Background

Dan Hays, who was diagnosed with HIV in 1986, has not had the usual disease course. Dan has been living through a nightmare of bone failure and hip replacement surgery with a reluctant San Francisco HMO (Kaiser Permanente) and inexperienced doctors. Recent disturbing statistics and studies tell us that Dan's problems, hip bone death (avascular necrosis) and bone mineral loss (osteoporosis, osteopenia), are becoming more and more common in the HIV-infected community. The causes have yet to be determined. Currently, experts speculate that the problems could result from HIV's effect on the human endocrine system and/or the side effects of AIDS treatments.

Dan's complications began when he was diagnosed in February 1996 with Addison's disease, an adrenal gland condition that leads to reduced production of the steroid hormone cortisol. Addison's disease is one of the less common HIV complications; it is not known exactly how HIV causes Addison's. Dan was treated with a common therapy – 30 mg hydrocortisone per day. By the summer of 1997 Dan was having severe groin pain, both stationary and moving from side to side. "I saw several doctors at an HMO who refused to believe that it was avascular necrosis," he said. After five months of Dan's being crippled and in excruciating pain, the HMO agreed to a simple MRI scan. It was then obvious that Dan's right hip bone had died.

The HMO agreed to replace the hip through surgery, but when Dan awoke after the operation, he was told that the surgeons had replaced only the outer bone head and not the cup or joint section where the leg connects. "They did this to save money," Dan remarked. After the operation, Dan remained in severe pain. He sought a second opinion and was able to have the surgery redone in April 1998. The second time, the surgeon evidently did not place the new hip properly, and eventually it became dislocated.

He is now awaiting his third hip replacement surgery and has quit Kaiser Permanente for Medicare. "Most of the bone specialists that I have seen have had no experience with HIV and related bone problems," Dan said. It is almost unbelievable that doctors could have been treating Dan with hydrocortisone and not suspected avascular necrosis. The medical literature often mentions it as a potential side effect of therapy with anti-inflammatory steroids like hydrocortisone. Still, the doses used for cortisol replacement therapy, such as Dan was receiving, are not usually associated with bone loss or death per se.

Had Dan been a patient at San Francisco General Hospital (SFGH), the city's public hospital, he might have had a faster diagnosis and surgery. Doctors at General said that they have seen two types of bone problems emerge in people with HIV over the years: bone mineral loss and avascular necrosis. Guy Paiement, SFGH's Chief of Orthopedic Surgery, said that he has replaced about 50 hips in HIV patients during the past eight years. The pace has increased rapidly in the last two years, with Paiement performing 20 hip replacements. Paiement said that most of the hips he replaced were probably damaged from previous drug treatment with steroids.

The prevailing wisdom is that hip failures in persons with HIV are related to previous steroid use, and most studies propose this cause. But two reports, indicate that there may be other causes, such as abnormally high triglycerides and/or HAART (highly active antiretroviral therapy). Another report was a chart review of some 600 HIV patients, with eight found to have avascular necrosis. This study found no possible common risk factor other than protease inhibitor treatment and PI-induced lipodystrophy. Protease inhibitor or HAART therapy might explain the recent increase in hip replacements that Paiement has witnessed in the past two years. Like lipodystrophy, bone necrosis existed before HIV treatments, and both seem more common, not less, with HAART.

Loss of Bone Mineral Density

Another recently published study has profound and disturbing implications for long-term use of protease inhibitor-containing treatments. This study, by Pablo Tebas of Washington University, followed 60 male patients with HIV who were receiving a protease inhibitor. It compared them to 35 male HIV-positive patients on non-PI regimens and also to 17 HIV-negative male controls.

HIV-positive men receiving protease inhibitors were twice as likely to develop bone loss. Tebas and his team found that the PI-receiving group had an astounding 50% rate of low bone mineral density (osteopenia or osteoporosis, depending on the degree of loss). More than one-fifth (21%) were classified as having "severe osteoporosis." In the non-PI group, the overall rate of low bone density was 23%, with 11% having severe osteoporosis. Among the HIV-negative controls, 29% had low bone mineral density, and 6% had severe osteoporosis.

Patients' bone mineral density was gauged by full-body X-ray scans (DEXA). The Washington University authors concluded, "This association between HAART and osteopenia requires prompt examination." Though the paper did not link avascular necrosis to osteopenia, there was a suggestion that the two might be connected. Advanced stage osteoporosis and osteopenia can cause avascular necrosis and spine degeneration.

Dr. Tebas commented in an interview, "Avascular necrosis is a recognized complication of severe osteoporosis, but avascular necrosis might be attributed to hyperlipidemia [high blood lipids] or the intercurrent use of drugs like steroids. We saw avascular necrosis before the availability of potent antiretroviral therapy. The problem of osteopenia is a more recent one."

