Osteologie 2018; 27(01): 29-37
DOI: 10.1055/s-0038-1636976
Therapieinduzierte Osteoporose – Treatment-induced osteoporosis
Schattauer GmbH

Einfluss oraler Antidiabetika auf Knochenstoffwechsel und Frakturrisiko

Effects of diabetes drugs on bone metabolism and fracture risk
C. Traechslin
1   Klinik für Endokrinologie, Diabetologie und Metabolismus, Universitätsspital, Basel, Schweiz
,
J. Vavanikunnel
1   Klinik für Endokrinologie, Diabetologie und Metabolismus, Universitätsspital, Basel, Schweiz
,
M. Kraenzlin
2   Endonet, Endokrinologische Praxis & Labor, Basel, Schweiz
,
C. Meier
1   Klinik für Endokrinologie, Diabetologie und Metabolismus, Universitätsspital, Basel, Schweiz
2   Endonet, Endokrinologische Praxis & Labor, Basel, Schweiz
› Author Affiliations
Further Information

Publication History

eingereicht: 09 November 2017

angenommen: 29 November 2017

Publication Date:
07 March 2018 (online)

Zusammenfassung

Der Einsatz von oralen Antidiabetika ist in der Behandlung von Patienten mit Diabetes mellitus Typ 2 unverzichtbar. Durch eine verbesserte Blutzuckereinstellung werden mikro- und makrovaskuläre Spätkomplikationen verhindert. In den vergangenen Jahren haben wir die Erkenntnis gewonnen, dass die Diabeteserkrankung auch mit metabolischen Knochenveränderungen und Frakturen assoziiert ist. Die Pathogenese der diabetischen Knochenerkrankung ist multifaktoriell, mikrovaskuläre Veränderungen im Knochenmilieu und morphologische Veränderungen der skelettalen Mikroarchitektur werden als ursächliche Mechanismen diskutiert. Einige orale Antidiabetika üben einen Einfluss auf den Knochenstoffwechsel aus und können dadurch das Frakturrisiko mitbeeinflussen. In diesem Artikel werden Wirkweisen oraler Antidiabetika und deren Enfluss auf den Knochenmetabolismus zusammengefasst. Während Thiazolidinedione einen ungünstigen Effekt auf den Knochen ausüben, scheinen sich Metformin und inkretinbasierte Therapien eher protektiv oder zumindest neutral auf den Knochenstoffwechsel auszuwirken. Sulfonylharnstoff sind aufgrund ihres Hypoglykämierisikos mit Auftreten von sturzbedingten Frakturen assoziiert. Die Datenlage betreffend der seit Kurzem zur Verfügung stehenden SGLT-2-Inhibitoren ist unklar, insbesondere bei älteren Patienten mit längerer Diabetesdauer und eingeschränkter Nierenfunktion scheint eine erhöhte Sturz- und Frakturgefährdung aufgrund von Veränderungen des Flüssigkeitshaushaltes und des Körpergewichtes vorzuliegen. Entsprechend ist im klinischen Alltag in der Wahl eines Antidiabetikums auch dem individuellen Frakturrisiko Rechnung zu tragen.

Summary

The use of oral antidiabetic drugs is essential in the treatment of patients with type 2 diabetes. Recently it has been recognized that type 2 diabetes is associated with changes in bone metabolism and fractures. The pathogenesis of diabetic bone disease is multifactorial with microvascular changes and deterioration of skeletal microarchitecture being discussed as underlying mechanisms. Oral antidiabetic drugs may affect bone metabolism and thereby may modulate fracture risk. This article summarizes the mode of action of oral antidiabetic drugs and their influence on bone metabolism. While thiazolidinediones are known to be deleterious on bone with increased fracture risk in longterm users, metformin and incretin-based therapies appear to have a protective or at least neutral effect on skeletal integrity. Sulfonylureas are associated with fall-related fractures due to an increased risk of hypoglycemia. The data regarding the recently available SGLT-2 inhibitors is unclear, specifically in older patients with longstanding diabetes and renal impairment there seems to be an increased fall and fracture risk due to changes in fluid balance and body weight. In clinical practice the individual fracture risk has to be considered when choosing an oral antidiabetic medication.

