Doxy

An Interview with Dr. Kenneth Brandt

The most common form of arthritis, osteoarthritis is muscling in on Americans. While the condition generally affects older people, dedicated athletes in the prime of life are also sidelined by the degenerative joint disease.

Osteoarthritis (OA) typically affects the cartilage, the slippery tissue that covers the ends of bones in a joint. While healthy cartilage allows bones to gently glide over one another and absorb the shock of physical movement, over time OA may break down and wear away the surface layer of cartilage, allowing bones under the cartilage to rub together, causing pain, swelling, and loss of motion of the joint.

Treatments targeting the pain and stiffness of OA coupled with regular physical activity play a key role in self-care and wellness.

Recently, researchers discovered that a common antibiotic helped slow the progression of osteoarthritis. To find out more about this exciting breakthrough, the Post spoke with the principal investigator of the study, Dr. Kenneth Brandt, professor of medicine and orthopedic surgery at Indiana University School of Medicine.

Post: Could you tell Post readers about your recent study of a common antibiotic and its therapeutic potential in osteoarthritis?

Brandt: Osteoarthritis is the most common joint disease of mankind. It is estimated that there are about 25 million people with arthritis in the United States, most of whom have osteoarthritis. Because age is the most powerful risk factor for OA, given the increasing proportion of our citizens over the age of 65, OA will become an increasingly larger problem in the coming decades.

Knee osteoarthritis, in particular. is the major cause of chronic disability in people over 65. Huge social and economic costs are involved.

Until now, treatment of OA has focused largely on relieving joint pain. No one has shown that any drug changed the progression of joint damage in OA.

Our study was aimed principally at slowing damage to the tissues in the osteoarthritic joint particularly to the cartilage, which is the main tissue in the joint affected by OA. Joint cartilage is the extremely smooth weight-bearing surface that covers the ends of the bones in our joints and permits nearly frictionless movement.

We began our work with test tube experiments that weren't, in fact, aimed at OA, but attempted to provide a better understanding of how some of the molecular components in joint cartilage were metabolized in normal joints. That research led us to discover an enzyme called gelatinase that played a role in the turnover of the articular cartilage. In our initial studies, we tried to see if we could inhibit the activity of that enzyme with doxycycline.

Post: Why focus on doxycycline?

Brandt: The reason for using doxycycline dated back to a paper I had read in the dental literature a decade earlier, published by Dr. Golub in New York. He showed that gum disease in diabetes was not merely due to bacteria or poor oral hygiene, but to an enzyme--the same enzyme produced by cells in the inflamed gums that broke down the tissues. The researchers showed that the enzyme could be inhibited by doxycycline.

That was a very nice piece of research that lay in the back of my mind until we began this cartilage research.

It is important to point out that the fact doxycycline worked in OA does not suggest that OA is an infectious disease. Antibiotics, in general, do not inhibit the enzyme. Doxycycline works by virtue of its unique structure and action to inhibit some of the enzymes that soften and break down joint cartilage.

Many of these enzymes are produced by the cartilage cells, so in a sense the tissue is destroying itself. There is an element of inflammation in OA, and the enzymes may also be produced by the joint lining. That is a less important source, because inhibitors exist in our joints that can neutralize the enzymes that come from the lining. The enzymes that really do damage to the cartilage in OA are, to a large extent, produced by the cartilage cells themselves. Doxy inhibits those cells. Other antibiotics don't.

Post: What led to the trials?

Brandt: Our research team had a series of encouraging findings in preclinical studies that were confirmed by other labs in a variety of models. That led us to seek support for this clinical trial in people, and our research proposal was funded by the NIH.

Post: Could you discuss the study?

Brandt: The six-center study was geographically distributed across the states. We recruited 431 subjects, all of whom were women between the ages of 45-64, in the upper third of the population for body weight.

Each also had a conventional x-ray of the knees that showed definite OA in one knee, and a normal-appearing opposite knee.

We selected that special population--all female, overweight, and of a certain age--because a recent study had shown that over the next two years, the knee that is normal at the start will develop changes of OA in 50 percent of cases. We thought this is wonderful because we can, for the same price, look at the effects of treatment--doxy or placebo--on the progression of OA damage in the knee in which the disease is already present when we start treatment. At the same time. we can see whether doxy affects development of OA in the other knee, which was normal at the start. That was the premise. In fact, however, after we started the trial, we showed that the knee that appeared normal on x-ray at the outset already had early changes of OA. We published those findings after the doxy trial.

Post: What did the study show?

Brandt: The study showed that doxycycline slowed cartilage loss by about 30 percent. We measured cartilage thickness, with the assistance of a fluoroscope to highly standardize the position of the knee on each exam.

If you were to go to your hospital ER to get an x-ray of your knee on Monday, Tuesday, Wednesday, and Thursday, and measured the space between the bones as an indication of how much cartilage you have, the difference might be as great as 25 percent because of the difficulty of assuring the same position for each exam. The cartilage is not changing; the x-ray is changing.

We used the highly standardized x-ray method in all six of our clinical centers; the subject's knee was positioned with a fluoroscope for each exam, providing a very reproducible picture on each exam over the 30-month duration of the study.

After 30 months of treatment, we ended up with 70 percent of all patients who were enrolled still taking medication. We obtained follow-up x-rays at the end of the study on 85 percent of everyone who had been enrolled. And we had about 90 percent adherence to the dosing regimen--people took their medicines as prescribed.

