Top

Published in:

Open Access 01-10-2013 | Original Article

The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing

Authors: J. Jeyabalan, B. Viollet, P. Smitham, S. A. Ellis, G. Zaman, C. Bardin, A. Goodship, J. P. Roux, M. Pierre, C. Chenu

Published in: Osteoporosis International | Issue 10/2013

Abstract

Summary

The present study shows no adverse effects of the anti-diabetic drug metformin on bone mass and fracture healing in rodents but demonstrates that metformin is not osteogenic in vivo, as previously proposed.

Introduction

In view of the increased incidence of fractures in patients with type 2 diabetes mellitus (T2DM), we investigated the effects of metformin, a widely used T2DM therapy, on bone mass and fracture healing in vivo using two different rodent models and modes of metformin administration.

Methods

We first subjected 12-week-old female C57BL/6 mice to ovariectomy (OVX). Four weeks after OVX, mice received either saline or metformin administered by gavage (100 mg/kg/daily). After 4 weeks of treatment, bone micro-architecture and cellular activity were determined in tibia by micro-CT and bone histomorphometry. In another experiment, female Wistar rats aged 3 months were given only water or metformin for 8 weeks via the drinking water (2 mg/ml). After 4 weeks of treatment, a mid-diaphyseal osteotomy was performed in the left femur. Rats were sacrificed 4 weeks after osteotomy and bone architecture analysed by micro-CT in the right tibia while fracture healing and callus volume were determined in the left femur by X-ray analysis and micro-CT, respectively.

Results

In both models, our results show no significant differences in cortical and trabecular bone architecture in metformin-treated rodents compared to saline. Metformin had no effect on bone resorption but reduced bone formation rate in trabecular bone. Mean X-ray scores assessed on control and metformin fractures showed no significant differences of healing between the groups. Fracture callus volume and mineral content after 4 weeks were similar in both groups.

Conclusions

Our results indicate that metformin has no effect on bone mass in vivo or fracture healing in rodents.

Cheng AY, Fantus IG (2005) Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ 172:213–226PubMed

Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR (2007) The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 92:1305–1310PubMedCrossRef

Lecka-Czernik B (2010) Bone loss in diabetes: use of antidiabetic thiazolidinediones and secondary osteoporosis. Curr Osteoporos Rep 8:178–184PubMedCrossRef

Cortizo AM, Sedlinsky C, McCarthy AD, Blanco A, Schurman L (2006) Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture. Eur J Pharmacol 536:38–46PubMedCrossRef

Kanazawa I, Yamaguchi T, Yano S, Yamauchi M, Sugimoto T (2008) 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 375:414–419PubMedCrossRef

Jang WG, Kim EJ, Bae IH, Lee KN, Kim YD, Kim DK, Kim SH, Lee CH, Franceschi RT, Choi HS, Koh JT (2011) Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone 48:885–893PubMedCrossRef

Shah M, Kola B, Bataveljic A, Arnett TR, Viollet B, Saxon L, Korbonits M, Chenu C (2010) AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass. Bone 47:309–319PubMedCrossRef

Zhen D, Chen Y, Tang X (2010) Metformin reverses the deleterious effects of high glucose on osteoblast function. J Diabetes Complications 24:334–344PubMedCrossRef

Molinuevo MS, Schurman L, McCarthy AD, Cortizo AM, Tolosa MJ, Gangoiti MV, Arnol V, Sedlinsky C (2010) Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J Bone Miner Res 25:211–221PubMedCrossRef

10.

Wu W, Ye Z, Zhou Y, Tan WS (2011) AICAR, a small chemical molecule, primes osteogenic differentiation of adult mesenchymal stem cells. Int J Artif Organs 34:1128–1136PubMedCrossRef

11.

Kasai T, Bandow K, Suzuki H, Chiba N, Kakimoto K, Ohnishi T, Kawamoto S, Nagaoka E, Matsuguchi T (2009) Osteoblast differentiation is functionally associated with decreased AMP kinase activity. J Cell Physiol 221:740–749PubMedCrossRef

12.

Gao Y, Li Y, Xue J, Jia Y, Hu J (2010) Effect of the anti-diabetic drug metformin on bone mass in ovariectomized rats. Eur J Pharmacol 635:231–236PubMedCrossRef

13.

Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Jia CH, Wen ZH, Jin DD, Bai XC (2011) Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 112:2902–2909PubMedCrossRef

14.

Sedlinsky C, Molinuevo MS, Cortizo AM, Tolosa MJ, Felice JI, Sbaraglini ML, Schurman L, McCarthy AD (2011) Metformin prevents anti-osteogenic in vivo and ex vivo effects of rosiglitazone in rats. Eur J Pharmacol 668:477–485PubMedCrossRef

15.

