Hyaluronic Acid Preparations Research Articles

Hyaluronic acid increases tendon derived cell viability and proliferation in vitro: comparative study of two different hyaluronic acid preparations by molecular weight.

Hyaluronic Acid (HA) has been already approved by Food and Drug Administration (FDA) for osteoarthritis (OA), while its use in the treatment of tendinopathy is still debated. The aim of this study was to evaluate the effects of two different HA on human rotator cuff tendon derived cells in terms of cell viability, proliferation and apoptosis. An in vitro model was developed on human tendon derived cells from rotator cuff tears to study the effects of two different HA preparations: Sinovial HL® (High-Low molecular weight) (MW: 80-100 kDa) and KDa Sinovial Forte SF (MW: 800-1200), at various concentrations. Tendon derived cells morphology was evaluated after 0, 7 and 14 d of culture. Viability and proliferation were analyzed after 0, 24, and 48 h of culture and apoptosis occurrence was assessed after 24 h of culture. All the HAPs tested here increased viability and proliferation, in a dose-dependent manner and they reduced apoptosis at early stages (24 h) compared to control cells (without HAPs). HAPs enhanced viability and proliferation and counteracted apoptosis in tendon derived cells.

Potential Impact of Biologically Derived Hyaluronic Acid on Quality of Life in Patients with Knee Osteoarthritis in the United States.

IntroductionKnee osteoarthritis is one of the leading causes of disability in the world. Intra-articular hyaluronic acid (IA-HA) is a treatment modality that provides a minimally invasive treatment option for the management of osteoarthritis-related symptoms. This study examined the current and potential economic impact of using a biologically derived, high molecular weight hyaluronic acid preparation (Euflexxa) on the US population for the management of knee osteoarthritis.MethodsA model was developed to estimate the total number of patients with symptomatic knee osteoarthritis in the US in 2015, distributed by Kellgren–Lawrence (K–L) grade, and the number of people living with total knee arthroplasty (TKA). The potential utility of Euflexxa was applied to this model population to determine the current and potential impact of the treatment as the total number of quality adjusted life years (QALY) saved within the US population.ResultsThere are approximately 12 million people currently suffering from symptomatic knee osteoarthritis in the US, and approximately 5 million living with TKA. It was estimated that, with a target treatment group of K–L grades 2–3, there are approximately 4 million patients eligible for treatment with a high molecular weight intra-articular hyaluronic acid injection. With current use, it is estimated that Euflexxa can save 36,730 QALY/year among the US population, and has the potential to save an additional 369,181 QALY/year if used by all eligible patients.ConclusionsThis study demonstrates that more widely used, biologically derived, high molecular weight IA-HAs, such as Euflexxa, have the potential to save a substantial number of QALYs among the US population with symptomatic knee osteoarthritis. Funding: Ferring Pharmaceuticals Inc.

Hyaluronic acid-modified manganese-chelated dendrimer-entrapped gold nanoparticles for the targeted CT/MR dual-mode imaging of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. The early and effective diagnosis has always been desired. Herein, we present the preparation and characterization of hyaluronic acid (HA)-modified, multifunctional nanoparticles (NPs) targeting CD44 receptor-expressing cancer cells for computed tomography (CT)/magnetic resonance (MR) dual-mode imaging. We first modified amine-terminated generation 5 poly(amidoamine) dendrimers (G5.NH2) with an Mn chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), fluorescein isothiocyanate (FI), and HA. Then, gold nanoparticles (AuNPs) were entrapped within the above raw product, denoted as G5.NH2-FI-DOTA-HA. The designed multifunctional NPs were formed after further Mn chelation and purification and were denoted as {(Au0)100G5.NH2-FI-DOTA(Mn)-HA}. These NPs were characterized via several different techniques. We found that the {(Au0)100G5.NH2-FI-DOTA(Mn)-HA} NPs exhibited good water dispersibility, stability under different conditions, and cytocompatibility within a given concentration range. Because both AuNPs and Mn were present in the product, {(Au0)100G5.NH2-FI-DOTA(Mn)-HA} displayed a high X-ray attenuation intensity and favorable r1 relaxivity, which are advantageous properties for targeted CT/MR dual-mode imaging. This approach was used to image HCC cells in vitro and orthotopically transplanted HCC tumors in a unique in vivo model through the CD44 receptor-mediated endocytosis pathway. This work introduces a novel strategy for preparing multifunctional NPs via dendrimer nanotechnology.

