|Not a day goes by when I am not asked about what patients can do to alter the arthritis changes that affect their joints resulting in pain and impairment in their daily lives. Below is an article from an online reference that explores the issue of protecting what cartilage remains in the arthritis joint. |
Osteoarthritis is a common, chronic, and debilitating disease. There are few effective treatments, with joint replacement a primary exception. A joint replacement, however, is costly to the healthcare system, and the procedure carries risk. The remaining therapies are moderately effective at best, and none have been clearly demonstrated to alter the natural history of the disease. For this reason a large focus of drug development in osteoarthritis is identification of a disease modifying osteoarthritis drug (DMOAD) that is safe and provides some structural modification. Several therapeutic targets have been identified, with the most frequent target involving cartilage. The term chondroprotection is now used to categorize these agents.
We will review briefly the potential molecular targets, the agents thus far developed, and the evidence for their use.
There are a number of molecular targets for DMOAD development. These include inhibiting molecules that break down cartilage, such as Interleukin-1(IL-1), aggrecanases, and matrix metalloproteinases (MMPs); components of healthy cartilage and synovial fluid, such as glucosamine, chondroitin sulfate, and hyaluronan; and promoters of cartilage growth and repair (TGFβ, such as bone morphogenic protein.)
Doxycycline and Diacerein
Tetracyclines appear to be inhibitors of several MMPs, including collagenase and gelatinase, which are known to be upregulated in arthritic cartilage. In animal models and in some human trials, doxycycline appeared to have a modest benefit. In one human study, the rate of joint space narrowing in the group receiving doxycycline was 33% less, although there was no effect on pain.
Diacerein, available only in Europe, has an active metabolite that inhibits IL-1β, a known component of immune response in osteoarthritis. A recent systematic review showed a modest pain benefit in osteoarthritis. The data on structural benefits, however, are weak.
Hyaluronan is an integral component of healthy cartilage and synovial fluid in joints. It serves numerous functions within the joint and has been identified as an important molecule in the pathogenesis of osteoarthritis. Synthetic hyaluronan (what I often refer to as "joint lubricants" or viscosupplements) has been available as a therapeutic agent with the potential to improve pain, joint function, and joint structure. A recent meta-analysis comparing hyaluronan in intra-articular corticosteroids showed a relative pain benefit with hyaluronan; another comparing hyaluronan to placebo confirmed a modest but statistically significant benefit for hyaluronan. Early data suggest that there may be some disease-modifying effects as well, but larger studies are needed.
Nutritional micronutrients are known to be important for cartilage health. Numerous micronutrients have been proffered as therapies, including selenium, beta carotene, and vitamins C, D, E, and K. The data supporting their use are limited, and toxicity at high doses is a concern for several, including vitamin D.
Several herbal remedies for knee osteoarthritis have been advocated, including avocado/soybean unsaponifiables (ASU) and rose hip extracts. ASU has a variety of potential effects, including promotion of immunomodulation and cartilage synthesis. It has been shown to have modest pain benefit compared with placebo in knee osteoarthritis. Rose hip is thought to have antioxidant properties due to high vitamin C and lycopene content, and it has been shown to improve pain in knee osteoarthritis in a meta-analysis of several small studies. Data on structural modification are lacking for both of these agents.
Glucosamine and Chondroitin
Glucosamine and chondroitin are important components of cartilage. Increasing the level of these substrates could, theoretically, aid in cartilage repair or slow cartilage destruction. Their use as osteoarthritis treatment has received a great deal of attention and controversy. Although several studies have shown a symptomatic benefit, a large nonindustry-sponsored study demonstrated no benefit for knee osteoarthritis. Meta-analyses support a modest pain benefit, but the results are heterogeneous. Evidence that these agents modify structure shows a modest, but statistically significant benefit, but the results were heterogeneous, making interpretation difficult.
Clinical guidelines vary for each of the agents currently available. Several support the use of hyaluronan, glucosamine, and chondroitin, while the American Academy of Orthopaedic Surgeons does not recommend use of either. The remaining agents have not been mentioned in clinical guidelines due to insufficient data. The clinician must balance the relative safety of these agents, the desires of the patient, and the emerging evidence when recommending them.
Development of a DMOAD that demonstrates halting or slowing of structural damage in osteoarthritis is a major focus of research efforts. Some have been found to improve pain in osteoarthritis, but the data for structural modification are relatively weak. More evidence will be required. Additionally, we must consider whether to accept structural benefit without a pain benefit when designing new studies. Lastly, identification of DMARDs likely requires a more sensitive biomarker than the X-rays used in most of these studies.
Wednesday, May 18, 2011
Posted by Dr. Jim Mazzara at 9:37 AM