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Metformin: Is It the Well Wisher of Bone Beyond Glycemic Control in Diabetes Mellitus?

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Abstract

Both diabetes mellitus and osteoporosis constitute a notable burden in terms of quality of life and healthcare costs. Diabetes mellitus affecting the skeletal system has been gaining attention in recent years and is now getting recognized as yet another complication of the disease, known as diabetic bone disease. As this condition with weaker bone strength increases fracture risk and reduces the quality of life, so much attention is being paid to investigate the molecular pathways through which both diabetes and its therapy are affecting bone metabolism. Out of many therapeutic agents currently available for managing diabetes mellitus, metformin is one of the most widely accepted first choices worldwide. The purpose of this review is to describe the effects of biguanide-metformin on bone metabolism in type 2 diabetes mellitus including its plausible mechanisms of action on the skeleton. In vitro studies suggest that metformin directly stimulates osteoblasts differentiation and may inhibit osteoclastogenesis by increasing osteoprotegerin expression, both through activation of the AMPK signaling pathway. Several studies in both preclinical and clinical settings report the favorable effects of metformin on bone microarchitecture, bone mineral density, bone turnover markers, and fracture risk. However, animal studies were not specific in terms of the diabetic models used and clinical studies were associated with several confounders. The review highlights some of these limitations and provide future recommendations for research in this area which is necessary to better understand the role of metformin on skeletal outcomes in diabetes.

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References

  1. American Diabetics Association (2018) Introduction: standards of medical care in diabetes-2018. Diabetes Care 41:S1-s2

    Google Scholar 

  2. Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL (2017) Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol 13:208–219

    CAS  PubMed  Google Scholar 

  3. McCarthy AD, Cortizo AM, Sedlinsky C (2016) Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy. World J Diabet 7:122–133

    Google Scholar 

  4. Bahrambeigi S, Yousefi B, Rahimi M, Shafiei-Irannejad V (2019) Metformin; an old antidiabetic drug with new potentials in bone disorders. Biomed Pharmacother 109:1593–2160

    CAS  PubMed  Google Scholar 

  5. Jiating L, Buyun J, Yinchang Z (2019) Role of metformin on osteoblast differentiation in type 2 diabetes. Biomed Res Int 2019:9203934

    PubMed  PubMed Central  Google Scholar 

  6. 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 60:1695–1700

    CAS  PubMed  Google Scholar 

  7. Marycz K, Tomaszewski KA, Kornicka K, Henry BM, Wronski S, Tarasiuk J, Maredziak M (2016) Metformin decreases reactive oxygen species, enhances osteogenic properties of adipose-derived multipotent mesenchymal stem cells in vitro, and increases bone density in vivo. Oxid Med Cell Longevity 2016:9785890

    Google Scholar 

  8. Gu Q, Gu Y, Yang H, Shi Q (2017) Metformin enhances osteogenesis and suppresses adipogenesis of human chorionic villous mesenchymal stem cells. Tohoku J Exp Med 241:13–19

    CAS  PubMed  Google Scholar 

  9. Ma J, Zhang ZL, Hu XT, Wang XT, Chen AM (2018) Metformin promotes differentiation of human bone marrow derived mesenchymal stem cells into osteoblast via GSK3β inhibition. Eur Rev Med Pharm Sci 22:7962–7968

    CAS  Google Scholar 

  10. Wang P, Ma T, Guo D, Hu K, Shu Y, Xu HHK, Schneider A (2018) Metformin induces osteoblastic differentiation of human induced pluripotent stem cell-derived mesenchymal stem cells. J Tissue Eng Regen Med 12:437–446

    CAS  PubMed  Google Scholar 

  11. 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 25:211–221

    CAS  PubMed  Google Scholar 

  12. 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 101:177–186

    CAS  PubMed  Google Scholar 

  13. 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 536:38–46

    CAS  PubMed  Google Scholar 

  14. 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 Diabet 116:333–340

    CAS  Google Scholar 

  15. 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 375:414–419

    CAS  PubMed  Google Scholar 

  16. 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 48:885–893

    CAS  PubMed  Google Scholar 

  17. Mu W, Wang Z, Ma C, Jiang Y, Zhang N, Hu K, Li L, Wang Z (2018) Metformin promotes the proliferation and differentiation of murine preosteoblast by regulating the expression of sirt6 and oct4. Pharmacol Res 129:462–474

