Improved Joint Health Following Oral Administration of Glycosaminoglycans with Native Type II Collagen in a Rabbit Model of Osteoarthritis.

A prospective, experimental, randomized, double blinded study was designed to evaluate the effects of glycosaminoglycans, with or without native type II collagen (NC), in an osteoarthritis model induced by cranial cruciate ligament transection. The following compounds were tested: chondroitin sulfate (CS), glucosamine hydrochloride (GlHCl), hyaluronic acid (HA) and NC. Fifty-four female 12-week-old New Zealand rabbits were classified into three groups: CTR (control-no treatment), CGH (CS + GlHCl + HA) and CGH-NC (CS + GlHCl + HA + NC). Each group was subdivided into three subgroups according to survival times of 24, 56 and 84 days. Over time, all rabbits developed degenerative changes associated with osteoarthritis. CGH-NC showed significantly improved values on macroscopic evaluation, compared to CTR and CGH. Microscopically, significantly better results were seen with CGH and CGH-NC, compared to CTR, and synovial membrane values were significantly better with CGH-NC compared to CGH. A significant improvement in magnetic resonance imaging biomarkers was also observed with CGH-NC in cartilage transversal relaxation time (T2) and subchondral bone D2D fractal dimension in the lateral condyle. In conclusion, our results show beneficial effects on joint health of CGH and CGH-NC and also supports that adding NC to CGH results in even greater efficacy.

[SYSADOA place in degenerative-dystrophic joints diseases treatment of neurological practice from the standpoint of evidence-based medicine]. / Mesto preparatov SYSADOA v lechenii degenerativno-distroficheskikh zabolevanii sustavov v nevrologicheskoi praktike s pozitsii dokazatel'noi meditsiny.

Neurologists in their practice often face pain syndrome against the background of degenerative-dystrophic changes in the spine, in the therapy of which drugs of delayed-action symptomatic therapy of osteoarthritis (OA) (Symptomatic Slow Acting Drugs for OsteoArthritis, SYSADOA) are used. SYSADOA includes medicinal drugs (MD) containing chondroitin sulfate (CS), glucosamine, avocado/soy unsaponifiables (ASU), diacerein, intra-articular hyaluronic acid, which can give symptomatic benefit with low toxicity, and with prolonged (up to 6 months) the course of treatment. In Russia, they are guided by the clinical recommendations of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), in which the algorithm for managing patients with knee joint OA with the appointment of CS and glucosamine sulfate (GS) form the basic part of the treatment of OA (Step 1). In order to achieve the expected clinical effects in patients with OA medical drugs (MD) of the SYSADOA class must meet the following criteria: 1) be of pharmaceutical quality and standardization with studied pharmacokinetics; 2) meet the criteria of evidence-based medicine (to have randomized clinical trials (RCTs), to have confirmed the effectiveness of meta-analyses of studies and /or systematic reviews, to have confirmed the safety of use in comorbid patients, to have the conclusions of fundamental and clinical studies of recent years justifying the need for its use); 3) be approved by the regulator - the Ministry of Health of the Russian Federation (be present in the current Clinical Recommendations of the Ministry of Health of the Russian Federation and standards for the treatment of diseases of the musculoskeletal system); 4) be approved and recommended by international and Russian professional communities, associations, experts; 5) have clinical and economic advantages in terms of the outcomes of therapy and the lowest cost-effectiveness coefficient per patient. After analyzing the research materials, it was concluded that the pharmacologically standardized CS (Chondroguard®) satisfies all the above criteria for the reasonable choice of a SYSADOA class MD for the treatment of patients with OA of various localization.

¿Conlleva la desprescripción de condroprotectores en pacientes con artrosis un incremento del consumo de analgésicos? Estudio observacional retrospectivo / Does the deprescription of chondroprotectors in patients with osteoarthritis lead to an increase in the consumption of analgesics? Observational retrospective study

