## 4 Discussion
### In Vitro Studies
[64] found no difference compared to the control and its biomaterial releases up to 50 ppm in culture medium after 24 h, while [PERSON] et al. [62] reported that the addition of Sr had an inhibitory effect on ALP. However, considering that the effect of strontium on osteoblastic cells is dose-dependent and that both studies did not evaluate the amount of strontium released from the biomaterials, it is possible that the inhibitory effects may be associated with a release of strontium ions at toxic concentrations. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Article** & **Animal Type** & **Test Performed** & **Effects** \\ \hline [PERSON] et al. [56] & Sprague-Dawley rats & Histology, histomorphometry, and SEM & Increased new bone formation \\ \hline [PERSON] et al. [21] & Male Balb/c mice & \begin{tabular}{c} Intramuscular implantation of \\ Sr-BCP scaffolds; histological \\ analysis, TRAP staining, IHC \\ staining for CTSK \\ \end{tabular} & \begin{tabular}{c} Enhanced ectopic osteogenesis and \\ reduced osteoclastogenesis compared to \\ BCP scaffolds \\ \end{tabular} \\ \hline [PERSON] et al. [21] & Sprague-Dawley rats & 3D fused PET-CT image & Similar to the control \\ \hline [PERSON] et al. [58] & Rats & \begin{tabular}{c} Histology, histomorphometry, and \\ immunohistochemistry \\ \end{tabular} & Increased bone area \\ \hline [PERSON] et al. [23] & New Zealand white rabbits & VEGF histological marking & Increased angiogenesis \\ \hline [PERSON] et al. [24] & New Zealand white rabbits & Histology, X-ray & Accelerated bone repair \\ \hline [PERSON] et al. [27] & Wistar rats & Histology & Similar to the control \\ \hline [PERSON] et al. [30] & Rat calvarial defect model & Micro-CT, histological analysis & \begin{tabular}{c} Enhanced bone and blood vessel \\ regeneration, highest in 10\% Sr-doped \\ mmHg group \\ \end{tabular} \\ \hline [PERSON] et al. [33] & New Zealand rabbits & 3D-CT analysis, histological evaluation & \
\begin{tabular}{c} Significant bone formation and faster \\ degradability in Sr10-TBC group, new \\ bone area ratio higher in Sr10-TBC group \\ compared to TBC \\ \end{tabular} \\ \hline [PERSON] et al. [34] & Sprague-Dawley rats & X-ray, Micro-CT, removal torque &
\begin{tabular}{c} Accelerated bone repair in the 10\% \\ concentration and increased removal \\ torque (5 and 10\%). \\ \end{tabular} \\ \hline \hline \end{tabular}
\end{table} 
Table 5: Parameters evaluated in the in vivo studies. The ALP activity in bone tissue is usually high. This protein plays an essential role in the modulation of bone tissue activity since it is responsible for providing phosphate ions to the formation of the mineralized extracellular matrix [71]. The high prevalence of articles that evaluate the effect of the biomaterial with strontium on this protein is due to its essential role in the formation of bone tissue. It occurs since ALP is an important confirmatory parameter that Sr is working on each biomaterial model tested. On the other hand, limiting the investigation to ALP does not add much to the understanding of the mechanisms of action of the ion on the cells/tissues. In fact, other proteins should be  
\begin{table}
\begin{tabular}{c c c c} \hline \hline
considered in future studies to elucidate the cellular response promoted by the presence of the biomaterial. The cytotoxicity of strontium-doped biomaterials was less frequently reported. [PERSON] et al. [27] concluded that the presence of strontium increased the cytotoxicity of the biomaterial compared with control. In that study, materials with the theoretical incorporation of strontium of 10 and 20% were analyzed, but no results were reported regarding the amount of this ion released, complicating the analysis of the possible causes of cytotoxicity. Since other studies with similar percentages of substitution have obtained divergent results [32], it is not possible to determine the molar ratio of calcium substitution by strontium that promotes in vitro toxicity.