    CAS  PubMed  Google Scholar 

  18. Zheng L, Shen X, Ye J, Xie Y, Yan S (2019) Metformin alleviates hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway. Life Sci 216:29–38

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  20. Shao X, Cao X, Song G, Zhao Y, Shi B (2014) Metformin rescues the MG63 osteoblasts against the effect of high glucose on proliferation. J Diabet Res 2014:453940

    Google Scholar 

  21. Salai M, Somjen D, Gigi R, Yakobson O, Katzburg S, Dolkart O (2013) Effects of commonly used medications on bone tissue mineralisation in SaOS-2 human bone cell line: an in vitro study. Bone Joint J 95:1575–1580

    PubMed  Google Scholar 

  22. 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 Org 34:1128–1136

    CAS  Google Scholar 

  23. Patel JJ, Butters OR, Arnett TR (2014) PPAR agonists stimulate adipogenesis at the expense of osteoblast differentiation while inhibiting osteoclast formation and activity. Cell Biochem Funct 32:368–377

    CAS  PubMed  Google Scholar 

  24. 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 221:740–749

    CAS  PubMed  Google Scholar 

  25. Lee YS, Kim YS, Lee SY, Kim GH, Kim BJ, Lee SH, Lee KU, Kim GS, Kim SW, Koh JM (2010) AMP kinase acts as a negative regulator of RANKL in the differentiation of osteoclasts. Bone 47:926–937

    CAS  PubMed  Google Scholar 

  26. 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 112:2902–2909

    CAS  PubMed  Google Scholar 

  27. Zang M, Zuccollo A, Hou X, Nagata D, Walsh K, Herscovitz H, Brecher P, Ruderman NB, Cohen RA (2004) AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J Biol Chem 279:47898–47905

    CAS  PubMed  Google Scholar 

  28. Li Y, Su J, Sun W, Cai L, Deng Z (2018) AMP-activated protein kinase stimulates osteoblast differentiation and mineralization through autophagy induction. Int J Mol Med 41:2535–2544

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bertolio R, Napoletano F, Mano M, Maurer-Stroh S, Fantuz M, Zannini A, Bicciato S, Sorrentino G, Del Sal G (2019) Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism. Nat Commun 10:1326

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  31. Wan Y (2010) PPARγ in bone homeostasis. Trends Endocrinol Metab 21:722–728

    CAS  PubMed  Google Scholar 

  32. Kawai M (2013) Adipose tissue and bone: role of PPARγ in adipogenesis and osteogenesis. Hormone Mol Biol Clin Investig 15:105–113

    CAS  Google Scholar 

  33. Khan MP, Singh AK, Joharapurkar AA, Yadav M, Shree S, Kumar H, Gurjar A, Mishra JS, Tiwari MC, Nagar GK, Kumar S, Ramachandran R, Sharan A, Jain MR, Trivedi AK, Maurya R, Godbole MM, Gayen JR, Sanyal S, Chattopadhyay N (2015) Pathophysiological mechanism of bone loss in type 2 diabetes involves inverse regulation of osteoblast function by PGC-1α and skeletal muscle atrogenes: adipoR1 as a potential target for reversing diabetes-induced osteopenia. Diabetes 64:2609–2623

    CAS  PubMed  Google Scholar 

  34. Papadopouli AE, Klonaris CN, Theocharis SE (2008) Role of OPG/RANKL/RANK axis on the vasculature. Histol Histopathol 23:497–506