Comparative safety profile of hyaluronic acid products for knee osteoarthritis: a systematic review and network meta-analysis

Intra-articular (IA) hyaluronic acid (HA) is considered a safer alternative to oral Non-Steroidal Antiinflammatory Drugs (NSAIDs) and opioids for knee osteoarthritis (OA). A recent review raised potential safety concerns about HA, warranting further review of safety outcomes. We examined the risks of HA compared with IA placebo and investigated whether the risks vary among individual HA preparations. We searched all relevant databases from inception to October 2015 and sought unpublished data. We included all knee OA trials which compared any of the 18 HA products and reported on adverse events (AEs) and withdrawals. We calculated odds ratios for safety data reported at the longest follow-up. Network meta-analysis was performed using a Bayesian hierarchical random effects model for mixed multiple treatment comparisons. We identified 74 studies involving 13,032 participants aged between 45 and 75 years. The proportion of women ranged from 28% to 100%. The overall incidence of local reactions reported across all products was 8.5%. Commonly reported AEs were transient local reactions, such as pain, swelling and arthralgia, which subsided rapidly. None of the HA products were statistically significantly different from IA placebo or from each other with regard to incidence of AEs. Three treatment-related serious adverse events (SAEs) were reported among 9214 participants. Given the very low incidence of any particular AEs, we conclude that HA products are relatively well tolerated. These products have a similar safety profile compared to each other. This information along with the comparative effectiveness profile and relative cost would be helpful for clinicians in delivering individualized patient care.

Pre-injection of hyaluronic acid does not affect the systemic effects of intra-articular depot betamethasone injection at the knee joint.

Intra-articular injection (IAI) of both hyaluronic acid (HA) and depot-steroid preparations had the advantage of quick and prolonged favorable effects on pain relief among patients with symptomatic osteoarthritis of the knee (OAK). The effect of IAI of HA on the systemic effects of the intra-articular steroids had not been investigated. Non-selected patients attending the rheumatology clinic with symptomatic OAK who failed NSAIDS and physical therapy were offered an IAI of HA at the knee joint followed 20min later by an IAI of 1ml of Celestone Chronodose at the same joint (group 1). Morning serum levels of cortisol were obtained just prior to the IAI and 1, 2 and 8days later. Demographic, clinical, and laboratory parameters were obtained also from all the patients. Age- and sex-matched group of patients from the same clinic were recruited as a control group (group 2). Mean baseline serum cortisol levels in group 1 was 381 ± 154mmol/l vs. 376 ± 119 in group 2 (p = 0.954). Morning serum cortisol levels at day 1 and day 2 were 24 ± 6 and 22 ± 6mmol/l, respectively, in group 1 patients vs. 27 ± 5.8 (p = 0.214) and 25 ± 5.6mmol/l (p = 0.200), respectively, in group 2. These levels were significantly lower than baseline levels in each group. Morning serum cortisol levels at day 8 in group 1 and group 2 were 349 ± 128 and 314 ± 99mmol/l, respectively (p = 0.419). Pre-injection of HA at the knee joint did not affect the systemic effect on the hypothalamic-pituitary-adrenal axis of IAI of Celestone Chronodose.

Use of hyaluronic acid preparations in the combination therapy of osteoarthritis

The current recommendations for the pharmacotherapy of osteoarthritis (OA) primarily focus on analgesics and main concern is with the use of paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs). Intraarticular injections of first of all hyaluronic acid (HA) preparations that have proven to be effective in clinical practice are a promising treatment for OA. By taking into account the favorable safety profile of HA preparations, it may be suggested that these injections may be an acceptable alternative to NSAIDs or successfully used in combination with the latter. There have been recently the recommendations for the administration of HA preparations in OA treatment, which characterize the current practice of HA use for OA and had been prepared by a group of experts from 5 European countries. The experts consider that there is today rather solid evidence to demonstrate the efficacy of HA in mild and moderately severe knee OA; moreover, its effect is clinically significant in such patients. In the authors’ view, topical HA therapy should be a compulsory component of treatment for knee OA, since the alternative possibilities of therapy for this disease are limited. Although the optimal effect of HA is observed when it is applied in the early stage of OA, this treatment may be also useful in its late stage. HA should be regarded as an adjunct method that must be applied if surgery cannot be performed in these patients.

