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Bone metabolism derangements have been reported in HIV-infected children and adolescents. Nuclear factor kappa B ligand (RANKL) and osteoprotegerin potently stimulate and inhibit, respectively, osteoclast formation and activity. We investigated the possible role of RANKL and osteoprotegerin on bone metabolism alterations in paediatric patients.A prospective controlled longitudinal study. Measurements were obtained before and 6 months after switching antiretroviral regimen.We studied 27 vertically HIV-infected children and adolescents (aged 4.9–17.3 years) on long-term HAART (70.1 ± 1.5 months). All patients received lamivudine, stavudine and one protease inhibitor (PI). During follow-up, the PI was replaced with efavirenz and stavudine with tenofovir. We also enrolled 336 healthy children, aged 4.8–17.9 years. Concentrations of bone-specific alkaline phosphatase (BALP), N-terminal telopeptide of type I collagen (NTx), RANKL, and osteoprotegerin were measured at baseline and 6 months after switching.BALP serum concentrations and NTx urine levels of HIV-infected patients were significantly higher than those of healthy children both at baseline and after 6 months (P < 0.001). Baseline osteoprotegerin and RANKL concentrations of HIV-infected patients were significantly higher than in healthy children (P < 0.0001). Both concentrations decreased after 6 months, and RANKL levels were no longer different to controls. At baseline the RANKL/osteoprotegerin ratio was significantly higher (P = 0.02) in HIV-infected children (0.27 ± 0.07) compared with healthy children (0.078 ± 0.01).A marked alteration in the RANKL/osteoprotegerin system is present in patients receiving PI-based HAART. Short-term data indicate that replacing stavudine and PI with tenofovir and efavirenz restores the RANKL/osteoprotegerin equilibrium, and may thus lead to a reduction in the bone resorption rate.