A new model for the pathogenesis of osteoarthritis, based on detailed studies of joint microvasculature, suggests that this disorder has its pathogenic roots in the same vascular disease processes that lead to coronary atherosclerosis and myocardial infarction.

The emerging picture implies that these extremely common chronic diseases may be far more closely related than conventional medical thinking has previously recognized.

Histologic analysis of joint tissue obtained from osteoarthritis (OA) patients suggests that the primary driver of this disease is a propensity to form clots and lipid aggregations in the venules and, to a lesser extent, the arterioles supplying the joints. The blockages, in turn, create pressure in the joint spaces. This ultimately leads to leakage of fluid into the surrounding extravascular spaces, release of inflammatory mediators, and eventually, erosion of the chondral surfaces and necrosis of the underlying bone.

In a sense, one could think of OA as “coronary artery disease of the joints,” and it is interesting to note that epidemiologically, there’s a strong overlap between arthritis and coronary atherosclerosis. This is due to far more than simply aging, said Philip Cheras, PhD, deputy director of the Austrialian Center for Complementary Medicine Education and Research, Brisbane.

For the better part of the last 20 years, Dr. Cheras has been studying the microvasculature of femoral heads obtained from OA patients undergoing hip replacement. What began as a doctoral thesis project could radically change the way clinicians view and treat OA.

“These findings are giving us a whole new perspective on the causes of OA, and it opens up a bunch of new possibilities for early diagnostic tools to detect pre-clinical changes as well as a direction for better, more comprehensive approaches to treatment,” said Dr. Cheras, who described this new model of OA at a press conference in New York late last year.

Common But Misunderstood

OA is the leading cause of musculoskeletal disability across all continents, and all developed nations. It is the most common chronic disease, claiming more sufferers than cardiovascular disease, hypertension and diabetes combined. Though it does not kill people, it exacts a frightening toll in morbidity and medical expenditure. Currently, about 21 million Americans have OA, and this number is expected to double in the next 14 years. According to recent figures from the Centers for Disease Control, the annual price tag for medications, surgeries, office visits, disability, and lost productivity was about $128 billion in 2003, the last year for which we have data. The number is expected to rise in proportion to the age and weight of the population. The trends in Australia and most other industrialized nations are very similar, said Dr. Cheras.

He believes that medicine’s narrow organ-system focus—the tendency to view the pathogenesis of a disorder only through the relatively narrow window of the physiology of the affected organ—has prevented physicians from understanding the broader systemic processes that lead to a disease like OA. It also results in inadequate and sometimes misguided treatment, in this case, over-reliance on anti-inflammatory drugs to manage a disorder that reflects far more than just inflammation.

While short-term use of anti-inflammatories to reduce symptoms makes sense in many cases, long term use of these drugs, especially COX-2 inhibitors, may actually worsen OA because it has the potential to amplify a patient’s predisposition to form clots, a tendency Dr. Cheras believes is part of the core pathology in OA.

Lots of Clots

As early as the late 1940s, researchers like F. A. Chandler had suggested that osteonecrosis may be related to vascular problems. Chandler went so far as to call osteonecrosis “coronary disease of the hip.” This was clearly a fringe view for the ensuing 50 years. But Dr. Cheras said the idea always made sense to him in light of the histological, biochemical and clinical findings in OA.

There has never been a pathogenic model in conventional medicine to adequately explain the root causes of OA. This was particularly troubling to Dr. Cheras, given how commonplace this disease has become, and the huge burden of suffering it brings about.

Suspecting that Chandler may have been on to something, and that the synovitis, edema and inflammation characterizing OA might have something to do with the microvasculature, Dr. Cheras began “slicing and dicing tiny cubes of bone” from arthritic femoral heads. Using radiolabeled probes to detect various biomarkers, he found that the OA tissue samples showed very characteristic and consistent patterns of clots in the venules and to a lesser extent the arterioles.

He also found fat droplets blocking the tiny vessels of the joint tissues (Cheras P. Osteoarth Cartilage. 1999; 1: 219–252). This corroborated an earlier hypothesis by Dr. John Paul Jones, Jr., suggesting that lipid blockage of the vessels supplying the bones was a major contributing cause of osteonecrosis.

Areas surrounding the blocked vessels in Dr. Cheras’ samples showed all the signs of oxygen starvation. Microvascular blockage ultimately leads to progressive necrosis of the cartilage, bone and even bone marrow. “In the areas adjacent to these focal regions of dead bone, we find both bone resorption and bone formation side by side. Osteoclasts and osteoblasts are both highly active.”

