From the early '80s appearances of Kaposi's sarcoma to current battles with lipodystrophy, the history of HIV disease has been one in which patients—and their physicians—have had to confront a series of uncommon diseases. Now another complication has been added to the mix: the disabling bone disease osteonecrosis.

steonecrosis, or bone death, is a form of avascular necrosis. It occurs when blood flow to a certain bone is blocked or reduced due to damage to or the narrowing of blood vessels. Without this blood flow, the bone dies and ultimately collapses. (Many physicians use the phrase avascular necrosis, or AVN, interchangeably for the more specific osteonecrosis. AVN refers to the death of any part of the body caused by lack of blood flow.)

Michael, a 46-year-old man who lives in New York City, knows about this disease all too well. HIV-positive since at least 1984, Michael, who has been on highly active antiretroviral treatment, always thought of himself as a healthy person with HIV. But all that changed in January 1999. "I was having this pain in my legs," he recalls, "and the pain just kept getting worse. Soon, every time I went up or down stairs it would hurt. So I finally went to the doctor."

After a referral to an orthopedist, Michael learned he had osteonecrosis in both hips and in both shoulders. "I left the doctor's office and just sat in my car and cried," he says. "Then I went home and got on the Internet to learn what this was, because I'd never heard of anyone who had it."

Reports of osteonecrosis in people with HIV have been trickling out over the past few years. The disease caught the attention of physicians at the National Institutes of Health in May 1999, when two men with HIV disease were diagnosed with osteonecrosis of the hip just days apart.

"These men came in with groin pain, and we weren't initially sure what it was," recalls Joseph Kovacs, MD, an HIV specialist at the NIH hospital's Critical Care Medicine Department. "The symptoms can sound like a pulled muscle, but it's a pull that doesn't get better. And when it didn't get better, we did further tests, including magnetic resonance imaging, and in each of the cases the men had AVN."

Those two patients were the catalysts for the NIH to initiate a study on the prevalence of osteonecrosis in people with HIV disease. Using magnetic resonance imaging, which can detect chemical changes in bone marrow and find osteonecrosis at its earliest stages, researchers found that 15 of the 339 people with HIV in the study had the bone lesions seen in osteonecrosis in one or both hips. Since none of the patients had pain yet, this was a surprise to them—and to their doctors.

The NIH reported the results of its study in September. Three months earlier researchers at the University of California, San Francisco, reported that they had seen 11 people who were using protease inhibitors who had developed osteonecrosis. That one-two punch left HIV specialists scrambling to learn more about a disease few physicians ever encounter.

Pat Dalton, MD, an internist specializing in HIV in New York City, has 350 patients and has seen four with osteonecrosis since 1997. "When the first patient came in complaining of hip pain, I was shocked to find that he had AVN because you don't see this very often in any population," he says. "Also, neither he nor the other patients had any of the factors typically associated with osteonecrosis."

Until now the disease has typically been seen in people who used corticosteroids for extended periods of time to treat inflammation caused by illnesses such as lupus and rheumatoid arthritis. Other factors linked to the 10,000 to 20,000 cases of osteonecrosis that develop in the United States each year include bone injury, alcoholism, infection, and scuba diving. Although they may have different root causes, each of these factors can contribute to the decreased bone blood supply that leads to osteonecrosis.

No one knows yet, though, what is causing the disease to develop in people with HIV or why it is happening now. "Part of this is that if you aren't looking for it, you don't see it," says Galen Joe, MD, a senior staff fellow at the NIH who specializes in rehabilitative medicine. "It's possible that people with HIV were diagnosed with this but that it was attributed to other factors such as trauma, steroid exposure, or alcohol use."

Given that certain antiretroviral drugs have been associated with an array of metabolic abnormalities, it would be easy to assume that these cases of osteonecrosis are linked to the use of anti-HIV regimens. According to Guy Paiement, MD, the associate professor of orthopedic surgery who conducted the study at UCSF, the fact that protease inhibitors increase levels of fat in the circulatory system could contribute to osteonecrosis, since these fat molecules could decrease blood flow to bone tissue.

Researchers at the NIH, however, are quick to emphasize that any such cause-and-effect relationship has not yet been proved. "We looked at a number of factors, but one factor that did not come out was specific antiviral regimens," says Kovacs. "The problem for us to be able to identify that as a risk factor is that 90% of the patients in the study from 1996 on were on HAART regimens containing protease inhibitors. Our impression is that something is different now than it was five, six, or seven years ago, and certainly a good candidate would be the drugs, given the metabolic effect that we know they have in other situations and other metabolic abnormalities. But in our study we couldn't identify that."

