Bone loss linked to low CD4 count on treatment - is bone a reservoir for HIV?

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A review of 3512 patients receiving HIV treatment in the San Francisco area has found no evidence for an increased risk of bone disease related to specific HIV drugs. Instead, the analysis found that reduced bone mineral density, osteoporosis and fractures were related to a low CD4 cell count despite controlled viral load.

The finding has led the authors to suggest that bone weakening and loss in HIV-positive individuals may be driven by ongoing, low levels of HIV replication in osteocytes and osteoblasts, where the virus would be sequestered from antiretroviral drugs by poor blood flow.

In addition, they suggest that low CD4 cell counts despite viral load suppression below 400 copies/ml may be a consequence of ongoing apoptosis of CD4 cells in bone marrow, driven by the release of cytokines and HIV proteins generated by HIV replication in cortical osteons (the active cells in the outer layer of bone).

Glossary

discordant

A serodiscordant couple is one in which one partner has HIV and the other has not. Many people dislike this word as it implies disagreement or conflict. Alternative terms include mixed status, magnetic or serodifferent.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

epidemiology

The study of the causes of a disease, its distribution within a population, and measures for control and prevention. Epidemiology focuses on groups rather than individuals.

cytokines

Chemical "messengers" exchanged between immune cells that affect the function of the immune system. Interleukins such as IL-2 are a particular type of cytokine.

bone mineral density (BMD)

The higher your bone mineral content, the denser your bones are. And the denser your bones, the stronger they are and the less likely they are to break. A bone density test uses X-rays to measure how many grams of calcium and other bone minerals are packed into a segment of bone. The bones that are most commonly tested are in the spine, hip and sometimes the forearm. 

Several previous epidemiological studies have failed to find an association between particular drugs and bone loss, noting instead that bone loss and osteonecrosis were more common in people not receiving treatment for their HIV infection.

This study set out to investigate the discrepancy noted in several previous studies; namely, that people with osteonecrosis tended to have lower CD4 cell counts than case controls without osteonecrosis, despite also having lower viral load.

3512 male patients receiving treatment through Kaiser Permanente in the San Francisco area were analysed, of whom 72 had bone disease (23 cases of osteonecrosis). Patients were analysed for discordant CD4 cell count and viral load (CD4 < 350 cells/mm3 and viral load below 500 copies/ml. In those with bone disease, the measurement used were those closest to the date of diagnosis of bone disease.

Patients’ pharmacy records for the preceding five years were also analysed, to determine whether low CD4 cell levels or bone disease were associated with any medications. No link was found between medication and bone disease or lymphopenia.

Previous studies have suggested that patients with advanced HIV infection and greater duration of HIV infection have a discordant response to HIV therapy more frequently. However, when patients in the Kaiser cohort were analysed by duration of infection, no difference was found in the frequency of discordant viral load and CD4 count.

There was a significant difference in the proportion of patients with bone disease who had a discordant CD4 cell count and viral load, however. 36.1% of those with bone disease had discordant CD4 cell count and viral load, compared to 20.5% of those without bone disease (p<0.01).

Further information

Osteonecrosis

Osteoporosis

References

Fessel JW, Hurley LB. Is HIV sequestered in bone? Possible implications of virological and immunological findings in some HIV-infected patients with bone disease. AIDS 17: 255-267, 2003.