HIV infection is associated with loss of bone mass and an increased incidence of fractures, which are exacerbated by antiretroviral therapy (ART) during the first 2 years of treatment. A new study shows that reconstitution of the T-cell population in immunocompromised mice (mimicking ART-induced T-cell expansion and immune activation) recapitulates the bone loss observed with ART. “If validated in humans, these findings suggest, for the first time, that some or all of the bone loss associated with ART might be a consequence of inflammatory responses initiated by immune recovery, rather than, or in addition to, direct effects of antiretroviral drugs,” explains co-lead investigator Neale Weitzmann.

The investigators transplanted syngeneic T cells into T-cell-deficient mice (a model of immunodeficiency) by adoptive transfer. T-cell repopulation induced production of the osteoclastic cytokines receptor activator of nuclear factor κB ligand (RANKL) and tumour necrosis factor (TNF), and increased bone resorption and loss of BMD. Remarkably, bone loss was fully prevented in T-cell-reconstituted mice by a single injection of zoledronic acid (a long-acting antiresorptive agent) at the time of adoptive transfer, without impairing T-cell reconstitution.

The researchers are currently conducting a phase II double-blinded, placebo-controlled study in humans to test whether a single administration of zoledronic acid can fully, or partially, prevent the accelerated bone loss driven by ART. “If successful, zoledronic acid treatment might be an immediate, practical and safe way to protect patients from the bone loss associated with ART, and to diminish fracture incidence and the resulting morbidity and mortality,” speculates Weitzmann.