Are Bisphosphonates Associated with Adverse Metabolic and Cognitive Effects? A Study in Intact Rats and Rats Fed High-Fat High-Fructose Diet

Osteocalcin, known as a bone gla protein, is considered a regulator of energy metabolism and behavior in its undercarboxylated form (ucOC). Antiresorptive drugs, such as alendronate, reduce serum level of ucOC. The purpose of the current study was to verify if alendronate might impact on energy metabolism and animal behavior by reducing ucOC level and to find out if the presence of metabolic alterations would further worsen these potential adverse effects. Four groups of male Wistar rats (12 per group) were used: a control group, a group receiving high-fat high-fructose diet (HFHF), a group treated with alendronate, and a group receiving alendronate and HFHF. Alendronate was administered subcutaneously in a dose of 50 mcg/kg thrice weekly. Study duration was 15 weeks. Animals were tested for locomotion, anxiety and spatial memory. Glucose and insulin tolerance tests evaluated the glucose metabolism. Visceral obesity was assessed by the weight of right retroperitoneal fat pads. Concentration of ucOC was measured in the serum. Alendronate reduced serum ucOC concentration, increased fasting blood glucose level, and worsened insulin sensitivity. It did not increase visceral adiposity. Fat index was negatively correlated with ucOC in all animals and in the alendronate-treated rats. Alendronate worsened spatial memory of the animals and ucOC levels correlated positively with their cognitive performance.