A drug commonly prescribed to prevent blood clots has reduced cartilage damage, inflammation and mobility problems in animals with knee osteoarthritis, raising the possibility of a new treatment for a condition affecting more than 500 million people worldwide.
The drug, dabigatran, was found to improve knee movement and preserve cartilage in experiments involving monkeys and mice with surgically induced osteoarthritis. Researchers believe its effects may partly result from blocking inflammatory signals associated with the deterioration of cartilage.
Osteoarthritis develops when cartilage, which cushions the ends of bones within joints, deteriorates, causing inflammation, pain and stiffness. Existing painkillers and anti-inflammatory medicines can relieve symptoms, but no approved drugs have been shown to halt or slow the progression of the disease.
“We have nothing to offer our patients apart from suggesting weight loss, or offering drugs that provide pain relief,” said Tonia Vincent of the University of Oxford, who was not involved in the research.
The study, led by Chuan-Ju Liu of Yale University and his colleagues, examined whether simultaneously targeting two inflammatory molecules, tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1-beta), could provide better results than targeting either one independently.
Both molecules are believed to contribute to the inflammation that aggravates osteoarthritis. However, previous clinical trials involving drugs that block either molecule have been unsuccessful. Liu and his colleagues suggested that this could be because the two molecules compensate for each other when one is inhibited.
To investigate the possibility of targeting both pathways, the researchers surgically removed part of the cartilage in the left knee joints of eight monkeys to reproduce the damage associated with osteoarthritis. One month later, four animals began receiving daily doses of dabigatran mixed into their food, while the remaining four continued their normal diets as a control group.
Dabigatran is commonly used to reduce the risk of blood clots and strokes in people vulnerable to such conditions. It has also been found to interfere with inflammatory signalling involving TNF-alpha and IL-1-beta.
After seven months, magnetic resonance imaging (MRI) scans showed that the cartilage in the treated monkeys’ left knees was approximately 60 per cent thicker, on average, than in the control animals. Liu said the findings suggested that the drug had reduced cartilage damage and slowed the progression of osteoarthritis.
The treated monkeys also demonstrated a roughly 15 per cent greater range of movement in their affected knees than the control group. “Monkeys receiving dabigatran showed a more natural walking pattern and a greater range of knee movement,” Liu said. He added that the improvements were consistent with reduced joint stiffness and discomfort.
Further experiments involving mice with surgically induced knee osteoarthritis produced similar findings. The researchers found that dabigatran reduced inflammation in the affected knee joints by approximately 60 per cent.
Vincent said the researchers had used some of the best available animal models of osteoarthritis and suggested that independent replication of the findings could justify a small clinical trial in humans.
However, several uncertainties remain. Liu said it was not yet clear whether the treatment could reverse cartilage damage that had already occurred. More importantly, dabigatran’s ability to reduce blood clotting creates a risk of bleeding, making its use as a long-term osteoarthritis treatment potentially problematic.
The research team is therefore developing alternative drugs that target TNF-alpha and IL-1-beta without interfering with blood clotting. These compounds will first be tested in mice before any potential human clinical trials.
Vincent also cautioned that some of the improvements observed in the experiments could have resulted from dabigatran’s anti-clotting properties rather than its effects on inflammation. Previous studies have suggested that inhibiting molecules involved in blood clotting may itself relieve osteoarthritis symptoms. Comparisons with drugs that block the two inflammatory molecules without affecting clotting could help establish which mechanism is responsible for the benefits.
