Tuesday, October 9, 2012

Metal ions may lead to the generation of free radicals

From AAOS (Feb issue 2011)...testified in the FDA hearings as well.


Young-Min Kwon, MD, PhD, FRCS, FRACS, an assistant professor at Harvard Medical School, explained that biologic reactions to MoM may be systemic or local. Metal ions may lead to the generation of free radicals, which, in turn, can induce DNA cross-linking. “Because the permanent modification of genetic material is a first step in carcinogenesis, this raises questions and concerns about the potential for carcinogenesis in these patients,” he said.

He went on, however, to note that precise prevalence of adverse local and remote tissue responses is unknown and recommended a systematic approach for assessing painful MoM hips. Dr. Kwon presented three such approaches—one from the U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA), a diagnostic algorithm published earlier this year in the Journal of Arthroplasty, and one from a scientific exhibit displayed during the 2012 AAOS Annual Meeting.

“In summary,” he concluded, “the systemic adverse biologic reaction to metal-on-metal remains a concern because current studies are limited. This represents an important part of our future research. We also need to further standardize histologic evaluation of periprosthetic tissues in patients with adverse soft-tissue reaction. The various reactions indicate dose dependency as well as patient susceptibility, which point to a complex biologic interplay between the implant and patient, as well as surgical factors. Further research is still required to gain insight and identify the multifactorial etiology of local adverse soft-tissue reaction in patients.”

Full reprint below:

Research probes pseudotumors in MoM hips

By Terry Stanton
Award-winning Young Investigator examines reasons for revision
Metal-on-metal hip resurfacing arthroplasty (MoMHRA) has undergone a resurgence as a treatment option for young and active patients with significant hip osteoarthritis, notes Young-Min Kwon, MD, PhD, FRCS, FRACS, winner of the 2011 Kappa Delta Young Investigator Award. Although 5-year survivorship rates are 95 percent or above, more attention is being paid to device failures, especially those involving abnormal periprosthetic soft-tissue masses (pseudotumor) (Fig.1).
on_Young-Min.gifSuch complications are relatively rare, but reports of them—with or without cystic elements—are increasing. When they occur, they are serious, causing local tissue destruction and often resulting in the need for revision surgery.
Dr. Kwon notes that according to National Joint Registry data, the reasons for failure are “unexplained” in up to 21 percent of cases. Although adverse biologic metal wear debris is commonly cited as a potential cause, few confirming studies have been conducted.
Young-Min Kwon, MD,

Aiming to fill that gap, Dr. Kwon, who currently is an orthopaedic surgeon at Massachusetts General Hospital, Harvard Medical School, has pursued a number of clinical studies on these issues and the questions surrounding them.

“As a surgeon-scientist, I believe that it is critically important to investigate and gain insights into any unexpected complication that adversely affects patient outcomes, using an evidence-based approach to form the foundation for clinical recommendations to minimize such complications,” said Dr. Kwon.

Prevalence and metal sensitivity
A clinical study designed to establish the prevalence of and the relationship between serum levels of metal ions and presence of pseudotumors in patients with MoMHRA, for example, found an overall prevalence of asymptomatic pseudotumors of 4 percent, considerably higher than previous reports, which dealt with symptomatic patients. Pseudotumors were more frequently found in women than in men, and particularly among women who had bilateral MoMHRA implants.

The patients with pseudotumors also had significantly higher levels of cobalt and chromium in their blood and in joint fluid. This association may be important; according to Dr. Kwon, “Pseudotumors are likely to be a biologic reaction to the large amount of metal debris generated in vivo due to excessive wear.”

A second study, also conducted at the Nuffield Orthopaedic Center, University of Oxford, measured the relationship between a patient’s hypersensitivity to metal and the development of pseudotumors. The results of this study also pointed to wear debris as a possible source of the pseudotumors.

Dr. Kwon then began to examine, on a cellular level, the impact of cobalt and chromium on the development of pseudotumors. Again, the results pointed to the involvement of wear debris, particularly of minute cobalt particles (nanoparticles). A build-up of cobalt nanoparticles can be cytotoxic, resulting in cell death and local adverse biologic effects.

The impact of wear and loading
The correlation of wear with elevated ion concentrations led Dr. Kwon to investigate the source of the wear. He focused his next study on MoMHRA implants removed from patients with pseudotumors, comparing them to implants that had been removed for other reasons. He wanted to measure the amount of wear in the two sets of implants, and to see where the wear occurred.
Edge-loading, in which the femoral component comes into contract with the edge of the acetabular component, had been suggested as a mechanism for increased wear, but direct assessment of wear and occurrence of edge-loading had not previously been performed in patients with pseudotumors.
The results demonstrate that MoMHRA implants revised due to pseudotumor were associated with significantly greater linear wear rates of both femoral and acetabular cup components. Additionally, in the implants removed due to pseudotumor, wear on the acetabular cup components always involved the edge.

A follow-up study to quantify edge-loading during functional activities in MoMHRA patients with pseudotumors and in those with well-functioning implants without pseudotumors reinforced these conclusions. During walking, for example, all of the patients with pseudotumor experienced edge-loading—compared with fewer than 1 in 4 patients without pseudotumors.

From this series of studies, Dr. Kwon concluded, “Soft-tissue pseudotumors are likely to represent a local reaction to high amounts of metal debris generated by excessive metal implant wear. Edge-loading is likely to be an important mechanism contributing to increased wear of these implants, leading to damage of periprosthetic soft tissues in susceptible patients.”

As a result, surgeons need to be alert for pseudotumors in MoMHRA patients even if the patient’s radiographs are normal. Surgeons should exercise great care in MoMHRA procedures, especially in women who require small implant sizes, because even with satisfactory acetabular component positioning, pseudotumors can occur.

Although the results of his studies do not support the routine use of preoperative metal sensitivity testing, Dr. Kwon recommends that patients with these implants be reassessed regularly. “Patients should know that most metal-on-metal hip implants function very well. If, however, patients have significant pain, they should be evaluated by their orthopaedic surgeon, because a possible cause of their symptoms may include adverse soft tissue reaction to excessive metal wear.”
Heightened concerns over toxicity may be justified, he says, and “the evidence presented in this manuscript reinforces the need for continuing clinical surveillance as well as the need for further studies to understand and reduce wear in patients with MoMHRA.”

Disclosure information: Dr. Kwon reports no conflicts.

Terry Stanton is senior science writer for AAOS Now. He can be reached at tstanton@aaos.now
February 2011 Issue

No comments:

Post a Comment