Wang C, Li H, Chen SG, He JW, Sheng CJ, Cheng XY, Qu S, Wang KS, Lu ML, Yu YC (2012) The skeletal effects of thiazolidinedione and metformin on insulin-resistant mice. J Bone Miner Metab 30:630–637PubMedCrossRef

16.

Vestergaard P, Rejnmark L, Mosekilde L (2005) Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetologia 48:1292–1299PubMedCrossRef

17.

Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ (2009) Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373:2125–2135PubMedCrossRef

18.

Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, Kravitz BG, Yu D, Heise MA, Aftring RP, Viberti G (2008) Rosiglitazone-associated fractures in type 2 diabetes: an analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 31:845–851PubMedCrossRef

19.

Mancini T, Mazziotti G, Doga M, Carpinteri R, Simetovic N, Vescovi PP, Giustina A (2009) Vertebral fractures in males with type 2 diabetes treated with rosiglitazone. Bone 45:784–788PubMedCrossRef

20.

Tzoulaki I, Molokhia M, Curcin V, Little MP, Millett CJ, Ng A, Hughes RI, Khunti K, Wilkins MR, Majeed A, Elliott P (2009) Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ 339:b4731PubMedCrossRef

21.

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 (2010) Effect of rosiglitazone, metformin and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab 95:134–142CrossRef

22.

Burt-Pichat B, Lafage-Proust MH, Duboeuf F, Laroche N, Itzstein C, Vico L, Delmas PD, Chenu C (2005) Dramatic decrease of innervation density in bone after ovariectomy. Endocrinology 146:503–510PubMedCrossRef

23.

Jeyabalan J, Shah M, Viollet B, Roux JP, Chavassieux P, Korbonits M, Chenu C (2012) Mice lacking AMP-activated protein kinase (AMPK)-alpha 1 catalytic subunit have increased bone remodeling and modified skeletal responses to hormonal challenges induced by ovariectomy and intermittent PTH treatment. J Endocrinol 214:349–358PubMedCrossRef

24.

Harrison LJ, Cunningham JL, Stromberg L, Goodship AE (2003) Controlled induction of a pseudarthrosis: a study using a rodent model. J Orthop Trauma 17:11–21PubMedCrossRef

25.

Amanat N, McDonald M, Godfrey C, Bilston L, Little D (2007) Optimal timing of a single dose of zoledronic acid to increase strength in rat fracture repair. J Bone Miner Res 22:867–876PubMedCrossRef

26.

Chappard D, Palle S, Alexandre C, Vico L, Riffat G (1987) Bone embedding in pure methyl methacrylate at low temperature preserves enzyme activities. Acta Histochem 81:183–190PubMedCrossRef

27.

Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ (1997) Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 100:1475–1480PubMedCrossRef

28.

Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610PubMedCrossRef

29.

Zaman G, Sunters A, Galea GL, Javaheri B, Saxon LK, Moustafa A, Armstrong VJ, Price JS, Lanyon LE (2012) Loading-related regulation of transcription factor EGR2/Krox-20 in bone cells is ERK1/2 protein-mediated and prostaglandin, Wnt signaling pathway-, and insulin-like growth factor-1 axis-dependent. J Biol Chem 287:3946–3962PubMedCrossRef

30.

Amini H, Ahmadiani A, Gazerani P (2005) Determination of metformin in human plasma by high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 824:319–322PubMedCrossRef

31.

Kaneb HM, Sharp PS, Rahmani-Kondori N, Wells DJ (2011) Metformin treatment has no beneficial effect in a dose–response survival study in the SOD1(G93A) mouse model of ALS and is harmful in female mice. PLoS One 6:e24189PubMedCrossRef

32.

Fryer LG, Parbu-Patel A, Carling D (2002) The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 277:25226–25232PubMedCrossRef

33.

Janghorbani M, Van Dam RM, Willett WC, Hu FB (2007) Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 166:495–505PubMedCrossRef

34.

Yamamoto M, Yamaguchi T, Yamauchi M, Kaji H, Sugimoto T (2009) Diabetic patients have an increased risk of vertebral fractures independent of BMD or diabetic complications. J Bone Miner Res 24:702–709PubMedCrossRef

35.

Oner G, Ozcelik B, Ozgun MT, Ozturk F (2011) The effects of metformin and letrozole on endometrium and ovary in a rat model. Gynecol Endocrinol 27:1084–1086PubMedCrossRef

36.

Wang XF, Zhang JY, Li L, Zhao XY, Tao HL, Zhang L (2011) Metformin improves cardiac function in rats via activation of AMP-activated protein kinase. Clin Exp Pharmacol Physiol 38:94–101PubMedCrossRef

37.

Souza-Mello V, Gregorio BM, Cardoso-de-Lemos FS, de Carvalho L, Aguila MB, Mandarim-de-Lacerda CA (2010) Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet. Clin Sci (Lond) 119:239–250CrossRef

38.

