Effect of local application of biphosphonates on improving peri-implant osseointegration in type-2 diabetic...

Type 2 diabetes mellitus (T2DM), a leading cause of osteoporosis, remains a contraindication for bone implant therapy. Although associated with side effects when systemically administered, biphosphonates (BPs) play a positive role in diabetic osteoporosis treatment. We hypothesized that local BP therapy would prevent decayed implant osseointegration under T2DM conditions. To assess cell proliferation and determine the optimal BP concentration, bone marrow-derived mesenchymal stem cells (BMSCs) and bone marrow macrophages (BMMs) were treated with BPs at various relatively low concentrations (10^-9 mmol/L) for different periods of time. Our in vitro study results demonstrated that BP application reversed the process by which high glucose inhibits bone formation and stimulates bone resorption through osteoclast-specific gene and protein expression (P<0.05). In vivo, fat accumulation and insulin resistance were induced in T2DM rats. We used crosslinked hyaluronic acid as the drug delivery vehicle for BPs to ensure that BPs administered at a dose of 30 µg/kg could settle into the prepared hole in rats. Thereafter, implants were inserted into cylindrical holes of a specific size, created parallel to the long axis of the femora. The outcomes of the in vivo study revealed that BPs promoted bone formation, which reversed the reduction in the DM group according to double fluorescence labeling, micro-CT, biomechanical and histomorphometric analyses (P<0.05). Furthermore, intergroup comparisons revealed significant correlation coefficients (P<0.05) between the micro-CT and biomechanical parameters. Therefore, local administration of BPs could stimulation bone remodeling and represent an effective treatment strategy for preventing decayed implant osseointegration under T2DM conditions.