That is the real success in this study. Up to this point, the general notion in academia and in the pharmaceutical industry was that because the rate of advance of cartilage damage in OA is so slow and so variable, this type of study would take years and require thousands of patients.

Post: When did you begin to see a positive effect from doxycycline?

Brandt: We were able, in fact, to show the effect of doxy compared to placebo in as early as 16 months. The success we had with the conduct of the trial--keeping the patients invested in the study, getting them to return for x-rays and take medications as prescribed--is due to the superb nurse coordinators in each center.

This permitted us to show that doxy slowed the progression of cartilage damage in the involved knee by about 30 percent.

Post: How is OA diagnosed?

Brandt: OA patients are diagnosed on the basis of history and clinical evaluation. The pain of OA is typically aggravated by activity. For example, the pain in the OA knee gets worse with weight-bearing activity and is relieved by rest. In general, the diagnosis of OA is not difficult, even without an x-ray. An x-ray may be confirmatory, but the correlation between the severity of the x-ray and severity of symptoms is not great. Some people have severe OA pain with an x-ray that may be normal or nearly normal. Others have a terrible x-ray--no cartilage remaining with bone grinding on bone--but have no symptoms whatsoever.

Post: Was this the first large, multicenter trial to test the hypothesis of an antibiotic in osteoarthritis?

Brandt: Yes. But I would deemphasize the word "antibiotic." This is a class of drugs called disease-modifying, or structure-modifying, OA drugs (DMOAD), whose main action is not on symptoms but on slowing or preventing structural damage in the joint. It appears that our work has demonstrated that doxy has a DMOAD effect. It is fortuitous that doxy is an antibiotic. People should not take antibiotics indiscriminately for knee pain or OA. That would be a serious mistake. The effectiveness of doxy in inhibiting enzymes that damage cartilage has nothing to do with its antibiotic action. A different part of the molecule is responsible for that activity. I would hope that on the basis of this research, we will be able to design better molecules to inhibit those enzymes.

Indiscriminate use of doxy, however--with no follow-up of patients who are taking it on their own because the drug is so widely available and inexpensive--would concern me. We noted no serious side effects during our trial. Doxy has been around a long time and has a very good track record with respect to safety, but some people can experience sun sensitivtty, GI complaints, stomach upset, yeast infection, and other side effects, so people who take this drug should be followed by a physician. I regularly receive calls and e-mails from physicians and patients who are aware of the research and asking about it. If doxy treatment is undertaken, it should be done under the supervision of a physician. We are talking about a therapy that may need to be maintained indefinitely because once the medication is discontinued, the disease mechanisms are likely to resume.

Post: If you had to sum up the significance of the study, what would you say it is?

Brandt: First, we showed that studies of disease-modifying OA drugs are feasible in humans, meaning that they can be done relatively economically in a relatively short period of time with a relatively modest number of patients.

Second, we showed that with simple measures, like with an x-ray, albeit with a very rigorous standardized x-ray protocol, we could see an effect with doxy in as soon as 16 months. Perhaps it occurred sooner. Third, we showed something that really had not been properly demonstrated before and remained a question mark. It appeared there was clinical benefit to the slowing of cartilage damage. Subjects who experienced less cartilage loss experienced fewer increases in knee pain. Given the relatively low level of knee pain In our subjects at the start of the trial, we are not able to say whether doxy would have decreased the severity of knee pain in patients who had a higher level of pain. That question still needs to be addressed. Doxy is not a good general analgesic, however. One would not take it for a migraine or a fractured ankle. For OA pain, if doxycycline has an effect on the cartilage or on the synovial lining, by decreasing inflammation perhaps, will that reduce knee pain? That question remains unanswered.

Post: Independent of drug therapy, what lifestyle factors can individuals with OA take to reduce disability from the disease?

Brandt: You ask an extremely important question. The keystone of osteoarthritis management is based on nonpharmacological measures, such as educating the patient about how to protect the arthritic joint from stress and damage, proper footwear, weight reduction if the patient is obese, and use of thermal modalities (heat/ice).

Post: Obesity, of course, is epidemic and adds to the problem.

Brandt: Yes. There has been some reckoning in the United States that if we eliminated obesity in the U.S., we would eliminate one-third of knee OA in women and one-quarter of all knee OA in men. That's a tough job, though. We have better reasons than knee osteoarthritis to lose weight, such as death from cardiovascular disease. We need to respond to obesity, not merely as a social or cultural problem but also as a serious public-health issue.

STAGES IN OSTEOARTHRITIS

The process by which articular cartilage begins to break down may be genetically determined. Gradually this cartilage becomes thinner and roughened. When the bone underneath the cartilage eventually erodes, bone surfaces rub directly against one another, causing severe discomfort. However, joints may be painfully inflamed only occasionally; minor degrees are quite common, and can be treated. Only a few people have progressive joint damage.

Normal joint structure Healthy articular cartilage lubricated by synovial fluid allows ease of movement.

1 When articular chondrocytes (cartilage cells) die, surface cracks appear; this allows synovial fluid to leak in, causing greater cartilage degeneration. Pieces of this weakened cartilage break off, inflaming the synovial membrane.

2 Eventually, a gap developing in the cartilage reaches the underlying bone. Blood vessels begin to grow, and a plug made of fibrocartilage fills the gap.

3 The fibrocartilage plug wears away, thus exposing the bone surface. If surface cracks deepen, synovial fluid can leak into the marrow space, and may form a cyst surrounded by weakened bone. Small outgrowths called osteophytes may further deform the bone surface.

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