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Effect of protease inhibitors on bone
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Special report by Donald P. Kotler, MD, St Luke's-Roosevelt Medical Center, New York City
Steven Teitelbaum, from Washington University of St. Louis, presented a review of his laboratory's work on the effects of protease inhibitors upon bone formation. The work arose from the observations of osteopenia in HIV infection at a time soon after the identification of lipodystrophy, and the initial supposition that the problem was related to protease inhibitor use. In fact, it is now known that lipodystrophy is not related solely to protease inhibitor use. Osteopenia also is not related solely to protease inhibitor therapy, as osteopenia may be present in protease-inhibitor naive, or even antiretroviral-naive patients. In addition, several studies have shown that bone mineral content may remain stable while on antiretroviral therapy. However, the work presented was thought-provoking and consistent with other recent scientific findings of protease inhibitor effects.
As background, bone mineral content is the net result of bone formation by osteoblasts, and bone breakdown by osteoclasts. Both cell types are active throughout life, with bone formation predominating during the first few decades, and bone breakdown predominating thereafter. Many factors affect either bone formation or breakdown, under normal or pathologic circumstances. Inflammation is a relevant factor which leads to increased bone breakdown, and many inflammatory diseases are associated with osteopenia.
Dr. Teitelbaum's laboratory carefully examined several aspects of bone metabolism. He isolated osteoblast precursor cells and grew them in vitro for 4 weeks, at which time cells producing bone mineral can easily be detected. Incubation with indinavir, but not other protease inhibitors, led to an inhibition of cells capable of producing bone. The effects of indinavir were seen at physiologically relevant concentrations. Addition of indinavir during the first two weeks of culture produced the inhibitory effect, while addition of indinavir only during the second two weeks of the incubation was without effect. The effect was reproduced in organ culture when fetal bone, as opposed to cells, was incubated (ex vivo). The effect also was seen when baby mice were fed indinavir early in life and bone development determined in vivo. The specific mechanism underlying the inhibition of differentiation of osteoblasts was not elucidated, at least not yet.
Dr. Teitelbaum's laboratory also examined the development and function of osteoclasts. Osteoclasts are macrophage-like cells that develop and function after stimulation by specific cytokines, including a macrophage colony-stimulating factor and a cytokine known as RANK ligand. This latter cytokine is a member of the TNF superfamily and its regulation is very similar to that of TNF. Activation of osteoclasts leads directly to bone resorption by a mechanism similar to the activation of macrophages. There are several signal transduction pathways linking activation and cell function, including the nuclear factor kappa B (NFKB) pathway. NFKB as a transcriptional activator which leads to DNA transcription of a series of messenger RNA's for a series of related proteins. In the case of osteoclasts, the proteins act together to release bone mineral from its matrix. TNF also acts via NFKB and promotes the prcduction of a series of pro-inflammatory proteins in mononuclear cells. Of note, NFKB signalling in HIV-infected mononuclear cells also leads to promotion of HIV replication.
Dr. Teitelbaum's studies showed that ritonavir decreased the function of osteoclasts (Editorial note: and so, ritonavir may have a protective effect, but at what dose level?), as opposed to cell differentiation and osteoclast development. For this reason, the anti-resorptive effect of ritonavir is reversible. The mechanism of ritonavir action is complicated and indirect but appears to work at the level of NFKB. NFKB activity is under tight control in the cell. In resting cells, NFKB exists in the cytoplasm bound to a molecule named IKB. After appropriaqte signalling, NFKB is released from its bond to IKB and translocates to the nucleus, where it binds to DNA and promotes transcription. Control of this system is related, in part, to the degradation of IKB in a structure called the proteosome. The proteosome contains a protease, which is inhibited by ritonavir. As a result, NFKB is less efficiently released from the IKB complex, which decreases osteoclast function. Thus, ritonavir indirectly blocks osteoclast activity. Other studies have shown that inhibition of proteosome activity may be responsible, at least in part, for the development of hypertriglyceridemia and of lipoatrophy.
Thus, it appears that protease inhibitors may have diverse effects on bone. Some protease inhibitors, such as indinavir, may block the differentiation of precursor cells into osteoblasts, thus diminishing the rate of new bone formation. Other protease inhibitors, such as ritonavir, may block bone breakdown, thus protecting bone mineral. The observed effect may be related to which protease inhibitor is used, and where patients start out in reference to bone mineral. For example, a patient with slowly progressive HIV disease and relatively normal bone mineral content who starts therapy with indinavir may develop progressive osteopenia. Conversely, a patient with rapidly progressive HIV disease and chronic inflammation who starts therapy with ritonavir may initially have significant osteopenia that remains stable, or even improves during therapy. Thus, while the results of Dr. Teitelbaum's studies, at first, do not seem at all relevant to HIV-infection in humans, they may be consistent with clinical observations. They also provide further evidence of intra-class differences in protease inhibitor effects. At the very least, the results of these studies provide a framework for further investigations in the field.
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