| Metallic ion | Role | Mechanisms of action |
| Li (I) | Osteogenesis | Inhibit GSK3, which is a negative regulator of the Wnt signaling pathway. Activates b-catenin-mediated T cell factor (TCF)-dependent transcription during bone and cartilage fracture healing. b-catenin is known for its central role as signaling mediator in the canonical Wnt signaling pathway. |
| Zn (II) | Osteogenesis | In the cellular microenvironment, zinc is thought to stop the osteoclastic resorption process and stimulate the osteoblastic bone building process. |
| Mg (II) | Angiogenesis | Magnesium induces nitric oxide production in endothelial cells which is essentially the same mechanism that VEGF uses to induce angiogenesis. |
| Sr (II) | Osteogenesis | Strontium stimulates bone formation by a dual mode of action: a stimulatory role on bone-forming osteoblast cells and an inhibitory role on bone resorbing osteoclast cells. It activates CaSR and downstream signaling pathways. This promotes osteoblast proliferation, differentiation, and survival; at the same time, it induces apoptosis in osteoclast cells resulting in decreased bone resorption. Activation of the CaSR in osteoblasts simultaneously increases OPG production and decreases RANKL expression. OPG is a protein that inhibits RANKL-induced osteoclastogenesis by operating as a decoy receptor for RANKL. |
| Cu (I) | Angiogenesis | Copper-induced angiogenesis is probably caused by the upregulation of VEGF expression. Copper-induced toxicity: at high concentration, copper can generate ROS in the presence of superoxide radical anions (O2). These ROS induce oxidative damage to cells through DNA strand breaks and oxidation of bases. |
| Co (II) | Angiogenesis | It is believed that Co (II) ions induce hypoxia on the cellular level by stabilizing HIF-1a. Cells compensate for this hypoxic environment by expressing genes (such as VEGF and EPO) that promote neovascularization and angiogenesis. Cobalt-induced toxicity: like copper, cobalt also causes oxidative damage to cells by ROS. Increased soluble Co (II) ion levels might cause serious adverse reactions to the surrounding tissues as well as systemic toxicity. Co (II) ions can activate and increase bone resorbing osteoclast cell differentiation resulting in osteolysis aseptic implant loosening. |
| B (III) | Osteogenesis/ angiogenesis | Thought to play a role in the upregulation of TGF-b and VEGF. |
| Mn (II)/(III) | Osteogenesis | Thought to have implications in the PTH signaling pathway, a key regulator of calcium. MnSOD is believed to neutralize the formation of ROS, which contribute to increased osteoclastogenesis and decreased osteoblastogenesis. |
| Si (IV) | Osteogenesis/ angiogenesis | Has been shown to induce angiogenesis by upregulating NOS leading to increased VEGF production. Osteogenic mechanisms are not well understood, but Si (IV) has been shown to play a vital role in the mineralization process. |