Dr. Loeser
CHICAGO—Many therapies are being investigated to find new interventions for osteoarthritis (OA) that would curb disease progression and joint replacements in an aging population, said Richard F. Loeser Jr., MD, MACR, Joseph P. Archie Jr. Eminent Professor in the Division of Rheumatology, Allergy and Immunology and director of the Thurston Arthritis Research Center at the University of North Carolina at Chapel Hill. Dr. Loeser presented the Oscar Gluck Memorial Lecture at ACR Convergence 2025.
Aging and obesity are two major risk factors of OA, a common form of arthritis that affects more than 500 million people worldwide, noted Dr. Loeser. The number of people living with OA is growing, driven by the aging of baby boomers and increased rates of obesity among adults. In addition, knee and hip replacement surgeries are on the rise because of a lack of disease-modifying drugs to treat pain from an injury, he noted.
“Our goal is really to be able to find some new interventions that would slow or stop the progression of OA so that we could reduce the number of joint replacement surgeries,” Dr. Loeser said.
Current Treatment Approaches
Dr. Loeser discussed current approaches to treating patients with OA that include nonpharmacological recommendations, such as exercise, weight loss and self-management programs. Non-steroidal anti-inflammatory drugs (NSAIDs) continue to be the main drugs used to treat joint pain, he said. “When we turn to pharmacological measures, NSAIDs, of course, are still commonly used because we don’t have other great ways of controlling pain pharmacologically.”
Such supplements as glucosamine and chondroitin sulfate lack proven efficacy, Dr. Loeser noted. In addition, the ACR recommends against use of growth factors, cell-based injections and platelet-rich plasma as part of standard care for OA, although they have been studied in clinical trials.
A U.S. Food & Drug Administration (FDA) decision to name OA a serious disease should be helpful in future drug discovery efforts, noted Dr. Loeser. The designation provides a regulatory mechanism for approval of a disease-modifying drug faster than what was available in the past. “This is of a lot of benefit to companies that want to get into disease modification,” he said.
Dr. Loeser’s lecture included a discussion of a clinical trial that studied the use of anabolic growth factor called human fibroblast growth factor 18 (FGF18) for cartilage and other joint tissues. The primary outcome measure in a two-year trial was articular cartilage thickness. “There was a significant improvement compared to placebo in the cartilage thickness but unfortunately, there was no improvement in pain,” he said, “and for disease modification, we really want drugs that both improve pain as well as structure.”
Follow-up studies to develop drugs that could promote cartilage regeneration continue but so far results haven’t been “as promising as we hoped,” he said.
Cell-based therapies have been studied in several clinical trials including one published in Nature Medicine that compared bone marrow aspirate, stromal cell fraction and mesenchymal stem cells to corticosteroid.1 Results revealed a response in the first few months but indicated no difference among the groups over the trial duration. Some trials are ongoing but so far these therapies “have not really panned out,” Dr. Loeser said.
Stopping Disease Progression Earlier
“With osteoarthritis, one of the issues is that we’re often seeing people that have more advanced disease,” he said, adding that clinical trials frequently enroll patients who have radiographic OA at grade two or grade three. “When we intervene at this stage, so far, other than things like exercise and weight loss, we really have not been that successful.
“The idea in the field is maybe we need to pick up people earlier, if we’re going to slow or stop disease progression before it gets too far,” he said. “So, finding this pre-radiographic stage and finding the right group of people to intervene on is sort of the way people are thinking about for the future, and for that, we’re going to need better risk biomarkers.”
Biomarkers
To predict onset and progression of OA, researchers have studied biomarkers in blood, synovial fluid and imaging and investigated whether how a person walks or runs can identify abnormal gait mechanics that foreshadow development of the disease.
Cartilage acidic protein (CRTAC1) is one of several promising biomarkers identified through plasma proteomic studies, including one study of a biomarker panel that could possibly predict the onset of incident OA in advance of five to 10 years. “We’re getting to the point where we might have some prediction biomarkers,” he noted.
Some signs of progress have been seen, Dr. Loeser said. “Once we find the good biomarkers this might be really helpful for the future.”
Osteoarthritis has a variety of influences, such as genetics, environment, joint shape and multiple phenotypes, endotypes and therotypes, Dr. Loeser noted. That means investigating and developing effective therapies may require targeting OA subtypes instead of betting on the idea of one drug to suit all patients.
“Joint tissue destruction is mediated by a host of pro-inflammatory mediators and matrix degrading enzymes,” Dr. Loeser explained. “We don’t yet know (of) a master cytokine like TNF [tumor necrosis factor] that turned out to be so important in RA [rheumatoid arthritis] and so many other diseases. … We haven’t found that yet, but it may be a host of things rather than a single cytokine.”
In Sum
Dr. Loeser emphasized a key message that disease-modifying interventions will need to be initiated at an earlier phase if they are to succeed. If started too late, the chance of reversing OA is slim and the risk for irrevocable joint damage increases.
Whether a breakthrough is just around the corner or further up the road, the search continues to discover OA therapies in new as well as existing targets. For example, ongoing clinical trials investigating colchicine and GLP-1 agonists indicate potential for reduction of pain and fewer joint replacements in patients with OA, Dr. Loeser said.
“I think there’s a lot of work being done out there that’s promising,” he said. “We’re not there yet, but I think we’re getting closer and closer.”
Catherine Kolonko is a medical writer based in Oregon.
Reference
- Mautner K, Gottschalk M, Boden SD, et al. Cell-based versus corticosteroid injections for knee pain in osteoarthritis: A randomized phase 3 trial. Nat Med. 2023 Dec;29(12):3120–3126.
