Bisphosphonate-related osteonecrosis of the jaw: a mechanobiology perspective

Abstract

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a dramatic disintegration of the jaw that affects patients treated with bisphosphonates (BPs) for diseases characterized by bone loss. These diseases are often metastasizing cancers (like multiple myeloma, breast cancer and prostate cancer (Aragon-Ching et al., 2009)) as well as osteoporosis. BRONJ is incompletely understood, although it is believed to arise from a defect in bone remodeling-the intricate process by which sensory osteocytes signal to osteoclasts and osteoblasts to resorb and form bone in response to stimuli. Further, tooth extraction and infection have been overwhelmingly linked to BRONJ (Ikebe, 2013). Because bone cells are highly networked, the importance of multicellular interactions and mechanotransduction during the onset of these risk factors cannot be overstated. As such, this perspective addresses current research on the effects of BPs, mechanical load and inflammation on bone remodeling and on development of BRONJ. Our investigation has led us to conclude that improved in vitro systems capable of adequately recapitulating multicellular communication and incorporating effects of osteocyte mechanosensing on bone resorption and formation are needed to elucidate the mechanism(s) by which BRONJ ensues.

Keywords: Bisphosphonate; Inflammation; Mechanical trauma; Mechanobiology; Mechanotransduction; Osteonecrosis.

Fig. 1

Chemical structure of a BP. If a nitrogen or amino group is present, the drug is termed “nitrogen-containing.”

Fig. 2

Mechanisms involved in osteocyte mechanotransduction. The Wnt/β-catenin pathway initiates with binding of Wnt to the complex made up of frizzled and lipoprotein receptor 5/6 (LRP5/6) co-receptors which leads to a cascade of events including the eventual phosphorylation of GSK-3β (Bonewald and Johnson, 2008). β-catenin accumulates and is translocated to the nucleus; here, it forms a complex with the T cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to mediate expression of key genes associated with bone cell function (Krishnan et al., 2006; He et al., 2004). In osteocytes, the α5β1 integrin interacts with gap junction gene, Cx43, to control opening of Cx43 hemichannels (Cx43 HC) activated by fluid flow. Osteocytes perceive mechanical load at αVβ3 integrin attachment locations (Marie et al., 2014). Via release of PGE2, shear stress triggers Akt and cAMP/PKA signaling, which together inactivate GSK-3. This results in further build-up of nuclear β-catenin (Bonewald, 2011). In effect, osteocytic gene expression is altered, mediating osteoblast and osteoclast activity.