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Advances in Treatments for Osteoarthritis

  • Authors: Antonios O. Aliprantis, MD, PhD
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Target Audience and Goal Statement

This activity is intended for rheumatologists, primary care providers, and nurses.

The goals of this activity are to discuss recent advances in osteoarthritis management, including advances in agents with disease-modifying potential, and an update on new data supporting OA pain management approaches, with a focus on nonpharmacologic and pharmacologic management interventions.

Upon completion of this activity, participants will be able to:

  1. Recognize the long-term consequences of failure to manage or suboptimally manage osteoarthritis (OA) pain
  2. Interpret the advantages and limitations of current pain control therapies, particularly as they relate to gastrointestinal side effects
  3. Summarize key advances in pain control therapies for OA, particularly agents with an improved adverse-effect profile and their potential in the clinical setting for improved patient outcomes


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  • Antonios O. Aliprantis, MD, PhD

    Instructor, Harvard Medical School, Boston, Massachusetts; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts


    Disclosure: Antonios O. Aliprantis, MD, PhD, has disclosed the following relevant financial relationships:
    Received grants for clinical research from: Merck & Co., Inc. to former postdoctoral mentor, Dr. Laurie Glimcher, who supported some of the research


  • Helen Fosam, PhD

    Scientific Director, MedscapeCME


    Disclosure: Helen Fosam, PhD, has disclosed no relevant financial relationships.

CME Reviewer/Nurse Planner

  • Laurie E. Scudder, MS, NP

    Accreditation Coordinator, Continuing Professional Education Department, MedscapeCME; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC; Nurse Practitioner, School-Based Health Centers, Baltimore City Public Schools, Baltimore, Maryland


    Disclosure: Laurie E. Scudder, MS, NP, has disclosed no relevant financial relationships.

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Advances in Treatments for Osteoarthritis

Authors: Antonios O. Aliprantis, MD, PhDFaculty and Disclosures



A significant number of individuals over the age of 65 years demonstrate clinical and/or radiographic evidence of osteoarthritis (OA), making this degenerative joint disease the most common affliction of the skeletal system.[1] Patients with OA suffer from pain, stiffness, and functional impairment, often culminating in unrelenting symptoms -- primarily pain -- and the need for total joint replacement. The cause of this disease has not been resolved, but risk factors include aging, female sex, obesity, prior trauma, and malalignment as well as genetic factors and biochemical changes in aging joint tissues.[2,3] Despite the prevalence of OA and its associated negative impact on patients' quality of life, there are currently no therapeutic agents approved by the US Food and Drug Administration capable of mitigating the changes in cartilage and bone characteristics of OA, which include progressive denudation of the articular cartilage and osteophytes, respectively. At the American College of Rheumatology (ACR) 2009 Annual Scientific Meeting, several studies were presented that evaluated pharmacologic or nutritional interventions for this condition. Moreover, recent exciting work in animal models of OA has identified 2 new potential targets for therapeutic intervention in this disease. These studies are summarized below.

Pharmacologic and Nutritional Interventions

Glucosamine: Effect on Structural Changes Associated With Knee OA?

Glucosamine is a nutritional supplement sold over the counter that is often used by patients with degenerative joint disease. Although previous studies have failed to demonstrate a consistent effect of glucosamine on pain in patients with OA,[4] the effect of this preparation on structural disease progression remains unresolved. At the 2009 ACR meeting, results of the Joints on Glucosamine (JOG) trial, designed to address this issue in patients with knee OA, were presented.[5] In this 24-week, double-blind, placebo-controlled trial, 201 patients with knee OA and mild-to-moderate knee pain were randomly sampled to receive either 1500 mg of glucosamine or placebo daily. Each patient underwent a 3-T MRI of the affected knee at baseline and at 24 weeks. Of the 201 patients, 49% were women. Dropout rates were similar between each group. On an intention-to-treat analysis, no differences were observed in the progression of cartilage lesions between the treatment and placebo arms over the 24-week study. Moreover, glucosamine did not reduce levels of urinary type II collagen fragments, a biomarker for cartilage turnover. Taken together, these data suggest that glucosamine does not inhibit structural progression in knee OA, although this study is limited by its relatively small sample size and short follow-up, especially in light of the fact that OA lesions develop and progress over several years. These data are consistent with results of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), which failed to show a significant effect of combination therapy with glucosamine and chondroitin on radiographic joint space narrowing in knee OA over a 24-month study.[6] However, a recent meta-analysis of multiple clinical trials suggested that longer-term follow-up (3 years) may be needed to observe statistically significant benefits of these agents.[7] Additional long-term studies are needed to resolve the true benefit of these common supplements in limiting the progression of knee OA.

Nutraceutical for Hip OA: Are Avocado-Soybean Unsaponifiables Effective Treatment for OA Pain?

Avocado-soybean unsaponifiables (ASU) are an extract of avocado and soybeans that has been studied for over 15 years, predominantly in Europe, as a treatment for OA pain.[8] At the 2009 ACR meeting, results of a 3-year trial to evaluate the efficacy of ASU to prevent progression of hip OA were presented.[9] In this trial, 399 patients with symptomatic hip OA were randomly sampled to receive either placebo or ASU (300 mg) once daily. Patients in the placebo and ASU-treated groups had similar demographics at baseline and received baseline and yearly x-rays of the hip. At 3 years, no differences were observed between the placebo and ASU-treated groups in the primary outcome, which was change in joint space width. However, a statistically significant 20% reduction in progression, defined as > 0.5 mm reduction in joint space width, was observed in the treatment arm. No effects were observed on patients' symptoms and ASU was generally well tolerated. Interpretation of the findings from this study is limited by the high patient dropout rate from the study of 41% and a failure to observe a significant difference in the primary outcome. Additional studies are needed to conclusively determine whether ASU has structure-modifying benefits in hip OA and could delay the need for joint replacement procedures.

