## 4 Discussion
### Involvement of Signaling Pathways
The ERK pathway is known for its role in promoting osteogenic differentiation and angiogenesis, enhancing the expression of critical proteins like Runx2, BSP, and VEGF. [PERSON] et al. [21] showed that strontium-substituted hydroxyapatite coatings on polyetheretherketone (PEEK) implants enhance osseointegration and bone formation through the activation of the ERK pathway. This pathway's activation promotes the expression of osteogenic and angiogenic factors while simultaneously suppressing pathways such as p38, JNK, and AKT, involved in osteoclastogenesis, in a balance that is crucial for ensuring effective bone regeneration. [PERSON] et al. [35] demonstrated increased secretion of growth factors such as bFGF and VEGF in vivo, particularly in the presence of ceramic material implants containing strontium, which supports the role of the ERK pathway in enhancing vascularization and bone regeneration. Growth factors are of high relevance in bone metabolism and are also targets for stimulation during the development of smart materials. It has already been shown that the presence of strontium associated with calcium phosphate-based materials significantly increased the expression and release of bFGF and VEGF [23]. [PERSON] et al. [35] demonstrated in vivo that there was an increase in the secretion of both growth factors, especially in the presence of the ceramic material implant containing 8% strontium substitution. These data make it possible to hypothesize that this type of material can increase the vascularization in the implant site, which is essential to the process of regeneration of any lesion. [PERSON] et al. [28] proposed that the presence of a ceramic with 8% substitution of calcium ions by strontium can decrease TNF-a secretion while increasing OPG expression and decreasing RANK-L secretion. The combination of these factors could result, in vivo, in the reduction of inflammatory cells migration to the lesion site, thus accelerating the regeneration of the bone tissue. This hypothesis requires confirmation and the study of other inflammatory cytokines in addition to TNF-a, since [PERSON] et al. [23] have shown that there is an increase in the expression of PECAM-1 in the presence of strontium. Due to the complexity of the bone tissue, the increase in the expression of this gene could be related to inflammatory signaling, promoting an increase in the population of leukocytes. It could also provide further evidence that Sr-doped calcium phosphates favor the formation of new blood vessels, which is essential to the process of injury regeneration [23]. The literature evidence indicates that incorporating strontium into calcium phosphate-based biomaterials holds significant potential for enhancing bone regeneration through the activation of key signaling pathways such as Wnt/\(\beta\)-catenin, BMP-2, Runx2, and ERK. These pathways play vital roles in regulating osteoblast differentiation, mineralization, and angiogenesis, essential for effective bone tissue regeneration. Future studies should continue exploring these pathways and their interactions to optimize the design and functionality of strontium-doped biomaterials for bone repair and regeneration. In this systematic review, several limitations must be acknowledged. First, the search key was restrictive and may have missed studies involving more complex presentations of strontium-doped hydroxyapatite or other biomaterials. Second, the review focused primarily on in vitro and in vivo studies, potentially overlooking significant clinical correlations and results from human trials. Lastly, the limitation to complete reports might have excluded valuable data from published abstracts and other partial publications. Despite these limitations, the review provides substantial evidence supporting the positive effects of strontium incorporation into calcium phosphate-based biomaterials. Strontium has been shown to enhance osteogenic differentiation, mineralization, and cellular proliferation, while maintaining favorable cytocompatibility.