Multi-fragment fractures are still a challenge:​ current clinical practice relies on plates and screws. Treatment of fractures of the proximal humerus has the intra-operative risk of articular damage when inserting multiple screws. Distal-varus collapse of the head is a frequent complication in osteoporotic patients. The aim of this biomechanical study was to investigate if an Innovative-cement-technique (the screws are replaced by injection of cement) provides the same or better stability of the reconstructed head compared to the Standard-technique (locking screws). A four-fragment fracture was simulated in twelve pairs of humeri, with removal of part of the cancellous bone to simulate osteoporotic “eggshell” defect. One humerus of each pair was repaired either with a Standard-technique (locking plate, 2 cortical and 6 locking screws), or with the Innovative-cement-technique (injection of a partially-resorbable reinforced bone substitute consisting of PMMA additivated with 26% beta-TCP). Cement injection was performed both in the lab and under fluoroscopic monitoring. The reconstructed specimens were tested to failure with a cyclic force of increasing amplitude. The Innovative-cement-technique withstood a force 3.57 times larger than the contralateral Standard reconstructions before failure started. The maximum force before final collapse for the Innovative-cement-technique was 3.56 times larger than the contralateral Standard-technique. These differences were statistically significant. The Innovative-cement-technique, based on the reinforced bone substitute, demonstrated better biomechanical properties compared to the Standard-technique. These findings, along with the advantage of avoiding the possible complications associated with the locking screws, may help safer and more effective treatment in case of osteoporotic multi-fragment humeral fractures.