The Biological Effects of Magnesium-Based Implants on the Skeleton and Their Clinical Implications in Orthopedic Trauma Surgery

Abstract

Magnesium (Mg)-based implants have evolved as a promising innovation in orthopedic trauma surgery, with the potential to revolutionize the treatment of bone diseases, including osteoporotic fractures and bone defects. Available clinical studies mostly show excellent patient outcomes of resorbable Mg-based implants, without the need for subsequent implant removal. However, the occurrence of radiolucent zones around Mg-based implants seems to be a noticeable drawback for a more widespread clinical use. Mechanistically, both in vivo and in vitro studies demonstrated beneficial effects on the formation of new bone, a unique characteristic of Mg-based implants. In this regard, Mg has been shown to exert pleiotropic functions on osteogenic differentiation and migration of osteoblasts and their precursors. Additionally, collective evidence suggests that Mg-based implants promote angiogenesis in newly formed bone and exert immunomodulatory effects in the bone microenvironment. Likewise, Mg-based implants and their degradation products were shown to inhibit bone resorption by impairing osteoclastogenesis. The purpose of this review is to provide a state-of-the-art summary of the clinical and basic science evidence regarding the performance of currently used Mg-based implants. In addition to the status of in vivo and in vitro research and clinical applications, future challenges and perspectives of Mg-based orthopedic implants are discussed.

Fig. 1.

Schematic illustration of the distribution of Mg (Mg²⁺) throughout the human organism and its primary storage locations. Artwork created with Biorender.com.

Fig. 2.

Mechanisms by which Mg-based implants promote bone healing and regeneration in in vitro and in vivo studies. (A) In vitro effects of Mg-based implants on bone cells. Mg (Mg²⁺) enhances the proliferation of mesenchymal stem cells (MSCs) and their differentiation into osteoblasts, leading to an increased expression of key osteoblastic markers (RUNX2, ALPL, and OPN). It also activates several key signaling pathways, including the WNT/β-catenin, PI3K/AKT, and MAPK pathways. Mg promotes cell adhesion and migration, supporting osteoblast function, while inhibiting osteoclastogenesis, which together improve bone formation and inhibit bone resorption. Moreover, Mg increases cell viability, enhancing the regenerative capacity of bone marrow stem cells (BMSCs). (B) In vivo mechanisms of Mg-based implants in bone healing and regeneration. Mg implants have been demonstrated to stimulate angiogenesis by increasing the expression of VEGFA and to modulate the immune response through the differentiation of macrophages into an anti-inflammatory M2 phenotype, thereby reducing the production of pro-inflammatory cytokines (TNFα and IL1β). Additionally, Mg has been shown to enhance CGRP secretion from dorsal root ganglia (DRG), which stimulates osteoblast activity, inhibits osteoclastogenesis, and enhances MSC migration to the fracture site. Overall, these combined biological effects of Mg are considered to result in improved bone regeneration and fracture healing. Artwork created with Biorender.com.

Fig. 3.

Influence of magnesium ions on osteoblasts, immune cells, and osteoclasts. (A) Magnesium ions (Mg²⁺) have been shown to exert pleiotropic effects on the osteogenic differentiation and migration of osteoblasts and their precursors. The 3 signaling pathways, including RAS/RAF/MEK/ERK, WNT/β-catenin, and PI3K/AKT/mTOR, are essential parts of a global cellular response induced by Mg exposure that is considered to ultimately enhance osteogenesis. (B) Mg induces a switch in macrophage phenotype to M2 and increase the expression of anti-inflammatory markers CD206, IL10, and IL1ra while decreasing the expression of pro-inflammatory CCR7 and TNFα. Mg ions promote the expression of osteogenic-related cytokines BMP2 and VEGF and activate the BMP/SMAD pathway. This results in an immunoregulatory and osteogenic effect. (C) Mg-based implants may inhibit bone resorption through (i) a direct inhibitory effect of Mg ions on osteoclastogenesis and osteoclast function, (ii) an increase in local pH levels, and (iii) an inhibitory impact of released H₂ ions on osteoclastogenesis. (D) Mg ions enhance angiogenesis by stimulating the secretion of CGRP, which in turn up-regulates VEGFA and VEGFR2, key factors in the formation of new blood vessels. This angiogenic effect contributes to improved bone healing and regeneration.