Nutraceutical Approach to Chronic Osteoarthritis: From Molecular Research to Clinical Evidence.

Osteoarthritis (OA) is a degenerative inflammatory condition of the joint cartilage that currently affects approximately 58 million adults in the world. It is characterized by pain, stiffness, and a reduced range of motion with regard to the arthritic joints. These symptoms can cause in the long term a greater risk of overweight/obesity, diabetes mellitus, and falls and fractures. Although the current guidelines for the treatment of OA suggest, as the gold standard for this condition, pharmacological treatment characterized by non-steroidal anti-inflammatory drugs (NSAID), opioids, and cyclooxygenase (COX)-2-specific drugs, a great interest has been applied to nutraceutical supplements, which include a heterogeneous class of molecules with great potential to reduce inflammation, oxidative stress, pain, and joint stiffness and improve cartilage formation. The purpose of this review is to describe the potential application of nutraceuticals in OA, highlighting its molecular mechanisms of actions and data of efficacy and safety (when available).

Efficacy of Chondroprotective Food Supplements Based on Collagen Hydrolysate and Compounds Isolated from Marine Organisms.

Osteoarthritis belongs to the most common joint diseases in humans and animals and shows increased incidence in older patients. The bioactivities of collagen hydrolysates, sulfated glucosamine and a special fatty acid enriched dog-food were tested in a dog patient study of 52 dogs as potential therapeutic treatment options in early osteoarthritis. Biophysical, biochemical, cell biological and molecular modeling methods support that these well-defined substances may act as effective nutraceuticals. Importantly, the applied collagen hydrolysates as well as sulfated glucosamine residues from marine organisms were strongly supported by both an animal model and molecular modeling of intermolecular interactions. Molecular modeling of predicted interaction dynamics was evaluated for the receptor proteins MMP-3 and ADAMTS-5. These proteins play a prominent role in the maintenance of cartilage health as well as innate and adapted immunity. Nutraceutical data were generated in a veterinary clinical study focusing on mobility and agility. Specifically, key clinical parameter (MMP-3 and TIMP-1) were obtained from blood probes of German shepherd dogs with early osteoarthritis symptoms fed with collagen hydrolysates. Collagen hydrolysate, a chondroprotective food supplement was examined by high resolution NMR experiments. Molecular modeling simulations were used to further characterize the interaction potency of collagen fragments and glucosamines with protein receptor structures. Potential beneficial effects of collagen hydrolysates, sulfated glycans (i.e., sulfated glucosamine from crabs and mussels) and lipids, especially, eicosapentaenoic acid (extracted from fish oil) on biochemical and physiological processes are discussed here in the context of human and veterinary medicine.

Gut-microbiota modulation: The impact of thegut-microbiotaon osteoarthritis.

Osteoarthritis (OA) is one of the most common medical conditions affecting > 300 million people globally which represents the formidable public health challenge. Despite its clinical and financial ramifications, there are currently no approved disease modifying OA drugs available and symptom palliation is the only alternative. Currently, the amount of data on the human intestinal microbiome is growing at a high rate, both in health and in various pathological conditions. With an increase in the amount of the accumulated data, there is an expanded understanding that the microbiome provides compelling evidence of a link between thegut microbiomeand development ofOA. The microbiota management tools of probiotics and/or prebiotics or symbiotic have been developed and indeed, commercialized over the past few decades with the expressed purpose of altering the microbiota within the gastrointestinal tract which could be a potentially novel intervention to tackle or prevent OA. However, the mechanisms how intestinal microbiota affects the OA pathogenesis are still not clear and further research targeting specific gut microbiota or its metabolites is still needed to advance OA treatment strategies from symptomatic management to individualized interventions of OA pathogenesis. This article provides an overview of the various preclinical and clinical studies using probiotics and prebiotics as plausible therapeutic options that can restore the gastrointestinal microbiota and its impact on the OA pathogenesis. May be in the near future the targeted alterations of gut microbiota may pave the way for developing new interventions to prevent and treat OA.

Health effects of a low-inflammatory diet in adults with arthritis: a systematic review and meta-analysis.

