Zoledronic Acid Relieves Knee OA Pain and Shrinks Bone Marrow Lesions

LONDON – A single 5-mg infusion of zoledronic acid, a bisphosphonate, in patients with knee osteoarthritis led to significant pain reduction and shrinkage of bone marrow lesions in a randomized, placebo-controlled study with 59 patients.

The zoledronic acid treatment led to an average 15-point drop in pain (on a visual analog scale of 0-100) beyond what occurred in the placebo group, and the active treatment was also linked with an average 170-mm² reduction in maximal bone marrow lesion (BML) area beyond the placebo-treated patients, which was a cut in BML area of about 37%, compared with the starting BML area, Dr. Graeme Jones said at the annual European Congress of Rheumatology. Dr. Jones visualizes BMLs using MRI knee scans.

Dr. Graeme Jones

"This is the first intervention shown to work on BMLs" in patients with osteoarthritis (OA), said Dr. Jones, professor of rheumatology and epidemiology and head of the musculoskeletal unit at the Menzies Research Institute Tasmania, Hobart, Australia.

"This is exciting for treating existing OA. It is one of the first positive structure modification trials," commented Dr. Philip Conaghan, professor and chairman of musculoskeletal medicine at the University of Leeds (England).

"Results from several studies have linked BMLs with pain and cartilage damage in OA patients. The larger the BML, the faster the cartilage loss and the worse the pain," Dr. Jones said in an interview. Based on studies his group has done, about 20% of BMLs that are associated with knee OA spontaneously enlarge over the course of 3 years, another 20% shrink in size, and about 60% remain the same, he said. Their earlier research findings also showed that BMLs are independently linked with fast progression of OA and the need for knee replacement. "If you reduce BMLs, it should produce good outcomes in patients," he said.

"The next step is to show that treatment with zoledronic acid not only reduces BML size but also slows cartilage loss. Sixty patients followed for 12 months were not enough to assess cartilage. We will need about 400 patients followed for 2 years," Dr. Jones added.

Despite not yet having information on cartilage effects, he said that his results so far have convinced him that treatment with zoledronic acid is reasonable for patients with painful knee OA and BMLs.

"I use it off label. Patients need to know it’s off label, and they [therefore] must be willing to pay for it, but I use it. It’s been shown to work, and nothing else works. Zoledronic acid [Reclast] is available, we know about its safety, and it’s been used for a long time to treat osteoporosis and cancers. If you have OA patients with BMLs, this is something to actively consider for them. Patients with OA have very limited treatment options. This can make a large difference in their pain, and it has long-lasting benefit so it can be given once a year," Dr. Jones said.

He recommended an infusion of 5 mg of zoledronic acid for patients who are at least 50 years old with knee OA that fulfills the American College of Rheumatology clinical criteria, and knee BMLs that are visible on an MRI scan of the affected knee. In his experience, 88% of these knee OA patients have BMLs. Dr. Jones noted that he does not use a maximal BML area threshold for initiating treatment, although in his study the average maximal BML area was about 465 mm². About one-third of people aged 50 years or older with no clinical evidence of OA also have BMLs, he noted.

The benefits of zoledronic acid that were seen in his study might be a class effect that may be replicated by treatment with another bisphosphonate, but zoledronic acid is more potent than oral bisphosphonates and hence the drug’s beneficial effect on pain and BML shrinkage may exceed the effect that other bisphosphonates might have, he said.

The pain benefit appeared to start wearing off about a year after the zoledronic acid injection. Dr. Jones said that he has a small number of patients whom he has infused a second time, which produced a second round of pain reduction. He has not yet given any OA patients a third dose of the drug.

The 59 patients who were enrolled in the study had an average age of about 60 years, with an average knee pain score of about 52 on the visual analog scale; all patients had BMLs as seen on MRI scans of their affected knees. In all, 31 patients received a 5-mg infusion of zoledronic acid and 28 patients received a placebo infusion. All patients also continued their conventional pain medication regimens. The zoledronic acid infusion was well tolerated: Although infusion reactions were reported in 90% of the patients who received the drug and in 43% of the placebo patients, serious adverse effects occurred in only 19% of the patients who received zoledronic acid and in 4% of the placebo patients.