April 2012

OA summit examines therapeutic challenges

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Newly published proceedings of an inter­dis­ciplinary osteoarthritis summit hosted by the Hospital for Special Surgery ex­plore how researchers are working to under­stand the complexities of the disease and break down the barriers facing the development of new interventions.

By Cary Groner

In February, the Hospital for Special Surgery (HSS) in New York published the papers presented at its recent osteoarthritis summit; taken together they paint a portrait of a disease whose vexing complexities are gradually yielding to determined research.1 And although the articles make it clear that breakthrough preventive or therapeutic interventions may still be years away, they also clarify some of the reasons for this—which, better understood, may help lift those therapies over some of the existing scientific and regula­tory hurdles.

For its event, the International Arthritis Summit: Frontiers in Osteoarthritis Research, Prevention, and Care, the hospital brought together a multidisciplinary group of researchers and clinicians from several countries, as well as representatives from the US government and the pharmaceutical, device, and insurance industries. The breadth of interests represented was one of the most unusual aspects of the conference, according to its codirector, Steven Goldring, MD, chief scientific officer at HSS.

“In general, people who study bone go to the bone specialty meetings, and it’s the same for those who study cartilage, or inflammation,” Goldring told LER. “These disciplines of both clinical research and basic science get compartmentalized, and we wanted to remove those barriers by bringing these people together to communicate and exchange information.”

A complex disease

The reasons for this approach stem from the complicated nature of OA itself, Goldring said.

“As we’ve learned more about this disease, it’s now clear that all the components of the joint are adversely affected,” he explained. “It isn’t just about cartilage; the factors that contribute to both risk and progression are multifactorial and include biomechanical, inflammatory, and metabolic factors. Beyond that, there are public health implications; how do you impact outcomes in larger popula­tions in the context of our present healthcare system?”

The public health implications for an aging population are staggering, in fact. Roughly 27 million Americans have osteo­arthritis.2 The annual economic impact for all forms of arthritis, of which OA is the most common, is $128 billion ($81 billion in direct medical costs and $47 billion in lost income), and arthritis results in 992,000 hospitalizations and 44 million outpatient visits each year.3 Moreover, the only therapy that approaches a “cure”—total hip or knee replacement—is performed 770,000 times annually, at an annual cost expected to exceed $65 billion by 2015—and those numbers will only grow as the population ages.4

Asking the right questions

Summit presentations and the corresponding HSS Journal articles addressed issues such as criteria that might be used to develop a classification system for OA, including dichotomizing it to either spontaneous or induced osteoarthritis—the latter describing an acute joint injury rather than the long-term factors that may contribute to disease onset in older people.

One article, for example, examined the relationship between acute joint injury and post-traumatic arthritis (PTA). Researchers from Duke University reported that 12% of osteoarthritis occurs as a result of acute trauma such as intraarticular fractures.5 Their research suggested that inflammation was associated with PTA development, but they noted that no systemic or local pharmacologic interventions have been shown to decrease PTA incidence.

Other papers outlined the types of joint damage that may occur due to biomechanical and metabolic factors. For example, one delineated the risks of developing knee OA following meniscal removal or degradation; because the menisci transmit about half of the compressive load across the knee, the absence of a functioning meniscus drastically increases peak and average contact stresses in the medial compartment.6

Howard Hillstrom, PhD, director of the Leon Root Motion Analysis Laboratory at HSS, said that such findings have already influenced medical practice. For example, surgeons are much more cautious about performing meniscectomies than they used to be.

“The meniscus is really a critical structure that has to be preserved whenever possible, because it dissipates the stress that comes axially down the femur. Without it, you concentrate that stress in more central regions of the femoral-tibial joint, potentially damaging the cartilage matrix,” Hillstrom said.

Hillstrom is particularly interested in how knee mechanics may contribute to osteoarthritis.

“Because osteoarthritis patients often stand slightly flexed, and may have changes in their transverse plane coupling with sagittal plane motion, you can expect differences in sagittal moments between OA patients and healthy people,” he said.

And although the extent to which such factors contribute to osteoarthritis incidence or progression remains hard to quantify, Hillstrom’s research has determined that medial joint space and peak adduction angle may be useful for predicting pain in patients with medial knee osteoarthritis.7

“Those two variables—one structural, one functional—predict 73 percent of the variance in a model of pain,” Hillstrom said. “That’s just from a biomechanical perspective, and argues for improved strategies to offload those structures.”

Physics and chemistry

Hillstrom acknowledged that biomechanical forces are just one part of the picture.

“What is OA?” he asked. “It’s the biomechanical and biochem­ical destabilization of all the tissues in the diarthrodial joint. You can’t really tease apart the biomechanics and the biochemistry; they’re related. One contemporary theory is that the aberrant loading—whether from a high body mass index, or malalignment, or derangement of soft tissues—initiates a cascade of biochemical responses. You have enzymes chewing up the cartilage mix, bits and pieces of which end up floating in the synovial fluid. Inflammation swells the joint, and there are changes in the metabolism of the subchondral bone.”