The aim is to systematically assess the health impact of a low-inflammatory diet intervention (full-diet or supplement), compared to usual diet or other dietary interventions, on weight change, inflammatory biomarkers, joint symptoms, and quality of life in adults with osteoarthritis, rheumatoid arthritis or seronegative arthropathy (psoriatic, reactive, ankylosing spondylitis or IBD-related), on outcomes assessed in prospective studies within 6 months of intervention commencement (PROSPERO CRD42019136567). Search of multiple electronic library databases from inception to July 2019, supplemented by grey literature searches, for randomised and prospective trials assessing the above objective. After exclusion of 446 ineligible studies, five randomised and two prospective trials involving 468 participants with either osteoarthritis or rheumatoid arthritis were included. GRADE assessment for all outcomes was very low. Meta-analyses produced the following standardised mean differences (SMD) and 95 % confidence interval (CI) 2-4 months following commencement of the diets favouring the low-inflammatory diet: weight SMD -0⋅45 (CI -0⋅71, -0⋅18); inflammatory biomarkers SMD -2⋅33 (CI -3⋅82, -0⋅84). No significant effects were found for physical function (SMD -0⋅62; CI -1⋅39, 0⋅14), general health (SMD 0⋅89; CI -0⋅39, 2⋅16) and joint pain (SMD -0⋅98; CI -2⋅90, 0⋅93). In most studies, the quality of dietary intervention (dietitian input, use of validated dietary compliance tool) could not be gauged. In conclusion, very low-level evidence suggests that low-inflammatory diets or supplements compared to usual diets are associated with greater weight loss and improvement in inflammatory biomarkers. More high-quality trials are needed to assess the health effects of a low-inflammatory diet more comprehensively and conclusively in arthritic conditions.

Of Mesenchymal Stem/Stromal Cells and Osteoarthritis: Time to Merge the Latest Breakthroughs.

Osteoarthritis (OA) is a degenerative joint disease of the articular cartilage with subchondral bone remodeling and synovial inflammation. There is currently no cure for OA, making effective management extremely challenging. During the last years, significant advances has been made to develop regenerative medicine based on the use of stem cells as alternative for treating OA. Because of their several advantages including availability, expandability, transplantability, and ethical implications. mesenchymal stem/stromal cells (MSCs) appear thus to be a promising tool for the field. Based on the recent paper of Klemen Camernik et al. in Stem Cell Reviews and Reports, we highlighted some challenges and possible strategies to enhance the therapeutic potential of MSCs for OA.

Shea Nut Oil Extracts Enhance the Intra-Articular Sodium Hyaluronate Effectiveness on Surgically Induced OA Progression in Rats.

Osteoarthritis (OA) progression is associated with joint pain and stiffness. Intra-articular hyaluronic acid (IAHA) injection in knee OA restores the viscoelasticity of the joint and prevents cartilage damage. Shea nut oil extract (SNO) was shown to provide chondroprotection on surgically-induced OA progression in rats. Here we aim to examine IAHA injection supplemented with SNO diet for a synergetic evaluation on the disease progression in OA rats. We employed an anterior cruciate ligament transection plus medial meniscectomy-induced knee OA rat model with up to 12 weeks of sign/behavior observation (knee width, weight-bearing) and histological assessments of joint damage. We found both IAHA and SNO alone significantly attenuated histological changes of cartilage degeneration and synovial reactions in these knee OA rats. Nonetheless, oral SNO alone mitigated OA pain and inflammation while IAHA alone had no significant impact on the weight-bearing test and knee joint swelling. Moreover, with IAHA-treated rats fed with oral SNO diet, additional anti-inflammatory and anti-nociceptive effects were found, which further enhanced and maintained IAHA protection. Given the differential phenotype of oral SNO vs. IAHA, a regimen of IAHA coupled with SNO supplement provides a long-term effect of IAHA treatment. Taken together, the SNO supplement can be safely used as an adjuvant diet for chronic symptomatic relief of OA coupled with IAHA management.

Osteoporosis and osteoarthritis are two sides of the same coin paid for obesity.

