Objective
To assess the efficacy and safety of combination therapy with chondroitin sulfate (CS) and glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis ...(OA).
Methods
A multicenter, randomized, double‐blind, placebo‐controlled study was performed in 164 patients with Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA and moderate‐to‐severe knee pain (mean ± SD global pain score 62.1 ± 11.3 mm on a 100‐mm visual analog scale VAS). Patients were randomized to receive either combined treatment with CS (1,200 mg) plus GS (1,500 mg) or placebo in a single oral daily dose for 6 months. The mean change from baseline in the VAS global pain score was set as the primary end point. Secondary outcomes included the mean change in the investigator's global assessment of disease activity, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain and function subscale scores on the WOMAC, responder rates based on the Outcome Measures in Rheumatology (OMERACT)–Osteoarthritis Research Society International (OARSI) 2004 response criteria, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was instituted to ensure patient safety and data accuracy.
Results
Intriguingly, in the modified intent‐to‐treat (mITT) population, CS/GS combination therapy was inferior to placebo in the reduction of joint pain (mean ± SD change in VAS global pain score over 6 months −11.8 ± 2.4 mm 19% reduction in patients receiving CS plus GS versus −20.5 ± 2.4 mm 33% reduction in patients receiving placebo; peak between‐group difference in global pain score at 6 months 8.7 mm 14.2%, P < 0.03), but no between‐group differences were seen in the per‐protocol completers. Both placebo treatment and CS/GS combination treatment improved to a similar extent the total WOMAC score as well as the pain and function WOMAC subscale scores, both in the mITT population and in the per‐protocol completers. Neither the OMERACT–OARSI responder rate nor the frequency of rescue medication use differed between the treatment groups. Severe adverse events were uncommon and equally distributed.
Conclusion
The results of this trial demonstrate a lack of superiority of CS/GS combination therapy over placebo in terms of reducing joint pain and functional impairment in patients with symptomatic knee OA over 6 months. Further research might fully elucidate the suitability of CS/GS combination therapy in patients with OA.
Background and Purpose
The pathogenesis of osteoarthritis implicates a low‐grade inflammation associated to the innate immune system activation. Toll like receptor (TLR) stimulation triggers the ...release of inflammatory mediators, which aggravate osteoarthritis. We studied the preventive effect of 6‐shogaol, a potential TLR4 inhibitor, on the treatment of experimental knee osteoarthritis.
Experimental Approach
Osteoarthritis was induced in C57BL6 mice by surgical section of the medial meniscotibial ligament, which received 6‐shogaol for eight weeks. Cartilage damage, inflammatory mediator presence and disease markers were assessed in joint tissues by immunohistochemistry. Computational modelling was used to predict binding modes of 6‐shogaol into the TLR4/MD2 receptor and its permeability across cellular membranes. Employing LPS‐stimulated chondrocytes and MAPK assay, we elucidated 6‐shogaol action mechanisms.
Key Results
6‐Shogaol treatment prevented articular cartilage lesions, synovitis and the presence of pro‐inflammatory mediators, and disease markers in osteoarthritis animals. Molecular modelling studies predicted 6‐shogaol interaction with the TLR4/MD‐2 heterodimer in an antagonist conformation through its binding into the MD‐2 pocket. In cell culture, we confirmed that 6‐shogaol reduced LPS‐induced TLR4 inflammatory signalling pathways. Besides, MAPK assay demonstrated that 6‐shogaol directly inhibits the ERK1/2 phosphorylation activity.
Conclusion and Implications
6‐Shogaol evoked a preventive action on cartilage and synovial inflammation in osteoarthritis mice. 6‐shogaol effect may take place not only by hindering the interaction between TLR4 ligands and the TLR4/MD‐2 complex in chondrocytes, but also through inhibition of ERK phosphorylation, implying a pleiotropic effect on different mediators activated during osteoarthritis, which proposes it as an attractive drug for osteoarthritis treatments.
Osteoarthritis treatment should contemplate the improvement of subchondral bone quality. This therapeutic approach must be individualized in each patient depending on the BMD status and the ...physiopathological subgroup of osteoarthitis (OA). BMD: bone mineral density; SB: subchondral bone.
