Evocalcet derivative attenuates diabetic osteoporosis and promotes osteogenesis

doi:10.12092/j.issn.1009-2501.2026.09.005

Abstract

Abstract:

AIM: To evaluate the ameliorative effect of calcium-sensing receptor (CaSR) agonist evocalcet derivative on osteoporosis in diabetic mice and its stimulative effect on osteogenesis. METHODS: The C57BL/6 mice were randomly divided into a normal control group, a model group, and an evocalcet derivative group. A type 2 diabetes mellitus (T2DM) mouse model was established by a high-fat diet combined with intraperitoneal injection of low-dose streptozotocin (30 mg/kg). The mice in the treatment group were daily administered with an evocalcet derivative (0.6 mg/kg, i.g.) in 0.5% CMC-Na solution, while the mice in other groups were administered with an equal volume of 0.5% CMC-Na solution for 6 weeks. During the administration period, the body weight and the fasting blood glucose levels of the mice were dynamically monitored at 2-week intervals. Serum calcium (Ca) and phosphorus (Pi) levels were measured in each group. Micro-CT was used to detect bone mineral density and bone microstructure, and a three-point bending biomechanics test was performed to detect the mechanical parameters at the mid-shaft of the mice femur. HE staining and ALP staining were respectively used to detect bone histomorphology and osteoblasts, and Western blot was carried out to measure the protein expression of CaSR downstream molecules and osteogenic-related molecules. RESULTS: After intervention with an evocalcet derivative, serum Ca and Pi levels in mice were significantly reduced (P<0.05). Micro-CT showed a significant increase in bone mineral density (P<0.05) and in trabecular thickness (P<0.05), and a significant decrease in trabecular bone separation (P<0.001); moreover, the area percentage of trabecular bone was dramatically enhanced (P<0.05) at the proximal end of the mice tibia. Biomechanical tests showed a significant elevation in maximum load, maximum deformation, and elastic deformation (P<0.05) at the diaphysis of the mice femur. As compared to the model group, the drug treatment induced a significant increase (P<0.01) in the number of osteoblasts. The Western blot results showed that the evocalcet derivative elevated the expression ratio of p-ERK/ERK (P<0.001) and up-regulated protein expression (P<0.05) of Runx2 and COL-Ⅰ in the bone tissue of T2DM mice. CONCLUSION: The new generation calcimimetic agent evocalcet derivative could directly act on CaSR in bone, followed by stimulating its downstream ERK/Runx2/COL-Ⅰ signaling pathway, thereby improving diabetic osteoporosis by exerting its osteogenic effect.

Key words: diabetic osteoporosis, evocalcet derivative, bone, osteoblastic differentiation

CLC Number:

R965.2

Meixuan CHEN, Kai LIU, Yuan XU, Yuan HUA, Yixun GUO, Kai ZHANG, Yan ZHANG. Evocalcet derivative attenuates diabetic osteoporosis and promotes osteogenesis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(9): 1193-1199.

Figures/Tables 9

Fig.1 Chemical structures of evocalcet and its derivative

Fig.2 Experimental timeline

Fig.3 Changes in body weight and fasting blood glucose of mice A: body weight; B: fasting blood glucose; #P<0.05, ##P<0.01, ###P<0.001, compared with control group.

Fig.4 Ca and Pi levels in serum of mice A: serum calcium level; B: serum phosphorus level; ##P<0.01, ###P<0.001, compared with control group; &P<0.05, compared with model group.

Fig.5 Bone mineral density, structural parameters, and three-dimensional architecture of trabecular bone at the proximal tibia A: 3D structure of trabecular bone; B: biological parameters of trabecular bone #P<0.05,##P<0.01, compared with control group; &P<0.05,&&&P<0.001, compared with model group.

Fig.6 Mechanical parameters of the mid-shaft femur #P<0.05, ##P<0.01, ###P<0.001, compared with control group; &P<0.05, compared with model group.

Fig.7 HE staining of the proximal tibia A: HE staining; B: area percentage of trabecular bone; ###P<0.001, compared with control group; &P<0.05, compared with model group.

Fig.8 ALP staining of the proximal tibia A: ALP staining; B: ALP staining-positive intensity; ###P<0.001, compared with control group; &&P<0.01, compared with model group.

Fig.9 Protein expression of osteogenic factors in femur A-C: immunoblotting detection; D: quantitative expression of proteins; ##P<0.01, ###P<0.001, compared with control group; &P<0.05,&&&P<0.001, compared with model group.

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