Obesity is characterized by adipose tissue expansion and chronic low-grade inflammation. Among the inflammatory mediators related to obesity development are the adipokines. These cytokines are released from fatty tissues and act in an autocrine, paracrine, or endocrine manner. Adipocytes influence the comorbidities of obesity such as osteoporosis (OP) and osteoarthritis (OA). It is still controversial as to whether OP is associated with either a low or high body mass index, but it is quite clear that the latter condition increases the risk for OA development. Bone marrow adipocytes (BMAs) have the same precursors of osteoblasts, which are the primary cells involved in bone formation, and the amount of BMAs appears to be inversely related to bone mineral density. Although adipokines released by these adipocytes influence bone loss progress, their exact role remains controversial. Differently, the infrapatellar fat pad (IPFP) is indicated to protect the function of joint regarding OA. However, there is relatively limited information about the secretion of adipokines and other inflammatory mediators by the IPFP. Despite some inconsistencies, nutritional interventions targeting obesity may also benefit patients with OP and OA. The association among obesity, OP, and OA is quite complex, and many factors need to be explored that are mainly related to the role of adipokines derived locally rather than from visceral and subcutaneous adipose tissue. Also, nutritional intervention may affect fatty tissue mass and secretion of inflammatory mediators that may, at least in part, influence other tissues in the organism such as bone and articular cartilage. The aim of this review was to present the latest knowledge about the interrelationship between obesity and OA or OP and to discuss whether a dietary intervention for obesity will hold promise for patients with OA or OP.

Dietary patterns and nutrient intake of individuals with rheumatoid arthritis and osteoarthritis in the United States.

OBJECTIVE: The aim of this study was to investigate the differences in adherence to the Mediterranean diet, assessed by the alternative Mediterranean Diet (aMED) score, and diet quality, assessed by Healthy Eating Index 2015 to 2020 (HEI-2015), between presence and type of arthritis (rheumatoid arthritis and osteoarthritis). Additionally, the study investigated the association between aMED scores and HEI-2015 scores and the presence of arthritis. METHODS: Cross-sectional data from four cycles (2007-2014) of the National Health and Nutrition Examination Survey were used and weighted to produce a nationally representative sample. Arthritis information was extracted from the Medical Conditions file and recoded into relevant variables. Food group and nutrient data from the 24-h recall was transformed to provide aMED and HEI-2015 scores. RESULTS: Individuals with arthritis had significantly worse adherence to the Mediterranean diet and diet quality. aMED scores were 3.43 ± 0.04 for individuals with arthritis and 3.54 ± 0.03 for individuals without arthritis (P = 0.014). HEI-2015 scores were also lower in individuals with arthritis (51.41 ± 0.37) than in those without (53.50 ± 0.28; P < 0.001). There were no significant differences in aMED or HEI-2015 scores between individuals with rheumatoid arthritis and those with osteoarthritis. There were also no associations between aMED scores or HEI-2015 scores and the presence of arthritis. CONCLUSIONS: Individuals diagnosed with arthritis can take steps to improve their diet quality as a possible route to reduce arthritis symptoms and maintain a healthy body weight. Further research on dietary patterns and their potential to treat and manage arthritis is warranted.

Dieta mediterránea y artrosis / Mediterranean diet and osteoarthritis

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Nutrition, osteoarthritis and cartilage metabolism.

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease and a leading cause of adult disability. There is no cure for OA and there is no effective treatment to stop its progression. Current pharmacologic treatments such as analgesics and non-steroidal anti-inflammatory drugs may improve the pain and offer some relief but they do not affect the progression of the disease. The chronic intake of these drugs may result in severe adverse events. The aim of this review is to revise the effects of nutrition on cartilage metabolism and OA progression. METHODS: A systematic literature search was performed including those related to macro- and micro-nutrients' actions on cartilage and OA outcome. We selected peer-reviewed articles reporting the results of human clinical trials. RESULTS: Glucosamine and chondroitin sulfate have shown to delay OA knee progression in several clinical trials. The effectiveness of some products considered nutraceuticals has been widely reviewed in the literature. This article presents a general description of the effectiveness and mechanism of action of nutrients, vitamins, antioxidants and other natural components considered as part of the normal diet. Many in vitro studies indicate the efficacy of specific nutrients in cartilage metabolism and its involvement in OA. However, rigorous clinical studies needed to evaluate the efficacy of these compounds in humans are still missing. The influence of nutrients and diet on the metabolism of cartilage and OA could represent a long-term coadjuvant alternative in the management of patients with OA. Effects of diet modifications on lipid and cholesterol profiles, adequate vitamin levels and weight reduction in obese patients could influence the course of the disease. CONCLUSION: This review demonstrates that nutrition can improve the symptoms of OA. Glucosamine and chondroitin sulfate have shown robustly to delay the progression of knee OA in several well-designed studies, however more controlled clinical trials are needed to conclude that nutritional changes slow down the progression of the disease.