Two exciting aspects of the research, Goldring said, have been the development of better imaging to document synovitis and tissue analysis that can help researchers learn more about the mechanisms in play.

“The potential is that we can take what we’ve learned in inflammatory or autoimmune arthritis and identify subsets of patients where some of the same strategies to target inflammation may be of benefit,” he said. “Ideally we want to target some of the upstream mechanisms that might drive the release of these factors that adversely affect the joint.”

One summit article clarified the current thinking that OA is a whole joint disease, noting that cartilage degeneration can be induced by altered mechanical loading of chondrocytes (cartilage cells), which in turn may initiate a destructive chemical cascade within the joint.8 Another outlined the destructive biomechanical effects of joint instability.9 Still another described the risk factors for cartilage loss, noting the roles of both biomechanical and inflammatory components.10

Eyeing interventions

It’s now clear that excessive joint loading—either cumulative or from an acute injury—causes progressive joint degeneration. In one paper, however, the authors reported that reactive oxygen species (ROS) released from mitochondria following excessive articular cartilage loading can cause chondrocyte death and matrix degeneration, and that associated fibronectin fragments may have the same effect.11 The clinical implications are apparent; if a way could be found to inhibit these molecular pathways, the cascade leading to OA might be ameliorated or aborted.

The author of that paper, Joseph Buckwalter, MD, chair of the Department of Orthopedics at the University of Iowa School of Medicine, emphasized that, like many tissues, the joints require some stress to stay healthy.

“A certain level of repetitive oxidative stress helps the cell tissues withstand forces; too much is damaging, but none would be damaging as well,” he explained. “We’re working toward a strategy of preventing the damage caused by that initial burst of oxygen free radicals. If we interrupt that, we may prevent the release of the fibronectin fragments; but we may also have to look at ways of counteracting their effects.”

Buckwalter and other scientists suspect that similar processes apply whether the insult is chronic or acute.

“In our research, we’ve studied acute injury because that has a definite starting point, then we use that to help us understand chronic overloading,” he said, adding that a few existing pharmaceuticals—oxygen free radical scavengers and a synthetic erythropoietin analog—could be used in clinical trials to test the theory.

A good drug is hard to find

Although the development of pharmaceutical interventions could conceivably revolutionize osteoarthritis treatment, halting disease progression and drastically reducing the need for total joint replacements, the summit made clear that the prospects for bringing new drugs to market aren’t promising, according to Steven Goldring.

“Despite this huge, unmet need, many of the large pharma­ceutical companies have basically closed down their OA research programs due to the costs of getting these drugs approved,” he said.

“One of the challenges is that osteoarthritis is really a syndrome,” he continued. “There are changes in the compositional, structural, and functional properties of the joint, but in any individual these mechanisms can be very different. The pharmaceutical industry wants a ‘one-fer’—one treatment for all patients at all stages of the disease—but given OA’s pathophysiology, that’s not a rational approach. People are recognizing that therapeutics need to be targeted to patient cohorts, and for that we need better biomarkers for identifying patients at specific stages.”

Goldring cited the example of rheumatoid arthritis, for which tumor necrosis factor (TNF) was discovered to be the master regulator. No such key yet exists for osteoarthritis, but there are tantalizing suspects.

“We’ve identified cytokines and mediators in the synovium that haven’t been optimal treatment targets in rheumatoid arthritis, but could hold promise in osteoarthritis,” he said. “A number of companies have compounds essentially sitting on the shelf—inhibitors of metalloproteinase, which degrades cartilage, and aggrecanase inhibitors—for which the animal data look great. But when you add up the costs and regulatory challenges of expanding those studies, the pharmaceutical industry has so far chosen not to move forward. It’s not really their fault, it’s not the fault of the FDA, it’s just kind of a perfect storm. We’re disheartened by that, but we feel that we’re on the threshold of great opportunity, and that eventually those barriers will be overcome.”

Risk and prevention

In the meantime, researchers and clinicians are pooling their understanding and experience to optimize existing treatment options. Even as scientists better understand the molecular composition of joint tissues, as well as OA disease pathways, clinicians are still seeking the best ways to translate this knowledge absent the advent of novel drugs.

“OA has been considered a natural process of aging, and we’re now rethinking that in a major way,” Goldring said. “We’re still very limited in our therapeutic interventions to restore normal physiologic joint function, and that’s pushed us to think about risk factors. What strategies could delay the onset of osteoarthritis? Prevention has emerged as a critically important piece of this.”

According to one paper presented at the summit, nonpharm­acologic approaches that could target lifestyle issues and improved metabolism consist largely of exercise and weight loss, but should also include adjunctive therapies such as bracing, taping, and thermal treatment. Pharmacologic care consists primarily of over-the-counter analgesics including NSAIDs (nonsteroidal anti­inflammatory drugs) and topical agents (e.g., capsaicin creams), as well as intra-articular therapies (glucocorticoids and hyaluro­nates), and for some patients, stronger painkillers such as tramadol.12

A study of exercise interventions in older knee OA patients, reported at the summit, showed low- to moderate-intensity exercise was safe and effective and slowed the decline in knee function, but did not affect disease progression. Weight loss was also associated with decreased pain and better function.13

In another paper gait modification was shown to be only moderately effective.14 In that case, effective learned modifications to reduce peak knee adduction moment included knee medialization and increased medial-lateral trunk sway. The most effective assisted modifications were lateral wedge insoles with subtalar strapping, variable stiffness shoes with a softer medial side, and bilateral hiking poles. The author noted, however, that gait modification can be hard to teach and sustain, that decreases in peak knee adduction moment don’t guarantee a drop in peak medial contact force, and that the measure should be reevaluated as a clinical target.

