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| Clifton Bingham, M.D.
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Abstract 263: Significant PlaceboImprovement Occurs by Six Months and is Maintained Through 24 Months in a Study of Knee OA Pain and Function Evaluating an agent as a structure modifying therapy in OA presents many challenges including subject retention over long periods of time. This study presents clinical data from a 2 year North American study of 3 doses of risedronate in 1232 patients with osteoarthritis of the knee. Methods: Subjects were enrolled with knee OA and medial JSW of 2-4 mm using a standardized and reproducible semi-flexed fluoroscopically positioned technique. Approximately 300 patients were randomized in each group to receive risedronate at 5mg/d, 50 mg/wk, or 15 mg/day or matching placebo. Background analgesics were permitted, however a five day stepped analgesic reduction and 48 hour analgesic withdrawal were performed before each study visit and assessments of pain based on the 48 hours preceding the study visit. Results: Subjects were well matched in groups with 61% female, age 60.5 years, BMI 30.3, and analgesic use. Mean baseline levels of total WOMAC pain were moderate at 40.2 and WOMAC pain at 37.2. In all treatment groups, including placebo, there was a significant reduction from baseline in total WOMAC and WOMAC pain scores. There was no difference however in any of the risedronate treated patients and placebo treated patients. This improvement was seen at the first assessment at 6 months and persisted through the entire 2 years of the study. The magnitude of improvement was similar to that seen in analgesic studies. Similar effects were reported in a separate study of 1251 subjects conducted in Europe. Risedronate was well tolerated even at high doses with remarkable retention of almost 75% of study subjects at two years. Dropouts were similar in all groups including placebo. Editorial Comment: Although no treatment effect was seen with risedronate, this study was important in demonstrating the difficulties encountered in long term studies of potential structure modifying therapy for OA. This study demonstrated the impressive placebo benefit that may be seen in clinical trials. The magnitude of this improvement was seen at six months and remarkably retained through 2 years. This placebo improvement may be in part responsible for the very high retention rates at the study endpoint. The study design incorporated that allowed patients to receive background analgesics with a stepped reduction may have facilitated subject retention to assess the structure endpoint, but may also have contributed to the long lasting symptomatic improvements from baseline. The levels of baseline pain in this study were quite low, with levels similar to those seen at end of studies with analgesics; nonetheless even with this low level of background pain a clinically detectable improvement was noted. | ||
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Several bisphosphonates have been demonstrated to decrease progression in animal models of OA. Elevated markers of bone turnover (NTX-I, CTX-I) have been associated with progression in OA suggesting the participation of subchondral bone in the disease. Levels of CTX-II, a marker of cartilage degradation, have been associated with disease progression in OA. This study was undertaken to evaluate the effect of risedronate as a structure modifying therapy for osteoarthritis of the knee. This presentation focused on the biochemical effect of risedronate on markers of bone and cartilage degradation. Methods: 1251 European patients with medial compartment knee OA were enrolled in a 2 year study of risedronate (5 mg/d, 35 mg/wk, or 15 mg/d) or placebo. 1000 subjects from the this study of risedronate in OA who had full baseline, 3, 12, and 24 month follow up measurements of markers of bone and cartilage degradation were evaluated. Baseline levels of CTXII were elevated in all groups compared to non OA controls. A dose dependent reduction in levels of CTXII was seen with risedronate with the lowest dose (5 mg/day) associated with a 31% reduction and the highest dose (15 mg/day) associated with a 53% reduction in CTXII at 6 months. The reductions were maintained throughout the study. Levels of bone turnover as assessed by NTX-I and CTX-I were dose-dependently decreased as expected. These results were also confirmed in a separate study of 835 patients in North America entered into a separate protocol. Editorial Comment: This is the first large prospective study to demonstrate that markers of cartilage degradation are decreased with bisphosphonate therapy. Although group mean changes in CTXII were significant, the standard errors of these changes were large, nonetheless clear dose-dependent effects were noted. Other studies presented at this meeting demonstrated that markers of cartilage degradation are correlated with bone marrow lesions on MRI, and that both markers are independently associated with progression. Recent publications have shown that bisphosphonate users have lower levels of CTX-II and lower rates of bony changes on MRI compared to nonusers. Even though the primary endpoint of the study (decrease in joint space narrowing as measured by radiography) was not achieved, these results suggest a favorable biochemical effect of bisphosphonate therapy in OA. | ||
