Abstract
Diabetes be it type 1 or type 2 is associated with an increased risk of fragility fractures. The mechanisms underlying this increased risk are just being elucidated. Anti-diabetes medications are crucial for maintaining glucose control and for preventing micro- and macrovascular complications in diabetes. However, they may modulate fracture risk in diabetes in different ways. Thiazolidinediones have demonstrated an unfavorable effect on the skeleton, while metformin and sulfonylureas may have a neutral if not beneficial effect on bone. The use of insulin has been associated with an increased risk of fragility fractures though it is not clear whether it is due to direct influence of insulin or whether it is mediated through hypoglycemia and increased falls risk. The overall effect of incretin mimetics appears to be beneficial; however, this has to be elucidated further. The bone effects of pramlintide, a synthetic analog of amylin, have not been explored fully. Finally, issues regarding bone safety of SGLT2 (sodium-dependent glucose transporter 2) inhibitors, the newest anti-diabetic medications on the market are of concern. The purpose of this review is to provide a comprehensive overview of the effect of these medications on bone metabolism and the studies exploring the risk or lack thereof of these medications on bone loss and fragility fractures.
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References
Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR et al (2006) Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 91(9):3349–3354
Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J et al (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(4):1305–1310
Bilezikian JP, Josse RG, Eastell R, Lewiecki EM, Miller CG, Wooddell M et al (2013) Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus. J Clin Endocrinol Metab 98(4):1519–1528
Borges JLC, Bilezikian JP, Jones-Leone AR, Acusta AP, Ambery PD, Nino AJ et al (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-naïve type 2 diabetes mellitus patients. Diabetes Obes Metab 13(11):1036–1046
Bone HG, Lindsay R, McClung MR, Perez AT, Raanan MG, Spanheimer RG et al (2013) Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 98(12):4691–4701
Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP et al (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355(23):2427–2443
Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M et al (2009) Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373(9681):2125–2135
Loke YK, Singh S, Furberg CD (2009) Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 180(1):32–39
Zhu ZN, Jiang YF, Ding T (2014) Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials. Bone 68:115–123
Colhoun HM, Livingstone SJ, Looker HC, Morris AD, Wild SH, Lindsay RS et al (2012) Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs. Diabetologia 55(11):2929–2937
Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR et al (2008) Use of thiazolidinediones and fracture risk. Arch Intern Med 168(8):820–825
Habib ZA, Havstad SL, Wells K, Divine G, Pladevall M, Williams LK et al (2010) Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 95(2):592–600
Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR (2009) PROactive investigators. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf 32(3):187–202
Gruntmanis U, Fordan S, Ghayee HK, Abdullah SM, See R, Ayers CR et al (2010) The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone increases bone resorption in women with type 2 diabetes: a randomized, controlled trial. Calcif Tissue Int 86(5):343–349
Harsløf T, Wamberg L, Møller L, Stødkilde-Jørgensen H, Ringgaard S, Pedersen SB et al (2011) Rosiglitazone decreases bone mass and bone marrow fat. J Clin Endocrinol Metab 96(5):1541–1548
Berberoglu Z, Gursoy A, Bayraktar N, Yazici AC, Bascil Tutuncu N, Guvener Demirag N et al (2007) Rosiglitazone decreases serum bone-specific alkaline phosphatase activity in postmenopausal diabetic women. J Clin Endocrinol Metab 92(9):3523–3530
Zinman B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG et al (2010) Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab 95(1):134–142
Xiao WH, Wang YR, Hou WF, Xie C, Wang HN, Hong TP et al (2013) The effects of pioglitazone on biochemical markers of bone turnover in the patients with type 2 diabetes. Int J Endocrinol 2013:290734
