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  May 22, 2012
• Multiple Painful Joints Require Comprehensive Approach
  May 21, 2012
• Knee and Hip Osteoarthritis in Older Athletes
  May 20, 2012
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The suggestion that indomethacin accelerates the bone destruction in osteoarthritis of the hip was first made by Coke in 1967;¹⁰³ subsequent reports have been numerous that provide further clinical evidence of the damaging effects of non-steroidal anti-inflammatory drugs on osteoarthritic hips.^104-107 In one retrospective investigation of the relationship between the use of non-steroidal anti-inflammatory drugs on hip destruction in primary osteoarthritis of the hip, 70 hips were studied in 64 patients. Cranial acetabular migration, a measure of acetabular destruction, was present in 37 hips and absent in 33. Regular intake of NSAIDs was noted for 31 of the 37 migrating hips. In regard to the other six, three took NSAIDs on and off and only three of the 37 did not take NSAIDs. Those patients with serious hip destruction when compared with those who did not have the acetabular destruction did not differ in sex, age, pain grading, or walking ability. The only significant difference was the amount of NSAIDs taken. According to the researchers, NSAID use was associated with progressive formation of multiple small acetabular and femoral subcortical cysts and subchondral bone thinning. They concluded, “The association of acetabular bone destruction with regular NSAID intake in patients with osteoarthritis of the hip adds further evidence to the clinical and experimental observations on the powerful and potentially harmful effects of these drugs on cartilage and bone.”108 In this study the NSAIDs used regularly and associated with acetabular migration in this series were indomethacin (14 hips); ibuprofen (8 hips); naproxen (3 hips); sulindac, aspirin, and piroxicam (2 hips each); flurbiprofen, azapropazone, diclofenac, fenclofenac, and ketoprofen (1 hip each). The authors noted, “This study suggests caution in the widespread use of NSAIDs for osteoarthritis of the hip…”

Researchers in Norway studied the course of osteoarthritis in 294 hips of 186 patients with radiographs over a three year period. The development of the disease in patients treated with an NSAID was compared with that in a control group (no NSAID). In the NSAID group the OA disease progressed at a level of statistical significance more frequently and severely. Specifically the researchers found that in the three year period of the study, the osteoarthritic hips treated with the NSAID had more cysts, altered bone structure, and overall hip destruction. The way they put it was, “In the present study, loss of trabecular structure in the subchondral bone seems to be a characteristic feature in ‘indomethacin joint destruction’ as well as disappearance of normal joint contours and multiple small cysts.”¹⁰⁹ Solomon reported similar destruction in osteoarthritic hip joints as “new events” during treatment with NSAIDs. He performed further investigations on the extirpated (cut out from surgery) femoral heads with examination of cut surface, slab radiographs, and histology. Many of the heads, and especially those with changes attributable to NSAIDs, were found to have microscopic fragmentation of the bony trabeculae giving the appearance of a jammed marrow space.¹¹⁰ To see if these sort of damaging changes occurred with NSAID use on osteoarthritic knees the Longitudinal Investigation of Nonsteroidal Anti-inflammatory Drugs in Knee Osteoarthritis (LINK) study group was formed in England. They did a large study to compare the rate of radiographic progression in knee osteoarthritis comparing indomethacin (NSAID) with placebo. The study involved 20 rheumatology clinics in the United Kingdom. Patients received indomethacin 25mg three times daily or a placebo. The average person in each group was around 60 years of age and had osteoarthritis in the knee for over five years. The study involved 85 clients in the indomethacin group and 85 in the placebo group. Radiographic analysis was done yearly and the radiographic grade was judged by two observers using a six point scale. The average length of follow-up was three years. By the third year of the study, the results were so dramatic demonstrating the acceleration of the degeneration of the articular cartilage in the knee osteoarthritic patient treated with indomethacin that this part of the study had to be stopped. There were more than twice as many patients showing deterioration in the indomethacin group as the placebo. The difference between the two groups was highly statistically significant (p=0.009). The authors noted that the risk of deterioration within a one year period in patients taking indomethacin relative to placebo was 2.1 (risk ratio).¹¹¹ The authors concluded firmly, “Our study confirms beyond a reasonable doubt that indomethacin increases the rate of radiological deterioration of osteoarthritic knees.”

What actually happens to patients who take NSAIDs on a regular basis? If NSAIDs, by inhibiting pain and inflammation in osteoarthritic joints, cause people with OA to overuse a damaged joint, this should result in accelerating joint degeneration and joint replacements at an earlier time or, alternatively, if treatment with NSAIDs alters cartilage metabolism and inhibits joint healing, an acceleration of articular cartilage degeneration should be seen. Numerous studies have shown that non-steroidal anti-inflammatory drugs, particularly indomethacin, increase the rate of progression of osteoarthritis of the hip and knee.^112-117 Statistically significant progression of hip radiographs in osteoarthritic patients can be seen within one year of those patients taking NSAIDs. In one study, the authors noted, “…a statistically significant correlation between the NSAID consumption score and changes in the radiological parameter (p=0.0001). This statistically significant difference was retained when the percentage of days taking NSAIDs was added (p = 0.0004).”¹¹⁸

In a recent landmark study, Dutch researchers studied more than 1600 subjects with hip OA and 635 with knee OA. The researchers evaluated radiographs of the hip and knee at baseline and follow-up. The researchers assessed the associations between different types of NSAIDs and the progression of OA. The mean follow-up period was 6.6 years. They found that long-term use of the NSAID diclofenac was associated with a more than twofold increase in radiologic progression of hip osteoarthritis and a threefold increase in progression observed in the knee. Ibuprofen use was also shown to be associated with a statistically significant increase in progression of the users’ knee and hip OA.¹¹⁹ The interesting point of this study is that the study population was healthy. The authors noted that this may have resulted in an underestimation of the reported associations. Their conclusion noted,“…these data suggest that diclofenac may induce accelerated progression of hip and knee OA. Whether this occurs because of a true deleterious effect on cartilage or because of excessive mechanical loading on a hip or knee following pain relief, remains to be investigated.” Another study comparing diclofenac with placebo, as seen in Figure 17, accelerated OA in knees as evidenced by a greater decline in joint space width on X-rays compared to placebo.¹²⁰