Does Metformin Treatment Influence Bone Formation in Patients with Nonalcoholic Fatty Liver Disease?

Abstract

Antidiabetic drug metformin that improves insulin sensitivity and used in the treatment of nonalcoholic fatty liver disease (NAFLD), may affect the bone health. Our study was designed to investigate a possible effect of metformin on bone formation marker, procollagen type I N-terminal propeptide (P1NP) in patients with NAFLD.

In a randomized, placebo controlled study, 63 patients with NAFLD were assigned to one of 2 groups: Group 1 received daily metformin and Group 2 received placebo. Metabolic parameters, insulin resistance markers, and P1NP were determined.

Although circulating P1NP levels did not differ significantly between the groups at baseline, at the end of the study, P1NP was significantly lower in patients treated with metformin than in the placebo group (p<0.007). Within-group analysis indicated that P1NP levels significantly decreased (p=0.023) in patients receiving metformin during 4-month follow-up period, while no change in P1NP was observed in placebo group (p=0.359). In general linear model metformin treatment was the only significant independent predictor of endpoint P1NP.

Metformin treatment was associated with decrease in P1NP levels in patients with NAFLD. The effect on P1NP was independent of glucose lowering effect and caused from exposure to metformin per se.

Key words

osteoporosis - osteoblast - metformin - procollagen type I N-terminal propeptide

• References

• 1 Li M, Xu Y, Xu M, Ma L, Wang T, Liu Y, Dai M, Chen Y, Lu J, Liu J, Bi Y, Ning G. Association between Nonalcoholic Fatty Liver Disease (NAFLD) and Osteoporotic Fracture in Middle-Aged and Elderly Chinese. J Clin Endocrinol Metab 2012; 97: 2033-2038
• 2 Pardee PE, Dunn W, Schwimmer JB. Non-alcoholic fatty liver disease is associated with low bone mineral density in obese children. Aliment Pharmacol Ther 2012; 35: 248-254
• 3 Syn WK, Choi SS, Liaskou E, Karaca GF, Agboola KM, Oo YH, Mi Z, Pereira TA, Zdanowicz M, Malladi P, Chen Y, Moylan C, Jung Y, Bhattacharya SD, Teaberry V, Omenetti A, Abdelmalek MF, Guy CD, Adams DH, Kuo PC, Michelotti GA, Whitington PF, Diehl AM. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 2011; 53: 106-115
• 4 Haukeland JW, Dahl TB, Yndestad A, Gladhaug IP, Løberg EM, Haaland T, Konopski Z, Wium C, Aasheim ET, Johansen OE, Aukrust P, Halvorsen B, Birkeland KI. Fetuin A in nonalcoholic fatty liver disease: in vivo and in vitro studies. Eur J Endocrinol 2012; 166: 503-510
• 5 Fernández-Real JM, Ortega F, Gómez-Ambrosi J, Salvador J, Frühbeck G, Ricart W. Circulating osteocalcin concentrations are associated with parameters of liver fat infiltration and increase in parallel to decreased liver enzymes after weight loss. Osteoporos Int 2010; 21: 2101-2107
• 6 Kanazawa I, Yamaguchi T, Yano S, Yamauchi M, Sugimoto T. Metformin enhances the differentiation and mineralization of osteoblastic MC3T3-E1 cells via AMP kinase activation as well as eNOS and BMP-2 expression. Biochem Biophys Res Commun 2008; 375: 414-419
• 7 Jang WG, Kim EJ, Bae IH, Lee KN, Kim YD, Kim DK, Kim SH, Lee CH, Franceschi RT, Choi HS, Koh JT. Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone 2011; 48: 885-893
• 8 Zhen D, Chen Y, Tang X. Metformin reverses the deleterious effects of high glucose on osteoblast function. J Diabetes Complications 2010; 24: 334-344
• 9 Vestergaard P, Rejnmark L, Mosekilde L. Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetologia 2005; 48: 1292-1299
• 10 Zinmam B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG, Paul G, Jones NP, Aftring RP, Viberti G, Kahn SE. and the A Diabetes Outcome Progression Trial Study Group . Effect of rosiglitazone, metformin and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab 2010; 95: 134-142
• 11 Vasikaran S, Eastell R, Bruyère O, Foldes AJ, Garnero P, Griesmacher A, McClung M, Morris HA, Silverman S, Trenti T, Wahl DA, Cooper C, Kanis JA. IOF-IFCC Bone Marker Standards Working Group . Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 2011; 22: 391-420
• 12 Sofer E, Boaz M, Matas Z, Mashavi M, Shargorodsky M. Treatment with insulin sensitizer metformin improves arterial properties, metabolic parameters, and liver function in patients with nonalcoholic fatty liver disease: a randomized, placebo-controlled trial. Metabolism 2011; 60: 1278-1284
• 13 Zinmam B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG, Paul G, Jones NP, Aftring RP, Viberti G, Kahn SE. and the A Diabetes Outcome Progression Trial Study Group . Effect of rosiglitazone, metformin and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab 2010; 95: 134-142
• 14 Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Kurioka S, Yano S, Sugimoto T. Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. J Clin Endocrinol Metab 2009; 94: 45-49
• 15 Cortizo AM, Sedlinsky C, McCarthy AD, Blanco A, Schurman L. Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture. Eur J Pharmacol 2006; 536: 38-46
• 16 Shah M, Kola B, Bataveljic A, Arnett TR, Viollet B, Saxon L, Korbonits M, Chenu C. AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass. Bone 2010; 47: 309-319
• 17 Wu W, Ye Z, Zhou Y, Tan WS. AICAR, a small chemical molecule, primes osteogenic differentiation of adult mesenchymal stem cells. Int J Artif Organs 2011; 34: 1128-1136
• 18 Kasai T, Bandow K, Suzuki H, Chiba N, Kakimoto K, Ohnishi T, Kawamoto S, Nagaoka E, Matsuguchi T. Osteoblast differentiation is functionally associated with decreased AMP kinase activity. J Cell Physiol 2009; 221: 740-749
• 19 Gao Y, Li Y, Xue J, Jia Y, Hu J. Effect of the anti-diabetic drug metformin on bone mass in ovariectomized rats. Eur J Pharmacol 2010; 635: 231-236
• 20 Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Jia CH, Wen ZH, Jin DD, Bai XC. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 2011; 112: 2902-2909
• 21 Wang C, Li H, Chen SG, He JW, Sheng CJ, Cheng XY, Qu S, Wang KS, Lu ML, Yu YC. The skeletal effects of thiazolidinedione and metformin on insulin-resistant mice. J Bone Miner Metab 2012; 30: 630-637
• 22 Jeyabalan J, Viollet B, Smitham P, Ellis SA, Zaman G, Bardin C, Goodship A, Roux JP, Pierre M, Chenu C. The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing. Osteoporos Int 2013; 24: 2659-2670