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

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Abstract

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.

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Funding

The current study is supported by Science Fund of Medical University of Varna, Bulgaria (Grant No. 15004).

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  1. Department of Pharmacology and Clinical Pharmacology and Therapeutics, Medical University of Varna, 55 Marin Drinov Str, 9002, Varna, Bulgaria

    Silvia Gancheva & Maria Zhelyazkova-Savova

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  1. Silvia Gancheva
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  2. Maria Zhelyazkova-Savova
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Contributions

MZ designed the study, SG and MZ contributed to the experimental work and statistical analysis. SG prepared the first draft of the paper. MZ revised the paper.

Corresponding author

Correspondence to Silvia Gancheva.

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Conflict of interest

Silvia Gancheva and Maria Zhelyazkova-Savova declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

The study was performed on experimental animals. The use of experimental animals was ethically approved by the Commission of Foods Safety in the Bulgarian Ministry of Agriculture and Foods (Document No. 140/2016) and was conducted in agreement with the National Policies and the Council Directive (2010/63/EU). Informed consent statement about human rights is not applicable.

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Gancheva, S., Zhelyazkova-Savova, M. Are Bisphosphonates Associated with Adverse Metabolic and Cognitive Effects? A Study in Intact Rats and Rats Fed High-Fat High-Fructose Diet. Calcif Tissue Int 107, 41–51 (2020). https://doi.org/10.1007/s00223-020-00684-5

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