Huang, Weijia; (2024) Investigating the role of bisphosphonates on bone cells and the potential of ionic therapy to restore bone regeneration in osteonecrosis of the jaw. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe side effect of antiresorptive bisphosphonates (BPs) used to treat patients with cancer and osteoporosis. The mechanism underlying BRONJ remains unclear, and there are no effective therapies, making it a significant clinical challenge. Surgical removal of necrotic bone is often the only available option, a similar approach to that used in the Victorian era. Novel therapies, such as tissue engineering strategies, have emerged as a promising approach. Here, we investigate the use of therapeutic ions (silicate (Si) and cobalt (Co) ions that can be released from bioactive glasses), as a possible method to either prevent or restore bone regeneration in patients with BRONJ. A systematic review of existing literature (123 papers investigating the in vitro role of BPs were included for quantitative analysis) revealed a concentration-dependent effect of BPs on cells regardless of cell type or experimental conditions. Increasing BP concentrations had an increased frequency of undesirable outcomes. The mean BP concentration reported to have undesirable effects (50 µM) was higher than the concentration reported to have desirable outcomes (20 µM) (P<0.01). Furthermore, nitrogen-containing BPs caused undesirable cellular outcomes at lower concentrations than non-nitrogen containing BPs. The main cellular pathways studied in response to BPs in vitro include inflammation, oxidative stress, apoptosis and angiogenesis. Based on the literature review, the effect of Zoledronate (ZA) and Alendronate (AL) on both osteoblasts (OBs) and osteoclasts (OCs) behavior was investigated. ZA and AL had concentration-dependent effects. ZA at concentrations below 1.8 µM did not inhibit OB metabolic activity or proliferation but it did inhibit ALP production. ZA also inhibited bone nodule formation at all concentrations (from 0.067 to 1.8 µM), except the lowest dose of 0.067 µM ZA which increased bone nodule formation (P<0.01). In addition, both ZA and AL above 0.067 µM inhibited OC differentiation (P<0.05). This is the first study to investigate BPs using a bone nodule formation assay for up to 21 days and the OC subclone. In the context of ionic therapy, Si inhibited ROS availability caused by ZA treatment, and this may account for the partially restored bone formation (at D7) observed in Si-treated OBs exposed to ZA. Whilst the addition of Co ions, to BP-treated (ZA and AL) OCs, restored OC differentiation as determined by the expression of the OC-specific marker TRAP5b and OC number. The hypoxia mimetic and iron chelator DFO also restored OC formation in treated cells, suggesting that Co restoration may be via the HIF-1α pathway or iron chelation and inhibition of iron-dependent enzymes involved in metabolism and OC differentiation. Based on our findings, Si and Co released from materials (e.g. from bioceramic coated dental implants or bioactive glass [BG] particles used for bone fillers) may provide a novel approach for managing BP-induced inhibition of bone regeneration by modulating both OB and OC behavior. Currently, this approach is not applying in clinical practice. Our findings provide evidence for the potential repurposed use of these materials in treating BRONJ or patients at risk. Furthermore, new BGs containing Co ions can be tailored according to this evidence.

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