A review of the latest insights into the mechanism of action of strontium in bone

Interest in strontium (Sr) has persisted over the last three decades due to its unique mechanism of action: it simultaneously promotes osteoblast function and inhibits osteoclast function. While this mechanism of action is strongly supported by in vitro studies and small animal trials, recent large-scale clinical trials have demonstrated that orally administered strontium ranelate (SrRan) may have no anabolic effect on bone formation in humans. Yet, there is a strong correlation between Sr accumulation in bone and reduced fracture risk in post-menopausal women, suggesting Sr acts via a purely physiochemical mechanism to enhance bone strength. Conversely, the local administration of Sr with the use of modified biomaterials has been shown to enhance bone growth, osseointegration and bone healing at the bone-implant interface, to a greater degree than Sr-free materials. This review summarizes current knowledge of the main cellular and physiochemical mechanisms that underly Sr's effect in bone, which center around Sr's similarity to calcium (Ca). We will also summarize the main controversies in Sr research which cast doubt on the 'dual-acting mechanism'. Lastly, we will explore the effects of Sr-modified bone-implant materials both in vitro and in vivo, examining whether Sr may act via an alternate mechanism when administered locally.