A systematic review of osteoarthritis prevention and management with dietary phytochemicals from foods.

Osteoarthritis is the most prevalent chronic inflammatory joint disease affecting mobility in humans, as well as in companion and captive animals. Understanding the effect of dietary phytochemical intake from foods on osteoarthritis and its long-term outcomes may inform public health strategies for osteoarthritis prevention and management, reducing healthcare costs globally. The aim of this systematic review was to examine the effects of dietary phytochemical intake from foods on osteoarthritis in adult populations. A literature search was performed using Scopus, Web of Science, MEDLINE, PubMed and the Cochrane Library for human studies to identify randomised controlled trials (RCTs) and observational studies focused on osteoarthritis up to May 2018. From 5879 articles, five RCTs and four cross-sectional studies were identified. Dietary carotenoids were examined in the observational studies, while dietary intakes of polyphenols from foods were assessed in the RCTs. Dietary polyphenol intake from foods (e.g., freeze-dried strawberries and tart cherry juice) may slow the progression of osteoarthritis via decreased inflammation and reduced cartilage degradation. However, there were relatively few studies and a lack of uniformity in the biomarkers used and the measurements of pain, quality of life and physical activity relating to osteoarthritis. The heterogeneity among the studies suggests that there is insufficient evidence related to phytochemical intake from foods. High-quality epidemiological studies and controlled trials are therefore required. Nevertheless, exploring dietary phytochemical intake from foods may complement current dietary strategies for the management of osteoarthritis and help in the formulation of more economical and manageable strategies for osteoarthritis.

Effect of a commercially available fish-based dog food enriched with nutraceuticals on hip and elbow dysplasia in growing Labrador retrievers.

The aim of this study was to evaluate the prevalence of hip and elbow dysplasia in a group of growing Labrador retrievers fed a fish-based diet enriched with nutraceuticals with chondroprotective properties. The puppies ranged from 3 to 12 mo of age and were divided into 2 groups, each fed a different diet. The control diet consisted of a high quality, chicken-based dog food, while the test diet was a fish-based dog food, enriched with nutraceuticals. Hip and elbow joints were radiographed and scored at 6 and 12 mo of age. Overall, 42 dogs completed the study. At 12 mo of age, no differences were found between the groups in the prevalence of hip and elbow dysplasia, although dogs fed the fish-based food enriched with nutraceuticals had a less severe grade of osteoarthritis at 12 mo. It was concluded that the fish-based diet with nutraceuticals did have beneficial effects on the development of severe osteoarthritis.

L'objectif de la présente étude était d'évaluer la prévalence de dysplasie de la hanche et du coude dans un groupe de chiens Labrador en croissance nourris avec une diète à base de poisson enrichie de neutraceutiques ayant des propriétés chondroprotectrices. L'âge des chiots variait de 3 à 12 mois et ils ont été divisés en deux groupes, chacun étant nourri avec une diète différente. La diète témoin consistait d'un aliment de haute qualité pour chien à base de poulet, alors que la diète test était un aliment pour chien à base de poisson et enrichi avec des neutraceutiques. Les articulations des hanches et des coudes ont été radiographiées à 6 et 12 mois d'âge. Un total de 42 chiens a complété l'étude. À 12 mois d'âge, aucune différence n'a été trouvée entre les groupes dans la prévalence de dysplasie de la hanche et du coude, bien que les chiens nourris avec la diète à base poisson enrichie de neutraceutiques avaient un score d'ostéoarthrite moins sévère à 12 mois. Il a été conclu que la diète à base de poisson enrichie de neutraceutiques avait des effets bénéfiques sur le développement d'ostéoarthrite sévère.(Traduit par Docteur Serge Messier).

