Highly active anti-retroviral therapy (HAART) is a principal therapy method for AIDS. However, HAART is also one of crucial factors inducing bone mass loss and osteoporosis but its related mechanisms are obscure. Of note, nucleotide reverse transcriptase inhibitor (NRTI) and protease inhibitors (PI) may play key roles in inducing osteoporosis. This review summarizes the research progress in epidemiology and associated mechanisms on osteoporosis induced by NRTI and PI.