Objetivo: El objetivo del estudio es evaluar si la desprescripción de medicamentos considerados de bajo valor intrínseco como los condroprotectores o SYSADOA, conlleva un empeoramiento sintomáti-co de la artrosis, incrementándose el consumo de analgésicos.Material y métodos: Siguiendo la práctica clínica habitual se retiró el tratamiento con SYSADOA a pa-cientes de un Centro de Atención Primaria (pobla-ción asignada: 34.382 habitantes, 17% mayores de 65 años) en base a la evidencia científica publicada y a la recomendación de la administración sanitaria de reducir los tratamientos con medicamentos de bajo valor intrínseco. Mediante un estudio obser-vacional post-intervención se analizaron diferen-cias de consumo de analgésicos y AINEs entre un periodo anterior a la retirada y el mismo periodo post-retirada.Resultados: Se analizaron 354 pacientes (68,4% mujeres, media de edad 66,2 años). No se encon-traron diferencias estadísticamente significativas en el consumo de analgesia total en el periodo de 6 meses post-retirada (media de 3,97 envases) com-parado con el periodo de 6 meses previo (media de 4,04 envases). Al estratificar por código ATC, edad y género, únicamente se encontraron diferencias en el consumo de otros analgésicos y antipiréticos teniendo en cuenta el sexo.Conclusión: Se concluye que, considerar con el paciente la desprescripción de SYSADOA a criterio del médico, es seguro y no conlleva un aumento del consumo de analgésicos (otros analgésicos y anti-piréticos, AINE, opioides menores, opioides mayo-res) sugiriendo que no implica un empeoramiento de la enfermedad artrósica. La desprescripción de SYSADOA, además, puede contribuir a reducir la po-limedicación sin alterar la situación clínica y evitar posibles riesgos de efectos adversos o interaccio-nes potenciales (AU)

Objective: The objective of this study is to assess if the deprescription of medications that are consid-ered low intrinsic value medications such as the chondroprotectors or SYSADOA entails a symptom-atic worsening of the arthrosis and consequently an increase of the consumption of analgesics.Material and Methods: Following the usual clinical practise, the SYSADOA treatment was withdrawn to the patients from a Primary Health Care Centre (assigned population: 34,382 inhabitants, 17% up to 65 years old) according to the published scientific proof and the recommendation of the health ad-ministration consisting of reducing the treatments with low intrinsic value medications. Differences in consumption of analgesics and AINEs between a previous period before the withdrawn and the same period post-withdrawn were studied through an observational post-intervention study.Results: 354 patients were analysed (68,4% wom-en, average age 66,2 years). There were not found significant differences from a statistical point of view in the total consumption of analgesia in the 6 months period post-withdrawn (average of 3,97 packagings) compared to the previous period of 6 months (average of 4,04 packagings). When stratifying by ATC code, age and gender, there were only found differences in the consumption of other analgesics and antipyretics taking into account the sex.Conclusion: It is concluded that considering togeth-er with the patient the deprescription of SYSADOA according to doctor’s criteria is safe and does not involve an increase of analgesics consumption (other analgesics, antipyretics, AINEs, major and minor opiods) suggesting that it does not suppose a worsening of the arthrosis disease. Besides, the deprescription of SYSADOA may contribute to re-duce polymedication without disrupting the clinical situation and avoid possible risks of adverse effects or potential interactions

Efficacy Treatment of Osteoarthritis with Combine Chondroitin and Glucosamine.

Osteoarthritis led to the articular cartilage damage and cause different kind of problems - from social to biological. The analysis of existing research unfortunately subjected questioned the reliability of spontaneous regeneration of damaged cartilage, which makes it necessary to focus on the possibilities of protection of the tissue from further its degradation. Treatment of osteoarthritis require to use many drugs, which would lead to slowdown the this process. The aim of below publication is to analyse the practical, clinical biological possibilities of articular cartilage protection with a usage of SYSADOA - (symptomatic slow acting drugs of OA). Osteoarthritis is most frequent disease of the joints and prescription of the SYSADOA should be main principle of that treatment.

Impact of terminating reimbursement of symptomatic slow-acting drugs in osteoarthritis in France on volume and cost of drug deliveries, assessed with administrative databases.

