Gluck lecturer discusses emerging therapies targeting the role of bone in OA

Ongoing research continues to elucidate the role of bone in the pathogenesis and progression of osteoarthritis, helping researchers identify new targets for therapeutic intervention, said Marc Hochberg, MD, MPH, who delivered this year’s Oscar S. Gluck, MD Memorial Lecture on Sunday, Nov. 7.

Dr. Hochberg’s lecture, Osteoarthritis Is a Disease of the Whole Joint: The Role of Bone in OA, can be viewed by registered meeting participants through March 11, 2022.

To provide some historical context about the ongoing quest to develop effective OA treatments, Dr. Hochberg began his lecture with a brief primer on the discipline of paleopathology.

“The bony changes of osteoarthritis — primarily eburnation and osteophytes — have been described in fossils of Neanderthal, Cro-Magnon, and Paleolithic specimens, as well as Egyptian mummies and skeletal specimens worldwide,” said Dr. Hochberg, Professor of Medicine and Epidemiology & Public Health, and Head of the Division of Rheumatology and Clinical Immunology at the University of Maryland School of Medicine.

“So, this is indeed an ancient disease,” he said.

Fast forward a millennium or so, and the manifestations of OA remain largely the same. But our understanding of OA has advanced significantly, especially in recent years, he said.

“Over the last 20 years, we’ve recognized the importance of bone marrow lesions, which represent localized bone microdamage and remodeling and reparative changes,” Dr. Hochberg said. “However, treatments directed at altering bone turnover, including bisphosphonates, have not been demonstrated convincingly to have efficacy for either structural progression or symptom relief in patients with knee osteoarthritis.”

That may soon change, he said, as recent clinical trials have demonstrated the promise of two new therapeutic agents that target mechanisms of bone remodeling and osteophyte formation in knee osteoarthritis.

An ongoing multicenter randomized trial in the U.S., currently in phase 3, is looking at the small molecule drug lorecivivint and its potential for inhibiting and modulating Wnt signaling in OA.

“Excessive Wnt signaling has been shown to be associated with the development of osteoarthritis. Furthermore, the absence of Wnt signaling also leads to OA, so modulation of Wnt signaling is important,” Dr. Hochberg explained.

Results from the earlier phases of the trial demonstrated positive outcomes for symptom improvement, as well as potential structure modification, he noted.

Dr. Hochberg also described a recently completed phase 2 clinical trial looking at the efficacy of a novel cathepsin K inhibitor for symptom relief and structure modification in knee OA.

In this study conducted in six countries in the European Union, patients were randomized to receive two doses — a lower dose and a higher dose — of the cathepsin K inhibitor compound MIV-711 or placebo. Co-primary outcomes included a numerical rating scale pain score and changes in medial femoral bone area.

“There was an improvement in symptoms, not only in the treatment group but also in the placebo group. But there was a difference in the increase in bone area, where both doses of MIV-711 demonstrated a reduced increase in bone area over six months compared to the placebo group,” Dr. Hochberg said. “There was a trend for the lower dose to be associated with a reduced decline in femoral cartilage thickness on MRI. Overall, the drug was well tolerated and is hopefully being carried forward into phase 3.”