Kanazawa I, Yamaguchi T, Yano S, Yamamoto M, Yamauchi M, Kurioka S et al (2010) Baseline atherosclerosis parameter could assess the risk of bone loss during pioglitazone treatment in type 2 diabetes mellitus. Osteoporos Int 21(12):2013–2018
Glintborg D, Andersen M, Hagen C, Heickendorff L, Hermann AP (2008) Association of pioglitazone treatment with decreased bone mineral density in obese premenopausal patients with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab 93(5):1696–1701
van Lierop AH, Hamdy NAT, van der Meer RW, Jonker JT, Lamb HJ, Rijzewijk LJ et al (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(4):711–716
Wang L, Li L, Gao H, Li Y (2012) Effect of pioglitazone on transdifferentiation of preosteoblasts from rat bone mesenchymal stem cells into adipocytes. J Huazhong Univ Sci Technol Med Sci 32(4):530–533
Beck GR, Khazai NB, Bouloux GF, Camalier CE, Lin Y, Garneys LM et al (2013) The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes. Transl Res 161(3):145–155
Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL et al (2005) Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology 146(3):1226–1235
Cho ES, Kim MK, Son YO, Lee KS, Park SM, Lee JC et al (2012) The effects of rosiglitazone on osteoblastic differentiation, osteoclast formation and bone resorption. Mol Cells 33(2):173–181
Broulík PD, Sefc L, Haluzík M (2011) Effect of PPAR-γ agonist rosiglitazone on bone mineral density and serum adipokines in C57BL/6 male mice. Folia Biol (Krakow) 57(4):133–138
Lecka-Czernik B, Ackert-Bicknell C, Adamo ML, Marmolejos V, Churchill GA, Shockley KR et al (2007) Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo. Endocrinology 148(2):903–911
Mieczkowska A, Baslé MF, Chappard D, Mabilleau G (2012) Thiazolidinediones induce osteocyte apoptosis by a G protein-coupled receptor 40-dependent mechanism. J Biol Chem 287(28):23517–23526
Gustafson B, Eliasson B, Smith U (2010) Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis. Diabetologia 53(3):536–540
Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B et al (2007) Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology 148(6):2669–2680
Seto-Young D, Avtanski D, Parikh G, Suwandhi P, Strizhevsky M, Araki T et al (2011) Rosiglitazone and pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase. Horm Metab Res 43(4):250–256
Mabilleau G, Mieczkowska A, Edmonds ME (2010) Thiazolidinediones induce osteocyte apoptosis and increase sclerostin expression. Diabet Med 27(8):925–932
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(7):1292–1299
Melton LJ, 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(8):1334–1342
Solomon DH, Cadarette SM, Choudhry NK, Canning C, Levin R, Stürmer T et al (2009) A cohort study of thiazolidinediones and fractures in older adults with diabetes. J Clin Endocrinol Metab 94(8):2792–2798
Monami M, Cresci B, Colombini A, Pala L, Balzi D, Gori F et al (2008) Bone fractures and hypoglycemic treatment in type 2 diabetic patients: a case-control study. Diabetes Care 31(2):199–203
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(3):414–419
Napoli N, Strotmeyer ES, Ensrud KE, Sellmeyer DE, Bauer DC, Hoffman AR et al (2014) Fracture risk in diabetic elderly men: the MrOS study. Diabetologia 57(10):2057–2065
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(1–2):38–46
Kanazawa I, Yamaguchi T, Yano S, Yamauchi M, Yamamoto M, Sugimoto T et al (2007) Adiponectin and AMP kinase activator stimulate proliferation, differentiation, and mineralization of osteoblastic MC3T3-E1 cells. BMC Cell Biol 8:51
Zhen D, Chen Y, Tang X (2010) Metformin reverses the deleterious effects of high glucose on osteoblast function. J Diabetes Complicat 24(5):334–344
Molinuevo MS, Schurman L, McCarthy AD, Cortizo AM, Tolosa MJ, Gangoiti MV et al (2010) Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J Bone Miner Res 25(2):211–221
Schurman L, McCarthy AD, Sedlinsky C, Gangoiti MV, Arnol V, Bruzzone L et al (2008) Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. Exp Clin Endocrinol Diabetes 116(6):333–340
Tolosa MJ, Chuguransky SR, Sedlinsky C, Schurman L, McCarthy AD, Molinuevo MS et al (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(2):177–186
Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L et al (2011) Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 112(10):2902–2909
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(7):943–947