Preparation, characterization and cytotoxicity studies of a novel bioconjugate hyaluronan and a-linolenic acid

Event Abstract Back to Event Preparation, characterization and cytotoxicity studies of a novel bioconjugate hyaluronan and α-linolenic acid Gloria Huerta-Angeles1, Martina Brandejsova1, Jaromir Kulhanek1, Hana Vagnerova1, Daniela Smejkalova1, Vojtech Pavlik1, Kristina Nesporova1, Martina Moravcova1 and Vladimir Velebny1 1 Contipro Pharma, Research and Development, Czechia Introduction: Hyperpigmentation is a usually harmless condition in which patches of skin become darker that follows an injury or inflammatory disorder. Hyaluronic acid (HA), a ubiquitous component of extracellular matrix (ECM) is involved in many anti-inflammatory processes and used to treat skin disorders. Alpha-Linolenic acid (ALA or C18:3), an essential fatty acid is known to inhibit melanin production in vitro[1]. HA- alpha-linolenic acid conjugates (HA-C18:3) may give a synergistic effect of both components, enhance the therapeutic effect of the fatty acid by improving skin penetration and improve stability and solubility of the fatty acid. The development of HA-ALA, as a novel derivate was tested in semi-industrial scale. For that reason, selected physico-chemical properties were studied to determine shelf-life i.e. oxidative products, thermal stability, and possible degradation. The safety of the derivative was also evaluated over the time. Materials and Methods: The preparation of hyaluronic acid (HA) linked with alpha-linolenic acid (HA-C18:3) was investigated[2]. A complete characterization of several batches was performed by NMR, SEC MALLS and GC. Autoxidation of the fatty acid was also followed, using gas chromatography (GC-MS). A complete stability test was carried out under EU-Pharmacopoeia regulations[3]. The effect of air/inert atmosphere, and temperature (-25, 8, 25 °C) on stability were studied. A complete cytotoxicity study of the derivative was performed in 3T3-NIH cells and followed during storage (3, 6 up to 12 months). Thermogravimetric analysis (TGA) was used to evaluate possible structural changes and evaluate the reaction reproducibility. Results and Discussion: Degradation products, reaction impurities and volatiles such as 1-penten-3-one, 2-hexenal, 2-heptenal and 2, 4-Heptadienal, or isopropyl linolenate were identified during the lipid peroxidation and reaction. The amounts were acceptable under EU-pharmacopeia. Hexanal, a known marker was used to evaluate the degree of oxidation. Figure 1 depicts the effects of HA-C18:3 on cell viability after 12 weeks of storage. After that time, negligible effects were observed. The median of the viable cells to control was evaluated to find statistically significant differences in cell-viability in several batches. HA-C18:3 stored under nitrogen overcome the oxidation of the fatty acid. Furthermore, the effect of storage temperature was not statistically significant. The derivatives stored under nitrogen were found to be non-cytotoxic for all tested conditions (P>0.05). Oppositely, the effect of temperature drastically affects the cytocompatibility of the derivative stored under air. The cytotoxicity effect of the derivative was found to be insignificant only for storage at low temperature (-20°C) with no significant changes observed as effect of concentration (100 and 500 ug/ml, P˂0.001). Degradation of the molecular weight and degree of substitution were not detected. TGA and DSC experiments showed a substantial change on thermal behaviour of HA-C18:3 stored under nitrogen or air at different temperatures. The in vitro studies have demonstrated a decreased hyperpigmentation after applying HA-C18:3 Conclusions: In this work, the grafting of hyaluronan with the fatty acid (HA-C18:3) changes the physico-chemical properties of the polysaccharide. Furthermore, the covalent conjugation allows the stabilization the fatty acid against autoxidation, making HA-C18:3 a potential and safe candidate for hyperpigmentation treatment.

Highly stretchable hydrogels obtained by controlled self-assembly of hyaluronic acid and chitosan and preparation thereof

Highly stretchable hydrogels obtained by controlled self-assembly of hyaluronic acid and chitosan and preparation thereof

Efficacy of single-dose hyaluronic acid products with two different structures in patients with early-stage knee osteoarthritis.

