Advances in Treatments for Osteoarthritis

[KenNiemann]

From MedscapeCME Rheumatology
Advances in Treatments for Osteoarthritis
Antonios O. Aliprantis, MD, PhD

Authors and Disclosures

Posted: 12/18/2009

Introduction
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]

[KenNiemann]

Treating Osteoarthritis Pain: Update on Pharmacologic and Biomechanical Interventions CME/CE
Antonios O. Aliprantis, MD, PhD

Posted: 12/18/2009


Inroduction
Many individuals over the age of 65 years demonstrate clinical and/or radiographic evidence of osteoarthritis (OA), making this disease the most common affliction of the skeletal system.[1] OA affects multiple joints, with the small joints of the fingers and the knees, hips, and spine being the most common sites. Patients with OA suffer pain and functional impairment, often culminating in the need for total joint replacement in the case of knee and hip disease. Risk factors for OA include advancing age, female sex, obesity, prior trauma, malalignment, and genetic factors.[2,3] Despite the high prevalence of OA, there are currently no therapeutics approved by the US Food and Drug Administration (FDA) that retard structural joint deterioration. Thus, OA is managed with a combination of approaches, including lifestyle modification, exercise, and pharmacologic and biomechanical interventions aimed at pain relief, including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opiates, braces, and canes.[4-6] At the American College of Rheumatology (ACR) 2009 Annual Scientific Meeting, a number of presentations evaluated pharmacologic or biomechanical interventions to control OA pain.

Pharmacologic Interventions
Tanezumab*: A Novel Biologic Therapy to Treat OA Pain
Biologic therapies, such as antibodies to tumor necrosis factor-alpha, have improved the treatment of rheumatoid arthritis.[7] Currently, there are no approved biologic therapies for OA. Tanezumab is a fully humanized monoclonal neutralizing antibody against nerve growth factor, a secreted molecule involved in pain transmission.[8] At the 2009 ACR meeting, an open-label extension study, which followed a placebo-controlled trial, was reported to evaluate the efficacy of tanezumab in controlling the pain associated with knee OA.[9] In the preceding placebo-controlled trial, a dose-dependent reduction in knee OA pain was observed. In this study, 281 patients completing the placebo-controlled trial received intravenous tanezumab at a dose of 50 ?g/kg at weeks 0 and 8 and then every 8 weeks thereafter, at the discretion of the investigator. Patients who had received tanezumab at a dose below 50 ?g/kg reported improvement in pain scores compared with patients who had received a dose higher than 50 ?g/kg; the patients also reported worsening of their pain scores. Suppression of pain scores appeared to persist for at least 32 weeks. Mild and transient abnormalities in peripheral sensation were described in 6% of patients. A rigorous statistical analysis of the data was not presented in the submitted abstract, tempering enthusiasm for the findings. Taken together, this study suggests that biologic therapies could be used to control pain associated with knee OA. Future studies should confirm these findings, evaluate the long-term safety of this agent on the nervous system, and determine whether this drug is a cost-effective option.

*Denotes off-label use

S-Adenosylmethionine* for OA Pain
Previous placebo-controlled trials suggested that S-adenosylmethionine (SAMe) might reduce OA pain, although the effect size may be small.[10] NSAIDs are recommended and commonly used to mitigate OA pain.[11] At the 2009 ACR meeting, a double-blind, placebo-controlled trial was presented comparing SAMe with a traditional NSAID, nabumetone, for painful knee OA.[12] In this study, 134 Korean patients with symptomatic knee OA were randomly assigned to receive either nabumetone (1000 mg once daily) or SAMe (400 mg 3 times daily) for 8 weeks. Both agents demonstrated a statistically significant reduction in pain scores at 8 weeks compared with baseline, and no differences in efficacy were observed between the 2 treatment arms. Although no significant differences were seen in adverse clinical or laboratory events between the groups, the analysis is limited by the small sample size and short follow-up. Taken together, these data suggest that SAMe may be as effective as nabumetone for the treatment of OA pain, although a larger trial is necessary to confirm the broader applicability of this observation and gather additional safety data.

*Denotes off-label use

Are Topical NSAIDs an Effective Alternative for OA Pain in Elderly Patients?

