Monday, March 4, 2013

Taking Another Look at Osteolysis


AAOS Journal  Jan 2013
OREF grant recipient examines the role that fluid pressure plays

Mark Crawford

Osteolysis is one of the persistent barriers to long-term success of total joint arthroplasty, with debris due to implant wear considered a major culprit. The impact of dynamic fluid pressure on bone resorption and osteolysis, however, is unknown.

Denis Nam, MD

Denis Nam, MD, an adult reconstruction and joint replacement fellow at the Hospital for Special Surgery (HSS) Weill Medical College of Cornell University (Weill Cornell) in New York City, is exploring this hypothesis, using a 2011 Orthopaedic Research and Education Foundation (OREF)/American Association of Hip and Knee Surgeons Resident Clinician Scientist Training Grant made possible by Zimmer Holdings Inc.

While formulating an idea for a research project, Dr. Nam spoke with scientists working with Mathias P. G. Bostrom, MD, professor of orthopaedic surgery at Weill Cornell. Among them was Anna Fahlgren, PhD, a lecturer and the Marie Curie Vinmer Fellow at Linköping University, Linköping, Sweden.

“I was drawn to Dr. Fahlgren’s idea that fluid pressure may be causing bone loss around implants,” said Dr. Nam. “We all know debris particles are important, but maybe fluid and hydrostatic pressure, and pressure within the joints and around the implants, also contribute to bone loss.”

What if … ?
The accepted theory is that debris erodes from implant surfaces, triggering a response from the body that engulfs the debris and also removes bone,” said Dr. Nam. “Our study explores the possibility that fluid pressure can also cause osteolysis. For example, considerable literature in the trauma world has shown that even the slightest instability during surgery can cause fluid fluctuations, which result in superficial bone resorption.”

If hydrostatic pressure and fluid flow velocity in the tissues adjacent to the prosthesis activate an alternative signaling pathway that leads to osteoclast activation, this dynamic may be more critical than the classic pro-inflammatory pathway during specific stages of aseptic loosening.

“It is quite probable that both factors contribute at different times to loosen implants,” said Dr. Nam. “At one point, pressure fluctuations may be causal; at another, particles may be the primary factor. In fact, they’re probably working synergistically to cause bone loss. Because wear debris is understood to be a long-term phenomenon, fluid pressure may help explain why some implants fail before debris accumulates.”

Building on past studies
Dr. Nam will use a well-established rat model that uses a piston to apply fluctuating hydrostatic pressure to the bone by compressing a soft-tissue membrane that forms underneath the piston. Cyclic motion of the piston perpendicular to an isolated bone surface creates fluid pressure and flow around the proximal tibia (Fig. 1).

Fig. 1 (left) Retrieved tibial specimen after loading, with fibrous tissue located centrally underneath the piston, (right) corresponding cross-sectional, histologic specimen
Courtesy of Denis Nam, MD

This model has been shown to reliably produce osteolytic lesions both directly below the piston and in adjacent porous bone. The lesions are connected through preformed cavities, leading to pressure-induced bone resorption.

Before the piston is activated, a soft tissue membrane is allowed to form within a 1-mm space underneath the piston. Applying force to the piston transmits load to the soft-tissue through the skin via a dynamometer. Once loading is initiated, an 8N transcutaneous force is applied under anesthesia for 20 cycles at a frequency of 0.17 Hz, twice a day. This stimulus is based on previous levels that have experimentally created osteolytic lesions.

After 5 days of loading, specimens will be prepared for histomorphometry, immunohistochemistry, and microCT (micro-computed tomography) analyses. Osteolysis indicators will be assessed under light microscopy, at 4 times and 40 times magnification, using hematoxylin and eosin stains. The presence of fibroblasts, macrophages, polymorphonuclear cells, and round cells will then be recorded.

Promising results
Results so far have confirmed that a direct correlation exists between increased fluid pressure loading and bone loss (Fig. 2).

“We hope this work will lead to new pharmacologic treatments or implant designs that prevent early loosening,” said Dr. Nam. “Perhaps these results will lead to engineering implants in a way that limits the flow of fluid around the implant. For example, an optimal design might require other innovations to mitigate fluid flow factors.”

Fig. 2 (left) microCT image of the bone quality of a controlled, unloaded specimen, (right) microCT image of the significant amount of volumetric loss seen in a specimen loaded for 5 days.
Courtesy of Denis Nam, MD

Excellent mentors
Dr. Nam said he was inspired to take on the challenge of a dual career as a clinician and a scientist by others who worked hard and achieved results.

“My dad is a pulmonologist who immigrated from Korea and always worked hard. I remember coming home from school and always finding him reading Harrison’s textbook on internal medicine,” he recalled. “I’m extremely lucky to have my dad’s example—and support from Drs. Bostrom and Fahlgren and others in the lab—to guide me. I honestly couldn’t do this without them.”

Mark Crawford is a contributing writer for OREF and can be reached at

January 2013 Issue

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