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Abstract 1718: Traditional Chinese Acupuncture is Effective as Adjunctive Therapy in Patients with Osteoarthritis of the Knee The use of alternative or complementary therapies in osteoarthritis is widespread. Acupuncture has been shown in several studies to have a beneficial effect in decreasing pain from knee OA. This was a 26-week NIH-funded randomized multicentered trial to evaluate the efficacy of traditional Chinese acupuncture (TCA) compared to sham acupuncture (SA) or a course of education. Methods: 570 patients with symptomatic (moderate or greater pain) knee OA were recruited from 3 sites. 190 patients were randomized to each group. The patients in the acupuncture group received 23 treatments with 32 needles at 9 points with electrical stimulation. In the sham group, 2 sham points on the abdomen were used and at 9 additional sites, guide tubes were applied and a mock TENS unit was used. The group receiving education attended the arthritis self-help course for 12 weekly 2 hour sessions. Background analgesics and anti-inflammatories were permitted. Assessors of outcome data were blinded to treatment group. Results: Improvements in levels of pain and function were seen in all groups over time. The group receiving education had the least improvement, however a reduction in pain was seen extending out to 26 weeks in this group. Surprisingly the group receiving sham acupuncture achieved improvements in pain greater than those receiving education revealing an impressive placebo benefit. The magnitude of improvement for the group receiving TCA was even greater than the group receiving sham acupuncture. The reduction in WOMAC pain was 3.79 units versus 2.92 units (p=0.003) from baseline mean levels of pain of 8.94. Similarly an improvement was seen in function that was statistically significant between the groups. Editorial Comment: The overall magnitude of the clinical responses was quite small. Though the differences were statistically significant, the effect sizes of these improvements were very low (0.25). As pointed out in an accompanying commentary session, the effect size expected with an NSAID is on the order of 0.4. Clinically relevant effect sizes are felt to be approximately 0.3. The effect due to a placebo improvement from the sham acupuncture was greater than the magnitude of the effect between the sham acupuncture and the actual TCA showing the importance of assessing a placebo response in studies of either traditional or complimentary therapies. A higher drop out rate was seen in the group receiving education which may have affected the validity of these outcomes but possibly indicated that this intervention was not as effective in longer term pain reduction. Nonetheless the group receiving education alone also had a reduction in pain and improvement in function from baseline. A confounder to the analysis was the allowance of background analgesics and anti-inflammatory therapy. It is not clear in the analysis that results were stratified for analgesic consumption. There may have also been an unmasking of assignment to the TCA and sham acupuncture groups because the groups receiving TCA were more likely to believe they were receiving the actual therapy than the sham group. Overall this was a well conducted and designed study to assess the adjunctive role of acupuncture. Based on these results we can conclude that the benefit of traditional Chinese acupuncture as adjunctive therapy in OA of the knee is at best very low in comparison to a sham acupuncture. The benefit attributable to placebo is of a magnitude greater than that derived from the treatment itself. | ||
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Abstract 829: Antiresorptive Agents Used in the Treatment of Postmenopausal Osteoporosis Have Different Impact on Markers of Cartilage Degradation Tanko, Kasper, Qvist, et al Recent studies have demonstrated that patients with OA of the knee who are taking bisphosphonates have fewer MRI bone marrow lesions (Carbone et al, Arthritis Rheum 2004; 50: 3516-25). Another study at this meeting (Abstract 1754, Garnero et al) demonstrated that risedronate decreased a markers of cartilage degradation, CTX II. This study evaluated subjects who participated in clinical trials of raloxifen, alendronate, and tibolone for osteoporosis to evaluate changes in markers of bone turnover and cartilage degradation. Methods: 341 subjects enrolled in studies of various doses of raloxifene (n=203), alendrone (n=68), and tibolone (n=70) had serum CTX-I, a marker of bone turnover, and urine CTX-II, a marker of cartilage degradation measured. Results: As anticipated with drugs to treat osteoporosis, all agents caused a decrease in markers of bone turnover with a 70% reduction seen with alendronate, 50% reduction with tibolone, and 35% reduction with raloxifen. Both alendronate and raloxifen caused a dose dependent reduction in CTX II as well indicating a biochemical effect on cartilage metabolism. The magnitude of reduction was 50% with the highest doses of each drug (20 mg/d for alendronate and 150 mg/day for raloxifen). Editorial Comment: These results, along with other emerging data, again show that agents that affect bone remodeling have positive effects on markers of cartilage degradation. These results support the idea that improving subchondral bone structure may be a beneficial strategy for osteoarthritis. | ||
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Abstract: 1759 Small Weight Losses Can Yield Significant Improvements in Knee OA Symptoms | ||
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