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Particulates can have biologic response after THR

Three parameters can dictate biologic response: wear volume and particle size, access of particles to the bone of implant-bone interface, biologic variation in patients.

Issue: July 2004

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Since Sir John Charnley, DSc, began his pioneering work in total hip replacement in the late 1950s, the procedure has become increasingly popular and effective. But despite many advances in implant design and surgical techniques, periprosthetic osteolysis, a problem that bedeviled Charnley, is still a major issue.

There is no denying that total joint arthroplasty has been remarkably effective in restoring patient mobility and function. But over the years, increasing numbers of younger and more active patients have opted for hip replacement. This patient population has stressed conventional metal-on-polyethylene hips to the limit, leading to material failure and osteolysis. It is estimated that nearly 300,000 hip replacements are performed each year in the United States, and osteolysis is the major cause in up to 20% of orthopedic implant failures.

“This really emerged as one of, if not the, major problem in joint replacement surgery in the early ‘90s, and it probably continues as our greatest challenge in joint replacement surgery today,” said Joshua J. Jacobs, MD, of Rush-Presbyterian-St. Luke’s Medical Center in Chicago.

Jacobs and other researchers have found that the main culprit in osteolysis is particulate debris from implant bearing surfaces, not polymethylmethacrylate (PMMA) bone cement as initially thought. Research into how the body reacts to debris has continued, with investigators considering the role of bearing surface materials, as well as debris size and volume.

Minimizing particulate debris

When it became clear that a certain volume of particles of any kind — polyethylene, ceramic or metal — could induce osteolysis, researchers set about developing alternative bearing surfaces designed to produce less debris. The result has been implants featuring highly crosslinked polyethylene, metal-on-metal or ceramic-on-ceramic bearing surfaces.

But researchers and surgeons must remember that newer bearing surfaces alone will not solve the problem, said Thomas P. Schmalzried, MD. “Having a very wear-resistant bearing does not guarantee the longevity of an arthroplasty. Clinical success is multifactorial and simply identifying and utilizing a very wear-resistant bearing does not guarantee clinical success,” he told Orthopedics Today.

Some researchers have taken a different approach and have begun investigating ways to inhibit the osteoclastic bone resorption that characterizes osteolysis. While still in the early stages, research into the role of bisphosphonates, tumor necrosis factor antagonists and other drugs still in development could play a role. To make those modalities effective, however, research into the biology of osteolysis must continue.

The osteolysis puzzle

When Charnley observed cases of osteolysis, he thought they were due to infection. After further observation, he came to believe that PMMA might be the culprit. A study he published in 1968 on the reaction of bone to self-curing cement later influenced thinking on the issue. In 1976, William H. Harris, MD, published an influential article that reported on four patients with extensive localized bone resorption and loose prostheses that Harris concluded were due to PMMA particles. “Cement disease” became part of the orthopedic lexicon and sparked the design of cementless implants.

It wasn’t until 1977 that Hans Willert, MD, of the University of Gottingen in Germany, published an article in English concluding that migration of wear particles into the area surrounding total hip implants was responsible for osteolysis. Subsequent research has elucidated how a variety of particles can stimulate a macrophage response that results in the release of bone resorbing cytokines and prostaglandins.

“There are three important parameters that are going to dictate the biologic response. The first is wear volume and the size of the particles. The second is the access of the particles to the bone of the implant-bone interface. Then you have the individual’s biologic variation, the biologic response itself,” said William J. Maloney, MD, of Stanford University School of Medicine in Palo Alto, Calif.

A lot of research has been done on wear volume and particle size in conventional metal-on-polyethylene hips, much of it by Schmalzried and colleagues at the Joint Replacement Institute in Los Angeles. A study published in the Journal of Bone and Joint Surgery in 1995 showed that a 28-mm diameter bearing with a conservative linear wear rate of 0.05 mm per year generates 500 billion particles equal in volume to a 0.5 mm-diameter sphere. That equals 500,000 particles per step for a patient who takes 1 million steps a year. But in the same situation, wear would result in only 63 million 10-mm diameter particles, or only 63 wear particles per step.

Wear volume

Wear volume is a key component of the “lysis threshold,” Maloney said. “You need a critical volume of wear particles to create a significant biologic response. Below that level, you’re going to have some particles, but they’re not going to be very important because there are not enough of them around to cause a problem.”

Schmalzried agreed that particle volume is key. “To get a macrophage excited, it has to have enough stimulation from enough small particles. There’s debate about whether it’s a cell surface interaction or an intracellular event that starts the cascade, but what’s clear is that it takes numerous small particles to start the biologic cascade from a macrophage,” he said.

Particle size

The issue of particle size goes hand-in-hand with particle volume. “There are particles that are several hundred microns or even bigger, but the ones that are under a micron are the ones that we now think activate the histiocytes, and it’s the activation of the histiocytes that leads to the bone resorption that we see in osteolysis,” said John J. Callaghan, MD, of the University of Iowa College of Medicine.