    CAS  PubMed  Google Scholar 

  35. Anandarajah AP (2009) Role of RANKL in bone diseases. Trends Endocrinol Metab 20:88–94

    CAS  PubMed  Google Scholar 

  36. 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 Endodont 38:943–947

    Google Scholar 

  37. Halleen JM, Alatalo SL, Suominen H, Cheng S, Janckila AJ, Väänänen HK (2000) Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption. J Bone Miner Res 15:1337–1345

    CAS  PubMed  Google Scholar 

  38. Janckila AJ, Nakasato YR, Neustadt DH, Yam LT (2003) Disease-specific expression of tartrate-resistant acid phosphatase isoforms. J Bone Miner Res 18:1916–1919

    CAS  PubMed  Google Scholar 

  39. Adeyemi WJ, Olayaki LA, Abdussalam TA, Fabiyi TO, Raji TL, Adetunji AA (2020) Co-administration of omega-3 fatty acids and metformin showed more desirable effects than the single therapy on indices of bone mineralisation but not gluco-regulatory and antioxidant markers in diabetic rats. Biomed Pharmacother 121:109631

    CAS  PubMed  Google Scholar 

  40. Asadipooya K, Uy EM (2019) Advanced glycation end products (AGEs), receptor for AGEs, diabetes, and bone: review of the literature. J Endocr Soc 3:1799–1818

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou Z, Tang Y, Jin X, Chen C, Lu Y, Liu L, Shen C (2016) Metformin inhibits advanced glycation end products-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFκB pathway suppression. J Diabetes Res 2016:4847812

    PubMed  PubMed Central  Google Scholar 

  42. Brandi ML (2009) Microarchitecture, the key to bone quality. Rheumatology 48(4):3–8

    Google Scholar 

  43. Dalle Carbonare L, Giannini S (2004) Bone microarchitecture as an important determinant of bone strength. J Endocrinol Invest 27:99–105

    CAS  PubMed  Google Scholar 

  44. 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 635:231–236

    CAS  PubMed  Google Scholar 

  45. 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 668:477–485

    CAS  PubMed  Google Scholar 

  46. 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 30:630–637

    CAS  PubMed  Google Scholar 

  47. 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. Osteopor Int 24:2659–2670

    CAS  Google Scholar 

  48. 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 13:1036–1046

    CAS  PubMed  Google Scholar 

  49. Zinman B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG, Paul G, Jones NP, Aftring RP, Viberti G, Kahn SE (2010) Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab 95:134–142

    CAS  PubMed  Google Scholar 

  50. 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 166:711–716

    PubMed  Google Scholar 

  51. Bilezikian JP, Josse RG, Eastell R, Lewiecki EM, Miller CG, Wooddell M, Northcutt AR, Kravitz BG, Paul G, Cobitz AR, Nino AJ, Fitzpatrick LA (2013) Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus. J Clin Endocrinol Metab 98:1519–1528

    CAS  PubMed  Google Scholar 

  52. Mori H, Okada Y, Tanaka Y (2017) The effects of pioglitazone on bone formation and resorption markers in type 2 diabetes mellitus. Intern Med 56:1301–1306

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kanazawa I, Yamaguchi T, Yano S, Yamamoto M, Yamauchi M, Kurioka S, Sugimoto T (2010) Baseline atherosclerosis parameter could assess the risk of bone loss during pioglitazone treatment in type 2 diabetes mellitus. Osteopor Int 21:2013–2018

    CAS  Google Scholar 

  54. Hegazy SK (2015) Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab 33:207–212

    CAS  PubMed  Google Scholar 

  55. Stage TB, Christensen MH, Jorgensen NR, Beck-Nielsen H, Brosen K, Gram J, Frost M (2018) Effects of metformin, rosiglitazone and insulin on bone metabolism in patients with type 2 diabetes. Bone 112:35–41

    CAS  PubMed  Google Scholar 

  56. Nordklint AK, Almdal TP, Vestergaard P, Lundby-Christensen L, Boesgaard TW, Breum L, Gade-Rasmussen B, Sneppen SB, Gluud C, Hemmingsen B, Jensen T, Krarup T, Madsbad S, Mathiesen ER, Perrild H, Tarnow L, Thorsteinsson B, Vestergaard H, Lund SS, Eiken P (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. Osteopor Int 29:2517–2526

