For people infected with the HIV virus, treatment with highly active antiretroviral therapy, such as HIV protease inhibitors that block an enzyme used by the virus, has been associated with unexplained bone loss. Now, thanks to research supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), scientists have begun to learn how such agents affect bone, and have discovered that one HIV drug - ritonavir - may actually preserve bone.
In test-tube studies, scientists at Washington University in St. Louis looked at the impact of ritonavir and another commonly used protease inhibitor, indinavir, on the formation and function of bone-building cells called osteoblasts as well as bone-resorbing cells called osteoclasts. Under normal circumstances, the two types of cells work together in a finely orchestrated process to keep bone strong and healthy. But when osteoclastic resorption outpaces osteoblastic formation - that is, old bone breaks down faster than new bone is being built - bones begin to lose mass, sometimes to the point that they become brittle and subject to fractures. In HIV patients taking protease inhibitors, the scientists suspected, bone resorption outpaced formation. They were partly right.
"What we found was that indinavir did nothing to the bone-resorbing osteoclasts, but ritanovir did," says F. Patrick Ross, Ph.D., research professor of pathology and immunology, one of the study's authors. "In fact, ritonavir seemed to impact osteoclast differentiation (the production of osteoclasts from their precursor cells) as well as stopping the ability of mature cells to resorb bone."
To see if their finding held true in animals, the scientists gave injections of parathyroid hormone (PTH) - a standard technique to stimulate bone resorption - to a large number of mice. They then gave ritonavir to some of the PTH-treated mice. Later, when the scientists examined the bones of both groups of mice as well as mice that had neither treatment, they found that, as expected, the mice given parathyroid hormone had more osteoclasts than untreated mice. However, in the mice given ritonavir as well, osteoclasts were shut down, Ross says. "It would appear in animal studies that ritonavir is suppressing bone loss."
Whether ritonavir may do the same in people is not known; yet because of its potential to inhibit bone loss, doctors may want to consider the drug as part of their package for HIV treatment, says Ross.
Because drugs may lose their effectiveness over time, doctors often prescribe a cocktail of medications in various combinations over the course of HIV infection, Ross explains. For that reason, ritanovir alone is not appropriate. And it's not a magic bullet. While ritonavir appears to preserve bone, like other drugs it carries the risk of potentially serious adverse effects as well. "Doctors need to integrate all of the information about all of the different effects and side effects of these drugs alone and together before prescribing them," he says.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov
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Wang MW, et al. The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling. J Clin Invest2004:114(2):206-213.