Advertisement

Preventative effects of metformin on glucocorticoid-induced osteoporosis in rats

  • Jianrong Zhao
  • Yingbin Li
  • Hao Zhang
  • Dongying Shi
  • Qingnan Li
  • Li ZuoEmail author
  • Yan MengEmail author
Original Article

Abstract

This study evaluated the preventative effects of metformin (Met) on glucocorticoid (GC)-induced osteoporosis in a rat model, compared with alendronate (Aln). Twenty-eight 3-month-old female Sprague–Dawley rats were randomly assigned into four groups: normal control (Ctr), methylprednisolone (MP, 13 mg/kg/day, sc, 5 days per week), MP plus Aln orally (1 mg/kg/day), and MP plus Met orally (200 mg/kg/day). After 9 weeks, serum bone metabolic biochemistry, bone densitometry and histomorphometry were performed. The GC-induced osteoporosis model was characterized by decreased osteocalcin, increased tartrate-resistant acid phosphatase-5b (TRAP-5b), and decreased bone mineral density (BMD) in the femur and fifth lumbar vertebra (L5). Histomorphometrically, MP significantly decreased trabecular bone volume, decreased bone formation and increased bone resorption in proximal metaphysis, compared with the controls. Aln and Met increased the BMDs of femur (0.305 ± 0.011 vs. 0.280 ± 0.012, P < 0.05; 0.304 ± 0.019 vs. 0.280 ± 0.012, P < 0.05) and L5 (0.399 ± 0.029 vs. 0.358 ± 0.022, P < 0.05; 0.397 ± 0.022 vs. 0.358 ± 0.022, P < 0.05), compared with the model group. Met increased osteocalcin and decreased TRAP-5b, but Aln only decreased TRAP-5b, compared with model group. In histomorphometry of tibial proximal metaphysis, Aln and Met increased trabecular bone volume (39.21 ± 2.46 vs. 30.98 ± 5.83, P < 0.05; 38.97 ± 5.56 vs. 30.98 ± 5.83, P < 0.05), while Met increased the bone formation dynamic parameters and decreased bone resorption dynamic parameters, but Aln just decreased bone resorption dynamic parameters, compared with model group significantly. These findings suggest that metformin prevents GC-induced bone loss by suppressing bone resorption and stimulating bone formation in trabecular bone. The action mode of metformin was different from alendronate, which only suppressed bone resorption.

Keywords

Metformin Glucocorticoid-induced osteoporosis Histomorphometry Alendronate Rats 

Notes

Acknowledgements

We thank Dr. Ping Sun for her kind help in facilitating the cooperation among the facilities. This work was supported by the Natural Science Foundation of Inner Mongolia Autonomous Region, China (No. 2014BS0807), the Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region, the Beijing Natural Science Foundation (No. 7162193), the Innovative Talents Group Foundation of Nephrology Department, Affiliated Hospital, Inner Mongolia Medical University of the Fifth Inner Mongolia ‘Prairie Meritocrat’ Project, and the Doctorial Scientific Research Starting Foundation of the Affiliated Hospital, Inner Mongolia Medical University (No. NYFYBS2015013).

Compliance with ethical standards

Conflict of interest

All the authors have no conflicts of interest.