Topical NSAIDs are currently marketed as a safer alternative to oral NSAIDs because of lower systemic absorption.[13] The comparative efficacy of these preparations in older vs younger patients with OA is not known. At the 2009 ACR meeting, pooled data were presented from three 12-week, randomized controlled trials that evaluated topical diclofenac sodium 1% gel (DSG) vs vehicle (placebo) for the treatment of painful knee OA.[14] In this analysis, patients were divided into 2 groups: those under age 65 years (n = 602) and those over age 65 years (n = 374). Both older and younger patients showed statistically significant improvements in pain and functional scores with DSG treatment compared with placebo, with no differences in treatment efficacy. Skin reaction at site of DSG application was the most common adverse event reported, occurring in 5.6% and 8.8% of younger and older patients, respectively. The study authors concluded that DSG is an effective and well-tolerated treatment for painful knee OA in both older and younger individuals. The study, however, is limited by the relatively small sample size and short follow-up resulting in insufficient power to detect clinically relevant adverse effects of chronic DSG use, such as gastrointestinal bleeding, ischemic cardiac events, and nephrotoxicity.[13]

Safety of Opiates and Selective COX-2 Inhibitors (Coxibs) Compared With Nonselective NSAIDs in Elderly Patients With OA

The relative safety of nonselective NSAIDs, cyclooxygenase (COX)-2 (coxibs), and opiates in elderly patients is not well defined. At the 2009 ACR meeting, results from a large pharmacoepidemiologic study of Medicare beneficiaries initiating analgesic therapy for arthritis were presented.[15] Participants were on average 80 years old, and 84% of the study population were women. The most common indication for analgesic therapy was OA (89%). Compared with nonselective NSAIDs, both coxibs and opioid analgesics displayed an increased risk for cardiac events, hospitalized adverse events, and all-cause mortality. Moreover, opioids were associated with an increased risk for fracture compared with coxibs and nonselective NSAIDs. No differences were observed in the rates of gastrointestinal bleeding between the 3 treatment groups. Taken together, this nonrandomized observational study suggests that coxibs and opioid analgesics may not be a safer alternative to nonselective NSAIDs in elderly patients, and appear to be associated with multiple clinically relevant adverse events. Although the study authors indicated that baseline covariates of the 3 cohorts were well balanced, one cannot fully exclude that difference in unidentified covariates leading to prescribing bias for a portion of these findings. Given the importance of analgesia in the care of elderly patients with OA, this important observation warrants further investigation.

Biomechanical Interventions

Impact of Aggressive Knee Realignment on Symptomatic Medial Tibiofemoral OA

Mechanical factors, including abnormalities in knee alignment, are important in the genesis and progression of knee OA.[16] However, whether an optimal noninvasive protocol to improve knee alignment would mitigate pain in patients with medial compartment OA has not been established. At the 2009 ACR meeting, a 30-week, randomized, crossover trial was presented that evaluated a multimodal realignment regimen in patients with knee OA.[17] In this study, 80 patients with medial tibiofemoral OA received either multimodal therapy, consisting of a valgus knee brace, customized neutral foot orthoses, and motion control shoes, or control treatment, which consisted of a neutral knee brace, unsupportive orthoses, and flexible midsole shoes. Because this was a crossover trial, each patient received both treatments for 12 weeks, separated by a 6-week "washout" period. The average patient was an obese woman in her mid-60s. A small improvement in pain scores of borderline statistical and clinical significance was observed when patients were on multimodal therapy. The study authors concluded that the benefits of this regimen were equivocal. Future studies should optimize noninvasive realignment regimens and define patient subsets that are most likely to benefit from this potentially safe and cost-effective alternative to drugs and surgery.

Evaluation of the Effectiveness of Canes for Knee OA

Many patients with knee OA use canes, but the clinical impact of this intervention on pain is poorly defined.[6] At the 2009 ACR meeting a small, short-term study to evaluate the effect of cane use on knee OA was reported.[18] Twenty-one overweight or obese patients with knee OA were given a single-point cane to use contralateral to the affected knee for 8 weeks. Fifty percent of patients who used the cane ? 4 days a week experienced a 20% reduction in pain scores. Improvements in biomechanical measures of joint loading were also improved by cane use. Future studies should better define the effect size of cane use on OA pain and address the safety of this intervention.

