Clinicians who treat AIDS patients may be able to use the HIV protease inhibitor ritonavir to reduce bone loss, scientists at Washington University School of Medicine in St. Louis recently reported in The Journal of Clinical Investigation.
In a collaborative study initiated by their clinical colleagues, the scientists have shown that the AIDS drug ritonavir suppresses the creation and activity of cells that dismantle bone, potentially slowing bone loss and lowering the risk of osteoporosis in AIDS patients.
Bone researchers studied the effects of three highly active antiretroviral therapy (HAART) drugs on osteoclasts, cells that dismantle bones, and osteoblasts, cells that build bone. In healthy persons, the skeleton is regularly renewed about once every ten years mainly via the work of these two cell types.
In test tube experiments, the research team found that the drug indinavir inhibited the activity of osteoblasts, the bone builders. Another drug, ritonavir, blocked the formation of bone-dismantling osteoclasts. Scientists also found evidence that ritonavir can suppress the activity of osteoclasts created prior to the introduction of the drug. A third drug had no effect on either cell type.
“Confirming these effects in humans may mean we have a drug that is effective not only in preventing HIV replication but also in arresting the development of osteoporosis,” says senior investigator F. Patrick Ross, Ph.D., research professor of pathology and immunology.
Clinicians first noted problems with bone in young male HIV patients several years ago. HIV’s effects on the body are thought to contribute to the problem, but scientists suspect some of the drugs in the HAART cocktail may exacerbate bone loss.
In the new study, Ross’s postdoctoral fellow Michael W.-H. Wang, M.D. and colleagues reveal evidence that ritonavir is blocking a signaling pathway that fuses together simpler cells to make the more complex osteoclasts.
Scientists confirmed the effect in mice injected with parathyroid hormone, which stimulates osteoclast activity. Mice who received only the hormone had higher numbers of osteoclasts, but mice given both the hormone and ritonavir had unchanged osteoclast levels. In additional test tube studies, scientists found that suppression of the creation of new osteoclasts was reversible, with osteoclasts starting to develop again 2 to 4 days after scientists stopped adding the drug.
The findings suggest that clinicians may one day want to consider permanently keeping ritonavir or a similar bone-sparing drug in the changing mixture of treatments for AIDS patients, popularly known as the AIDS drug cocktail.
Wang M W-H, Wei S, Faccio R, Takeshita S, Tebas P, Powderly WG, Teitelbaum SL, Ross FP. The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling. The Journal of Clinical Investigation, July 2004, 206-212.
Funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Washington University School of Medicine’s full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.