[Purpose] There are many types of hyaluronic acid preparations, but no clear data are available about which preparations is more effective. The aim of this trial was to investigate the effectiveness of different types of hyaluronic acid preparations on pain and function of inpatients with knee osteoarthritis. [Subjects and Methods] All patients were diagnosed by clinical examination and x-ray. Ostenil PLUS® was injected into 28 patients (group 1, 1.6 million daltons), and MONOVISC® (group 2, 2.5 million daltons) was injected into 46 patients. Demographic data and Western Ontario and McMaster Universities Osteoarthritis Index and Visual Analog Scale scores were used for clinical evaluation at 1, 3, and 6 months post injection. [Results] In both groups, baseline Ontario and McMaster Universities Osteoarthritis Index and Visual Analog Scale scores were higher compared with those in subsequent evaluations. Based on the pre- and post-injection data, a significant reduction in all scores was observed after the injections for in both groups. According to intergroup comparisons, there was no significant difference in any of the scores between the two groups. [Conclusion] There were no difference in Ontario and McMaster Universities Osteoarthritis Index and Visual Analog Scale scores in patients with knee osteoarthritis injected with two different hyaluronic acid structures in short-term preparations.

Eye lid hygiene in chronic allergic blepharoconjunctivitis patients before laser refractive surgery

To evaluate the effectiveness of eyelid hygiene in patients with chronic allergic blepharoconjunctivitis (ABC) as a part of their preparation for laser refractive surgery. The study involved 32 patients (12 males and 20 females aged 25-42 years) with refractive errors, namely, compound myopic astigmatism (23 patients) and hyperopic astigmatism (9 patients) suffering from chronic ABC and secondary dry eye syndrome (DES). All the patients initially received a standard treatment for ABC and DES, that is olopatodin hydrochloride instillations - 1 mg/ml 2 times daily, preservative-free hyaluronic acid preparation - 1 mg/ml 3 times daily, and polyacrylic acid and dexpanthenol gel at night for one month. The scheme, however, appeared not effective enough. Hence, the patients were prescribed eyelid hygiene (Blepharolotion or Blepharosalfetka plus Blepharogel-1 2 times daily) to relive meibomian gland dysfunction (MGD). They also underwent a conventional ophthalmic examination, allergy tests, evaluation of ABC and DES signs and symptoms, tear film break-up time test, Schirmer's test, meibomian glands evaluation, optical coherence tomography with meniscometry, xerosis index evaluation, and lissamine green staining for lid wiper epitheliopathy. At the beginning of the study signs and symptoms of MGD-associated DES were predominant in all patients. Chronic ABC signs were mild. In 2-3 months, meibomian gland function and tear film break-up time improved significantly in most patients, while xerosis index decreased and lid wiper epitheliopathy resolved. Laser refractive surgery (LASIK) was performed in 81.25% of patients, all of whom were satisfied with the results. Inclusion of eyelid hygiene into preoperative management of patients with chronic ABC and DES allows to achieve optimum conditions for laser refractive surgery in most cases.

Intraosseous Pseudotumor After Knee Viscosupplementation: A Case Report.

A sixty-eight-year-old woman with osteoarthritis in the right knee who had received a single injection of a commercial hyaluronic acid preparation presented with an intraosseous mass that had not appeared in previous imaging studies. Open biopsy and curettage was performed, and a reactive pseudotumor related to viscosupplementation was diagnosed. At the last follow-up fourteen months after surgery, the patient had experienced no recurrence of the lesion. Viscosupplementation is considered a conservative treatment option for early-stage knee osteoarthritis. To the best of our knowledge, this complication, namely an intraosseous mass, has not been described previously in the literature.

Возможности использования в восстановительном лечении ревматоидного артрита ионизированных препаратов гиалуроновой кислоты

Возможности использования в восстановительном лечении ревматоидного артрита ионизированных препаратов гиалуроновой кислоты

The Research Progress in Hyaluronic Acid

Hyaluronic acid( HA) is a linear polysaccharide chain composed of alternating glucuronic acid and N-acetylglucosamine moieties. Because of the unique molecular structure and the physical and chemical properties,it has been successfully used in cosmetics,medical cosmetology,ophthalmic surgery,arthritis therapy. The recent advances in Hyaluronic acid and its derivatives,especially the preparation of hyaluronic acid come from living marine resources are noted. The application with different molecular weight as pharmaceutical carrier and others are also summarized.

