Selenium-Doped Calcium Hydroxide Nanoparticles Inhibit Osteoclasts and Promote Osteogenesis for Osteoporosis Treatment.

PURPOSE: Osteoporosis is characterized by an acidic and oxidative stress microenvironment driven by excessive osteoclast activity, which impairs osteogenesis and leads to dysregulated bone remodeling. This study aims to develop selenium-doped calcium hydroxide nanoparticles (SeCaNP) to simultaneously inhibit osteoclastogenesis and promote osteogenic differentiation, thereby providing a multi-targeted microenvironment-modulating strategy for osteoporosis therapy. METHODS: SeCaNP was synthesized via a coprecipitation method and characterized using TEM, XRD, and acid-neutralization assays. In vitro, bone marrow-derived macrophages (BMMs) and bone marrow mesenchymal stem cells (BMSCs) were co-cultured with SeCaNP to assess osteoclast activity and osteogenic differentiation. In vivo, an ovariectomy (OVX)-induced osteoporosis mouse model was established and treated with local injections of SeCaNP. Therapeutic efficacy and biosafety were systematically evaluated. RESULTS: SeCaNP significantly upregulated GPx1 expression, effectively scavenged reactive oxygen species (ROS), and neutralized the intracellular acidic microenvironment, thereby markedly inhibiting osteoclastogenesis. Concurrently, SeCaNP promoted BMSC cytoskeletal remodeling and significantly enhanced osteogenic differentiation and mineralization, upregulating key markers (RUNX2, ALP, OPN, OCN). RNA-seq analysis indicated that SeCaNP regulated osteogenesis-related membrane signaling platforms and extracellular matrix assembly. In vivo, SeCaNP treatment significantly ameliorated OVX-induced bone loss, notably improving bone mineral density (BMD) and trabecular microarchitecture parameters (BV/TV, Tb.N, Tb.Th). Furthermore, SeCaNP upregulated BMP-2 expression and serum BALP levels without inducing systemic toxicity. CONCLUSION: SeCaNP effectively overcomes the limitations of conventional osteoporosis therapies by integrating acid neutralization, antioxidant properties, and osteogenic support. Through a dual-regulatory mechanism that inhibits bone resorption and promotes bone formation, SeCaNP successfully reconstructs the pathological bone microenvironment and reverses bone loss, highlighting its significant potential as a microenvironment-modulating biomaterial for anti-osteoporotic therapy.