Jacobs said several studies have established that in conventional metal-on-polyethylene hips, the vast majority of particulate debris is polyethylene, and more than 90% of the particles are less than a micrometer, with a mean size of 0.5 µm. These smaller particles appear to be less stimulatory, and most research has suggested that phagocytosable particles (those less than approximately 7 µm) are the most biologically active, especially at higher doses.

Wear differences in total knee replacement result in polyethylene particles in the 10-mm to 100-mm range, likely accounting for the lower incidence of osteolysis following total knee replacement. What is still unclear, Jacobs said, is to what extent nanometer-sized particles are more or less bioreactive than micrometer-sized particles. “There have been a few studies that have looked at that, but in my mind the issue is kind of in doubt, largely because it’s so difficult to obtain very large amounts of very fine debris and then in turn study them in cell culture.”

Systemic effects

Some researchers have expressed concern over the potential systemic effects of particulate debris. In 2000, Jacobs published a study in the Journal of Bone and Joint Surgery that analyzed tissue specimens from 31 patients who had undergone total hip replacement. The analysis showed that the prevalence of metal and polyethylene particles in the liver and spleen was greater after reconstructions that failed, but in most patients the concentration of wear particles was relatively low and did not appear to be pathologically important.

“We haven’t studied other organs in detail, but we suspect, and others have reported, in fact, that even organs such as the heart and the kidneys may be sites where, to some extent, there is deposition of some of the debris from implants,” Jacobs told Orthopedics Today.

Schmalzried said systemic effects of particulate debris can be an issue with failed implants. “In that case, the systemic distribution of metal and plastic particulates can be substantial, but I am unaware of any disease or symptoms that occur with the distribution that is associated with a well-functioning joint.”

The role of polyethylene debris in osteolysis following implantation of conventional hips led orthopedic surgeons, researchers and manufacturers on a quest for newer bearing surfaces that would produce less wear debris. One candidate is polyethylene that is highly crosslinked through exposure to up to 10 Mrad of gamma radiation, a process that has been shown to decrease wear by up to 80%.

Particle generation reduction

Periacetabular osteolysis associated with severe polyethylene wear is noted on this AP radiograph of the hip. COURTESY OF JOSHUA J. JACOBS

Maloney, who is conducting several ongoing studies of highly crosslinked polyethylene, said that for the products he is familiar with, there has been a 90% to 95% reduction in particle generation. Schmalzried said studies have shown that the bioreactivity of particles from crosslinked polyethylene is higher than that of conventional polyethylene particles, but because there are so few of them, their functional biologic activity is much lower. Highly crosslinked polyethylene has already made significant inroads. According to some estimates, it accounts for 75% of the polyethylene sold for use in total joint replacement implants.

Another alternative bearing surface is metal-on-metal, which was commonly used before falling out of favor in the mid-1970s due to early cup loosening. In 1999, the Food and Drug Administration approved the Metasul implant, making it the first metal-on-metal bearing available in the United States in more than two decades.

To date, more than 150,000 Metasul hips have been implanted worldwide. While simulator studies have demonstrated that current metal-on-metal hips produce 20 to 100 times less particulate debris than conventional metal-on-polyethylene articulations, some researchers have expressed concern about long-term effects of metal particles and ions. These include hypersensitivity, toxicity and the risk of carcinogenesis.

“I think there is clinical evidence to support the fact that the risk of having an allergic reaction or a hypersensitivity reaction to an implanted prosthesis is higher if there is a metal-on-metal bearing than when there is some other type of articulation,” Schmalzried said. “That’s likely due to the fact that with elevated ion levels the chance that you’re going to form an ion-protein complex that stimulates the immune system is increased.”

A third alternative bearing surface is ceramic-on-ceramic. Like metal-on-metal articulations, ceramic-on-ceramic hips were available in the United States in the 1970s, but early failures and other problems made surgeons avoid them. The FDA has approved two implants and others are in development; simulator studies have demonstrated that ceramic-on-ceramic hips have the lowest wear volumes of all currently available options.

Despite the lower wear rates, researchers note that it is important to keep in mind that particulate debris from ceramic-on-ceramic hips can result in osteolysis if there is enough of it. “You hear some people saying that ceramic particles are inert or that they are less active than polyethylene particles, but that has not been our experience. They’re similar. It’s more a size issue and a volume issue than it is a material issue,” Maloney said.

Schmalzried believes that while research into alternative bearing surfaces is important, surgeons already have the tools they need to help lower the incidence of osteolysis. “Wear is a tertiary problem, so there are other things that have to be addressed before wear is recognized as a limitation. … You’ve got to have the basic mechanical equation worked out and you’ve got to have the fixation right, and then you get to worry about wear.”

He added that surgeons must remember that while the newer bearing surfaces are improvements in many ways, they also have potential downsides. “The newer bearings are more sensitive to impingement contact and impingement wear than the conventional polyethylenes were. … Proper orientation of the components is therefore more important, which presents a greater challenge to the surgeon. Large diameter bearings can reduce the risk of impingement,” Schmalzried said.

Dr. Maloney is a paid consultant to a company mentioned in this article.