## 5 Conclusions  
This systematic review aimed to investigate the biological effects of strontium-doped calcium phosphate biomaterials, focusing on their potential in bone therapy. The incorporation of strontium into calcium phosphate-based biomaterials has shown promising results in enhancing bone metabolism, osteoblast proliferation, and tissue regeneration. The review identified robust in vivo and in vitro evidence from various studies indicating that strontium-doped biomaterials can effectively stimulate osteoblast differentiation, proliferation, and new bone formation while inhibiting osteoclast activity, through the activation of key signaling pathways such as Wnt/\(\beta\)-catenin, BMP-2, Runx2, and ERK. The results also highlight the importance of the release profile of strontium ions, which plays a critical role in determining the biocompatibility and therapeutic effectiveness of the biomaterials. Controlled and sustained release of strontium is essential for achieving the desired biological effects without causing toxicity. The studies reviewed showed a wide  
Figure 3: Schematic representation of the effects of doping calcium phosphate-based biomaterials with strontium ions on biological events, from strontium to release into the biological medium to novel bone formation. Strontium ion release from the biomaterial [12; 19; 20; 21; 23; 30; 31; 37; 40; 44; 45; 47; 48; 52; 53; 54; 56; 54; 54; 57; 58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162; 163] Events, these cells turn into osteocytes, which produce mineralized tissue [36; 37; 43; 49; 50; 57] and novel bone formation [18; 24; 33; 34; 36; 43; 49; 50; 51; 53; 54; 56; 61; 63]. Strontium also induces the release of angiogenic factors, enhancing tissue regeneration [25; 31; 35; 43; 48; 54]. Additionally, its effects on monocyte cells through OPG [31; 35; 48; 63], Trance [18] and RANKL [18; 22; 29; 58] decrease osteoclast osteogenesis [18; 21; 22; 29], with reduced Pit [62], TRAP [21; 49], CAII [21] and osteoclast activity [18; 49; 62], resulting in lower bone resorption [58]. Together, these events contribute to novel bone formation. Arrows indicate molecules, genes, or events that are upregulated (\(\uparrow\)) or downregulated (\(\downarrow\)). Each number represents a reference providing evidence for the indicated event. range of strontium release concentrations, from 0.5 ppm to over 20,000 ppm, indicating the need for careful optimization of the release kinetics to balance efficacy and safety, and revealing the dose-dependent nature of strontium's biological effects. At lower concentrations (0.5% to 2.5%), strontium-doped biomaterials are non-cytotoxic and promote osteoblast activity and new bone formation. Moderate concentrations (2.5% to 5%) continue to support high osteoblast differentiation and proliferation with moderate osteoclast inhibition. However, higher concentrations (10% to 20%) exhibit increased cytotoxicity, reducing the overall efficacy of bone regeneration. This comprehensive analysis supports the potential of strontium-doped calcium phosphate biomaterials as a promising tool for bone tissue engineering and regenerative medicine. Conceptualization, J.A.C. and G.A. ; methodology, J.A.C., J.D., F.D. and G.A. ; validation, M.R.M., C.F.M. and G.A. ; formal analysis, C.F.M. and G.A. ; investigation, J.A.C., J.D., F.D., M.R.M., C.F.M. and G.A. ; writing--original draft preparation, J.A.C., J.D., F.D. and G.A. ; writing--review and editing, C.F.M. and G.A. ; supervision, C.F.M. and G.A. All authors have read and agreed to the published version of the manuscript. This research received no external funding. Not applicable.