In Vivo and Ex Vivo Effects of Metformin on Alterations of Bone Metabolism Associated with Fructose-Induced Metabolic Syndrome in Rats

FELICE, JUAN IGNACIO; SEDLINSKY, CLAUDIA; CORTIZO, ANA MARÍA; MOLINUEVO, MARÍA SILVINA; GANGOITI, MARÍA VIGINIA; TOLOSA, MARÍA JOSÉ; SCHURMAN, LEÓN; MCCARTHY, ANTONIO DESMOND

Boston, Massachusetts

Encuentro; The Endocrine Society's 93rd Annual Meeting & Expo; 2011

The Endocrine Society

Several clinical studies have shown that the Metabolic Syndrome (MS) is associated with a decrease in bone mass, and with an increase in the rate of non-vertebral osteoporotic fractures. We have recently found that orally administered Metformin induces osteogenic effects in rats, promoting the osteoblastic commitment of bone marrow progenitor cells (BMPC) and increasing bone lesion repair. In the present study we evaluated the effects of fructose-induced MS on bone metabolism in rats, and the possible modulation of these effects by orally administered Metformin. Male young Sprague Dawley rats (200g) were divided into 4 groups: C (no treatment), M (100mg/kg body weight/day Metformin in drinking water), F (10% fructose in drinking water) and FM (Fructose+Metformin in drinking water). All treatments were continued for 3 weeks, after which blood samples were taken prior to animal sacrifice by neck dislocation under anesthesia. Femurs were immediately dissected to obtain BMPC, and for evaluation of metaphyseal microarchitecture (trabecular volume and osteocytic density) by Hematoxilin-Eosin staining. BMPC were cultured in an osteogenic medium (with ascorbic acid and b-glycerophosphate) for 2-3 weeks and then evaluated for alkaline phosphatase activity (ALP), type 1 collagen secretion and extracellular mineralization. An increase in non-fasting blood glucose and triglycerides was observed in F versus C group, compatible with the onset of MS. After osteogenic induction, BMPC from F group showed a significant decrease in ALP (82% of C, p<0.05), type 1 collagen secretion (62% of C, p<0.01) and mineralization (81% of C, p<0.05). Metformin co-treatment (FM group) did not modulate this Fructose-induced decrease in ALP; however, it partly reverted the decrease in collagen secretion (74% of C), and completely abrogated the Fructose-induced inhibition of mineralization (103% of C). Analysis of femoral metaphyses showed that Fructose alone induced a decrease in trabecular volume (88% of C, p<0.05) and in osteocyte density (79% of C, p<0.05). Metformin co-treatment (FM group) showed a tendency to revert these decreases (96% of C for trabecular volume; 88% of C for osteocyte density). These results show for the first time, (a) that Fructose-induced MS in rats decreases the osteogenic potential of BMPC, additionally impairing trabecular bone microarchitecture; and (b) that these deleterious effects on bone can be partially or totally reverted by oral Metformin treatment.