Osteoarthritis (OA), the most common form of arthritis, is a debilitating and progressive disease that has become a major cause of disability and impaired quality of life in the elderly. OA is considered an organ disease that affects the whole joint, where the subchondral bone (SB) plays a crucial role. Regardless of whether SB alterations precede cartilage damage or appear during the evolution of the disease, SB is currently recognised as a key target in OA treatment. In fact, bone abnormalities, especially increased bone turnover, have been detected in the early evolution of some forms of OA. Systemic osteoporosis (OP) and OA share a paradoxical relationship in which both high and low bone mass conditions may result in induction and/or OA progression. Recent findings suggest that some drugs may be useful in treating both processes simultaneously, at least in a subgroup of patients with OA and OP. This review focuses on the role of SB in OA pathogenesis, describing relevant underlying mechanisms involved in the process and examining the potential activity as disease-modifying anti-osteoarthritic drugs (DMOADs) of certain SB-targeting agents currently under study.
Since publication of the European League Against Rheumatism (EULAR) recommendations for management of hand osteoarthritis (OA) in 2007 new evidence has emerged. The aim was to update these ...recommendations. EULAR standardised operating procedures were followed. A systematic literature review was performed, collecting the evidence regarding all non-pharmacological, pharmacological and surgical treatment options for hand OA published to date. Based on the evidence and expert opinion from an international task force of 19 physicians, healthcare professionals and patients from 10 European countries formulated overarching principles and recommendations. Level of evidence, grade of recommendation and level of agreement were allocated to each statement. Five overarching principles and 10 recommendations were agreed on. The overarching principles cover treatment goals, information provision, individualisation of treatment, shared decision-making and the need to consider multidisciplinary and multimodal (non-pharmacological, pharmacological, surgical) treatment approaches. Recommendations 1–3 cover different non-pharmacological treatment options (education, assistive devices, exercises and orthoses). Recommendations 4–8 describe the role of different pharmacological treatments, including topical treatments (preferred over systemic treatments, topical non-steroidal anti-inflammatory drugs (NSAIDs) being first-line choice), oral analgesics (particularly NSAIDs to be considered for symptom relief for a limited duration), chondroitin sulfate (for symptom relief), intra-articular glucocorticoids (generally not recommended, consider for painful interphalangeal OA) and conventional/biological disease-modifying antirheumatic drugs (discouraged). Considerations for surgery are described in recommendation 9. The last recommendation relates to follow-up. The presented EULAR recommendations provide up-to-date guidance on the management of hand OA, based on expert opinion and research evidence.
Chondrocytes in osteoarthritic (OA) cartilage acquire a hypertrophic‐like phenotype, where Hedgehog (Hh) signaling is pivotal. Hh overexpression causes OA‐like cartilage lesions, whereas its ...downregulation prevents articular destruction in mouse models. Mutations in EVC and EVC2 genes disrupt Hh signaling, and are responsible for the Ellis‐van Creveld syndrome skeletal dysplasia. Since Ellis‐van Creveld syndrome protein (Evc) deletion is expected to hamper Hh target gene expression we hypothesized that it would also prevent OA progression avoiding chondrocyte hypertrophy. Our aim was to study Evc as a new therapeutic target in OA, and whether Evc deletion restrains chondrocyte hypertrophy and prevents joint damage in an Evc tamoxifen induced knockout (EvccKO) model of OA. For this purpose, OA was induced by surgical knee destabilization in wild‐type (WT) and EvccKO adult mice, and healthy WT mice were used as controls (n = 10 knees/group). Hypertrophic markers and Hh genes were measured by qRT‐PCR, and metalloproteinases (MMP) levels assessed by western blot. Human OA chondrocytes and cartilage samples were obtained from patients undergoing knee joint replacement surgery. Cyclopamine (CPA) was used for Hh pharmacological inhibition and IL‐1 beta as an inflammatory insult. Our results showed that tamoxifen induced inactivation of Evc inhibited Hh overexpression and partially prevented chondrocyte hypertrophy during OA, although it did not ameliorate cartilage damage in DMM‐EvccKO mice. Hh pathway inhibition did not modify the expression of proinflammatory mediators induced by IL‐1 beta in human OA chondrocytes in culture. We found that hypertrophic—IHH—and inflammatory—COX‐2—markers co‐localized in OA cartilage samples. We concluded that tamoxifen induced inactivation of Evc partially prevented chondrocyte hypertrophy in DMM‐EvccKO mice, but it did not ameliorate cartilage damage. Overall, our results suggest that chondrocyte hypertrophy per se is not a pathogenic event in the progression of OA.
