Body composition, soluble markers of inflammation, and bone mineral density in antiretroviral therapy-naive HIV-1-infected individuals.

Osteoporotic fractures are a major source of morbidity and mortality in aging populations1. Among HIV-infected populations, the prevalence of osteoporosis is several fold higher than HIV-uninfected control populations and likely accounts for the emerging data suggesting a higher than expected risk of fragility fracture in HIV-infected patients2–6. The etiology of osteoporosis is multifactorial. While traditional risk factors, such as hypogonadism, smoking, heavy alcohol use, and certain components of antiretroviral therapy (ART) are important contributors, chronic infection with HIV and the resulting inflammation and immune activation have been hypothesized to lead to decreased bone mineral density (BMD). In pre-clinical models, both high levels of HIV-viral proteins and inflammatory cytokines, such as TNF-α and IL-6, have been associated with decreased osteoblast function and increased osteoclast formation and activity7–10, potentially leading to an uncoupling of bone formation and bone resorption and net bone loss. In untreated HIV-infected patients, a similar pattern is observed with higher markers of bone resorption and relatively lower concentrations of markers of bone formation11. However, the extent to which systemic inflammation is related to lower BMD in untreated HIV-infected persons has not been clearly established. Other factors may also influence BMD in untreated HIV-infected individuals. In the general population, lower lean body mass and lower fat mass have been independently associated with lower BMD 12;13. In HIV-infected populations, lower body mass index is a major contributor to the increased prevalence of osteoporosis 14. In addition, as in the general population15, relative higher levels of abdominal visceral fat have also been associated with lower BMD in HIV-infected populations16;17, although this has not been investigated to date in ART-naive, HIV-infected patients. Part of the effect of adipose tissue on bone may be mediated through the adipose derived hormones, adiponectin and leptin, which may be altered in HIV-infected populations and have been associated with BMD independently of fat mass in the general population18. Other biomarkers may also be associated with abnormal bone metabolism in untreated HIV-infected persons. Osteoprotegerin (OPG) and receptor activator of NFκB Ligand (RANKL) are osteoblast-secreted factors which have a major role in the coupling of bone formation and resorption. Secreted RANKL binds to RANK on the cell surface of osteoclast precursors, leading to osteoclast activation and bone resorption. As a control mechanism, OPG is also secreted by osteoblast precursors to bind to RANKL, thereby preventing the interaction of RANK and RANKL and slowing bone resorption19. Although these proteins act locally in the bone microenvironment, circulating concentrations of these markers and their ratio have been associated with osteoporosis in the general population 19. Interestingly, both of these cytokines are produced by activated immune cells20;21 and decrease with ART-initiation 11. To date most studies evaluating factors associated with BMD in HIV-infected populations have focused on patients receiving ART. In the current report, we assessed the prevalence of low BMD among ART-naive patients and determined the associations between soluble markers of inflammation, body composition, adipocytokines, and OPG/RANKL and site-specific BMD.