Conclusions
OA is a painful and disabling condition that afflicts millions worldwide.[19] Current pharmacologic pain control options include NSAIDs, acetaminophen, and opiates. Despite widespread use, the efficacy and safety of these agents are still uncertain, especially in aged patients. At this year's ACR meeting, we learned about potential novel treatments for OA pain, such as SAMe, topical NSAIDs, and the biologic agent tanezumab. In addition, a large pharmacoepidemiology study questioned the safety of opiates in elderly patients. Lastly, 2 trials suggested that interventions aimed at improving the biomechanics of patients with knee OA may lead to pain relief. Until the FDA approves additional treatments, the author suggests that physicians should read recently published guidelines on the management of OA.[5,11]



References

References
Felson DT. Clinical practice. Osteoarthritis of the knee. N Engl J Med. 2006;354:841-848. Abstract
Goldring MB. Update on the biology of the chondrocyte and new approaches to treating cartilage diseases. Best Pract Res Clin Rheumatol. 2006;20:1003-1025. Abstract
Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol. 2007;213:626-634. Abstract
Lee YC, Shmerling RH. The benefit of nonpharmacologic therapy to treat symptomatic osteoarthritis. Curr Rheumatol Rep. 2008;10:5-10. Abstract
Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis Cartilage. 2007;15:981-1000. Abstract
Gross KD, Hillstrom HJ. Noninvasive devices targeting the mechanics of osteoarthritis. Rheum Dis Clin North Am. 2008;34:755-776. Abstract
Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KF, Yocum DE. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum. 2005;34:819-836. Abstract
Abdiche YN, Malashock DS, Pons J. Probing the binding mechanism and affinity of tanezumab, a recombinant humanized anti-NGF monoclonal antibody, using a repertoire of biosensors. Protein Sci. 2008;17:1326-1335. Abstract
Lane NE, Schnitzer TJ, Birbara CA, et al. Long-term tanezumab use for treatment of moderate to severe osteoarthritic knee pain: an open-label extension study. Program and abstracts of the American College of Rheumatology (ACR) 2009 Annual Scientific Meeting; October 17-21, 2009; Philadelphia, Pennsylvania. Abstract 836.
Rutjes AW, Nuesch E, Reichenbach S, Juni P. S-Adenosylmethionine for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2009;(4):CD007321.
Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16:137-162. Abstract
Kim JH, Lee EY, Koh EM, et al. Comparative clinical trial of S-adenosylmethionine versus nabumetone in the treatment of knee osteoarthritis: an 8-week, multicenter, randomized, double-blinded study. Program and abstracts of the American College of Rheumatology (ACR) 2009 Annual Scientific Meeting; October 17-21, 2009; Philadelphia, Pennsylvania. Abstract 833.
Zacher J, Altman R, Bellamy N, et al. Topical diclofenac and its role in pain and inflammation: an evidence-based review. Curr Med Res Opin. 2008;24:925-950. Abstract
Altman R, Gloth FM, Gold MS, Petruschke R. Safety and efficacy of diclofenac sodium gel for knee osteoarthritis in patients aged <65 years versus ¡Ý 65 years. Program and abstracts of the American College of Rheumatology (ACR) 2009 Annual Scientific Meeting; October 17-21, 2009; Philadelphia, Pennsylvania. Abstract 840.
Solomon DH, Rassen J, Glynn R, Lee J, Levin R, Schneeweiss S. The comparative safety of analgesics in older adults with arthritis. Program and abstracts of the American College of Rheumatology (ACR) 2009 Annual Scientific Meeting; October 17-21, 2009; Philadelphia, Pennsylvania. Abstract 838.
Wilson DR, McWalter EJ, Johnston JD. The measurement of joint mechanics and their role in osteoarthritis genesis and progression. Rheum Dis Clin North Am. 2008;34:605-622. Abstract
Hunter DJ, Gross K, McCree PI, et al. A randomized trial of realignment therapy for treatment of medial tibiofemoral osteoarthritis. Program and abstracts of the American College of Rheumatology (ACR) 2009 Annual Scientific Meeting; October 17-21, 2009; Philadelphia, Pennsylvania. Abstract 828.
Lee SM, Heiney C, Perell KL, et al. Effect of cane use on lower limb biomechanics and pain in knee osteoarthritis. Program and abstracts of the American College of Rheumatology (ACR) 2009 Annual Scientific Meeting; October 17-21, 2009; Philadelphia, Pennsylvania. Abstract 830.
Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81:646-656. Abstract

[fitness001]

Great useful tips and information shared about Advances in Treatments for Osteoarthritis...


Same day crowns Las vegas