    CAS  Google Scholar 

  57. American Diabetes Association (2013) Treatment effects on measures of body composition in the TODAY clinical trial. Diabetes Care 36:1742–1748

    Google Scholar 

  58. Rubin MR, Manavalan JS, Agarwal S, McMahon DJ, Nino A, Fitzpatrick LA, Bilezikian JP (2014) Effects of rosiglitazone vs metformin on circulating osteoclast and osteogenic precursor cells in postmenopausal women with type 2 diabetes mellitus. J Clin Endocrinol Metab 99:E1933-1942

    CAS  PubMed  Google Scholar 

  59. 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 48:1292–1299

    CAS  PubMed  Google Scholar 

  60. 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 23:1334–1342

    PubMed  PubMed Central  Google Scholar 

  61. Solomon DH, Cadarette SM, Choudhry NK, Canning C, Levin R, Sturmer T (2009) A cohort study of thiazolidinediones and fractures in older adults with diabetes. J Clin Endocrinol Metab 94:2792–2798

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bilik D, McEwen LN, Brown MB, Pomeroy NE, Kim C, Asao K, Crosson JC, Duru OK, Ferrara A, Hsiao VC, Karter AJ, Lee PG, Marrero DG, Selby JV, Subramanian U, Herman WH (2010) Thiazolidinediones and fractures: evidence from translating research into action for diabetes. J Clin Endocrinol Metab 95:4560–4565

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Puar TH, Khoo JJ, Cho LW, Xu Y, Chen YT, Chuo AM, Poh CB, Ng JM (2012) Association between glycemic control and hip fracture. J Am Geriatr Soc 60:1493–1497

    PubMed  Google Scholar 

  64. Choi HJ, Park C, Lee YK, Ha YC, Jang S, Shin CS (2016) Risk of fractures and diabetes medications: a nationwide cohort study. Osteopor Int 27:2709–2715

    CAS  Google Scholar 

  65. Losada E, Soldevila B, Ali MS, Martinez-Laguna D, Nogues X, Puig-Domingo M, Diez-Perez A, Mauricio D, Prieto-Alhambra D (2018) Real-world antidiabetic drug use and fracture risk in 12,277 patients with type 2 diabetes mellitus: a nested case-control study. Osteopor Int 29:2079–2086

    CAS  Google Scholar 

  66. 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 31:199–203

    PubMed  Google Scholar 

  67. Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR (2008) Use of thiazolidinediones and fracture risk. Arch Intern Med 168:820–825

    CAS  PubMed  Google Scholar 

  68. Kanazawa I, Yamaguchi T, Yamamoto M, Sugimoto T (2010) Relationship between treatments with insulin and oral hypoglycemic agents versus the presence of vertebral fractures in type 2 diabetes mellitus. J Bone Miner Metab 28:554–560

    CAS  PubMed  Google Scholar 

  69. Colhoun HM, Livingstone SJ, Looker HC, Morris AD, Wild SH, Lindsay RS, Reed C, Donnan PT, Guthrie B, Leese GP, McKnight J, Pearson DW, Pearson E, Petrie JR, Philip S, Sattar N, Sullivan FM, McKeigue P (2012) Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs. Diabetologia 55:2929–2937

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Napoli N, Strotmeyer ES, Ensrud KE, Sellmeyer DE, Bauer DC, Hoffman AR, Dam TT, Barrett-Connor E, Palermo L, Orwoll ES, Cummings SR, Black DM, Schwartz AV (2014) Fracture risk in diabetic elderly men: the MrOS study. Diabetologia 57:2057–2065

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Napoli N, Schwartz AV, Schafer AL, Vittinghoff E, Cawthon PM, Parimi N, Orwoll E, Strotmeyer ES, Hoffman AR, Barrett-Connor E, Black DM (2018) Vertebral fracture risk in diabetic elderly men: the MrOS study. J Bone Miner Res 33:63–69

