Bone mass loss with the subsequent development of osteopenia and osteoporosis is related to HIV infection and antiretroviral treatment, even though the mechanisms involved have not yet been elucidated. In this report analyzes the early effects of some specific protease inhibitors on OPG/RANKL yielding and cell survival in osteoblast-like HOBIT cell line. None of the compounds, tested at scalar concentrations (C1, C2, C3), affected cell survival except for tipranavir that elicited a reliable induction of apoptosis at the highest concentration (C3). Atazanavir, saquinavir and indinavir did not affect OPG/RANKL in the cell surnatant in our experimental conditions. By contrast, at optimal concentration (C2), fosamprenavir induced a significant increase in OPG associated with a RANKL decrease whereas tipranavir down-regulated both OPG and RANKL (at C2 and C3) and darunavir increased RANKL only at C3 concentration. Together these data (coupled with the analysis of OPG/RANKL ratio) indicate that at early times and at optimal concentrations the PIs did not impair the OPG/RANKL system with the exception of fosamprenavir that showed a relative positive OPG/RANKL ratio regulation. Instead, cell cultures treated by the highest concentrations of tipranavir or darunavir showed a change in cell survival or an increase in RANKL, with a negative effect on the OPG/RANKL balance.