Ackert-Bicknell CL, Shockley KR, Horton LG, Lecka-Czernik B, Churchill GA, Rosen CJ (2009) Strain-specific effects of rosiglitazone on bone mass, body composition, and serum insulin-like growth factor-I. Endocrinology 150:1330–1340PubMedCrossRef

39.

Jeyabalan J, Shah M, Viollet B, Chenu C (2012) AMP-activated protein kinase pathway and bone metabolism. J Endocrinol 212:277–290

40.

Bak EJ, Park HG, Kim M, Kim SW, Kim S, Choi SH, Cha JH, Yoo YJ (2010) The effect of metformin on alveolar bone in ligature-induced periodontitis in rats: a pilot study. J Periodontol 81:412–419PubMedCrossRef

41.

Liu L, Zhang C, Hu Y, Peng B (2012) Protective effect of metformin on periapical lesions in rats by decreasing the ratio of receptor activator of nuclear factor kappa B ligand/osteoprotegerin. J Endod 38:943–947PubMedCrossRef

42.

Berlie HD, Garwood CL (2010) Diabetes medications related to an increased risk of falls and fall-related morbidity in the elderly. Ann Pharmacother 44:712–717PubMedCrossRef

43.

Loke YK, Singh S, Furberg CD (2009) Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 180:32–39PubMed

44.

Monami M, Cresci B, Colombini A, Pala L, Balzi D, Gori F, Chiasserini V, Marchionni N, Rotella CM, Mannucci E (2008) Bone fractures and hypoglycemic treatment in type 2 diabetic patients: a case–control study. Diabetes Care 31:199–203PubMedCrossRef

45.

Borges JL, Bilezikian JP, Jones-Leone AR, Acusta AP, Ambery PD, Nino AJ, Grosse M, Fitzpatrick LA, Cobitz AR (2011) A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naive type 2 diabetes mellitus patients. Diabetes Obes Metab 13:1036–1046PubMedCrossRef

46.

van Lierop AH, Hamdy NA, van der Meer RW, Jonker JT, Lamb HJ, Rijzewijk LJ, Diamant M, Romijn JA, Smit JW, Papapoulos SE (2012) Distinct effects of pioglitazone and metformin on circulating sclerostin and biochemical markers of bone turnover in men with type 2 diabetes mellitus. Eur J Endocrinol 166:711–716PubMedCrossRef

47.

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174PubMed

48.

Zhou Loder RT (1988) The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop Relat Res 232:210–216

49.

Chaudhary SB, Liporace FA, Gandhi A, Donley BG, Pinzur MS, Lin SS (2008) Complications of ankle fracture in patients with diabetes. J Am Acad Orthop Surg 16:159–170PubMed

50.

Hamann C, Goettsch C, Mettelsiefen J, Henkenjohann V, Rauner M, Hempel U, Bernhardt R, Fratzl-Zelman N, Roschger P, Rammelt S, Gunther KP, Hofbauer LC (2011) Delayed bone regeneration and low bone mass in a rat model of insulin-resistant type 2 diabetes mellitus is due to impaired osteoblast function. Am J Physiol Endocrinol Metab 301:E1220–E1228PubMedCrossRef

51.

Ogasawara A, Nakajima A, Nakajima F, Goto K, Yamazaki M (2008) Molecular basis for affected cartilage formation and bone union in fracture healing of the streptozotocin-induced diabetic rat. Bone 43:832–839PubMedCrossRef

52.

Retzepi M, Donos N (2010) The effect of diabetes mellitus on osseous healing. Clin Oral Implants Res 21:673–681PubMedCrossRef

53.

Hamann C, Kirschner S, Gunther KP, Hofbauer LC (2012) Bone, sweet bone—osteoporotic fractures in diabetes mellitus. Nat Rev Endocrinol 8:297–305PubMedCrossRef

Title: The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing
Authors: J. Jeyabalan
B. Viollet
P. Smitham
S. A. Ellis
G. Zaman
C. Bardin
A. Goodship
J. P. Roux
M. Pierre
C. Chenu
Publication date: 01-10-2013
Publisher: Springer London
Published in: Osteoporosis International / Issue 10/2013
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-013-2371-0

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing

Abstract

Summary

Introduction

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 10/2013

Micro-morphological properties of osteons reveal changes in cortical bone stability during aging, osteoporosis, and bisphosphonate treatment in women

Diagnostic measures for sarcopenia and bone mineral density

The risk of falls on initiation of antihypertensive drugs in the elderly

Failure after osteosynthesis of trochanteric fractures. Where is the limit of osteoporosis?

A Year of Fractures: a snapshot analysis of the logistics, problems and outcomes of a hospital-based fracture liaison service

Changes in frailty-related characteristics of the hip fracture population and their implications for healthcare services: evidence from Quebec, Canada