WITH OSTEOARTHRITIS (OA): As one of the leading causes of disability in adults worldwide, its toll on patients and its economic burden for payers are substantial. The issue of change in OA management with the evolution of reimbursement schemes needs to be addressed. OBJECTIVE: To assess the impact of terminating the reimbursement of symptomatic slow-acting drugs in OA (SYSADOAs) in France in terms of volume and cost, from a healthcare payer perspective. PRINCIPAL RESULTS: We obtained costs and volumes from French public national databases. We considered three exposure periods around cutoff dates according to decisions of decreased then terminated SYSADOA reimbursement. The periods included 19 345 (control), 20 066 (secondary), and 16 200 (primary) patients, respectively. Mean ages were 66.2 (±11.8), 65.3 (±11.6) and 64.6 (±11.5) years and about 70% were women. The volume of nonsteroidal anti-inflammatory drug (NSAID) deliveries estimated by defined daily doses (DDDs) decreased during the periods from 40.5 (±76.3) DDDs per patient in 2008 to 29.6 (±66.4) in 2015. The volume of analgesic deliveries increased slowly over the three periods, from 70.2 (±108.9) DDDs in 2008 to 76.9 (±123.1) in 2015 for all patients. MAJOR CONCLUSIONS: Our results did not show a measurable impact of terminating SYSADOA reimbursement on the delivery of NSAIDs and analgesics or on hospitalizations. However, neither do they allow for concluding that terminating SYSADOA reimbursement did not generate an increase in deliveries of non-reimbursed drugs, with their associated potential risks for public health.

[Multidomain approach in chronic non-specific back pain patient's treatment]. / Mul'tidomennyi podkhod k terapii patsientov s khronicheskoi nespetsificheskoi bol'yu v spine.

The concept of chronic nonspecific back pain (CNBP) as a pathology of the spine (osteochondrosis, spondylosis, intervertebral disc herniation, facet syndrome) is extremely outdated and has not justified itself, first of all, from the therapeutic view point. Numerous studies, including meta-analyzes and systematic reviews, have convincingly shown the ineffectiveness of the methods of CNBP treatment, aimed only at solving the problems of the spine itself and / or surrounding tissues. A substantial amount of special imaging studies have proven the dissociation between morphological vertebral changes and the clinical picture of pain. CNBP is the overall result of the interaction of numerous factors in the spine tissues (changes in the discs, joints, ligaments, fascia, muscles) and factors beyond the spine. The latter include, first of all, psychological and social factors, cognitive functions, the quality of night sleep, the level of physical activity, concomitant diseases (comorbidity). In each patient, the interaction of these factors determines the development of specific pathophysiological mechanisms of pain and, as a result, an individual clinical picture of pain (phenotype). Understanding these processes will allow for the reconsideration of the approach of searching for an anatomical pain source as the main pathogenetic factor; recognizing the multifocal generation of chronic pain as the result of a complex interaction of biological, psychological and social factors; the development of new principles and therapy algorithms. The authors propose to introduce into practice a multidomain screening approach for evaluating patients with CNBP, which would take into account the phenotype of pain, factors affecting its perception, and allow personalized treatment for each patient based on the biopsychosocial approach.

An international, multicentre, double-blind, randomized study (DISSCO): effect of diacerein vs celecoxib on symptoms in knee osteoarthritis.

OBJECTIVE: The objective of this study was to investigate whether diacerein has comparable efficacy with celecoxib in pain reduction for treatment in symptomatic knee OA patients. METHODS: This randomized double-blind multicentre non-inferiority trial evaluated diacerein vs celecoxib treatment in patients with Kellgren-Lawrence grade 2-3 and pain scoring ≥4 (10-cm VAS). Patients were randomized to 6 months of treatment with diacerein 50 mg (n = 187) once daily for 1 month and twice daily thereafter, or celecoxib 200 mg (n = 193) once daily. The primary outcome was the change in WOMAC pain score (0-50 cm) at 6 months, and the secondary outcomes were WOMAC sub-scores, VAS pain score, and the OMERACT-OARSI responder rate. RESULTS: In the per protocol population, the adjusted mean change from baseline in the WOMAC pain score was -11.1 ( 0.9) with diacerein (n = 140) and -11.8 (0.9) with celecoxib (n = 148). The intergroup difference was 0.7 (95% CI: -1.8, 3.2; P = 0.597), meeting the non-inferiority margin. Supportive analysis of the intention-to-treat population gave similar results. Other outcomes showed no significant difference between treatment groups. The incidence of treatment-related adverse events was low and balanced between groups, but a greater incidence of diarrhoea occurred with diacerein (10.2% vs 3.7%). Diarrhoea was considered mild-to-moderate in all but one case with complete resolution. CONCLUSIONS: Diacerein was non-inferior to celecoxib in reducing knee OA pain and improving physical function. Diacerein also demonstrated a good safety profile. TRIAL REGISTRATION: A multicentre study on the effect of DIacerein on Structure and Symptoms vs Celecoxib in Osteoarthritis is a National Institutes of Health (NCT02688400) and European Clinical Trial Database (2015-002933-23) registered phase III (Canada) or IV (Europe) study.

