| Author: Ross A Hauser, MD
Medical Director, Caring Medical and Rehabilitation Services, Oak Park, IL |
| A B S T R A C T |
| Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world for the treatment of osteoarthritis (OA) symptoms, and are taken by 20-30% of elderly people in developed countries. Because of the potential for significant side effects of these medications on the liver, stomach, gastrointestinal tract and heart, including death, treatment guidelines advise against their long term use to treat OA. One of the best documented but lesser known long-term side effects of NSAIDs is their negative impact on articular cartilage.
In the normal joint, there is a balance between the continuous process of cartilage matrix degradation and repair. In OA, there is a disruption of the homeostatic state and the catabolic (breakdown) processes of chondrocytes. It is clear from the scientific literature that NSAIDs from in vitro and in vivo studies in both animals and humans have a significantly negative effect on cartilage matrix which causes an acceleration of the deterioration of articular cartilage in osteoarthritic joints. The preponderance of evidence shows that NSAIDs have no beneficial effect on articular cartilage in OA and accelerate the very disease for which they are most often used and prescribed. Some of the effects of NSAIDs on the articular cartilage in OA include inhibition of chondrocyte proliferation, synthesis of cellular matrix components, glycosaminoglycan synthesis, collagen synthesis and proteoglycan synthesis. The net effect of all or some of the above is an acceleration of articular cartilage breakdown. In human studies, NSAIDs have been shown to accelerate the radiographic progression of OA of the knee and hip. For those using NSAIDs compared to the patients who do not use them, joint replacements occur earlier and more quickly and frequently. The author notes that massive NSAID use in osteoarthritic patients since their introduction over the past forty years is one of the main causes of the rapid rise in the need for hip and knee replacements, both now and in the future. While it is admirable for the various consensus and rheumatology organizations to educate doctors and the lay public about the necessity to limit NSAID use in OA, the author recommends that the following warning label be on each NSAID bottle: The use of this nonsteroidal anti-inflammatory medication has been shown in scientific studies to accelerate the articular cartilage breakdown in osteoarthritis. Use of this product poses a significant risk in accelerating osteoarthritis joint breakdown. Anyone using this product for the pain of osteoarthritis should be under a doctor’s care and the use of this product should be with the very lowest dosage and for the shortest duration of time. If NSAID use continues, then most likely the exponential rise in degenerative arthritis and subsequent musculoskeletal surgeries, including knee and hip replacements as well as spine surgeries, will continue to rise as well. Journal of Prolotherapy. 2010;(2)1:305-322. KEYWORDS: accelerating articular cartilage degeneration, articular cartilage, cox-2 inhibition, non-steroidal anti-inflammatory medication, NSAID, osteoarthritis, prostaglandin. |
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world for the treatment of osteoarthritis (OA) symptoms,1 and are taken by 20-30% of elderly people (defined as people over the age of 64 years) in developed countries.2 The worldwide pain management prescription drug market totaled approximately $24 billion in 2002 and passed $30 billion by 2006. Celebrex (celecoxib) led the pack with nearly $4 billion in sales in 2002.3 Each year, over 70 million prescriptions for NSAIDs are dispensed in the United States, 20 million in Great Britain and 10 million in Canada.4-6 These numbers do not include the 30 billion over-the-counter tablets sold each year in the United States alone.7, 8 The most common over-the-counter and prescription nonsteroidal anti-inflammatory drugs are seen in Figure 1.
Treatment guidelines in the United States, Great Britain, and Canada recommend NSAIDs as second-line treatment (after acetaminophen) for mild OA and as first-line treatment for moderate to severe OA.9-11 As baby boomers age, it is estimated that the number of NSAID users will continue to climb, despite the fact that over 100,000 people are hospitalized for gastrointestinal bleeding and of those 16,500 people die from NSAID toxicity each year.12, 13 In 2006, the Osteoarthritis Research Society International formed an international committee to review all guidelines and evidence available on OA. Based on the evidence of potentially serious adverse reactions to NSAIDs, the committee has advised against the long-term use of NSAIDs to treat OA.14 One of the most serious adverse reactions to NSAIDs, that is little appreciated, is that as a class of compounds they cause the breakdown of articular cartilage, thereby accelerating OA, the very disease for which they are most commonly prescribed.
In the normal joint, there is a balance between the continuous process of cartilage matrix degradation and repair. In OA, disruption of the homeostatic state occurs and the catabolic (breakdown) processes of chondrocytes are increased.
| Chondrocytes – the only cells in cartilage tissue responsible for the synthesis of collagen and proteoglycans that makeup the cartilage matrix |
| Cytokines are signaling molecules used extensively in cellular communications. |
The principal cytokines linked to the catabolism of cartilage and to the OA process are interleukin (IL)-1, tumor necrosis factor (TNF)-a, and IL-6. IL-1 is the prototypic inducer of catabolic responses in chondrocytes. This substance causes the increased secretion of proteinases (which breakdown cartilage matrix) including collagenase, the suppression of proteoglycan synthesis leading to the suppression of matrix synthesis, and ultimately the reduction of the number of chondrocytes.15, 16 (See Figure 2.) IL-1 is a potent inducer of prostaglandin (PG) synthesis by inducing PGE2 synthesis in human chondrocytes. The rate-limiting step for the synthesis of PGE2 and other prostaglandins is the conversion of arachidonic acid to prostaglandin endoperoxide by cyclooxygenase (COX), which exists in two isoforms, COX-1 and COX-2. All NSAIDs inhibit both COX 1 and 2 enzymes but most of the NSAIDs that have been developed in recent years show greater activity of COX 2 in order to decrease gastrointestinal side effects. (See Figure 3.) PGs act (among other things) as messenger molecules in the process of inflammation. It was hoped that the use of NSAIDs would decrease the catabolic program in OA, thereby having a disease-modifying effect. Research, unfortunately is showing PGs, like PGE2, stimulate chondrocyte proliferation and subsequent synthesis of cellular matrix components.17 The net result of their blockade and other NSAID effects is the acceleration of articular cartilage degeneration. To show how this occurs and to what extent, a basic understanding of articular cartilage anatomy is needed.
| Figure 1. Common over-the-counter and prescription nonsteroidal anti-inflammatory drugs (NSAIDs). |
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| Figure 2. The catabolic physiology leading to articular cartilage breakdown. Interleukin-1 is one of the principle cytokines that initiates a cascade that leads to chondrocyte cell death and extracellular matrix breakdown. NSAIDs inhibit prostaglandins, such as PGE2, from stimulating chondrocyte DNA matrix synthesis thereby contributing to articular cartilage degeneration. |
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| Figure 3. Inhibition of cyclooxygenase 1 and 2 by NSAIDs. Studies have shown that, although most NSAIDs inhibit both COX-1 and COX-2, it is the inhibition of COX-2 that is responsible for the anti-inflammatory effects of NSAIDS. On the other hand, inhibition of COX-1 by these agents causes damage to the GI tract. This has led to the development of a new generation of NSAIDs that specifically inhibit COX-2. |
 To read the full article by Dr. Hauser, please click here. |
