Effect of verapamil on bone mass, microstructure and mechanical properties in type 2 diabetes mellitus rats

Abstract

Background Verapamil was mainly used to treat hypertension, cardiovascular disease, inflammation and improve blood glucose in patients with diabetes, but its effects on bone mass, microstructure and mechanical properties were unclear. This study described the effects of verapamil on bone mass, microstructure, macro and nano mechanical properties in type 2 diabetic rats. Methods Rat models of type 2 diabetes were treated with verapamil at doses of 4, 12, 24 and 48 mg/kg/day by gavage respectively, twice a day. After 12 weeks, all rats were sacrificed under general anesthesia. Blood glucose, blood lipid, renal function and biochemical markers of bone metabolism were obtained by serum analysis, Micro-CT scanning was used to assess the microstructure parameters of cancellous bone of femoral head, three-point bending test was used to measure maximum load and elastic modulus of femoral shaft, and nano-indentation tests were used to measure indentation moduli and hardnesses of longitudinal cortical bone in femoral shaft, longitudinal and transverse cancellous bones in femoral head. Results Compared with T2DM group, transverse indentation moduli of cancellous bones in VER 24 group, longitudinal and transverse indentation moduli and hardnesses of cancellous bones in VER 48 group were significantly increased (p < 0.05). Furthermore, the effects of verapamil on blood glucoses, microstructures and mechanical properties in type 2 diabetic rats were dependent on drug dose. Starting from verapamil dose of 12 mg/kg/day, with dose increasing, the concentrations of P1NP, BMD, BV/TV, Tb. Th, Tb. N, maximum loads, elastic moduli, indentation moduli and hardnesses of femurs in rats in treatment group increased gradually, the concentrations of CTX-1 decreased gradually, but these parameters did not return to the level of the corresponding parameters of normal rats. Verapamil (48 mg/kg/day) had the best therapeutic effect. Conclusion Verapamil treatment (24, 48 mg/kg/day) significantly affected nano mechanical properties of the femurs, and tended to improve bone microstructures and macro mechanical properties of the femurs, which provided guidance for the selection of verapamil dose in the treatment of type 2 diabetic patients.

Verapamil and Its Role in Diabetes

“…Additionally, positive findings were revealed by Hong et al in mouse models of T2D, who demonstrated for the first time new mechanistic insights and novel links between TXNIP and proinflammatory cytokines and microRNA signaling [50]. Furthermore, latest research results by Wu et al revealed positive effects of verapamil use in type 2 diabetic rats on bone mass, microstructure as well as macro-and nano mechanical properties of the femur [64]. Taken together these several positive effects emphasize the important role of TXNIP and its effects on the pancreatic β-cell and TXNIP expression in T2D and underline through various systemic and cellular effects its potential as an adjunctive therapeutic approach.…”

Advanced Progress of the Relationship Between Antihypertensive Drugs and Bone Metabolism

“…An earlier animal experiment conducted by Samnegård et al 61 showed that verapamil had no significant effect on bone metabolism in weight-bearing bones of 5-week-old to 6-week-old female rats, but increased bone formation and BMD in nonweight-bearing bones. A further animal experiment 62 showed that verapamil increased femoral BMD in 7-week-old diabetic male mice, with the maximum dose (48 mg•[kg/d] −1 ) having the most significant effect, suggesting that verapamil protected the bone in a dose-dependent manner. Rejnmark et al 63 conducted a sizable case-control study in Denmark using nationwide computerized registers.…”