    PubMed  Google Scholar 

  72. Majumdar SR, Josse RG, Lin M, Eurich DT (2016) Does itagliptin affect the rate of osteoporotic fractures in type 2 diabetes? Population-based cohort study. J Clin Endocrinol Metab 101:1963–1969

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Oh TK, Song IA (2020) Metformin therapy and hip fracture risk among patients with type II diabetes mellitus: a population-based cohort study. Bone 135:115325

    CAS  PubMed  Google Scholar 

  74. 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 31:845–851

    CAS  PubMed  Google Scholar 

  75. Hidayat K, Du X, Wu MJ, Shi BM (2019) The use of metformin, insulin, sulphonylureas, and thiazolidinediones and the risk of fracture: systematic review and meta-analysis of observational studies. Obes Rev 20:1494–1503

    PubMed  Google Scholar 

  76. Salari-Moghaddam A, Sadeghi O, Keshteli AH, Larijani B, Esmaillzadeh A (2019) Metformin use and risk of fracture: a systematic review and meta-analysis of observational studies. Osteopor Int 30:1167–1173

    CAS  Google Scholar 

  77. Ferrari SL, Abrahamsen B, Napoli N, Akesson K, Chandran M, Eastell R, El-Hajj Fuleihan G, Josse R, Kendler DL, Kraenzlin M, Suzuki A, Pierroz DD, Schwartz AV, Leslie WD (2018) Diagnosis and management of bone fragility in diabetes: an emerging challenge. Osteopor Int 29:2585–2596

    CAS  Google Scholar 

  78. Lai SW (2019) Association between osteoporosis and statins therapy. Ann Rheumat Dis. https://doi.org/10.1136/annrheumdis-2019-216627

    Article  PubMed  Google Scholar 

  79. Fu J, Zhu J, Hao Y, Guo C, Zhou Z (2016) Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials. Sci Rep 6:29104

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Mamza J, Marlin C, Wang C, Chokkalingam K, Idris I (2016) DPP-4 inhibitor therapy and bone fractures in people with Type 2 diabetes - A systematic review and meta-analysis. Diabetes Res Clin Pract 116:288–298

    CAS  PubMed  Google Scholar 

  81. Tang HL, Li DD, Zhang JJ, Hsu YH, Wang TS, Zhai SD, Song YQ (2016) Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab 18:1199–1206

    CAS  PubMed  Google Scholar 

  82. Li X, Li T, Cheng Y, Lu Y, Xue M, Xu L, Liu X, Yu X, Sun B, Chen L (2019) Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: an updated meta-analysis. Diabetes Metab Res Rev 35:e3170

    PubMed  Google Scholar 

  83. Ruanpeng D, Ungprasert P, Sangtian J, Harindhanavudhi T (2017) Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Metab Res Rev. https://doi.org/10.1002/dmrr.2903

    Article  PubMed  Google Scholar 

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Acknowledgments

DV and ARS are grateful to the Indian Council of Medical Research (ICMR), New Delhi for providing fellowship to ARS. DV acknowledges the support provided by the Department of Science and Technology under the FIST program, University Grants Commission Special Assistance Program under DRS-II and All India Council of Technical Education underMODROBS scheme to Department of Pharmacology, SPER, Jamia Hamdard.

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  1. Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India

    Abdul Rahaman Shaik, Prabhjeet Singh & Divya Vohora

  2. Department of Pharmaceutical Analysis, University College of Pharmaceutical Sciences, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur, Andhra Pradesh, 522510, India

    Chandini Shaik

  3. Department of Medicine, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India

    Sunil Kohli

  4. Service and Laboratory of Bone Diseases, Department of Medicine, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland

    Serge Livio Ferrari

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  1. Abdul Rahaman Shaik
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Shaik, A.R., Singh, P., Shaik, C. et al. Metformin: Is It the Well Wisher of Bone Beyond Glycemic Control in Diabetes Mellitus?. Calcif Tissue Int 108, 693–707 (2021). https://doi.org/10.1007/s00223-021-00805-8

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