How to Treat Osteoarthritis in Obese Patients?

The close association between osteoarthritis (OA) and obesity is well established. Mechanisms linking obesity and OA involve multifactorial phenomena such as systemic factors (i.e. adipokines and pro-inflammatory cytokines), hormonal disturbances (hyperinsulinemia) and muscule changes (i.e. sarcopenia and lower muscular tone). The concomitant increasing prevalence of the two diseases have major health, social and economic consequences. However, to date no specific recommendation for the medical management of obese patients with OA have been published. Current recommendations only specify that obese patients must lose weight and practice regular physical activity in addition to the usual care. Weight loss improves not only OA symptoms but also metabolic abnormalities and cardiovascular risk factors commonly altered in subjects with obesity. OA symptoms' improvement has been shown to become clinically relevant from a weight loss > 5% of the body weight. In case of morbid obesity, bariatric surgery may be the only alternative for pain relief. After bariatric surgery, an appropriate calcium and vitamin D intake is recommended, since it has been shown that bariatric surgery was associated with a reduction in the bone mineral density and increased risk of fractures. An exercise program is essential for preserving healthy muscles during weight loss. Non-steroidal anti-inflammatory drugs and corticosteroids must be avoided, especially in obese patients with metabolic syndrome. In such patients symptomatic slow acting drugs for OA (i.e. glucosamine, chondroitin) and some anti-oxidant drugs (i.e. curcumin, ginger extracts, copper) may be helpful thanks to their excellent benefit/risk ratio and their mode of action which may have a positive impact on both OA and obesity-related metabolic disorders. Recent research focuses on the development of molecules aimed for promoting the production of heme oxygenase (HO-1). HO-1 decreases the production of oxygen free radicals and protects tissues from oxidative stress in the insulin resistance syndrome. Intra-articular (IA) injections of hyaluronic acid and corticosteroid have few adverse events. However, physicians must inform patients that IA treatments have a lower success rate in obese patients than in those with normal body mass index. Spa therapy contributes to relief pain, favour weight-loss and reduces metabolic abnormalities with a favourable risk/benefit balance.

Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis.

Osteoarthritis (OA) is characterized by deterioration of the joints and associated with considerable pain and disability. OA is a chronic disease that requires intervention with both non-pharmacological and pharmacological treatment modalities and, inevitably, disease progression may necessitate successive treatments throughout the course of the disease. There is increasing data on the shortfalls of current pharmacological treatment of OA, and safety concerns associated with analgesic therapy use in OA arising from increasing evidence of gastrointestinal, cardiovascular, hepatic and renal adverse events with paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs). Consequently, symptomatic slow-acting drugs for OA (SYSADOAs) may now be considered as a first-line treatment for knee OA, with a particular emphasis placed on the outstanding benefit: risk ratio of pharmaceutical-grade glucosamine and chondroitin sulfate formulations. In this short communication we review recent publications concerned with the safety of paracetamol, NSAIDs and SYSADOAs. Greater understanding of the benefits and limitations of current medications will lead to better disease management in OA. Furthermore, adherence to guideline recommendations across Europe and internationally, such as those from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), will promote evidence-based medicine and patient-centric care, ultimately leading to greater physician and patient satisfaction.

[What factors affect the effectiveness of long - term analgesic therapy for osteoarthritis? Data analysis of the multi - center 3-month PARACELSUS study].