Antioxidants and OA: Is There a Relationship?

The relationship between antioxidants and OA remains unresolved. At the 2009 ACR meeting, an interesting prospective cohort study was presented to assess the relationship between antioxidant intake and incident hip and knee OA.[10] The study authors queried data from the Malmö Diet and Cancer cohort, a large prospective study that followed the clinical course and diet of patients 45-73 years old for more than 10 years.[11] Over 1000 incident cases of severe OA of the hip and knee, defined as the need for total joint arthroplasty, occurred during follow-up. Higher intake of the antioxidants beta-carotene, vitamins E and C, and selenium were not associated with a reduction in the incidence of severe OA. Surprisingly, an association between high selenium intake and knee and hip OA was observed. This intriguing observation, which could influence how one counsels patients on the use of antioxidant supplements, needs to be confirmed with additional studies.

Strontium Ranelate*: An Inhibitor of Cartilage Turnover?

Degenerative disease of the lumbar spine is a highly prevalent condition and significant cause of morbidity and work disability.[12] In 2008, Bruyere and colleagues published a post-hoc analysis of 2 placebo-controlled trials of strontium ranelate for the treatment of postmenopausal osteoporosis.[13] In this publication, they found that strontium ranelate reduced the percentage of patients showing progression of spinal OA by approximately 40% over the 3-year study. At the 2009 ACR meeting, the investigators presented follow-up biochemical data from this study, examining the relationship of markers of cartilage turnover to the prevalence of lumbar disc disease and its response to therapy with strontium ranelate.[14] Of the patients in the placebo arm, levels of urinary type II collagen fragments, a marker of cartilage breakdown, were higher in patients with prevalent lumbar disc disease. Furthermore, treatment with strontium ranelate reduced levels of this marker, suggesting an explanation for the apparent benefit of this compound on disease progression. However, levels of this marker were not predictive of lumbar disc disease progression. An additional placebo-controlled trial, focused on addressing the structure-modifying effect of strontium ranelate on lumbar disc disease as the primary endpoint, is needed to resolve whether this molecule is efficacious in this condition.

*Denotes off-label use

Hope for Future Disease-Modifying Therapy From Animal Models of OA

Effect of Lubricin on Structural Damage in OA

Lubricin is a glycoprotein produced by joint lining cells (synoviocytes) that are thought to provide joint lubrication. Mutation in the gene encoding lubricin (PRG4) results in the rare condition camptodactyly-arthropathy-coxa vara-pericarditis syndrome, characterized by precocious joint failure.[15] Given the potential chondroprotective role of lubricin, the therapeutic efficacy of intra-articular injection of this molecule was investigated in a rat model of OA.[16] In this model, OA is induced by ligating the anterior cruciate ligament to cause joint instability. Over the course of weeks, the rats develop a noninflammatory, degenerative arthritis that resembles the histopathology of human OA. The investigators found that lubricin purified from cultures of human synoviocytes inhibited the progression of OA lesions after anterior cruciate ligament ligation when injected directly into the joint. Accordingly, intra-articular lubricin treatment resulted in lower levels of type II collagen fragments, a biomarker of cartilage damage, in the synovial fluid of arthritic joints. These data hold promise for future development of an intra-articular tribosupplement for the treatment of OA.

Syndecan-4: A Novel Regulator of Cartilage Catabolism

Type II collagen and the proteoglycan aggrecan are the major structural components of articular cartilage.[2] In patients with RA, a progressive loss of proteoglycans, mediated by enzymes called aggrecanases, is observed in the articular cartilage of affected joints.[2,3] At the 2009 ACR meeting, an exciting insight into the mechanism of aggrecanase activation in OA joints was presented with potential therapeutic application.[17] A study was presented that explored the role of a transmembrane proteoglycan, called syndecan-4, in OA. This study showed that syndecan-4 was upregulated in OA cartilage and that the level of expression correlated with histopathologic severity. Of note, both syndecan-4-deficient mice and wild-type mice treated with a syndecan-4-blocking antibody were dramatically protected from an experimental model of OA. Furthermore, the study authors showed that syndecan-4 deficiency resulted in less aggrecanase activity in osteoarthritic cartilage. Taken together, these data suggest that syndecan-4 is a promising new target to prevent proteoglycan degradation by aggrecanases and thereby limit OA progression.

Concluding Remarks

Despite the number of people affected by OA, there are no approved structure-modifying therapeutic agents to prevent the progressive joint damage that characterizes this condition. At the 2009 ACR meeting, several studies were presented with agents under investigation and in clinical development. Of note, ASU and strontium ranelate hold some promise for preventing structural damage in OA; however, additional studies are needed before they can be recommended for clinical use. Animal models have revealed 2 new potential drug targets, lubricin and syndecan-4, which await further therapeutic development. Until new treatments are available, recommendations are available for the management of knee and hip OA.[18,19]

This activity is supported by an independent educational grant from AstraZeneca.