Osteoporosis is a major chronic disease of aging, causing fractures, pain and disability. This skeletal fragility results from excessive bone catabolism in the face of declining bone anabolism. Whereas anti-resorptive drugs are well developed, only parathyroid hormone is capable to rebuild the altered bone structure. Hence, by gaining novel insights in the anabolic molecular processes of the matricellular protein called periostin, we hope to delineate new therapeutic targets to restore bone strength. By virtue of its signaling pathway and its spatial localization in osteocyte and osteoblast of the periosteal surface of cortical bone, we demonstrate its important role in the skeletal adaptations, and we are on the verge of revealing molecular mechanisms by which periostin regulates bone formation. Moreover, by its multiple facets, we highlight that periostin is a promising tool to improved therapeutic strategies and/or diagnosis of bone fragility through its association with cortical bone microarchitecture.