 
  • Literatur

  • 1 Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes a meta-analysis. Osteoporos Int 2007; 18 (04) 427-444.
  • 2 Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 2007; 166 (05) 495-505.
  • 3 Shanbhogue VV, Hansen S, Frost M, Brixen K, Hermann AP. Bone disease in diabetes: another manifestation of microvascular disease?. The lancet Diabetes & endocrinology. 2017 May 22.
  • 4 Leslie WD, Rubin MR, Schwartz AV, Kanis JA. Type 2 diabetes and bone. J Bone Miner Res 2012; 27 (11) 2231-2237.
  • 5 Shanbhogue VV, Mitchell DM, Rosen CJ, Bouxsein ML. Type 2 diabetes and the skeleton: new insights into sweet bones. The lancet Diabetes & endocrinology. 2015
  • 6 Meier C, Schwartz AV, Egger A, Lecka-Czernik B. Effects of diabetes drugs on the skeleton. Bone 2016; 82: 93-100.
  • 7 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 1-2 38-46.
  • 8 Kanazawa I, Yamaguchi T, Yano S, Yamauchi M, Yamamoto M, Sugimoto T. Adiponectin and AMP kinase activator stimulate proliferation, differentiation, and mineralization of osteoblastic MC3T3-E1 cells. BMC cell biology 2007; 08: 51.
  • 9 Zhen D, Chen Y, Tang X. Metformin reverses the deleterious effects of high glucose on osteoblast function. J Diabetes Complications 2010; 24 (05) 334-344.
  • 10 Molinuevo MS, Schurman L, McCarthy AD, Cortizo AM, Tolosa MJ, Gangoiti MV. et al. Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J Bone Miner Res 2010; 25 (02) 211-221.
  • 11 Jang WG, Kim EJ, Bae IH, Lee KN, Kim YD, Kim DK. et al. Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone 2011; 48 (04) 885-893.
  • 12 Marycz K, Tomaszewski KA, Kornicka K, Henry BM, Wronski S, Tarasiuk J. et al. Metformin Decreases Reactive Oxygen Species, Enhances Osteogenic Properties of Adipose-Derived Multipotent Mesenchymal Stem Cells In Vitro, and Increases Bone Density In Vivo. Oxidative medicine and cellular longevity 2016; 2016: 9785890.
  • 13 Schurman L, McCarthy AD, Sedlinsky C, Gangoiti MV, Arnol V, Bruzzone L. et al. Metformin reverts deleterious effects of advanced glycation endproducts (AGEs) on osteoblastic cells. Exp Clin Endocrinol Diabetes 2008; 116 (06) 333-340.
  • 14 Zhou Z, Tang Y, Jin X, Chen C, Lu Y, Liu L. et al. Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFkappaB Pathway Suppression. Journal of diabetes research 2016; 2016: 4847812.
  • 15 Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L. et al. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 2011; 112 (10) 2902-2909.
  • 16 Sedlinsky C, Molinuevo MS, Cortizo AM, Tolosa MJ, Felice JI, Sbaraglini ML. et al. Metformin prevents anti-osteogenic in vivo and ex vivo effects of rosiglitazone in rats. Eur J Pharmacol 2011; 668 (03) 477-485.
  • 17 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 1-3 231-236.
  • 18 Wang C, Li H, Chen SG, He JW, Sheng CJ, Cheng XY. et al. The skeletal effects of thiazolidinedione and metformin on insulin-resistant mice. J Bone Miner Metab 2012; 30 (06) 630-637.
  • 19 Kasai T, Bandow K, Suzuki H, Chiba N, Kakimoto K, Ohnishi T. et al. Osteoblast differentiation is functionally associated with decreased AMP kinase activity. J Cell Physiol 2009; 221 (03) 740-749.
  • 20 Jeyabalan J, Viollet B, Smitham P, Ellis SA, Zaman G, Bardin C. et al. The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing. Osteoporos Int 2013; 24 (10) 2659-2670.
  • 21 Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR. et al. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 2008; 31 (05) 845-851.
  • 22 Zinman B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG. et al. Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab 2010; 95 (01) 134-142.
  • 23 van Lierop AH, Hamdy NA, van der Meer RW, Jonker JT, Lamb HJ, Rijzewijk LJ. et al. 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 2012; 166 (04) 711-716.
  • 24 Hegazy SK. Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab 2015; 33 (02) 207-212.
  • 25 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 (07) 1292-1299.
