(1) Background: Bone substitutes are essential in orthopaedic surgery to fill up large bone defects. Thus, the aim of the study was to compare diverse bone fillers biomechanically to each other in a clinical-relevant test set-up and to detect differences in stability and handling for clinical use. (2) Methods: This study combined compressive strength tests and screw pullout-tests with dynamic tests of bone substitutes in a clinical-relevant biomechanical fracture model. Beyond well-established bone fillers (ChronOS^TM Inject and Graftys^® Quickset), two newly designed bone substitutes, a magnesium phosphate cement (MPC) and a drillable hydrogel reinforced calcium phosphate cement (CPC), were investigated. (3) Results: The drillable CPC revealed a comparable displacement of the fracture and maximum load to its commercial counterpart (Graftys^® Quickset) in the clinically relevant biomechanical model, even though compressive strength and screw pullout force were higher using Graftys^®. (4) Conclusions: The in-house-prepared cement allowed unproblematic drilling after replenishment without a negative influence on the stability. A new, promising bone substitute is the MPC, which showed the best overall results of all four cement types in the pure material tests (highest compressive strength and screw pullout force) as well as in the clinically relevant fracture model (lowest displacement and highest maximum load). The low viscosity enabled a very effective interdigitation to the spongiosa and a complete filling up of the defect, resulting in this demonstrated high stability. In conclusion, the two in-house-developed bone fillers revealed overall good results and are budding new developments for clinical use.