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

Abstract

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.

Keywords: Bone; Mechanism of action; Medicine; Physiology; Strontium.

Fig. 1

Cellular CaSR-dependent mechanisms for Sr’s action on osteoblasts and osteoclasts from in vitro findings. (Hurtel-Lemaire et al., 2009; Rybchyn et al., 2011; Peng et al., 2009; Fromigué et al., 2009; Peng et al., 2011b; Caverzasio, 2008).

Fig. 2

a) Localization of Sr in bone. Adapted from Frankær et al.(Frankær et al., 2014) b) Nanostructured organization of bone as well as the location of sacrificial bonds. Adapted from Gao et al. (2004).

Fig. 3

a) Structure of a Sr-CaSi glass, where the larger ionic radius of Sr²⁺ leads to a more expanded glass structure (Fredholm et al., 2012; Fredholm et al., 2010). b) Degradation/precipitation reaction of a bioactive Sr-CaSi glass, and how this favours osteoblast colonization, proliferation and gene expression.