Too Much Pressure

Blockage of the venules also creates back-pressure. The vessel walls become extremely leaky, meaning that fluid passes out of the vessels and into the joint spaces. This is responsible for much of the initial symptom burden.

Danish researcher Dr. Carl Arnoldi has shown that if pressure within a joint space exceeds 30 mmHg, an individual will experience pain. The normal pressure within a healthy joint is around 26 mmHg. In OA, the pressures within the joints can easily get up over 45 mmHg, said Dr. Cheras. Inside the bone, pressure can be as high as 60 mmHg; hence the advent of procedures to drill holes in osteonecrotic bones, to relieve the pressure. But this does nothing to resolve the fundamental problem.

In addition to the extravasation of fluid into the capsular spaces (aka, edema), pressure build-up within blocked vessels pushes inflammatory mediators out into the joint spaces. “This induces inflammation, and triggers white blood cells to release degradative enzymes that erode cartilage and the degrade the synovial fluid.”

In osteoarthritic femoral heads, synovial fluid can also reach the bone marrow to which it is poisonous. This, combined with low oxygen levels, results in the commonly observed necrotic bone marrow in samples obtained from OA patients.

Among his many experiments, Dr. Cheras has infused OA patients with radiolabeled fibrinogen, “so we could follow where it went. It leaks out of the blood vessels, where it is highly inflammatory and also promotes further clotting. It helps us localize the sites of blood clots.”

Early Diagnostic Signals

If OA has a vascular etiology, reasoned Dr. Cheras, there must be markers in the circulation that could potentially be used as early diagnostic signals in much the same way that physicians can predict cardiovascular risk from blood profiles. The second phase of his research has been focused on an extensive analysis of the blood of people with OA.

Compared with non-OA individuals, people with the disease tend to have increased triglycerides, increased LDL, increased platelet aggregability, increased blood viscosity (visit www.holisticprimarycare.net and see, “In the Thick of It: Blood Viscosity Emerges as Key Heart Risk Factor,” Spring 2007), and increased levels of two very specific markers of clot-formation: fibrinopeptide A, which is an indicator of impending clot formation, and d-dimer, which is only produced when clotting is in process.

OA patients also show decreased ability to lyse clots; euglobulin clot lysis times are substantially prolonged compared with non-OA patients. “People with OA have a markedly increased tendency to form clots, but reduced ability to clear them.”

The blood of OA patients also carries a substantially increased load of inflammatory mediators and markers, including interleukin-1, tumor necrosis factor-α, c-reactive protein (CRP) and increased numbers of peripheral blood monocytes.

Interestingly, Hulman and colleagues at Guy’s Hospital, London, showed that mildly increased levels of CRP are strongly associated with formation of triglyceride “clumps,” and formation of lipid droplets that look much like those found in the vasculature of OA joints.

Earlier detection of patients at risk for OA is possible using standard blood measures, contends Dr. Cheras. It is a matter of understanding that many of the indicators of cardiovascular disease are also signals for emerging OA. “We can and should be detecting people at the earliest stages, before the disease gets a hold in the joints.”

Treating a Web of Pathology

Dr. Cheras’ work should provoke a thorough re-thinking of how physicians treat patients with OA. The main point is that OA reflects “a web of pathology. The pain, synovitis, inflammation, cartilage breakdown and bone necrosis that patients experience reflect a confluence of coagulation and inflammation. They are inter-related. It is na?ve to think that simple anti-inflammatory agents alone will solve the problem.”

If OA does, as Dr. Cheras contends, have a vascular etiology, the long-term use of COX-2 inhibitors will only worsen the problem over time. “The old school NSAIDs tend to maintain hemostasis because they inhibit both pro- and anti-thrombotic activity. The COX-2 inhibitors mainly inhibit the latter, so they tip the balance toward a pro-clotting tendency. They can actually add to the risk already present in these patients because you’re giving someone who’s already got a predisposition to clotting something that has the potential to augment this predisposition.”

He believes effective treatment of OA must be multifaceted. “You need anti-inflammatory therapies, to be sure, but you are also likely to need lipolytic activity, fibrinolytic activity, and anti-coagulant activity.” Putting it in more positive terms, an ideal protocol for OA should increase blood flow to the joints, reduce inflammation, down-regulate the patient’s tendency toward coagulation, and minimize formation of lipid globules. This represents a huge opportunity for non-pharmaceutical holistic approaches.

