Thirty-two rats were divided into four groups (n = 8). The 1st group received saline and included the normal-control rats. Groups 2-4 received intra-articular injections of MIA (3 mg/50 µL) in the rats' knee joints to induce OA. Group 2 included the MIA-control rats. Groups 3 and 4 received intra-articular MIA followed by a 14-day oral eplerenone (50 and 100 mg/kg); respectively. KEY FINDINGS: Intra-articular injection of MIA in rats' knee joints caused significant inflammation and pain, elevation of Akt and ERK gene expression in knee joints along with significant alterations in the histological pictures of knee joints and OARSI scores. RANKL/OPG Axis was significantly disrupted. SIGNIFICANCE: Eplerenone treatment produced a significant improvement in motor coordination and spontaneous locomotor activity in rats and modulated the key inflammatory mediators in OA (TNF-α, NF-κß, and IL-6). Eplerenone also suppressed the qRT-PCR gene expression of Akt and ERK in knee joint tissues and improved the histological pictures and OARSI scores of knee joints of treated rats. Eplerenone caused a decline in RANKL concentration accompanied by a rise in OPG concentration thus modulating the RANKL/OPG Axis. Consequently, eplerenone is a candidate for OA therapy due to its potential anti-inflammatory effects.

Electroacupuncture ameliorates knee osteoarthritis in rats via inhibiting NLRP3 inflammasome and reducing pyroptosis.

Objective: Knee Osteoarthritis (KOA), is the most common joint disease worldwide. The pathogenesis of KOA is complex and electroacupuncture (EA) is an effective therapy for KOA, but the mechanism remains unclear. In this study, we aim to investigate the potential therapeutic effect of EA on the rat model of KOA induced by monosodium iodoacetate (MIA) and its relationship with NLRP3 inflammasome by immunohistochemistry and western blot. Methods: KOA was induced by intra-articular injection of MIA (3 mg/50 µL) into the right knee joint of rats. Forty-five male rats weighing 250-300 g were randomly divided into 3 groups: control group, KOA group, and KOA + electroacupuncture group (KOA+EA). EA treatment lasted for 2 weeks (6 times a week). Paw withdrawal threshold tests were used to assess mechanical allodynia once a week. Safranin O/Fast Green and hematoxylin and eosin (H&E) staining were used to assess the damage to cartilage, synovium, and subpatellar fat pad (IFP). Immunohistochemistry was used to observe NLRP3 inflammasome-associated protein-positive cells in the same field of view and western blot was used to detect the expression of the associated protein in cartilage tissue. Results: The KOA group showed mechanical hyperalgesia, joint inflammation, and significant cartilage tissue destruction. Safranin O/Fast Green and H&E staining revealed that EA alleviated the joint pathological changes caused by KOA and had a protective effect on cartilage, synovium, and IFP destruction. Mechanical allodynia pain and joint swelling were reduced in KOA rats after EA treatment. Immunohistochemistry and western blot showed significant inhibition of NLRP3 inflammasome-associated protein. Conclusion: The results indicate that EA can inhibit NLRP3 inflammasome and reduce pyroptosis, which results in the protection of cartilage tissue and the treatment of KOA. It provides reliable evidence for the development of EA in the treatment of KOA and the clinical application of acupuncture.

Possible synergic action of non-steroidal anti-inflammatory drugs and glucosamine sulfate for the treatment of knee osteoarthritis: a scoping review.