Facile preparation of hyaluronic acid and transferrin co-modified Fe3O4 nanoparticles with inherent biocompatibility for dual-targeting magnetic resonance imaging of tumors in vivo.

Clinical diagnosis of malignant tumors using nanoprobes needs severe improvements in the aspects of sensitivity and biocompatibility. Integrating a dual-targeting strategy with the selection of human-inherent elements and molecules as raw materials shows great potential in the development of a biosafe and sensitive nanoplatform. To carry out the proposed design, we constructed a biocompatible, dual-targeting MR imaging nanoprobe, based on Fe3O4 nanoparticles (NPs) co-modified with inherently innoxious hyaluronic acid (HA) and transferrin (Tf). HA was used as both a template and a targeting molecule to form Fe3O4@HA NPs through a one-step co-precipitation method, which were then further modified with Tf to obtain the dual-targeting Fe3O4@HA@Tf NPs at room temperature. The excellent biocompatibility of the nanoprobe was demonstrated via toxicity assays in vitro and in vivo. The desirable dual-targeting ability towards tumor cells was confirmed by a cellular uptake test (Hela cells, overexpressing both CD44 and transferrin receptors), and the developed nanoprobe was successfully applied in tumor-targeted MR imaging in vivo. In summation, we developed a dual-targeting Fe3O4 nanoprobe, following a facile procedure at room temperature. The nanoprobe showed a high targeting ability towards tumor cells and excellent biocompatibility, which showed its great potential to be applied in the clinical diagnosis of tumors.

Induction of protoporphyrin IX in patient-derived synoviocytes, cartilage explants and chondrons after application of 5-aminolevulinic acid or its methyl ester

ObjectiveTo compare the accumulation of protoporphyrin IX between synoviocytes of patients with rheumatoid arthritis (RA) or osteoarthritis (OA) and cartilage explants (CE) as well as chondrons of patients with OA after the application of 5-aminolevulinic acid (ALA) or its methyl ester (ALA-Me). Materials and methodsSamples of synovial and cartilage tissues were obtained from joint replacement surgeries. The accumulation of PpIX was determined by measuring fluorescence spectra from 2×105 synoviocytes or chondrons suspended in a glass tube or directly from CE surface after 2, 4, 8 and 24h of incubation with ALA or ALA-Me. ResultsNo differences were found between the average fluorescence intensity values of PpIX in synoviocytes of patients with RA and OA. These values were non-significantly higher after incubation with ALA in comparison with ALA-Me at almost all time points. The average fluorescence intensity of PpIX in CE and chondrons was about ten times lower than in synoviocytes. The presence of preparation of hyaluronic acid (HA) significantly enhanced PpIX induction in chondrons versus treatment only with ALA. ConclusionsA potential for the selective synovial sensitization with endogenous PpIX in comparison with cartilage tissue has been demonstrated in vitro after application of ALA or ALA-Me.

Place of hyaluronic acid preparations in therapy for osteoarthrosis

The paper gives data on the positive role of hyaluronic acid (HA) preparations in the treatment of knee and hip osteoarthrosis (OA). The clinical effect of intraarticular agents is not only due to their lumbricative, but also, to a greater degree, anti-inflammatory and chondroprotective activities. The efficacy of HA preparations do not practically depend on their molecular weight. Long-term HA cycles can delay the risk of joint replacement in OA.

HYALURONIC ACID IN TREATMENT OF KNEE OSTEOARTHRITIS

Osteoarthritis is an important medical and social problem. Оsteoarthritis affects 13% of the adult population in Russia. Knee and hip joints are affected most frequently. Оsteoarthritis therapy includes nonpharmacologic and pharmacologic methods. Hyaluronic acid is widely used in the treatment of osteoarthritis in recent years. Intraarticular injections of hyaluronic acid more effective than placebo, are not inferior to traditional treatments and can be used as a symptomatic treatment of OA. Local therapy with hyaluronic acid well tolerated, reduces pain and improves function. Intraarticular injections of hyaluronic acid used in patients with knee OA stages I-III, less than 65 years of age, in patients who do not respond adequately to conventional therapy or with contraindications to nonsteroidal anti-inflammatory drugs (NSAIDs). Hyaluronic acid preparations of different molecular weight are of comparable effectiveness. Repeated courses do not increase the risk of side effects.

