Research finds promise in cellular-level treatments after joint fractures
Osteoarthritis (OA) resulting from traumatic joint injury is a serious complication that can leave injured persons—often younger individuals involved in car crashes or sports accidents—with lifetime pain and disability. Yet current treatment options are limited, focus mainly on restoring normal anatomy, and often fail to address articular tissue degeneration.
A “benchtop to bedside” symposium cosponsored by the AAOS and the Orthopaedic Research Society took on some of the vexing questions and issues surrounding posttraumatic OA and the progress being made in both research and clinical practice. Presenters reported that some therapeutic agents show promise in the laboratory, while a practicing orthopaedic surgeon urged his colleagues to rethink the notion that functional outcomes hinge almost completely on the quality of anatomic reduction.
An estimated 10 percent to 15 percent of all symptomatic OA is the posttraumatic type, said Steven A. Olson, MD, who moderated the symposium with Thomas D. Brown, PhD. That represents about 6 million patients and billions of dollars in societal burden.
Posttraumatic OA is “unique in that, unlike most forms of arthritis, it is associated with an acute event, the trauma itself,” Dr. Olson said. Because it primarily affects younger people, “it has a tremendous impact on the most productive stage of society,” he said.
The diagnosis of posttraumatic OA is made mainly from clinical examination and radiographic changes. “There really aren’t serologic changes or clinical biomarkers that indicate a diagnosis of osteoarthritis,” said Dr. Olson. To improve the effectiveness of treatment of patients with joint injury, he said that, along with surgical restoration, physicians and researches need to focus on “mediating the effects of the impaction of cartilage and modifying the local articular response to an impact injury.”
Dr. Brown summarized some of the recent work in biomechanics and computer modeling and reviewed its relevance to clinical practice. In studying the effect of low-energy and high-energy impact on brittle solids, he said, researchers found a “one-to-one correlation between the energy that is liberated, or absorbed, and the amount of de novo new fracture surface area of the fragments.” As a result of this finding, measuring the surface area of fractures can provide an objective metric that can be used to predict degeneration leading to OA.
With comminuted fractures, fragments can be visualized and computationally reassembled by 3-D puzzle solving, Dr. Brown said. This technology segments bony fragments into individual geometric entities that can be manipulated to solve the puzzle. By matching the periosteal and subchondral surfaces of fragments in a sequential manner, starting with the biggest fragments, researchers can reconstruct the desired anatomy. Study of this technology is currently in the case series state.
To heal globally, act locally
Dr. Brown also discussed thin-film technologies and sensors that can be used to detect biomechanical changes occurring in trauma. “Pathology itself originates at local cell or matrix levels,” he said. “Orthopaedists need to think not just about the global joint but also about the local environment. Researchers need to develop measures that enable us to quantify mechanical abnormalities at the local level.”
Study of the local biologic response to joint trauma has been a research focus for Kyriacos A. Athanasiou, PhD, who summarized what he and his colleagues have learned so far.
Developing therapies for damaged articular cartilage is a challenge, he said, because, owing to its avascularity and relative acellularity, cartilage does not naturally repair adequately.
Dr. Athanasiou and colleagues studied the response of cartilage to trauma by subjecting specimens to either high impacts or low impacts and then culturing them for 4 weeks. Not surprisingly, the high-impact specimen showed gross damage and considerable cell death immediately after impact, while the control and the low-impact sample scored low in these categories. Parallel results were found for the release of sulfated glycosaminoglycans (sGAG), a major component of articular cartilage, and loss of stiffness; increased sGAG release is correlated with decreased stiffness.
What was surprising was that at 4 weeks, these values were about the same in both impact groups; in other words, the low-impact group had “caught up” to the high-impact group in these measures of degeneration (Fig. 1).
Because impact loading leads to tissue degeneration through cell death and matrix breakdown, prospective treatments that target these pathways should be examined, Dr. Athanasiou said. Three agents that have shown some promise are poloxamer 188 (P188), insulin-like growth factor 1 (IGF-1), and doxycycline.
P188 is a copolymer with both hydrophilic and hydrophobic regions that selectively inserts itself into cell membranes, thereby preventing ionic imbalance and loss of important cellular content. IGF-1 enhances chondrogenesis in cartilage defects, promotes further IGF-1 transcription, and has been shown to increase matrix synthesis in cartilage explants.
In a study measuring their effect in trauma-damaged cartilage, P188 reduced cell death at 1 week by up to 75 percent compared with untreated controls. IGF-1 reduced sGAG release up to 50 percent. However, in the high-impact group, the decrease in tissue stiffness observed at 24 hours worsened at 1 week, and neither treatment prevented this loss.
Dr. Athanasiou concluded, “P188 and IGF-1 stop further degeneration, which we were happy to see, but were not able to reverse the degeneration we saw in the impact.”
