Osteopenia and osteoporosis are common in HIV-1-infected individuals and represent a challenge in clinical and therapeutic management. Since the mechanisms underlying this degenerative process are largely unsettled and it has not yet been determined whether bone dysfunction is linked to HIV-1-mediated direct and/or indirect effects on osteoblasts/osteoclasts cross-talk regulation, this brief review analyzes an array of mechanisms that could account for the dramatic bone derangement (bone loss and osteopenia/osteoporosis) during the course of HIV-1 infection.