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High HIV Load Stymies Calcium Deposition in Bone-Forming Cells
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9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow
Mark Mascolini
People with uncontrolled HIV replication may run a higher risk of osteopenia and osteoporosis than people with controlled viremia, according to results of a cell-culture study at the University College Dublin [1]. The findings don't seem to mesh with a recent SMART substudy showing that people randomized to intermittent antiretroviral therapy lost significantly less bone mineral density (BMD) than people who kept HIV under tighter control because they took antiretrovirals continuously [2].
The Dublin group devised a cell study to test the hypothesis that "exposure to HIV alters human osteoblast [bone-forming cell] function and activity and ultimately leads to osteopenia/osteoporosis." They cultured human osteoblasts, supplementing growth medium with pooled serum from three separate groups: 5 people without HIV, 5 HIV-infected people with a low viral load (120 to 4000 copies), and 5 people with a high viral load (100,000 to 500,000 copies). None of the HIV-infected people ever took antiretrovirals.
The investigators then measured both osteoblast proliferation and calcium deposition. They also determined the effect of HIV-free and HIV-laden serum on RUNX-2, a transcription factor that promotes bone growth, and PPARG, a fat-promoting transcription factor.
Osteoblast proliferation did not differ significantly when exposed to serum with no, low, or high viral loads. However, calcium deposition proved significantly lower in osteoblasts exposed to high-load serum than in cells exposed to HIV-free serum (P < 0.0001). High-load serum also inhibited calcium deposition significantly more than low-load serum (P < 0.0001).
Expression of the bone-growth transcription factor RUNX-2 was 25% lower after exposure to high-load serum than after exposure to no-load serum (P < 0.05). In contrast, expression of the fat-promoting transcription factor PPARG in osteoblasts was higher upon exposure to high-load serum than upon exposure to no-load serum.
The Dublin investigators believe their findings "support the hypothesis that HIV itself, in addition to the well-described effect of antiretroviral therapy, can modulate bone phenotype and at least in part drive the osteopenia and osteoporosis which is increasingly seen in HIV patients."
In the SMART analysis femur and spine bone mineral density (BMD) fell significantly more over time in people taking antiretrovirals continuously than in those taking CD4-guided antiretroviral breaks. In people randomized to intermittent therapy, BMD remained stable in the first year of follow-up, then started declining in parallel with the drop charted in people on continuous therapy. The SMART team suggested that "this pattern is consistent with the increased antiretroviral therapy use after year 1 in the treatment-interruption group." Higher viral loads during the first year did not appear to contribute to bone loss in the interruption group.
These apparently conflicting in vitro and in vivo results underline the difficulty of sorting out the impact of HIV, antiretroviral therapy, and a host of other factors on bone density in an aging population of antiretroviral-treated people.
References
1. Chew NS, Cotter EJ, Doran PP, Powderly WG. High HIV viral load inhibits osteoblast function and signaling. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract O323.
2. Grund B, Carr A. Continuous antiretroviral therapy (ART) decreases bone mineral density: results from the SMART study. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC. Abstract H-2312a.
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