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Conducting more, better-designed studies should improve clinical cartilage repair
An independent cartilage registry might enhance clinical knowledge, researchers suggested.
Studies into outcomes of cartilage repair and regeneration methods have ranged in quality, leaving orthopaedic surgeons with more questions about what cartilage treatments work best.
Two renowned cartilage researchers said obtaining more reliable data in this area and delineating best practices may require conducting more randomized clinical trials, or establishing an independently operated cartilage repair registry.
Until then, orthopaedic surgeons should rely on the clinical guidance provided by results of some lesser quality or level-4 studies, said L. Stefan Lohmander, MD, PhD, and Lars Engebretsen, MD, PhD. These investigations can be particularly useful for selecting appropriate treatments for patients with focal knee cartilage defects, which are the cases most often treated and studied.
Lohmander and Engebretsen discussed these issues at the 7th World Congress of the International Cartilage Repair Society (ICRS).
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Bias alert
Right now, cartilage researchers have their work cut out for them. They must strive to design, conduct and publish the best, most unbiased studies possible.
“I think we’re still on slippery ice, but we’re slowly getting a good grip,” Engebretsen said of research progress.
According to Lohmander, “Even though there may be good studies out there — there are good systematic reviews — we need to be aware of the fact that the literature as printed, as published, is biased.”
Even Cochrane systematic reviews can be affected by bias because the published studies they cover are prone to bias, he added.
Treatments, results
Lohmander and Engebretsen discussed the evidence available for various techniques of treating cartilage lesions, including microfracture, mosaicplasty and all forms of autologous chondrocyte implantation (ACI), which varies based on length of follow-up and indications.
Regardless of the technique used, clinical results typically end up being highly similar after about 2 years. The solution: conduct more level-1 studies of cartilage repair treatments to determine which are most effective for given indications.
Lohmander encouraged would-be investigators to clearly define trial objectives and select appropriate, validated outcome measures. Clinical researchers must be clear about what their study demonstrates, he said.
Clear objectives
“Is the primary objective the well-being of the transplant or of the joint cartilage or of the joint?” Lohmander asked. “I would dare say it should be the patient. If you’re looking at a clinical trial, that’s your primary outcome.”
He said, “The objective of cartilage repair is really not to regenerate new cartilage. It is actually to decrease pain and improve function and quality of life for the patient.”
Lohmander emphasized how powerful the surgical placebo effect can be, as was elucidated in the now-famous Moseley arthroscopy trial.
“We need to consider the fact that our treatments have a very significant placebo effect in addition to the specific effect they might have through their treatment,” Lohmander said. Effects can peak, subside or drop off over time, which has been shown to occur in some ACL treatment studies, he noted.
Good level-4 studies
According to Engebretsen, extensive research conducted into cartilage repair methods over the past two decades has produced few high-quality studies. Many more have questionable methodology.
Orthopaedists trying to identify the optimal treatments for their patients should be wary of the claims made by some researchers, particularly those conducting studies with positive outcomes. They could be biased, depending who sponsored them, he said.
“There are some really good level-4 studies” that should not be disregarded, Engebretsen said. “You should read them almost like you read a level-1 study.”
Few trials
Engebretsen and colleagues recently repeated an analysis they performed a few years ago of the quality of cartilage studies. They identified only six randomized trials among about 4,000 ACI papers published through 2006. Of 673 abstracts originally reviewed, 61 were clinical studies boasting results beyond 2 years postop. Less than 10% were part of a randomized trial.
“There were 25 different scores used,” Engebretsen said. The Lysholm and Cincinnati scores were the most common. Only recently were the Lysholm and ICRS scores even validated for cartilage repair.
An average of 86% of patients treated with periosteal transplantation, mosaicplasty, microfracture or ACI had good to excellent results and high Lysholm scores. But based on other measures, scores were “all over the place” and results were roughly equivalent in four of the trials, Engebretsen said.
Quality studies
When they repeated the review, investigators included all the original studies, 18 new ones conducted from 2004 to 2006 with good or excellent outcomes and matrix-induced ACI trials not originally considered.
“It’s actually getting better,” Engebretsen said. Coleman methodology scores (CMS) for cartilage studies done in 1985, 1995 and 2005 improved significantly from 48 to 58 over the two decades (100=best methodology). Nearly 20% were part of randomized investigations. “However, only one study was actually level 1 and … the majority involved level-4 studies,” he said.
Levels of evidence for the new studies correlated well with the CMS, Engebretsen added.
Natural history
Both men agreed cartilage research suffers from ongoing problems, including a natural history of cartilage damage that is not yet fully known.
Lohmander said it is critical in any kind of trial to delineate the disease process from the surgical or treatment effect and to not mix treating different types of lesions.
Because he knows how difficult conducting an randomized clinical trials is, I’m tending to say that we need a non-industry-controlled registry,” Engebretsen said.
The Norwegian, Swedish and Danish ACL surgery registry has been successful thus far and will have a great impact on those surgeries. “I think it’s possible to do a similar thing here [just in Norway],” he said.
For more information:
Lars Engebretsen, MD, PhD, can be reached in the Department of Orthopaedic Surgery, University of Oslo, Ullevål Hospital, Oslo 0407, Norway; +47-22117464; e-mail: lars.engebretsen@medisin.uio.no. He has no direct financial interest in any products or companies mentioned in the article.
L. Stefan Lohmander, MD, PhD, can be reached in the Department of Orthopaedics, Lund University Hospital, SE-22185 Lund, Sweden; +46-45-171503; e-mail: stefan.lohmander@med.lu.se. He is a member of the scientific advisory board of Tigenix, Belgium.
References:
- Beadling L. Five-year data show no difference between ACI and microfracture. OrthoSupersite.com. 2006; http://www.orthosupersite.com/view.asp?rID=5518.
- Hasson M. No evidence autologous chondrocyte implantation is superior to conventional techniques. OrthoSupersite.com. 2006; http://www.orthosupersite.com/view.asp?rID=5248.
- Jakobsen R, Engebretsen L. An analysis of the quality of cartilage studies-an update. #14.2. Presented at the 7th World Congress of the International Cartilage Repair Society. Sept. 29-Oct. 2, 2007. Warsaw.
- Knutsen G, Drogset JO, Engebretsen, et al. A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am. 2007; 89:2105-2112.
- Knutsen G, Engebretsen L, Ludvigsen TC, et al. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg Am. 2004; 86:455-464.
- Lohmander LS. How to do good clinical cartilage studies: The road traveled, the road forward. #14.1. Presented at the 7th World Congress of the International Cartilage Repair Society. Sept. 29-Oct. 2, 2007. Warsaw.
- Moseley JB, O’Malley K, Peterson NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002; 347:81-88.