Sedlinsky C, Molinuevo MS, Cortizo AM, Tolosa MJ, Felice JI, Sbaraglini ML et al (2011) Metformin prevents anti-osteogenic in vivo and ex vivo effects of rosiglitazone in rats. Eur J Pharmacol 668(3):477–485
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(1–3):231–236
Wang C, Li H, Chen SG, He JW, Sheng CJ, Cheng XY et al (2012) The skeletal effects of thiazolidinedione and metformin on insulin-resistant mice. J Bone Miner Metab 30(6):630–637
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(12):1128–1136
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(4):368–377
Jeyabalan J, Viollet B, Smitham P, Ellis SA, Zaman G, Bardin C et al (2013) The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing. Osteoporos Int 24(10):2659–2670
Kasai T, Bandow K, Suzuki H, Chiba N, Kakimoto K, Ohnishi T et al (2009) Osteoblast differentiation is functionally associated with decreased AMP kinase activity. J Cell Physiol 221(3):740–749
Salai M, Somjen D, Gigi R, Yakobson O, Katzburg S, Dolkart O et al (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(11):1575–1580
Dormuth CR, Carney G, Carleton B, Bassett K, Wright JM (2009) Thiazolidinediones and fractures in men and women. Arch Intern Med 169(15):1395–1402
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(5):554–560
UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33. Lancet 352(9131):837–853
Lapane KL, Yang S, Brown MJ, Jawahar R, Pagliasotti C, Rajpathak S et al (2013) Sulfonylureas and risk of falls and fractures: a systematic review. Drugs Aging 30(7):527–547
Ma P, Gu B, Ma J, Lingling E, Wu X, Cao J et al (2010) Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. Metabolism 59(3):359–366
Ma P, Xiong W, Liu H, Ma J, Gu B, Wu X et al (2011) Extrapancreatic roles of glimepiride on osteoblasts from rat manibular bone in vitro: regulation of cytodifferentiation through PI3-kinases/Akt signalling pathway. Arch Oral Biol 56(4):307–316
Fronczek-Sokół J, Pytlik M (2014) Effect of glimepiride on the skeletal system of ovariectomized and non-ovariectomized rats. Pharmacol Rep 66(3):412–417
Campos Pastor MM, López-Ibarra PJ, Escobar-Jiménez F, Serrano Pardo MD, García-Cervigón AG (2000) Intensive insulin therapy and bone mineral density in type 1 diabetes mellitus: a prospective study. Osteoporos Int 11(5):455–459
Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ et al (2001) Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab 86(1):32–38
Ivers RQ, Cumming RG, Mitchell P, Peduto AJ (2001) Diabetes and risk of fracture: the Blue Mountains eye study. Diabetes Care 24(7):1198–1203
Nicodemus KK, Folsom AR (2001) Iowa Women’s Health Study. Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 24(7):1192–1197
Klein GL (2014) Insulin and bone: recent developments. World J Diabetes 5(1):14–16
Maor G, Karnieli E (1999) The insulin-sensitive glucose transporter (GLUT4) is involved in early bone growth in control and diabetic mice, but is regulated through the insulin-like growth factor I receptor. Endocrinology 140(4):1841–1851
Ogata N, Chikazu D, Kubota N, Terauchi Y, Tobe K, Azuma Y et al (2000) Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. J Clin Invest 105(7):935–943
Akune T, Ogata N, Hoshi K, Kubota N, Terauchi Y, Tobe K et al (2002) Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts. J Cell Biol 159(1):147–156
Shimoaka T, Kamekura S, Chikuda H, Hoshi K, Chung UI, Akune T et al (2004) Impairment of bone healing by insulin receptor substrate-1 deficiency. J Biol Chem 279(15):15314–15322
Abd El Aziz GS, Ramadan WS, El-Fark MO, Saleh HAM (2015) The beneficial roles of insulin and parathyroid hormones in the treatment of experimentally induced diabetic osteoporosis in female rats: bone mineral density, morphometric and histological studies. Folia Morphol
Bollag RJ, Zhong Q, Phillips P, Min L, Zhong L, Cameron R et al (2000) Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology 141(3):1228–1235
Pacheco-Pantoja EL, Ranganath LR, Gallagher JA, Wilson PJM, Fraser WD (2011) Receptors and effects of gut hormones in three osteoblastic cell lines. BMC Physiol 11:12
Lecka-Czernik B (2013) Safety of anti-diabetic therapies on bone. Clin Rev Bone Miner Metab 11(1):49–58
Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG et al (2009) Four-month treatment with GLP-2 significantly increases hip BMD: a randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD. Bone 45(5):833–842
