Following recent reports of bone loss and hip problems in patients with HIV and AIDS, the FDA queried the agency’s MedWatch side-effect reporting system and found a strong link between "aseptic" bone death (avascular necrosis) in the hip and the use of Megace in HIV-infected men. The search located three HIV-positive adult male patients who had taken Megace for six to 18 months and had suffered fracture or collapse in one of their hips’ femoral heads. (Megace, or megestrol acetate, is a synthetic version of the female steroid hormone progesterone. It is prescribed as an appetite stimulant for reversing weight loss in people with AIDS.) Aside from AIDS, these patients had no other risk factor for aseptic bone death (AIDS Patient Care and STDs, August 2000, 14(8):405-10).

The authors of the FDA paper include the Endocrine Division’s Elizabeth Koller, M.D., and Saul Malozowski M.D., Ph.D. "We receive information about adverse reactions from doctors and update [MedWatch] every 15 days or so. When we go to a clinic and see patients, we come back and look at the database," said Dr. Malozowski.

"We came up with three cases out of hundreds of reports related to Megace," Dr. Koller related. "Dr. Gibert, a co-author, had a good case report as well as MRI and x-ray films." Dr. Koller and her team were able to verify aseptic bone death and establish a link to Megace treatment. "It very well could be that if it were only AIDS patients, I’d dismiss it, but the first case was not an AIDS patient, it was prostate cancer," she said. Dr. Koller’s study found the problem only in male patients and worries that doctors may not be reporting the side effect in women taking Megace because doctors often associate women’s hip problems with other illnesses.

Dr. Koller is not absolutely sure that aseptic bone death is caused by Megace and thinks there might be other contributing factors. "It could be a multifactorial problem." she remarked. She is concerned that doctors may not be making the connection between Megace and bone death. Now that word is out, more reports may come in to the FDA’s MedWatch reporting system. "There is some uncertainty about how strong this relationship is. If there is a true connection, it should manifest over time." she said. Overall, Koller suspects drug toxicity. "If you have a bunch of people who are hypo-gonadal, you see lower bone mass [osteopenia]. I think osteopenia and aseptic necrosis are different problems because osteopenic women are not getting aseptic necrosis." Koller sees these conditions as an outgrowth of increased AIDS survival.

As far as prevalence is concerned, Malozowski does not have the answer. He suspects that Megace-related bone problems go unreported much of the time. "It’s impossible to speculate on this. I can assure you that there are many, many more cases of this out there. Usually when a drug is approved, we get a lot of reports of reactions. For example; we estimate that for every patient we have a fatality report of, there are up to nine patients who have died." Koller noted that there is little or no money at this time to monitor MedWatch for small problems. It takes huge signals before MedWatch can pick up any trends.

NIH Study Notes Other Factors

A study performed by the by the National Institutes of Health (NIH) drew somewhat more complicated conclusions (Infectious Disease Society of America Annual Meeting. September 7-10, 2000; abstract 15). The NIH doctors used magnetic resonance imaging (MRI) to analyze 339 HIV-positive patients, and 15 (4.4%) were found to have early signs of hip deterioration. None of these patients had reported hip pain. Some 118 HIV-negative patients were checked, too, and none had the problem. "These 15 patients with asymptomatic osteonecrosis had lesions in one or both hips," noted NIH Critical Care Medicine Chief Henry Masur. "Many of the lesions were large. Our concern is that the lesions will lead to clinical symptoms ultimately requiring total hip replacements.". Four NIH patients already have undergone this procedure.

The NIH researchers found no direct correlation to Megace, but there was an association with use of systemic corticosteroids, testosterone, body building and medications to lower blood levels of triglycerides and cholesterol. Corticosteroids – prednisone, for example – are analogs of adrenal hormones that reduce inflammation. Aseptic bone death is a well-known outgrowth of their use. Some of Megace’s established side effects do mimic those of corticosteroids.

Like the FDA scientists, the NIH researchers speculated that there may be other undiscovered risk factors within the AIDS population. Another doctor who worked on the NIH study, Dr. Joseph Kovacs, said that his colleagues and he have been following patients with HIV at the NIH Clinical Center for more than 17 years and had not seen this complication until about a year ago. "Longer patient survival, new therapies or lifestyle influences may somehow contribute to the development of this disorder. It’s important to find out why it’s happening." he said.

Dr. Koller and others suggest that patients presenting with hip pain should be x-rayed for hip ball flattening. If nothing shows up in the x–ray, an MRI should be performed. Patients with a history of testosterone replacement or treatment with Megace might consider checking for problems by x-ray and MRI, too. At present, researchers have no idea how to prevent hip fracture and subsequent replacement surgery even if problems can be caught at an early stage.

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