Effects of alendronate and vitamin D on metabolomic profiles in a rat model of osteoporosis

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

Osteoporosis is a progressive bone disease and a significant global medical issue, which places a serious economic and health burden on individuals, families and societies. It is well known that early diagnosis of osteoporosis has a vital role in reducing the burden and complications of excessive bone resorption. It is also known that bisphosphonate drugs play a key role in limiting bone loss. Our study hypothesis was that the identification of metabolites in plasma may serve as a diagnostic mechanism for measuring the extent of bisphosphonate drug suppression of bone loss in patients following long-term bisphosphonate therapy. Our objectives were first, to establish a metabolomic profile in a rat model of osteoporosis that is characteristic of the osteoporosis phenotype by using LC-MS/MS chromatography. Secondly, we wanted to characterize specific metabolites in this rat model that might serve as indicators of bisphosphonate-induced suppression of bone remodeling in osteoporosis. In addition to this work, we also performed Receiver Operator Characteristic (ROC) curve analysis of the metabolomic data to identify potential osteoporosis biomarkers. We also determined the correlation between bone mineral density and specific plasma metabolites in an effort to create an osteoporosis screening tool for use in clinical practice. To perform the metabolomic analysis we used a commercially available metabolomics kit (Biocrates p180), which was run on a Sciex Qtrap 4000 mass spectrometer equipped with an Agilent HPLC system. The study subjects were divided into three experimental groups: control rats dosed with vehicle, rats dosed with 0.12mg/kg alendronate twice weekly, and a third group of rats dosed with a combination of alendronate and vitamin D. Plasma from the three groups of rats was collected at baseline, and then at the 8-week study endpoint and subjected to metabolomics analysis and in vivo micro CT scan measurement to accurately determine bone volume. Our findings showed that alendronate regulated several key plasma metabolites, notably certain amino acids, a number of lipids, and glucose. These metabolites are likely involved in the processes of bone resorption and bone formation. A distinct metabolite “fingerprint” was detected following the drug treatment between control and treated groups, with distinct metabolic changes seen in the treated groups compared to the control groups. Our results indicated that there was a correlation between 4 metabolites (proline, trans-hydroxyproline, histamine and methionine) and CT-measured bone volume. These findings suggest that the use of metabolomic profiling as a clinical research tool holds great promise for elucidating both the biological activity and the toxicity of bisphosphonate drugs on bone burden. Such an approach would be of significant value in gauging the impact of long-term bisphosphonate drug usage in osteoporosis patients, in assessing the effectiveness of osteoporosis therapy, and the avoidance of bisphosphonate-related side effects such as osteonecrosis of the jaw.