The osteoprotective effects of artemisinin compounds and the possible mechanisms associated with intracellular iron: A review of in vivo and in vitro studies.

Osteoporosis is a progressive systemic disease characterized by low bone mineral density and deterioration of bone microarchitecture. The current therapies are effective to prevent further bone loss and fractures but they are accompanied by undesirable side effects and cost issues. The discovery of Chinese herbal medicines with osteoprotective effects provides alternative treatments to prevent bone loss without causing severe side effects. Artemisinin (ARS) and its related compounds have been clinically used as antimalarial agents. Interestingly, their bioactivity is not limited to antimalarial treatment. Experimental evidences indicate that ARS compounds are a potential type of therapeutic alternative medicine for bone loss induced by accelerated osteoclastic bone resorption. The present review intends to summarize the current understandings of ARS compounds and their molecular mechanisms of actions in preventing bone loss. ARS compounds selectively inhibit osteoclast differentiation by downregulation of pathways involved in receptor activator of nuclear factor kappa-B ligand (RANKL) -induced osteoclastogenesis, and have no effect on osteogenic differentiation of osteoblasts. The exact mechanism of activation and action of these anti-resorption effects are not fully elucidated. Considering the characteristic of high levels of intracellular iron in osteoclasts, ARS compounds may inhibit osteoclast differentiation via mechanisms associated with intracellular iron, including the cleavage of endoperoxide bridge, oxidative damage and ferroptosis. The anti-resorptive effects of ARS compounds need to be further investigated in bone loss models caused by different factors, and to be under clinical development.