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Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degradation, osteophyte formation, subchondral bone sclerosis, and synovitis. Systemic factors such as ...obesity and the components of the metabolic syndrome seem to contribute to its progression. Breakdown of cartilage ensues from an altered balance between mechanical overload and its absorption by this tissue. There is in this context a status of persistent local inflammation by means of the chronic activation of innate immunity. A broad variety of danger-associated molecular patterns inside OA joint are able to activate pattern recognition receptors, mainly TLR (toll-like receptor) 2 and 4, which are overexpressed in the OA cartilage. Chronic activation of innate immune responses in chondrocytes results in a robust production of pro-inflammatory cytokines and chemokines, as well as of tissue-destructive enzymes, downstream of NF-κB and MAPK (mitogen activated protein kinase) dependent pathways. Besides, the toxic effects of an excess of glucose and/or fatty acids, which share the same pro-inflammatory intracellular signalling pathways, may add fuel to the fire. Not only high concentrations of glucose can render cells prone to inflammation, but also AGEs (advanced glycation end products) are integrated into the TLR signalling network through their own innate immune receptors. Considering these mechanisms, we argue for the control of both primary inflammation and proteolytic catabolism as a preventive strategy in OA, instead of focusing treatment on the enhancement of anabolic responses. Even though this approach would not return to normal already degraded cartilage, it nonetheless might avoid damage extension to the surrounding tissue.
Introduction
Dental implant osseointegration can be impaired in medical conditions with low bone mass, such as glucocorticoid‐induced osteoporosis. Intermittent human parathyroid hormone (PTH) 1‐34 ...administration has shown relevant anabolic bone activity in various animal models of osteoporosis. Therefore, we studied the effects of intermittent PTH 1‐34 on bone response around titanium implants in experimental osteoporosis induced by ovariectomy and glucocorticoid administration.
Methods
Titanium dental implants were placed in the proximal tibia metaphysis in 38 animals. Twenty‐eight rabbits had undergone bilateral ovariectomy and further methylprednisolone administration for 4 weeks to induce osteoporosis. Ten healthy rabbits were used as controls. At week 8, osteoporotic rabbits started saline vehicle or intermittent PTH administration for 12 weeks. Bone mineral density (BMD) was assessed in peri‐implant area, lumbar spine, and global and subchondral knee bone at baseline, and weeks 6 and 20. Animal sacrifice was carried out at week 21. Afterward, tibiae were removed for μCT morphometry and undecalcified sections were evaluated by light and scanning electron microscopy.
Results
PTH increased bone‐to‐implant contact compared with control rabbits or vehicle administration in osteoporotic rabbits (P < 0.005). PTH‐induced new bone formation around external and internal surfaces of titanium implants led to a significant increase of BMD at peri‐implant area in osteoporotic rabbits at week 20, when compared with vehicle (P < 0.005). Likewise, PTH increased BMD in other analysed regions.
Conclusions
Intermittent administration of PTH 1‐34 enhances the bone response around titanium implants in a rabbit model of ovariectomy and glucocorticoid‐induced osteoporosis.
Cartilage is an avascular tissue and cartilage metabolism depends on molecule diffusion from synovial fluid and subchondral bone. Thus, nutrient availability is limited by matrix permeability ...according to the size and charge of the molecules. Matrix composition limits the access of molecules to chondrocytes, determining cell metabolism and cartilage maintenance. Lipids are important nutrients in chondrocyte metabolism and are available for these cells through de novo synthesis but also through diffusion from surrounding tissues. Cartilage status and osteoarthritis development depend on lipid availability. This paper reviews lipid transport and metabolism in cartilage. We also analyze signalling pathways directly mediated by lipids and those that involve mTOR pathways, both in normal and osteoarthritic cartilage.
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