The Synergistic Effect of Simvastatin and Hydroxyapatite in Bone Regeneration: A Systematic Review and Meta-Analysis

Abstract

Purpose: Reconstruction of osseous defects remains a major challenge in oral and maxillofacial surgery. Hydroxyapatite (HA) is widely used because of its osteoconductive properties but lacks intrinsic osteoinductive potential. Simvastatin (SIM), an HMG-CoA reductase inhibitor, has demonstrated osteogenic potential through upregulation of bone morphogenetic protein-2, vascular endothelial growth factor, and osteoblastic differentiation markers. This systematic review and meta-analysis aimed to evaluate whether incorporation of simvastatin into hydroxyapatite scaffolds enhances bone regeneration compared with hydroxyapatite alone or untreated controls.

Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. Electronic searches of PubMed, Embase, Scopus, and Web of Science were performed through September 2025. In vitro, in vivo, and clinical studies evaluating SIM incorporated into HA scaffolds for bone regeneration were included. Primary outcomes included bone volume fraction, bone mineral density, and histologic bone formation. Risk of bias in animal studies was assessed using the SYRCLE tool. Random-effects meta-analysis was performed for eligible quantitative in vivo studies.

Results: Eighteen studies met inclusion criteria, including eight in vitro investigations, seven animal studies, and three clinical studies. Three animal studies provided sufficient data for meta-analysis. Pooled standardized mean difference demonstrated significant improvement in bone regeneration with SIM+HA compared with HA or control (Hedges g = 2.05; 95% CI: 0.86–3.23; p < 0.001). Risk-of-bias assessment showed generally low selection bias but unclear reporting of blinding.

Conclusions: Simvastatin-loaded hydroxyapatite scaffolds significantly enhance bone regeneration in preclinical models.¹⁰,¹¹ Standardized dosing strategies and well-designed randomized clinical trials are required for translation into routine clinical practice.