Preparation and characterization of a novel hyaluronic acid–icariin conjugate hydrogel

To maintain the long-time bioactivity of hydrogel scaffold and promote chondrogenesis, hyaluronic acid–icariin (HA–Ica) conjugate hydrogel was prepared. Firstly, methacrylic anhydride (MA)-modified icariin (MIca) and MA-modified hyaluronic acid (HAMA) were synthesized. MIca in aqueous solution formed nanoparticles, which were characterized by scanning electron microscopy and dynamic light scattering. Then, MIca was dispersed uniformly in HAMA solution and covalently introduced into HAMA by the reaction of methacrylate groups between HAMA and MIca during the formation process of hydrogel. HA–Ica hydrogel exhibited the controlled release of Ica and good cytocompatibilty, suggesting that it could be potentially utilized as a scaffold for cartilage tissue engineering.

Antioxidant activity of hyaluronic acid investigated by means of chemiluminescence of equine neutrophil bursts and electron paramagnetic resonance spectroscopy.

Activated neutrophils (PMNs), the ROS/RNS released by PMNs and the derived inflammatory processes are involved in the pathogenesis and progression of human inflammatory airway diseases. Similar diseases are also present in horses which suffer from recurrent airway obstruction (RAO), exercise-induced pulmonary haemorrhage (EIPH) and inflammatory airway diseases (IAD). Hyaluronic acid (HA) plays numerous roles in modulating inflammatory processes. The aim of this study was to examine whether a preparation of HA (MW 900 000 Da) interferes with ROS/RNS during the course of equine PMN respiratory bursts, and to establish the lowest concentration at which it still has antioxidant activity by means of luminol-amplified chemiluminescence (LACL). Electron paramagnetic resonance (EPR) spectroscopy was also used to investigate the direct antiradical activity of HA. The hydroxyl radical was significantly scavenged in a concentration-dependent manner at HA concentrations ranging from 2.5 to 0.16 mg/mL. Superoxide anion, Tempol radical and the ABTS(•+) were significantly inhibited at concentrations ranging from 2.5 to 0.62 mg/mL. The LACL of stimulated equine neutrophils showed that HA induced a statistically significant concentration-effect reduction from 5 mg/mL to 1.25 mg/mL. These findings were confirmed also when l-Arg was added to investigate the inhibition of the resulting peroxynitrite anion. Our findings indicate that, in addition to the human use, HA can also be used to antagonize the oxidative stress generated by free radicals in horses peripheral blood mononuclear cells (PBMCs). In order to achieve therapeutic concentrations, a direct aerosol administration to horses with horse respiratory diseases can be considered, as this route of application is also recommended in human medicine.

Erratum to: The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses

The purpose of this study was to determine the effects of an oral preparation containing hyaluronic acid on osteoarthritic knee joint pain and function as well as changes in inflammatory cytokines, bradykinin, and leptin. We also used heavy water to determine the turnover rates of glycosaminoglycans in synovial fluid. This was a double-blind, randomized, placebo-controlled study of 40 subjects over a period of 3 months. Visual analog scale, Western Ontario McMaster pain, and WOMAC function scores were recorded. Serum and synovial fluid were measured by enzyme-linked immunosorbent assays for inflammatory cytokines, bradykinin, and leptin. In 20 subjects, terminal heavy water ingestion was used for spectral analyses of serum and joint fluid samples. There were statistically significant improvements in pain and function. Both serum and synovial fluid samples showed significant decreases for a majority of inflammatory cytokines, leptin, and bradykinin in the oral hyaluronic acid preparation group. Heavy water analyses revealed a significant decrease in hyaluronic acid turnover in the synovial fluid of the treatment group. A preparation containing hyaluronic acid and other glycosaminoglycans holds promise for a safe and effective agent for the treatment for patients with knee osteoarthritis and who are overweight. Further studies will be required to see whether this is a disease-modifying agent.