Specific bioactive collagen peptides (PETAGILE® ) as supplement for horses with osteoarthritis: A two-centred study.

The aim of the study was to evaluate the clinical efficacy of specific bioactive collagen peptides (BCP), here administered orally as PETAGILE® , on horses with mild to moderate, naturally occurring osteoarthritis. Data from a two-centred pilot study were used for the meta-analysis. Thirty-eight privately owned horses of various breeds were available. In one centre, 18 of these patients (6 ± 3 years; 519 ± 100 kg BW) received either 25 g (n = 6) or 50 g (n = 12) BCP/day orally for 12 weeks. In the second centre, 20 horses (18 ± 4 years; 413 ± 94 kg BW) received either a placebo (control; n = 10) or 25 g BCP/day. The attending veterinarians performed an orthopaedic examination including flexion tests and evaluated the degree of lameness, rotation pain, step length and arc of foot flight during trot (8 parameters) at the beginning and after 6 and 12 weeks. The horse owners answered a weekly questionnaire about their perception of lameness, mobility and the horses' willingness to run. In the 50 g BCP group, in six of eight parameters, a strong effect (Cohen's r > .5) was detected with two parameters (lameness and flexion pain) significantly improved already after 6 weeks. In the 25 g BCP group, a moderate effect (Cohen's r = .3-0.5) was seen in six parameters, with three parameters improved already after 6 weeks. The owners reported a strong effect for mobility and willingness to run (Cohen's r = .69 and .62, respectively) and a moderate effect (Cohen's r = .49 and 0.41) for the development of lameness in the 50 g and 25 g BCP group in comparison with the placebo treatment. This study revealed promising effects of the safe oral-specific BCP supplementation on symptoms of osteoarthritis in horses already after 3 months. The higher dosage of 50 g BCP/day had superior impact. Further long-term investigations on specific BCP efficacy in horses with osteoarthritis, preferably in blinded and placebo-controlled studies, should be performed to confirm these first positive results.

What is the evidence for a role for diet and nutrition in osteoarthritis?

As current treatment options in OA are very limited, OA patients would benefit greatly from some ability to self-manage their condition. Since diet may potentially affect OA, we reviewed the literature on the relationship between nutrition and OA risk or progression, aiming to provide guidance for clinicians. For overweight/obese patients, weight reduction, ideally incorporating exercise, is paramount. The association between metabolic syndrome, type-2 diabetes and OA risk or progression may partly explain the apparent benefit of dietary-lipid modification resulting from increased consumption of long-chain omega-3 fatty-acids from oily fish/fish oil supplements. A strong association between OA and raised serum cholesterol together with clinical effects in statin users suggests a potential benefit of reduction of cholesterol by dietary means. Patients should ensure that they meet the recommended intakes for micronutrients such as vitamin K, which has a role in bone/cartilage mineralization. Evidence for a role of vitamin D supplementation in OA is unconvincing.

Evaluation of the clinical effects of diet and physical rehabilitation in dogs following tibial plateau leveling osteotomy.