References

  1. 1.
    Iglesias JE, Salum FG, Figueiredo MA, Cherubini K (2015) Important aspects concerning alendronate-related osteonecrosis of the jaws: a literature review. Gerodontology 32:169–178CrossRefGoogle Scholar
  2. 2.
    Saita Y, Ishijima M, Mogami A, Kubota M, Baba T et al (2015) The incidence of and risk factors for developing atypical femoral fractures in Japan. J Bone Miner Metab 33:311–318CrossRefGoogle Scholar
  3. 3.
    Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD et al (2014) Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 29:1–23CrossRefGoogle Scholar
  4. 4.
    Armamento-Villareal R, Napoli N, Diemer K, Watkins M, Civitelli R, Teitelbaum S, Novack D (2009) Bone turnover in bone biopsies of patients with low-energy cortical fractures receiving bisphosphonates: a case series. Calcif Tissue Int 85:37–44CrossRefGoogle Scholar
  5. 5.
    Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301CrossRefGoogle Scholar
  6. 6.
    Tamura Y, Watada H, Sato F, Kumashiro N, Sakurai Y, Hirose T, Tanaka Y, Kawamori R (2008) Effects of metformin on peripheral insulin sensitivity and intracellular lipid contents in muscle and liver of overweight Japanese subjects. Diabetes Obes Metab 10:733–738CrossRefGoogle Scholar
  7. 7.
    Giugliano D, De Rosa N, Di Maro G, Marfella R, Acampora R, Buoninconti R, D’Onofrio F (1993) Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care 16:1387–1390CrossRefGoogle Scholar
  8. 8.
    Pradeep AR, Nagpal K, Karvekar S, Patnaik K, Naik SB, Guruprasad CN (2015) Platelet-rich fibrin with 1% metformin for the treatment of intrabony defects in chronic periodontitis: a randomized controlled clinical trial. J Periodontol 86:729–737CrossRefGoogle Scholar
  9. 9.
    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 13:1036–1046CrossRefGoogle Scholar
  10. 10.
    Melton LJ 3rd, Leibson CL, Achenbach SJ, Therneau TM, Khosla S (2008) Fracture risk in type 2 diabetes: update of a population-based study. J Bone Miner Res 23:1334–1342CrossRefGoogle Scholar
  11. 11.
    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 48:1292–1299CrossRefGoogle Scholar
  12. 12.
    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 112:2902–2909CrossRefGoogle Scholar
  13. 13.
    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 635:231–236CrossRefGoogle Scholar
  14. 14.
    Tolosa MJ, Chuguransky SR, Sedlinsky C, Schurman L, McCarthy AD, Molinuevo MS, Cortizo AM (2013) Insulin-deficient diabetes-induced bone microarchitecture alterations are associated with a decrease in the osteogenic potential of bone marrow progenitor cells: preventive effects of metformin. Diabetes Res Clin Pract 101:177–186CrossRefGoogle Scholar
  15. 15.
    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 25:211–221CrossRefGoogle Scholar
  16. 16.
    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 375:414–419CrossRefGoogle Scholar
  17. 17.
    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 536:38–46CrossRefGoogle Scholar
  18. 18.
    Nordklint AK, Almdal TP, Vestergaard P, Lundby-Christensen L, Boesgaard TW et al (2018) The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial. Osteoporos Int 29:2517–2526CrossRefGoogle Scholar
  19. 19.
    Jeyabalan J, Viollet B, Smitham P, Ellis SA, Zaman G, Bardin C, Goodship A, Roux JP, Pierre M, Chenu C (2013) The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing. Osteoporos Int 24:2659–2670CrossRefGoogle Scholar
  20. 20.
    Ortoft G, Andreassen TT, Oxlund H (2005) Growth hormone can reverse glucocorticoid-induced low bone turnover on cortical but not on cancellous bone surfaces in adult Wistar rats. Bone 36:123–133CrossRefGoogle Scholar
  21. 21.
    Mosekilde L, Thomsen JS, Mackey MS, Phipps RJ (2000) Treatment with risedronate or alendronate prevents hind-limb immobilization-induced loss of bone density and strength in adult female rats. Bone 27:639–645CrossRefGoogle Scholar
  22. 22.
    Quaile MP, Melich DH, Jordan HL, Nold JB, Chism JP, Polli JW, Smith GA, Rhodes MC (2010) Toxicity and toxicokinetics of metformin in rats. Toxicol Appl Pharmacol 243:340–347CrossRefGoogle Scholar
  23. 23.
    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 2:595–610CrossRefGoogle Scholar
  24. 24.
    Seibel MJ, Cooper MS, Zhou H (2013) Glucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives. Lancet Diabetes Endocrinol 1:59–70CrossRefGoogle Scholar
  25. 25.
    Hulley PA, Conradie MM, Langeveldt CR, Hough FS (2002) Glucocorticoid-induced osteoporosis in the rat is prevented by the tyrosine phosphatase inhibitor, sodium orthovanadate. Bone 31:220–229CrossRefGoogle Scholar
  26. 26.
    Duru N, van der Goes MC, Jacobs JW, Andrews T, Boers M, Buttgereit F, Caeyers N, Cutolo M, Halliday S, Da Silva JA, Kirwan JR, Ray D, Rovensky J, Severijns G, Westhovens R, Bijlsma JW (2013) EULAR evidence-based and consensus-based recommendations on the management of medium to high-dose glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 72:1905–1913CrossRefGoogle Scholar
  27. 27.
    Lekamwasam S, Adachi JD, Agnusdei D, Bilezikian J, Boonen S et al (2012) A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int 23:2257–2276CrossRefGoogle Scholar
  28. 28.
    Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, Curtis JR, Furst DE, McMahon M, Patkar NM, Volkmann E, Saag KG (2010) American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 62:1515–1526CrossRefGoogle Scholar
  29. 29.
    Reszka AA, Rodan GA (2003) Bisphosphonate mechanism of action. Curr Rheumatol Rep 5:65–74CrossRefGoogle Scholar
  30. 30.
    Teitelbaum SL, Seton MP, Saag KG (2011) Should bisphosphonates be used for long-term treatment of glucocorticoid-induced osteoporosis? Arthritis Rheum 63:325–328CrossRefGoogle Scholar
  31. 31.
    Buckley L, Guyatt G, Fink HA, Cannon M, Grossman J et al (2017) 2017 American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 69:1095–1110CrossRefGoogle Scholar
  32. 32.
    Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R (2014) Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 25:2359–2381CrossRefGoogle Scholar
  33. 33.
    UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865CrossRefGoogle Scholar
  34. 34.
    Gao Y, Xue J, Li X, Jia Y, Hu J (2008) Metformin regulates osteoblast and adipocyte differentiation of rat mesenchymal stem cells. J Pharm Pharmacol 60:1695–1700CrossRefGoogle Scholar
  35. 35.
    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 668:477–485CrossRefGoogle Scholar
  36. 36.
    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 48:885–893CrossRefGoogle Scholar
  37. 37.
    Schurman L, McCarthy AD, Sedlinsky C, Gangoiti MV, Arnol V, Bruzzone L, Cortizo AM (2008) Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. Exp Clin Endocrinol Diabetes 116:333–340CrossRefGoogle Scholar
  38. 38.
    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 30:630–637CrossRefGoogle Scholar
  39. 39.
    Hadjidakis DJ, Androulakis II (2006) Bone remodeling. Ann NY Acad Sci 1092:385–396CrossRefGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NephrologyThe Affiliated Hospital of Inner Mongolia Medical UniversityHohhotPeople’s Republic of China
  2. 2.Guangdong Legend Pharmaceutical Technology Co., Ltd.JiangmenPeople’s Republic of China
  3. 3.School of DentistryHubei University of MedicineShiyanPeople’s Republic of China
  4. 4.Guangdong Laboratory Animals Monitoring Institute and Key Laboratory of Guangdong Laboratory AnimalsGuangzhouPeople’s Republic of China
  5. 5.The Center for New Drug Function Research, School of Life Science and BiopharmaceuticsGuangdong Pharmaceutical UniversityGuangzhouPeople’s Republic of China
  6. 6.Department of NephrologyPeking University People’s HospitalBeijingPeople’s Republic of China

Personalised recommendations