The NIH study did find use of corticosteroids, weight training, bodybuilding, and having taken testosterone as risk factors for the development of the disease. But that does not mean people with HIV should kiss their gym memberships good-bye.

"All that we can say is that there is an association between those things," says Kovacs. "Whether it is a direct cause and effect, we can't determine because the numbers in our study are just too small. Maybe it's that people who tend to weight-lift might be those using testosterone, for example, but we just can't answer that based on this study."

Joe believes weight lifting is not a cause of osteonecrosis but may be a contributing factor to the progression of the disease. "Once the AVN has occurred for whatever reason and bone-cell death has taken place, then activities that cause increased forces through the hip joint may be confounding factors."

The hip area tends to be the first place on the body that osteonecrosis develops, although it can also occur in a shoulder, knee, or hand. "Because of the way we're wired," Joe explains, "the hip is an area where vascular compromise can more easily occur because of how blood vessels feed the femoral head." In most parts of the body, there is more than one way blood gets to the bone, Joe notes. But in the anterior portion of the femoral head—the inner side of the top of the hip bone— the blood supply comes in from only one area.

In January 2000 researchers reported that people with HIV were developing osteoporosis as a side effect of treatments for HIV. But while they are both bone problems, osteoporosis and osteonecrosis should not be confused. Bone continually breaks down and rebuilds; osteoporosis, a condition where bones become weak, brittle, and break easily, occurs when the cells do not rebuild as fast as they break down. In contrast, osteonecrosis is a condition where this rebuilding process comes to a halt because blood cannot get to the bone.

"We need that nutrient blood flow to help with the constant bone turnover we have," explains Joe. "Without the blood flow, the cells die, and the complete bone remodeling process doesn't take place, and all that you have is debris and dead bone cells."

Once bone death occurs, the bone is predisposed to further injury. "We've been advising patients who have AVN that they might want to avoid activities that will increase compressive forces through the hip joint like some weight lifting, squats, or carrying heavy weight on their shoulders as well as running on concrete," Joe says, "because that may put them more at risk for advancing the disease, even though there is nothing proved in the literature to show that will help slow the progression."

In fact, according to Kovacs, there are no treatments that indicate that once osteonecrosis is seen on an MRI scan, there is anything that can be done to halt the disease—whether a person is HIV-positive or not. Core-decompression surgery, which removes the inner layer of bone and thereby helps to increase blood flow and allow more blood vessels to form, may reduce pain and slow the progression of osteonecrosis—if the disease is found early on—but it cannot stop it. And once the disease has progressed, hip-replacement surgery is the only method of alleviating the pain.

Despite his own ever-increasing pain, Michael held off having surgery. "Then one morning," he recalls, "I went to get out of bed, and I just couldn't walk." At that point, surgery followed by six weeks of physical therapy was his only option. Because Michael found the recuperation so difficult, he intends to wait as long as possible before having the other hip replaced. "It's been more than a year since the surgery, and I can walk and I have no pain, but it's not the same," he says. "My hip feels odd. It feels heavy. It just doesn't feel like it's mine."

Although physicians now know that people with HIV disease appear to be at increased risk for osteonecrosis, what individuals should do if an MRI scan does show early signs of the disease is not yet clear. "There are still many questions that we don't yet know the answers to," says Kovacs. "Number 1 is, What's the natural history of having these lesions?"

Answering that question will give physicians the information they need to tell patients the best way to manage the disease. It is possible, for example, that some of the smaller lesions seen on MRI scans may not progress at all. To see if that is the case, Kovacs is continuing to follow patients who were identified as having osteonecrosis but did not have symptoms.

No one, however, is suggesting that all people with HIV go out and get bone scans. For now, physicians say, vigilance is best. "If someone has HIV or any disease known to be associated with AVN and has been on protease inhibitors or medications with known links to AVN and develops pain in the hip joint or groin area that occasionally radiates down to the knee, has stiffness in the hip area, or experiences less range of motion, then that warrants a good comprehensive physical exam," says Joe. "Individuals should also be examined if they have transient symptoms like stiffness in the hip upon awakening in the morning, mild limits in range of motion, or occasional aching after long periods of standing or walking."

Dalton says his experience has not changed how he manages his patient care. "It's not very common, and there is nothing you can really do about it," he says. "If someone comes in with severe pain, though, I can guess they have AVN."

Dalton has noticed, however, that increased information about osteonecrosis and HIV has been comforting to patients diagnosed with the disease. "One of my patients had one hip replaced and then needed to have the other one done, and he felt like he was from another planet," says Dalton. "He kept questioning why he got this. But this research finally has confirmed that, yes, this is something that is out there and happening to people who have HIV."