There are factors that can affect the effectiveness of treatment of osteoarthritis (OA). Aim to identify factors affecting the effectiveness of long - term analgesic therapy in OA. Materials and methods. The study included 6448 patients (70.9% female and 29.1% male), middle age 57.8±10.2 years, with severe pain [≥40 mm on the visual analog scale]. All patients received the preparation of avocado - soybean unsaponifiables (ASU) 300 mg/day. For pain relief at the beginning and during the study, the drug Ketoprofen lysine salt (KLS) 320 mg/day was used. The efficiency criterion was pain reduction ≥50% and satisfaction with treatment ≥4 on a 5-point scale. The influence of a number of factors on the result of treatment was evaluated. Results. For 3 months of treatment, the pain decreased from 63.7±12.0 to 14.2±11.7 mm VAS. The result was evaluated as "good" or "excellent" 81.7% of patients. Adverse reactions were rare. In total, a good response to therapy was noted in 87.4% of patients. Gender, body mass index ≥30 kg/m2, type 2 diabetes mellitus, poor effect of non - steroidal anti - inflammatory drugs (NSAIDs) and Symptomatic Slow-Acting Drugs in Osteoarthritis (SYSADOA) in history did not affect the result. The effect was lower in persons >65 years [odds ratio (OR) 0.418; 95% confidence interval (CI) 0.342-0.509, p2 by Kellgren-Lawrence (OR 0.556; 95% CI 0.298-0.738, p.

[The chondroprotector mucosat in an integrated approach to the treatment of nonspecific back pain]. / Khondroprotektor mukosat v integrirovannom podkhode k lecheniiu patsientov s nespetsificheskoi bol'iu v spine.

A nonspecific back pain is in the vast majority of all possible cases of dorsopathies. The sources of back pain may be myogenic dysfunction, intervertebral disc pathology or osteoarthritis of the archicular (facet) joints of the spine, including myofascial pain syndrome. A differentiated approach to the treatment of spondylarthrosis is still an unsolved problem. The article discusses important issues of integration of non-drug treatment methods and drug therapy of nonspecific back pain in patients with facet syndrome. Special attention is paid to SYSADOA group chemicals, in particular chondroitin sulfate (mucosat). These drugs have proven analgesic and anti-inflammatory effects and also are able to improve the structure of the cartilaginous tissue, slowing the progression of the disease.

Variability in the prescription of drugs with uncertain effectiveness. The case of SYSADOA in the Basque Country.

Background: The majority of clinical practice guidelines do not recommend the use of SYSADOA (Symptomatic Slow Action Drugs for Osteoarthritis) for the treatment of osteoarthritis because of the lack of evidence or uncertainty around their efficacy. Nevertheless, the Spanish Public Health Service continues funding these drugs. Aim: The aim of this study is to describe the prescription status of SYSADOA in the primary care units of the Basque Country during 2011; to determine if variability exists among them; and to examine if the variability could be explained by the health care region each PC unit belongs to. Methods: Prescription data for SYSADOA during 2011 was obtained from the Basque Ministry for Health. In the Basque Country, primary care is divided into seven regions, each region consisting of several primary care units, which were used as the unit of analysis. Defined daily doses (DDD) per 1,000 inhabitant-days (DHD) were calculated. Data were standardized by sex and age using the total population of the Basque Country as the reference population. Small area statistics were calculated (extremal quotient, coefficient of variation and systematic component of variation). The influence of the region to which primary care units belonged was also analysed. R software (version R-2.15.0) was used for the analysis. Results: SYSADOA prescription during 2011 accounted for an expense of 4.5 million euros for the Basque Health Service. The crude rate of consumption of SYSADOA was 7.81 DDD per 1,000 inhabitant-days. The obtained external quotient was 13.67. The prescription of SYSADOA of the primary care units located in the 95th percentile was six times higher than the ones located in the 5th percentile. The region to which units belonged accounted for 57% of the observed variability. Discussion: The uncertainty around these drugs could be reflected in the existing variability of their prescription level. The analysis of the variability in the prescription of drugs with no demonstrated efficacy could help in allocating resources into other services or health technologies supported by evidence, thereby contributing to the improvement of health outcomes.

[New possibilities of treatment of low back pain]. / Novye vozmozhnosti lecheniia patsienta s poiasnichnoi bol'iu.

Low back pain (LBP) is a syndrome caused by degenerative spine diseases and a common reason for referral for medical care. LBP is mostly often caused by osteoarthritis (OA) that needs long-term treatment with nonsteroidal anti-inflammatory drugs. The treatment is associated with a risk of side-effects. The authors consider the possibility of using slow-acting drugs for symptomatic treatment of OA (SYSADOA) in patients with LBP and present the data on anti-inflammatory effects of chondroitin sulfate on the chondral tissue in OA. The results of the studies on the use of SYSADOA in LBP are analyzed.

