Intra-articular inflammation contributes to joint health in vital and complex ways. In the short term, it stimulates cartilage degradation as part of the healing process. However, sustained inflammation furthers joint disease progression, directly impacting horses’ long-term athletic potential. “Inflammation-induced lameness leads to lapses in training and reduced effectiveness of exercise programs,” said James George, PhD student at Tarleton State University, in Stephenville, Texas. During his presentation at the 2025 Equine Science Society Symposium, held June 3-6, in Fort Collins, Colorado, George described his research on the effects of bisphosphonates on young horse joint health.

Bisphosphonates inhibit bone resorption, and the FDA has approved two for use in horses 4 years and older to control clinical signs of podotrochlosis (aka navicular syndrome). While equine veterinarians commonly use drugs extra-label, researchers continue to examine the implications of this practice with bisphosphonates.

Despite the approved indication, one of the drugs, clodronate, has been used extra-label  in young horses due to anecdotal assertions that it exerts anti-inflammatory and chondroprotective effects on the articulating joint, said George. With his study he aimed to evaluate the synovial (joint) metabolic profiles of juvenile exercising horses treated with the bisphosphonate clodronate.

George and his research colleagues split 16 Quarter Horse yearlings into two groups: one treated with intramuscular clodronate and a control group. They used a progressive exercise program, working the yearlings up to five days per week with a free panel exerciser to mimic sale preparation.

On Day 126 the researchers injected the yearlings’ carpal (knee) joints with lipopolysaccharide (LPS), an endotoxin derived from Escherichia coli, to elicit transient yet pronounced synovitis (inflammation), simulating an insult to the joint. By comparing treatment and control limbs, his team would evaluate the effects of clodronate on the synovial metabolome (the complete set of small molecules present in the joint environment) following inflammation onset.

“We collected synovial fluid at preinjection and six, 12, 24, and 336 hours post LPS injection,” said George. After extracting metabolites from joint fluid, he and his team found certain metabolites appeared at significantly higher concentrations in the treatment group than in the controls, regardless of time or LPS exposure.

“Metabolite diversity indicates that clodronate affects multiple metabolic pathways,” said George.

Future Research Directions

Researchers now know clodronate’s impact extends across several metabolic pathways in the joint. George said researchers on future studies could target specific metabolites to better understand the drug’s influence. Of particular interest are amino acids involved in joint repair and growth, he explained, as well as pro- and anti-inflammatory prostaglandins and other lipids.

Take-Home Message

George emphasized that he and his colleagues did not identify a single mechanism to support the anecdotal belief that clodronate is anti-inflammatory or chondroprotective. However, they did confirm clodronate influences multiple biological processes. Whether these effects prove beneficial, neutral, or harmful remains unclear. These findings highlight the need for further research to fully understand how clodronate interacts with joint health, he said. Until then, extra-label clodronate use merits caution, especially in young horses.