Outcomes were much the same for treatment with doxycycline, a member of the tetracycline family and a matrix metalloproteinase inhibitor. Applying doxycycline to tissue after impact did decrease sGAG release but not loss of tissue stiffness resulting from the initial mechanical insult. Also, no significant difference in sGAG release was seen in either dosage mode tested (continuous or alternating weeks), which Dr. Athanasiou said means that the first week after impact offers a therapeutic “window.”
“We need to identify a second window, a second series of treatments so that we can reverse the degeneration to baseline values,” Dr. Athanasiou said.
Because the tested agents halted but did not reverse tissue degeneration, “additional ameliorative, reparative, or regenerative agents should be considered to reverse detrimental effects of loads,” he said. A “single chondrocyte approach” might be worthwhile to elucidate a more fundamental pathway of response to mechanical insults, he concluded.
Of mice and synovium
Dr. Olson and his colleagues are studying the problem by creating a tibial plateau fracture in the knee of a mouse without requiring a surgical exposure. The original focus of the work emphasized the events immediately after fracture in the injured joint that lead to arthritis. Using the C57/BL6 strain of mice, the investigators impose an injury that leads to a displaced articular fracture that results in arthritic changes throughout the joint. Early findings suggest that a time-dependant sequence of events is triggered by the articular injury.
Recently, they applied the model to the so-called super healer mouse (MRL/MpJ) (Fig. 2). In this strain, arthritic changes did not develop after the fracture. As a result, researchers are attempting to understand how mechanisms differ in the C57/BL6 and the MRL/MpJ strains.
Preliminary work indicates that both strains have a similar initial response but a markedly different synovial response following fracture. Although the inflammatory response is similar—with an increase in interleukin (IL)-1β production locally in the joint, and IL1-β production systemically—following fracture, the inflammatory response, particularly in the synovium, is more robust and sustained in the C57/BL6 mouse.
Dr. Olson said that the potential role of the synovium following an articular injury has not been explored in-depth previously. He and his colleagues have developed the concept of “an articular fracture as an organ level injury” as an outgrowth of this line of research. The idea that the injury may modulate the synovial response, which in turn alters the local environment and potentially the local cartilage response, is “intriguing,” he said. A better understanding of these mechanisms may lead to “new opportunities for intervention strategies for our patients,” he concluded.
Shifting the paradigm
Offering the “bedside” perspective of a practicing orthopaedic surgeon, Douglas R. Dirschl, MD, called for “a paradigm shift in clinicians’ minds in how they approach joint injuries.” He observed that following basic tenets of fracture surgery can lead to a dogmatic approach.
“One of the most closely guarded of those tenets,” he said, “is that the objective of treatment is precise reconstruction of the articular surface and stable fixation. But what constitutes an anatomic reduction has changed over time. For the tibial plateau, for example, appropriate reduction has gone from 8 mm to 6 mm to less than 2 mm today. It seems to me that the adequacy of articular reduction more closely parallels the surgeon’s ability to achieve it than it does any strong outcomes data.”
Another tenet, he said, is that patient outcome will vary directly with the accuracy of the articular reduction, even though clinical experience doesn’t support this.
Dr. Dirschl urged physicians to recast their thinking about joint fracture healing. “A patient’s physiologic response to injury is clearly a strong component. Clinicians need to recognize that reduction of articular stepoff and articular cartilage injury, the body’s response to it, and something I’ll call factors other than articular reduction all have effects on functional outcome following articular fractures. Articular reduction alone is not the most important factor.”
He pointed to contrasting cases such as a patient with excellent radiographic restoration and poor functional outcomes and another patient with excellent mobility and function but poor radiographic results. “We need to treat patients, not X-rays,” he said.
Staying aware of current research about fracture healing is critical to improving outcomes. “Clinicians must begin to behave in ways that show their understanding of the existence of other factors. Otherwise, they may be slowing the progress of good research coming to the bedside.”
Disclosure information: Dr. Athanasiou—Synthes; Dr. Brown—AO, DePuy, EBI, Medtronic, National Institutes of Health, Sawbones/Pacific Research Laboratories, Smith & Nephew; Dr. Dirschl—Biomet, Stryker, Zimmer; Dr. Olson—Synthes.
Terry Stanton is senior science writer for AAOS Now. He can be reached at email@example.com
- Posttraumatic OA represents about 15 percent of all OA cases.
- Computational scanning can assist in reassembly of fracture fragments.
- Over time, low-impact and high-impact cartilage injuries demonstrate similar tissue degeneration levels.
- In vivo studies indicate that therapeutic agents P188, IGF-1, and doxycycline may prevent further degeneration but do not reverse it.
- Restoration of normal anatomy does not necessarily represent good functional outcome.