OBJECTIVE To assess clinical effects of an omega-3 fatty acid and protein-enriched diet, physical rehabilitation, or both in dogs following tibial plateau leveling osteotomy (TPLO) and arthroscopic surgery for cranial cruciate ligament (CCL) disease. DESIGN Randomized, prospective clinical trial. ANIMALS 48 dogs with unilateral CCL disease. PROCEDURES Dogs were randomly assigned to receive a dry omega-3 fatty acid and protein-enriched dog food formulated to support joint health (test food [TF]), a dry food formulated for maintenance of adult dogs (control food [CF]), TF plus rehabilitation (TF-R), or CF plus rehabilitation (CF-R). Data collected over 6 months included body weight, body condition score, ground reaction force data, tibial plateau angle, limb circumference measurements, subjective pain and lameness scores assigned by surgeons and dog owners, and daily activity measured by accelerometry. RESULTS Peak vertical force and vertical impulse were greater after surgery for dogs in the TF groups than in the CF groups; peak vertical force was greater after surgery in dogs that underwent rehabilitation than in those that did not. Owner scores indicated lower frequencies of lameness and signs of pain during some activities for the TF group, compared with other groups, and for the TF-R and CF-R groups, compared with the CF group. Sedentary time decreased and time spent in light-to-moderate or vigorous activity increased in all groups over time. Rehabilitation was significantly associated with greater time spent in light-to-moderate activity, regardless of diet. CONCLUSIONS AND CLINICAL RELEVANCE Feeding the TF and providing physical rehabilitation during the first 6 months after TPLO were associated with improvements in some indices of clinical outcome and function in dogs. Significant interactions between time and some outcome variables were observed, indicating further research is warranted.

Assessment of the effects of diet and physical rehabilitation on radiographic findings and markers of synovial inflammation in dogs following tibial plateau leveling osteotomy.

OBJECTIVE To determine the effects of an omega-3 fatty acid and protein-enriched diet, physical rehabilitation, or both on radiographic findings and markers of synovial inflammation in dogs following tibial plateau leveling osteotomy and arthroscopic surgery for treatment of cranial cruciate ligament disease. DESIGN Randomized, prospective clinical trial. ANIMALS 48 dogs with unilateral cranial cruciate ligament disease. PROCEDURES Dogs were randomly assigned to receive a dry omega-3 fatty acid and protein-enriched dog food formulated to support joint health (test food [TF]), a dry food formulated for adult canine maintenance (control food [CF]), TF plus rehabilitation, or CF plus rehabilitation after surgery. Synovial fluid prostaglandin (PG) E2 and interleukin-1ß concentrations, radiographic osteoarthritis scores, osteotomy site healing, and patellar ligament thickness were assessed at predetermined time points up to 6 months after surgery. RESULTS Dogs that received CF had significantly higher PGE2 concentrations over time following surgery than did dogs that received TF, regardless of rehabilitation status. Synovial fluid interleukin-1ß concentrations did not change over time in any groups. Diet and rehabilitation were both associated with osteoarthritis scores, with significantly lower scores over time for dogs that received TF versus CF and for dogs that underwent rehabilitation versus those that did not. Proportions of dogs with complete osteotomy healing 8 and 24 weeks after surgery were significantly lower for dogs that received TF than for dogs that received CF, regardless of rehabilitation status. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that feeding the TF can result in lower synovial fluid PGE2 concentrations and that both the TF and rehabilitation can reduce progression of osteoarthritis in the 6 months following tibial plateau leveling osteotomy; clinical relevance of slower osteotomy healing in dogs fed the TF was unclear.

Nutraceuticals and osteoarthritis pain.

Arthritis is a chronic disease of joints. It is highly prevalent, particularly in the elderly, and is commonly associated with pain that interferes with quality of life. Because of its chronic nature, pharmacological approaches to pain relief and joint repair must be safe for long term use, a quality many current therapies lack. Nutraceuticals refer to compounds or materials that can function as nutrition and exert a potential therapeutic effect, including the relief of pain, such as pain related to arthritis, of which osteoarthritis (OA) is the most common form. Of interest, nutraceuticals have recently been shown to have potential in relieving OA pain in human clinical trials. Emerging evidence indicates nutraceuticals may represent promising alternatives for the relief of OA pain. In this paper, we will overview OA pain and the use of nutraceuticals in OA pain management, focusing on those that have been evaluated by clinical trials. Furthermore, we discuss the biologic and pharmacologic actions underlying the nutraceutical effects on pain relief based on the potential active ingredients identified from traditional nutraceuticals in OA pain management and their potential for drug development. The review concludes by sharing our viewpoints that future studies should prioritize elucidating the mechanisms of action of nutraceuticals in OA and developing nutraceuticals that not only relieve OA pain, but also mitigate OA pathology.