That author, Benjamin Fregly, PhD, is a professor of mechanical and aerospace engineering at the University of Florida who holds affiliate appointments in biomedical engineering, orthopedics, and rehabilitation. In his own research, he strives to find answers for OA knee pain because he experiences it personally; he also knows how challenging it can be to change people’s gait.

“I have medial compartment osteoarthritis in my knees,” Fregly said. “I designed this modified walking for myself and I swear by it. But we have tried to teach others to do it, and it can be really tricky.”

And although peak knee adduction moment is often the indicator people propose to indirectly measure medial contact forces, Fregly is among the growing number of researchers whose work suggests that it may be a suboptimal target. He has been collaborating with scientists at Scripps Institute in San Diego, who have fit patients with force-measuring knee replacements.

“That has allowed us to test some of our hypotheses for gait modifications that would unload the medial compartment while looking at this external indicator, knee adduction moment,” he said. “We’ve shown that you can really drive down adduction moment without having much effect on medial contact force. It’s clear that adduction moment doesn’t tell the whole story, and we need to figure out a better indicator.”

In the same vein, Howard Hillstrom said more high-quality randomized studies should be conducted to determine the potential roles of knee bracing, orthoses, and special shoes for OA management.

“Most of the studies that have been done are fairly small samples without randomization or controls,” he pointed out. “Another issue is that there are many different strategies—whether you align the knee directly with a brace that applies opposing moments, or indirectly with foot orthoses, or you combine orthoses and a brace.”

He noted, moreover, that there is difference of opinion about the most effective shoe interventions.

“One works by imposing greater flexibility; another via dual cushioning in the rearfoot. Another group has designed a shoe that is worn only for rehabilitation,” Hillstrom said.

Ideally, more advanced research of the type described by Fregly may eventually sort out which interventions are most likely to help.

Surgery

Of course, until new pharmaceutical treatments become available, failure of preventive measures coupled with significant disease progression will lead, for many patients, to joint replacement surgery. Fortunately, as a paper presented at the summit pointed out, this approach continues to offer significant pain relief and better function, and techniques and materials are still improving.15 For example, 35-year follow-up of cemented total hip replacements shows a survival rate of 78%; in younger patients, 25-year survival is 93% for the femoral component.

Newer designs using biologic fixation via bone ingrowth show particular promise. Researchers are still trying to improve bearing surfaces, however, which are the components most likely to fail.

Barring an unexpected pharmaceutical breakthrough, it appears that such surgeries will be performed for many years to come.

Cary Groner is a freelance writer based in the San Francisco Bay Area.

REFERENCES

1. Cornell CN, ed. Hospital for Special Surgery Journal 2012;8(1).

2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58(1):26-35.

3. Centers for Disease Control and Prevention. Arthritis. Available at: http://www.cdc.gov/arthritis/basics/general.htm. Accessed March 27,2012.

4. Kurtz SM, Ong KL, Schmier J, et al. Future clinical and economic impact of revision total hip and knee arthroplasty. J Bone Joint Surg Am 2007;89(suppl 3):144-151.

5. Olson SA, Furman B, Guilak F. Joint injury and post-traumatic arthritis. HSS J 2012;8(1):23-25.

6. Hunter D. Degeneration of the meniscus and progression of osteoarthritis. HSS J 2012;8(1):13-14.

7. Zifchock RA, Kirane Y, Hillstrom H. Are joint structure and function related to medial OA pain? Clin Orthop Relat Res 2011;469(10):2866-2873.

8. Poole AR. Osteoarthritis as a whole joint disease. HSS J 2012;8(1):4-6

9. Wright T. Biomechanical factors in osteoarthritis: the effects of joint instability. HSS J 2012;8(1):15-17.

10. Goldring MB. Articular cartilage degradation in osteoarthritis. HSS J 2012;8(1):7-9.

11. Buckwalter JA. The role of mechanical forces in the initiation and progression of osteoarthritis. HSS J 2012;8(1):37-38.

12. Hochberg MC. Osteoarthritis: The rheumatologist’s perspective. HSS J 2012;8(1):35-36.

13. Messier SP. Effects of exercise interventions in older adults with knee osteoarthritis. HSS J 2012;8(1):49-50.

14. Fregly BJ. Gait modification to treat knee osteoarthritis. HSS J 2012;8(1):45-48.

15. Callaghan J. Surgical approaches to OA therapy: osteotomy and arthroplasty. HSSJ 2012;8(1):51–3.

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