Evidence from rodent and in vitro models suggests that activation of PPAR-γ by thiazolidinediones (TZDs) causes increased bone marrow adiposity and decreased osteoblastogenesis, resulting in bone loss. TZDs are prescribed for the treatment of diabetes, providing an opportunity to determine whether PPAR-γ activation also impacts bone in humans. In addition, since type 2 diabetes is associated with higher fracture risk, an understanding of the clinical impact of TZDs on bone is needed to guide fracture prevention efforts in this population. This review summarizes current findings regarding type 2 diabetes and increased fracture risk and then considers the available evidence regarding TZD use and bone metabolism in humans.