BACKGROUND: Several studies have reported that glucosamine sulfate (GS) can improve knee osteoarthritis (OA) symptomatology. In parallel, the disease-modifying effects of non-steroidal anti-inflammatory drugs (NSAIDs) in knee OA have also been investigated. However, limited literature has reported the combined effect of GS and NSAIDs. The aim of this scoping review is to describe the scope and volume of the literature investigating the potential benefits and synergistic effect of a combination of GS and NSAIDs in patients with knee OA. METHODS: PubMed and Embase were searched for studies published from inception through April 2022, evaluating the effects of the combination of GS and NSAIDs in OA patients, versus either treatment alone. Data are reported narratively. RESULTS: Five studies were included in this review; 4 were randomized control trials and one was a prospective observational study. The duration of combination treatment was 6 to 12 weeks. The combination was compared to celecoxib in 2 studies, meloxicam in 1, etoricoxib in 1, and a conventional NSAID in 1 (ibuprofen or piroxicam). All 5 studies reported that in patients with knee OA, the combination of GS plus NSAID yielded a significantly greater benefit than single-agent therapy, in terms of outcomes including pain reduction, function, joint stiffness, and markers of inflammatory activity and cartilage degradation. CONCLUSION: The 5 studies included in this scoping review all report a significantly greater clinical benefit with a combination of GS plus NSAID compared to either treatment alone. The evidence supports efficacy in reducing pain, improving function, and possibly regulating joint damage. However, further randomized trials with larger sample sizes are warranted to confirm these findings.

A randomized, double-blind placebo-controlled phase I clinical study on safety and efficacy of the G-Rup® syrup (a mixture of ginger extract and honey) in symptomatic treatment of knee osteoarthritis.

WHAT IS KNOWN AND OBJECTIVES: Present study evaluated the safety profile and efficacy of G-Rup® syrup (100 mg/ml ginger extract plus 150 mg/ml honey) in symptomatic treatment of knee osteoarthritis (OA). METHODS: Patients diagnosed with knee OA were randomly assigned (1:1) to receive either of a 30 ml twice daily regimen of G-Rup® syrup or placebo over a 12-week period. Primary endpoints of the study comprised of an improvement in the joint's stiffness, physical functioning and pain score, assessed by WOMAC questionnaire and the visual analog scale (VAS). Secondary objectives comprised of safety and tolerability of the syrup by patients. RESULTS AND DISCUSSION: The 30 ml twice-daily regimen of G-Rup® syrup was safe and well tolerated by patients. Moreover, in whole studied time points, treatment with G-Rup® syrup could significantly Power the VAS score (p < 0.001) whereas improving WOMAC total score (p < 0.001) and pain (p < 0.001), physical functioning (p < 0.001), and stiffness sub-scores (p = 0.006) compared to the placebo receiving group. WHAT IS NEW AND CONCLUSION: Based on obtained results, the G-Rup® syrup, composed of a combination of honey and ginger, may be a proper supplementary choice, along with routine therapeutic regimens, for improvement of symptomatic treatment of OA.

Analgesic effects and arthritic changes following intra-articular injection of diclofenac etalhyaluronate in a rat knee osteoarthritis model.

BACKGROUND: Diclofenac etalhyaluronate (DF-HA) is a recently developed analgesic conjugate of diclofenac and hyaluronic acid that has analgesic and anti-inflammatory effects on acute arthritis. In this study, we investigated its analgesic effect on osteoarthritis, using a rat model of monoiodoacetate (MIA). METHODS: We injected MIA into the right knees of eight 6-weeks-old male Sprague-Dawley rats. Four weeks later, rats were randomly injected with DF-HA or vehicle into the right knee. Seven weeks after the MIA injection, fluorogold (FG) and sterile saline were injected into the right knees of all the rats. We assessed hyperalgesia with weekly von Frey tests for 8 weeks after MIA administration. We took the right knee computed tomography (CT) as radiographical evaluation every 2 weeks. All rats were sacrificed 8 weeks after administration of MIA for histological evaluation of the right knee and immunohistochemical evaluation of the DRG and spinal cord. We also evaluated the number of FG-labeled calcitonin gene-related peptide (CGRP)-immunoreactive(ir) neurons in the dorsal root ganglion (DRG) and ionized calcium-binding adapter molecule 1 (Iba1)-ir microglia in the spinal cord. RESULTS: Administration of DF-HA significantly improved pain sensitivity and reduced CGRP and Iba1 expression in the DRG and spinal cord, respectively. However, computed tomography and histological evaluation of the right knee showed similar levels of joint deformity, despite DF-HA administration. CONCLUSION: DF-HA exerted analgesic effects on osteoarthritic pain, but did not affect joint deformity.