Osteoporosis studies require precise visualization of the morphological structures. The adult zebrafish represents an excellent model to investigate osteoporosis. However, few imaging methods can effectively detect the adult zebrafish bone structure in real time with high resolution and good penetration depth. In this paper, long-term in vivo monitoring of Prednisolone-induced osteoporosis is achieved with spectral-domain optical coherence tomography (SD-OCT). The SD-OCT is able to noninvasively visualize the skull injury and osteoporosis of adult zebrafish. Valuable phenomenon such as the skull defect and bone loss can be conducted based on the SD-OCT images at different time points during a period of 21 days.