Dr. Cheras noted that at the 2005 meeting of the Osteoarthritis Research Society International (OARSI), leaders in the field expressed an urgent need for complementary anti-arthritic therapies that are clinically proven safe and effective. “In light of the COX-2 withdrawal and warnings about adverse effects associated with NSAIDs, it would be prudent, both medically and legally, to focus on evidence-based complementary medicines as first line therapies,” Dr. Cheras said. He added that, “normalization of hemostasis should be one of the key objectives of OA treatment.”

Tou-Shea!

To this end, Dr. Cheras and his colleagues at the ACCMER are engaged in a study of a standardized extract from the nut of the shea tree (Butyrospermum parkii), which grows in West Africa. Shea “butter,” the thick semi-solid, triterpene-rich substance pressed from shea nuts has long been used both topically and orally in Africa as a remedy for many types of skin disorders as well as aches and pains.

It turns out that shea butter contains compounds that can also down-regulate several key inflammatory mediators including NF-kappa-β, TNF-α, and IL-6. But shea also has the added benefit of modulating lipid profiles as well. Shea butter is non-toxic, and when taken orally, shea triterpenes can reduce total cholesterol as well as LDL, and can shift the LDL: HDL ratio to a much more favorable profile. In light of the vascular model of OA pathogenesis, shea extract could potentially be an important new therapy.

Dr. Cheras is studying a standardized shea triterpene extract developed by BSP Pharma, Inc., a Danish nutraceutical company. “They’ve basically taken all of the fat out of the shea butter but left the triterpenes.” He and his colleagues are enrolling 100 OA patients from the greater Brisbane area. They will be randomized to treatment with either the BSP Pharma extract, at a dose of 2.25 grams per day or placebo.

Primary outcome measures will include changes in WOMAC scores (the standard measurement scale in arthritis trials), as well as changes on the more sensitive Comprehensive Osteoarthritis Test (COAT); impact on quality of life will be assessed using the standard SF36. The investigators will also gather an exhaustive list of biomarkers of hemostasis, renal function, liver function, inflammation, cartilage synthesis and breakdown, bone formation and degradation, coagulability and fibrinolysis.

The goal is to amass as much information as possible about the vascular aspects of OA as well as to determine the therapeutic value of the shea extract, which was recently introduced into the US nutraceutical market as a product called FlexNow® (visit www.flexnow.us for more information).

Anecdotally, the clinical experience with this product thus far suggests that, “a significant proportion of the people who take it can expect to experience major relief,” said Dr. Cheras. While clearly not a “cure” for OA, FlexNow has the potential to improve life, on both a subjective and objective basis, for many people with OA. One major aspect of the Queensland study is to tease out the biochemical mechanisms by which it confers these benefits.

Dr. Cheras, who has no financial ties to the company, said BSP’s approach in bringing this product to market “is a model for responsible development in complementary medicine.” It is also a model for sustainable and ecologically responsible natural products manufacturing. BSP obtains its raw shea butter from nuts harvested in the wild in areas of West Africa where the trees have been growing for hundreds, if not thousands of years.

Given the complex web of factors that underlie OA, no one treatment—natural or synthetic—will likely be the answer. Management of the disorder requires a multimodal approach that includes lifestyle modification. Moderate exercise is a key facet, as is weight loss for those who need it.

Other natural therapeutics like glucosamine/chondroitin certainly have a role to play, and Dr. Cheras noted that these work through similar, though not identical mechanisms compared with the shea extract. They may in fact be quite synergistic, and the addition of FlexNow may improve outcomes for patients who have had relatively little benefit from glucosamine and chondroitin alone.

He also sees a role for other natural therapies like omega-3 fatty acids and plant based anti-inflammatories such as those derived from ginger and turmeric. “We’ve got a range of things to choose from. So choose what’s got the best evidence base. And actually, if you look at the evidence base for COX-2 inhibitors in arthritis, it is pretty weak, beyond immediate pain relief.”

If coronary artery disease and osteoarthritis share a common pathogenic root then the good news is that a comprehensive holistic treatment strategy aimed at reducing the risk of one should have benefits for the other, said Dr. Cheras. If you’re preventing or reversing vascular blockage in the joints, odds are good you’re also attenuating the tendency to form atherosclerotic plaques in the coronary arteries.
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