New test shows promise for detecting warning signs of joint replacement failure

Investigators at the University of Nebraska Medical Center have developed a test that could be used in detecting the early stages of a major cause of failure in joint replacement implants, according to an American Chemical Society press release.

The findings could potentially help patients avoid having to be treated for joint replacement implant failure and receiving additional surgery, the investigators noted in their study, published online in Molecular Pharmaceutics.

“When pain or clear radiographic evidence is reported, unfortunately, considerable bone loss has already occurred, which cannot easily be restored,” wrote the authors.

“Wear particle-induced inflammation is considered to be the major cause of aseptic implant loosening and clinical failure after total joint replacement,” they added. “Due to the frequent absence of symptoms, early detection and intervention prior to implant failure presents a significant challenge.”

Detecting early inflammation and wear

According to the release, to provide an early diagnostic tool for implant failure, the investigators developed a polymer-based system — a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based optical imaging contrast agent (P-IRDye) — for imaging the inflammation that is associated with wear debris. The investigators employed the agent in a murine calvaria osteolysis model.

Twenty-four hours after particle implantation in mice, P-IRDye was administered. Live imaging of the animals 6 days after implantation, the abstract noted, revealed preferential distribution and sustained retention of macromolecular contrast agent at the side of implantation. Extensive uptake of the HPMA was noted, which the authors wrote accounted for retention of macromolecular probes at the inflammatory sites.

Therapeutic intervention potential was tested through the preparation of an acid-labile HPMA copolymer-dexamethasone conjugate, which the investigators reported showed it could prevent the particle-induced inflammation and bone damage in the calvaria osteolysis model.

The tests suggest the methods could help detect early stages of bone loss that might cause a joint implant to come loose, the release noted, adding the investigators also found they could tether an anti-inflammatory drug to the polymeric system to offer a method for treating inflammation and bone loss in early stages of wear.

“Using a modified murine calvarial osteolysis model, we show that imaging agents based on water-soluble macromolecules, such as HPMA copolymers, can be used to identify sites of inflammation associated with the early stage of particle-induced inflammation and subsequent osteolysis,” the authors concluded. “Adaptation of this system for the use of high-energy radioisotopes instead of optical imaging probes will permit development of imaging tools for human application.”

Reference:

Ren K, et al. Early detection and treatment of wear particle-induced inflammation and bone loss in a mouse calvarial osteolysis model using HPMA copolymer conjugates. Mol Pharmaceutics. Published online March 25, 2011. doi: 10.1021/mp2000555.

http://www.acs.org

Disclosure: The authors acknowledge funding from the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the American College of Rheumatology Research and Education Foundation.

The authors are to be congratulated for a well done study which tackles an important and timely issue. As the number of total hips and knees in service rises, methods for screening patients for complications that may require intervention is critical. Early detection of patients at risk would be very helpful, as revision surgery is always easier — and the results are better — prior to catastrophic failure.

What is less clear is if early detection could in some way avoid later operative intervention. At the present time, pharmalogical interventions for processes such as osteolysis have unfortunately not translated into useful therapies.

We also need to understand better, when the appropriate time to intervene in these processes is. Presently, surgeons have individual "triggers" for revision in response to wear and/or osteolysis, and a better understanding of when to intervene is necessary for a tool as the authors describe to be clinically useful. Similarly, when would be the appropriate time to screen patients with the type of testing described? At two years postoperatively? Ten years? And what will the cost of such screening be?

Finally, while what the authors report is interesting, it appears to be a few steps away at the present time from use in the clinical arena. If what they propose can be translated into clinical use, its cost efficacy will need to be determined.

— Craig J. Della Valle, MD
Associate professor of orthopaedic surgery
Rush University Medical Center

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