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<p>Type 2 diabetes mellitus (T2DM) disrupts normal bone remodeling and increases fracture risk; however, most antidiabetic therapies offer limited skeletal protection. This study evaluated the metabolic and bone-protective effects of alogliptin and metformin against diabetes-associated bone loss. Molecular docking was performed against key bone remodeling regulators, such as osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK), and its ligand (RANKL). Additionally, MTT assay and combination index (CI) analyses were performed in UMR-106 osteoblast-like cells to evaluate potential synergistic effects. Furthermore, T2DM was induced in female Wistar rats using a high-fat diet and low-dose streptozotocin, followed by 8 weeks of treatment with alogliptin, metformin, and their combination. Diabetic control rats showed hyperglycemia, increased homeostasis model assessment of insulin resistance (HOMA-IR), elevated dipeptidyl peptidase-4 (DPP-4) enzymatic activity, increased inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6]), and disrupted bone remodeling, characterized by elevated RANKL and reduced OPG. Micro-CT revealed significant deterioration in trabecular and cortical bone microarchitecture, with reduced structural indices (bone volume/total volume [BV/TV], trabecular thickness [Tb.Th], trabecular number [Tb.N], connectivity density [Conn.D], and bone mineral density [BMD]) and increased trabecular separation (Tb.Sp). Histology and immunohistochemistry confirmed thinner trabeculae, more osteoclasts, greater marrow adiposity, and higher DPP-4/RANKL with lower OPG expression. Both monotherapies improved metabolic and skeletal parameters; however, the combination treatment produced greater therapeutic response, significantly improving glycemic control, attenuating inflammatory cytokines (TNF-α, IL-6) and osteoclastic markers (TRACP-5b, RANKL), restoring the OPG/RANKL balance, and preserving bone microarchitecture. Moreover, both alogliptin and metformin exhibited dose-dependent effects, and the 1:8 alogliptin-metformin ratio demonstrated strong synergism (CI 0.04388). These findings suggest that alogliptin-metformin co-therapy ameliorates diabetes-associated skeletal complications through modulation of DPP-4 activity and OPG/RANKL signaling.</p>

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Alogliptin-metformin synergy ameliorates diabetes-associated bone loss via modulation of DPP-4 activity and OPG/RANKL signaling

  • 期刊论文

  • 发表日期：

    2026年5月28日

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  • Tufail Ahmad,
  • Syed Sufian Ahmad,
  • Faraha Ahmed,
  • Md. Rafi Haider,
  • Divya Goel,
  • Divya Vohora,
  • Manju Sharma

摘要

Type 2 diabetes mellitus (T2DM) disrupts normal bone remodeling and increases fracture risk; however, most antidiabetic therapies offer limited skeletal protection. This study evaluated the metabolic and bone-protective effects of alogliptin and metformin against diabetes-associated bone loss. Molecular docking was performed against key bone remodeling regulators, such as osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK), and its ligand (RANKL). Additionally, MTT assay and combination index (CI) analyses were performed in UMR-106 osteoblast-like cells to evaluate potential synergistic effects. Furthermore, T2DM was induced in female Wistar rats using a high-fat diet and low-dose streptozotocin, followed by 8 weeks of treatment with alogliptin, metformin, and their combination. Diabetic control rats showed hyperglycemia, increased homeostasis model assessment of insulin resistance (HOMA-IR), elevated dipeptidyl peptidase-4 (DPP-4) enzymatic activity, increased inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6]), and disrupted bone remodeling, characterized by elevated RANKL and reduced OPG. Micro-CT revealed significant deterioration in trabecular and cortical bone microarchitecture, with reduced structural indices (bone volume/total volume [BV/TV], trabecular thickness [Tb.Th], trabecular number [Tb.N], connectivity density [Conn.D], and bone mineral density [BMD]) and increased trabecular separation (Tb.Sp). Histology and immunohistochemistry confirmed thinner trabeculae, more osteoclasts, greater marrow adiposity, and higher DPP-4/RANKL with lower OPG expression. Both monotherapies improved metabolic and skeletal parameters; however, the combination treatment produced greater therapeutic response, significantly improving glycemic control, attenuating inflammatory cytokines (TNF-α, IL-6) and osteoclastic markers (TRACP-5b, RANKL), restoring the OPG/RANKL balance, and preserving bone microarchitecture. Moreover, both alogliptin and metformin exhibited dose-dependent effects, and the 1:8 alogliptin-metformin ratio demonstrated strong synergism (CI 0.04388). These findings suggest that alogliptin-metformin co-therapy ameliorates diabetes-associated skeletal complications through modulation of DPP-4 activity and OPG/RANKL signaling.