Bone and plasma citrate is reduced in osteoporosis.

High concentration of citrate exists in bone of humans and all osteo-vertebrates, and citrate incorporation imparts important biomechanical and other functional properties to bone. However, which cells are responsible for citrate production in bone remains unclear and whether the citrate component changes with bone loss during osteoporosis is also not known. Here, we show that the citrate content is markedly reduced in the bone of mice or rats with age-related, ovariectomy-induced or retinoic acid-induced bone loss. Plasmic citrate is also downregulated in osteoporotic animals. Importantly, the plasmic citrate level of aged osteoporotic males is significantly lower than that of young healthy males and positively correlates with human lumbar spine bone mineral density (BMD) and total hip BMD. Furthermore, citrate production increases with in vitro osteoblastic differentiation, accompanied by upregulation of proteins involved in citrate secretion, suggesting that osteoblasts are highly specialized cells that produce citrate in bone. Our findings establish a novel relationship between citrate content and bone loss-related diseases such as osteoporosis, suggesting a critical role of bone citrate in the maintenance of the citrate balance in the circulation. Serum citrate level may thus represent a novel marker for osteoporosis.