Effects of glucosamine sulfate on the use of rescue non-steroidal anti-inflammatory drugs in knee osteoarthritis: Results from the Pharmaco-Epidemiology of GonArthroSis (PEGASus) study.

BACKGROUND AND OBJECTIVE: The use of Symptomatic Slow-Acting Drugs in Osteoarthritis (SYSADOAs) may be expected to decrease the use of concomitant medications for rescue analgesia, including non-steroidal anti-inflammatory drugs (NSAIDs). The Pharmaco-Epidemiology of GonArthroSis (PEGASus) study was designed to assess this possibility. METHODS: PEGASus was a cohort study of continuous recruitment of patients with "dynamic" exposure to the investigated SYSADOA (crystalline glucosamine sulfate, glucosamine hydrochloride, chondroitin sulfate, diacerein, and avocado-soybean unsaponifiables, all at approved dosages). Investigators were rheumatologists or general practitioners randomly selected from French telephone lists. Patients diagnosed with knee osteoarthritis (OA) were recruited when consulting an investigator for a symptom flare and were prescribed, or not, one of the SYSADOAs as per clinical judgment. Follow-up visits were as per routine medical practice in the 12 months following enrollment, with telephone interviews after 1 month and at 4-month intervals thereafter up to 24 months. Use of NSAIDs was recorded, as well as the dynamism of treatment exposure consisting of continuing the prescribed SYSADOA, switching, discontinuation or initiation of a SYSADOA. Patient exposure was expressed in 2-month time units, with any NSAID use as Yes/No binary outcome during each unit. Odds ratios [OR and 95% confidence interval (CI)] of NSAID use were calculated for periods of exposure to each SYSADOA, by multivariate logistic regression for an 80% power and 95% confidence to see a decrease of at least 15%. RESULTS: This report consists of the full data pertaining to crystalline glucosamine sulfate, while results of other SYSADOAs were summarized as available from the French Health Authority (HAS) website (www.has-sante.fr). Of 6451 patients in the PEGASus cohort, 315 patients received crystalline glucosamine sulfate, they were exposed for 481 2-month time units and had an incident use of NSAIDs of 18.7%. In the control cohort (9237 time units) NSAID incident use was 23.8%. Crystalline glucosamine sulfate significantly decreased the risk of NSAID consumption by up to 36% (OR = 0.64; 95% CI: 0.45-0.92) in the primary analysis foreseen by the protocol; OR was 0.74 (95% CI: 0.54-1.01), i.e. at the very limit of significance, in a sensitivity analysis accounting for an extension of the study and of the control cohort. None of the other SYSADOAs showed any hint of a decrease in the use of NSAIDs. CONCLUSION: Crystalline glucosamine sulfate was the only SYSADOA that decreased the use of NSAIDs in this pharmaco-epidemiology study in patients with knee OA.

Short-term effect of the combination of hyaluronic acid, chondroitin sulfate, and keratin matrix on early symptomatic knee osteoarthritis.

OBJECTIVE: In the last years, symptomatic slow-acting drugs for osteoarthritis (SYSADOA) have been vastly studied and have generated considerable interest among clinicians. SYSADOA are generally used as a ground therapy with the main rationale to reduce the consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) and thus limit the related adverse events. MATERIAL AND METHODS: In this study, we evaluated the short-term effect of an oral combination of hyaluronic acid, chondroitin sulfate, and keratin matrix on early symptomatic knee osteoarthritis. Forty patients were treated for 1 month and were allowed to assume analgesics or NSAIDs if necessary. RESULTS: At 2 months, the mean reduction of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score was 36% (p<0.001), and the mean reduction of the WOMAC pains score was 40% (p<0.001). Only two patients reported a sporadic need to assume analgesics; no patient reported any side effect during the study period. CONCLUSION: This data demonstrates that the oral combination of hyaluronic acid, chondroitin sulfate, and keratin matrix is safe, well tolerated, and shows a rapid action reducing pain and improving joint function and stiffness in early symptomatic knee osteoarthritis.