Bunck MC, Eliasson B, Cornér A, Heine RJ, Shaginian RM, Taskinen MR et al (2011) Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes. Diabetes Obes Metab 13(4):374–377
Gilbert MP, Marre M, Holst JJ, Garber A, Baeres FMM, Thomsen H et al (2015) Comparison of the long-term effects of liraglutide and glimepiride monotherapy on bone mineral density in patients with type 2 diabetes. Endocr Pract 22(4):406–411
Mabilleau G, Mieczkowska A, Chappard D (2014) Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta-analysis of randomized clinical trials. J Diabetes 6(3):260–266
Su B, Sheng H, Zhang M, Bu L, Yang P, Li L et al (2015) Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists’ treatment: a meta-analysis of randomized controlled trials. Endocrine 48(1):107–115
Monami M, Dicembrini I, Antenore A, Mannucci E (2011) Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care 34(11):2474–2476
Hirshberg B, Parker A, Edelberg H, Donovan M, Iqbal N (2014) Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus. Diabetes Metab Res Rev 30(7):556–569
Mosenzon O, Wei C, Davidson J, Scirica BM, Yanuv I, Rozenberg A et al (2015) Incidence of fractures in patients with type 2 diabetes in the SAVOR-TIMI 53 trial. Diabetes Care 38(11):2142–2150
Choi HJ, Park C, Lee YK, Ha YC, Jang S, Shin CS et al (2016) Risk of fractures and diabetes medications: a nationwide cohort study. Osteoporos Int 27(9):2709–2715
Henriksen DB, Alexandersen P, Bjarnason NH, Vilsbøll T, Hartmann B, Henriksen EEG et al (2003) Role of gastrointestinal hormones in postprandial reduction of bone resorption. J Bone Miner Res 18(12):2180–2189
Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG et al (2007) Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women. Bone 40(3):723–729
Henriksen DB, Alexandersen P, Byrjalsen I, Hartmann B, Bone HG, Christiansen C et al (2004) Reduction of nocturnal rise in bone resorption by subcutaneous GLP-2. Bone 34(1):140–147
Tsukiyama K, Yamada Y, Yamada C, Harada N, Kawasaki Y, Ogura M et al (2006) Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion. Mol Endocrinol 20(7):1644–1651
Xie D, Cheng H, Hamrick M, Zhong Q, Ding KH, Correa D et al (2005) Glucose-dependent insulinotropic polypeptide receptor knockout mice have altered bone turnover. Bone 37(6):759–769
Yamada C, Yamada Y, Tsukiyama K, Yamada K, Udagawa N, Takahashi N et al (2008) The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 149(2):574–579
Nuche-Berenguer B, Moreno P, Esbrit P, Dapía S, Caeiro JR, Cancelas J et al (2009) Effect of GLP-1 treatment on bone turnover in normal, type 2 diabetic, and insulin-resistant states. Calcif Tissue Int 84(6):453–461
Ma X, Meng J, Jia M, Bi L, Zhou Y, Wang Y et al (2013) Exendin-4, a glucagon-like peptide-1 receptor agonist, prevents osteopenia by promoting bone formation and suppressing bone resorption in aged ovariectomized rats. J Bone Miner Res 28(7):1641–1652
Nuche-Berenguer B, Portal-Núñez S, Moreno P, González N, Acitores A, López-Herradón A et al (2010) Presence of a functional receptor for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor. J Cell Physiol 225(2):585–592
Sanz C, Vázquez P, Blázquez C, Barrio PA, Alvarez MDM, Blázquez E et al (2010) Signaling and biological effects of glucagon-like peptide 1 on the differentiation of mesenchymal stem cells from human bone marrow. Am J Physiol Endocrinol Metab 298(3):E634–E643
Mabilleau G, Mieczkowska A, Irwin N, Flatt PR, Chappard D (2013) Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor. J Endocrinol 219(1):59–68
Kim JY, Lee SK, Jo KJ, Song DY, Lim DM, Park KY et al (2013) Exendin-4 increases bone mineral density in type 2 diabetic OLETF rats potentially through the down-regulation of SOST/sclerostin in osteocytes. Life Sci 92(10):533–540
Sbaraglini ML, Molinuevo MS, Sedlinsky C, Schurman L, McCarthy AD (2014) Saxagliptin affects long-bone microarchitecture and decreases the osteogenic potential of bone marrow stromal cells. Eur J Pharmacol 727:8–14
Gallagher EJ, Sun H, Kornhauser C, Tobin-Hess A, Epstein S, Yakar S et al (2014) The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes. Diabetes Metab Res Rev 30(3):191–200
Glorie L, Behets GJ, Baerts L, De Meester I, D’Haese PC, Verhulst A et al (2014) DPP IV inhibitor treatment attenuates bone loss and improves mechanical bone strength in male diabetic rats. Am J Physiol Endocrinol Metab 307(5):E447–E455
