Risedronate appears to be no better than placebo at improving symptoms and slowing structural changes associated with osteoarthritis, but the drug did significantly reduce markers of bone resorption and cartilage degradation, providing some measure of hope that the drug may still prove useful in treating this disorder.
“In the groups that were receiving placebo, there was worsening of their cartilage degradation marker [C-terminal crosslinking telopeptide of type II collagen, or CTX-II], whereas there was a dose-dependent reduction in all of the rise dronate treated patients. To date, CTX-II is the leading biomarker for osteoarthritis in terms of one that may be predictive of patients who are at risk for progression,” Dr. Clifton O. Bingham III, the study's lead author and a rheumatologist at Johns Hopkins University, Baltimore, said.
Whether these changes in biomarkers will translate into a later clinically relevant change in joint preservation is unknown. “The fact that we are able to now show that certain treatments can affect this biomarker is really a very important piece for us in order to move forward in the development of therapeutics,” said Dr. Bingham, who reported receiving consulting fees from Procter & Gamble Pharmaceuticals Inc., maker of risedronate (Actonel).
The study was conducted at 42 sites in North America and at 44 sites in the European Union (Arthritis Rheum. 2006;54:3494–507). Patients were randomized to receive placebo or oral risedronate in dosages of 5 mg/day, 15 mg/day, 35 mg/week (Europe only), or 50 mg/week (North America only).
Patients aged 40–80 years were screened for inclusion if they had signal knee pain resulting from osteoarthritis (OA) most days during at least 1 month in a 3-month period, and had one of the following: morning knee stiffness lasting more than 30 minutes, or knee crepitus according to the American College of Rheumatology criteria for knee OA.
Patients were excluded if they had known inflammatory arthritis; body mass index (kg/m
All patients underwent radiography of the knee to confirm OA. For inclusion, patients had to have at least one osteophyte and minimal joint space width of 2–4 mm, inclusive, in the medial tibiofemoral compartment, and a medial compartment that was narrower than the lateral. Radiographic assessment was performed at baseline, 1 year, and 2 years.
Nonnarcotic analgesics, NSAIDs, or COX-2 inhibitors were allowed and monitored during the study. Patients underwent a stepped reduction and washout period for these medications prior to study visits, including the baseline visit. Patients were provided with 500 mg acetaminophen (North America) or paracetamol (Europe) and 50 mg diclofenac to be used as needed from 5 to 3 days prior to a visit. All pain medications were stopped 2 days prior to a visit.
The two primary end points were the effect of risedronate on structure and symptoms compared with placebo after 2 years. Patient symptoms were measured by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index and by Patient Global Assessment (PGA) scores. Structure was assessed by measuring joint-space narrowing in the medial tibiofemoral compartment.
Joint-space narrowing of the target knee was evaluated at the narrowest point in the medial tibiofemoral compartment at baseline and at 1 and 2 years follow-up. Radiographs were performed using a semiflexed view of the knee (fluoroscopically assisted). Radiographs were obtained at 13 regional radiographic facilities in Europe and 12 in the United States. All radiographs were sent to a quality control center in Amsterdam for review and then to the central analysis facility in London, where films were digitized and semiautomated computer measurements of minimal medial joint-space width were performed. The test-retest standard deviation—the difference between radiographs obtained 2 days apart—for this technique was approximately 0.2 mm.
Urine samples were also collected at baseline and at 6 months, 12 months, and 24 months. Samples were analyzed for N-terminal crosslinking telopeptide of type I collagen (NTX-I) to assess bone resorption and for CTX-II.
In the North American cohort, 301 participants were randomized to placebo, 306 to 5 mg/day risedronate, 302 to 15 mg/day, and 314 to 50 mg/week. In the European cohort, 312 participants were randomized to placebo, 322 to 5 mg/day risedronate, 307 to 15 mg/day, and 310 to 35 mg/week.
“In both the European and North American studies, no significant differences between treatment groups were noted in the mean change from baseline in total WOMAC score, scores for WOMAC components, or PGA scores,” the researchers said. Notably, those patients treated with placebo had a mean reduction of about 20% from baseline in total WOMAC scores.
“In all treatment groups, including the placebo, there was a clinically detectable improvement in pain that occurred at the 6-month point and was maintained over 2 years,” said Dr. Bingham. The results for the placebo patients highlight the importance of accounting for placebo benefit in osteoarthritis studies. Not only did placebo improvement occur, but it was maintained over time.