Low bone mineral density seems to have arisen concurrently with the use of protease inhibitors. Tebas as well as researchers at San Francisco General Hospital agreed that PI-containing regimens might be causing bone mineral loss, but most were very careful to avoid directly implicating protease inhibitors in avascular necrosis.

Diagnosing and Preventing Bone Loss

Dr. Morris Schambelan, a leading endocrinologist at San Francisco General Hospital said that he too is now screening HIV patients for bone loss using DEXA scans. Schambelan says that he is finding overall bone loss but is not yet sure which bones are losing minerals and mass. So far he is seeing what he termed "minor bone loss," but not from the sites usually seen in older women such as the spine. Schambelan too has noticed an increase in avascular necrosis patients since the advent of HAART.

According to Schambelan, DEXA is the best way to diagnose bone loss. It is preferable to have had a baseline scan at least two years earlier. In the absence of a previous scan, doctors can compare scan results with the standard values for a patient's age, weight and build. They then can make a finding to determine probable bone loss.

Could mineral bone loss be the result of a vitamin D deficiency? This vitamin helps the body maintain proper blood levels of calcium for building bones and conducting other metabolic processes. A Norwegian study checked 54 HIV-positive persons (44 males and 10 females) for levels of vitamin D3, the natural version of the vitamin. Twenty-nine patients had serum levels below normal range, and 18 had undetectable vitamin D3. All four patients diagnosed with wasting in the study had undetectable levels.

The researchers speculated that immune dysfunction or cytokines could be responsible for the deficiency. For example, tumor necrosis factor alpha (TNF alpha) created during the immune system's response to HIV could be blocking vitamin D3 uptake. The paper went on to suggest that even though the authors found only slightly lower than normal or normal calcium levels in the blood, compensatory mechanisms may have made calcium available. The calcium in the blood could have been taken from the bones.

Tebas was critical of the vitamin D paper and mentioned that he found no such deficiencies in the persons with HIV whom he had studied. As for people in Norway not getting enough sun and vitamin D, the study did compare the HIV patients to controls, who all had normal levels.

If vitamin D concentrations are suspect, might not supplementing vitamin D and calcium be a prudent approach? Margaret Davis RD, CNSD, a California nutrition expert with many years of HIV experience says that she usually recommends 500 to 1000 mg calcium daily for men and 1000 to 1500 mg calcium for women. She knew of no studies proving this would help, but thought that at least it could not hurt. All interviewed researchers agreed that overdosing vitamin D could be quite harmful. Too much vitamin D leads to excess calcium in the blood and not enough in the bones. The bones become demineralized while soft tissue calcifies. Kidney stones are also a risk.

Tebas thought that a person would get enough vitamin D in a regular diet that included dairy products. "People who do not eat dairy might want to supplement up to 400 IU vitamin D per day," he said.

Paiement mentioned that nearly all the vascular necrosis that he has seen in persons with HIV has been in the hip. As with Dan Hays, if one is experiencing groin pain or hip discomfort, he or she should tell the doctor as soon as possible. The best way to diagnose necrosis quickly is to have an MRI or x-ray of the hip area.

For now, patients and their doctors need to follow the current research very closely. People with HIV might be inclined to drop protease inhibitors when they learn of potential bone problems. Further studies may find, though, that the problems are not that serious or that they are correctable. Nobody yet knows how long a patient can safely take a protease inhibitor before bone loss begins. Participants in the Tebas study had evident problems by year two, but that study did not track bone loss progression over time. Progressive HIV practitioners are now referring patients for DEXA scans for various reasons. Persons undergoing treatment for HIV might consider annual DEXA scans to track bone density as well as lipodystrophy.

References

1. Stoval D Jr. and Young TR. Avascular Necrosis of the Medial Femoral Condyle in HIV-infected Patients. American Journal of Orthopedics. June 1998; 24(1):71-3.

2. Gautier C et. al. Incidence of Avascular Necrosis of the Hip in HIV-infected Individuals on HAART. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Sept 24-27 1998; abstract I-71.

3. Timpone J et al. Avascular Necrosis in HIV+ Patients a Potential Link to Protease Inhibitors, 6th Conference on Retroviruses and Opportunistic Infections, Jan 31-Feb 4 1999; abstract 680.

4. Tebas P et al. Accelerated Bone Mineral Loss in HIV-Infected Patients Receiving Potent Antiretroviral Therapy, AIDS 2000 Mar 10;14(4):F63-7.

5. Haug CJ et al. Severe Deficiency of 1,25-Dihydroxyvitamin D3 in Human Immunodeficiency Virus Infection: Associated with Immunological Hyperactivity and only Minor Changes in Calcium Homeostasis, J Clin Endocrinol Metab 1998 Nov;83(11):3832-8.

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