Cusick T, Mu J, Pennypacker BL, Li Z, Scott KR, Shen X et al (2013) Bone loss in the oestrogen-depleted rat is not exacerbated by sitagliptin, either alone or in combination with a thiazolidinedione. Diabetes Obes Metab 15(10):954–957
Kyle KA, Willett TL, Baggio LL, Drucker DJ, Grynpas MD (2011) Differential effects of PPAR-γ activation versus chemical or genetic reduction of DPP-4 activity on bone quality in mice. Endocrinology 152(2):457–467
Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D et al (2016) Evaluation of bone mineral density and bone biomarkers in patients with type 2 Diabetes treated with canagliflozin. J Clin Endocrinol Metab 101(1):44–51
Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD et al (2014) Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab 16(2):159–169
Kohan DE, Fioretto P, Tang W, List JF (2014) Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 85(4):962–971
Ptaszynska A, Johnsson KM, Parikh SJ, de Bruin TWA, Apanovitch AM, List JF et al (2014) Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Saf 37(10):815–829
Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G et al (2016) Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 101(1):157–166
Harada N, Inagaki N (2012) Role of sodium-glucose transporters in glucose uptake of the intestine and kidney. J Diabetes Investig 3(4):352–353
Taylor SI, Blau JE, Rother KI (2015) Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 3(1):8–10
Hinton PS, Rector RS, Linden MA, Warner SO, Dellsperger KC, Chockalingam A et al (2012) Weight-loss-associated changes in bone mineral density and bone turnover after partial weight regain with or without aerobic exercise in obese women. Eur J Clin Nutr 66(5):606–612
List JF, Woo V, Morales E, Tang W, Fiedorek FT (2009) Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 32(4):650–657
Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M et al (2011) Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 34(9):2015–2022
Ljunggren Ö, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjöström CD et al (2012) Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab 14(11):990–999
Bays HE, Weinstein R, Law G, Canovatchel W (2014) Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity (Silver Spring) 22(4):1042–1049
Ways K, Johnson MD, Mamidi RNVS, Proctor J, De Jonghe S, Louden C et al (2015) Successful integration of nonclinical and clinical findings in interpreting the clinical relevance of rodent neoplasia with a new chemical entity. Toxicol Pathol 43(1):48–56
Mamidi RNVS, Proctor J, De Jonghe S, Feyen B, Moesen E, Vinken P et al (2014) Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin. Chem Biol Interact 221:109–118
Bronský J, Průsa R (2004) Amylin fasting plasma levels are decreased in patients with osteoporosis. Osteoporos Int 15(3):243–247
Borm AK, Klevesath MS, Borcea V, Kasperk C, Seibel MJ, Wahl P et al (1999) The effect of pramlintide (amylin analogue) treatment on bone metabolism and bone density in patients with type 1 diabetes mellitus. Horm Metab Res 31(8):472–475
Cornish J, Callon KE, Cooper GJ, Reid IR (1995) Amylin stimulates osteoblast proliferation and increases mineralized bone volume in adult mice. Biochem Biophys Res Commun 207(1):133–139
Naot D, Cornish J (2008) The role of peptides and receptors of the calcitonin family in the regulation of bone metabolism. Bone 43(5):813–818
Cornish J, Callon KE, Bava U, Kamona SA, Cooper GJ, Reid IR et al (2001) Effects of calcitonin, amylin, and calcitonin gene-related peptide on osteoclast development. Bone 29(2):162–168
Dacquin R, Davey RA, Laplace C, Levasseur R, Morris HA, Goldring SR et al (2004) Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo. J Cell Biol 164(4):509–514
Horcajada-Molteni MN, Chanteranne B, Lebecque P, Davicco MJ, Coxam V, Young A et al (2001) Amylin and bone metabolism in streptozotocin-induced diabetic rats. J Bone Miner Res 16(5):958–965
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Manju Chandran does not have any conflict of interests to declare.
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Chandran, M. Diabetes Drug Effects on the Skeleton. Calcif Tissue Int 100, 133–149 (2017). https://doi.org/10.1007/s00223-016-0203-x
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DOI: https://doi.org/10.1007/s00223-016-0203-x