  • 26 Melton 3rd LJ, Leibson CL, Achenbach SJ, Therneau TM, Khosla S. Fracture risk in type 2 diabetes: update of a population-based study. J Bone Miner Res 2008; 23 (08) 1334-1342.
  • 27 Monami M, Cresci B, Colombini A, Pala L, Balzi D, Gori F. et al. Bone fractures and hypoglycemic treatment in type 2 diabetic patients: a case-control study. Diabetes Care 2008; 31 (02) 199-203.
  • 28 Napoli N, Strotmeyer ES, Ensrud KE, Sellmeyer DE, Bauer DC, Hoffman AR. et al. Fracture risk in diabetic elderly men: the MrOS study. Diabetologia 2014; 57 (10) 2057-2065.
  • 29 Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR. Use of thiazolidinediones and fracture risk. Arch Intern Med 2008; 168 (08) 820-825.
  • 30 Colhoun HM, Livingstone SJ, Looker HC, Morris AD, Wild SH, Lindsay RS. et al. Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs. Diabetologia 2012; 55 (11) 2929-2937.
  • 31 Ma P, Gu B, Ma J, E L, Wu X, Cao J. et al. Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. Metabolism 2010; 59 (03) 359-366.
  • 32 Fronczek-Sokol J, Pytlik M. Effect of glimepiride on the skeletal system of ovariectomized and nonovariectomized rats. Pharmacological reports: PR 2014; 66 (03) 412-417.
  • 33 Kanazawa I, Yamaguchi T, Yamamoto M, Sugimoto T. Relationship between treatments with insulin and oral hypoglycemic agents versus the presence of vertebral fractures in type 2 diabetes mellitus. J Bone Miner Metab 2010; 28 (05) 554-560.
  • 34 Dormuth CR, Carney G, Carleton B, Bassett K, Wright JM. Thiazolidinediones and fractures in men and women. Arch Intern Med 2009; 169 (15) 1395-1402.
  • 35 Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355 (23) 2427-2443.
  • 36 Hung YC, Lin CC, Chen HJ, Chang MP, Huang KC, Chen YH. et al. Severe hypoglycemia and hip fracture in patients with type 2 diabetes: a nationwide population-based cohort study. Osteoporos Int 2017; 28 (07) 2053-2060.
  • 37 Rajpathak SN, Fu C, Brodovicz KG, Engel SS, Lapane K. Sulfonylurea use and risk of hip fractures among elderly men and women with type 2 diabetes. Drugs Aging 2015; 32 (04) 321-327.
  • 38 Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL. Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 2002; 143 (06) 2376-2384.
  • 39 Shockley KR, Lazarenko OP, Czernik PJ, Rosen CJ, Churchill GA, Lecka-Czernik B. PPARg2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells. J Cell Biochem 2009; 106 (02) 232-246.
  • 40 Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B. Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology. 2007
  • 41 Lecka-Czernik B, Ackert-Bicknell C, Adamo ML, Marmolejos V, Churchill GA, Shockley KR. et al. 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 2007; 148 (02) 903-911.
  • 42 Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernik B. Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology 2004; 145 (01) 401-406.
  • 43 Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology 2005; 146 (03) 1226-1235.
  • 44 Sardone LD, Renlund R, Willett TL, Fantus IG, Grynpas MD. Effect of rosiglitazone on bone quality in a rat model of insulin resistance and osteoporosis. Diabetes 2011; 60 (12) 3271-3278.
  • 45 Wan Y, Chong LW, Evans RM. PPAR-gamma regulates osteoclastogenesis in mice. Nat Med 2007; 13 (12) 1496-1503.
  • 46 Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. Cmaj 2009; 180 (01) 32-39.
  • 47 Zhu ZN, Jiang YF, Ding T. Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials. Bone 2014; 68: 115-123.
  • 48 Viscoli CM, Inzucchi SE, Young LH, Insogna KL, Conwit R, Furie KL. et al. Pioglitazone and Risk for Bone Fracture: Safety Data From a Randomized Clinical Trial. J Clin Endocrinol Metab 2017; 102 (03) 914-922.
  • 49 Billington EO, Grey A, Bolland MJ. The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis. Diabetologia 2015; 58 (10) 2238-2246.
  • 50 Bilezikian JP, Josse RG, Eastell R, Lewiecki EM, Miller CG, Wooddell M. et al. Rosiglitazone Decreases Bone Mineral Density and Increases Bone Turnover in Postmenopausal Women with Type 2 Diabetes Mellitus. J Clin Endocrinol Metab. 2013
  • 51 Schwartz AV, Chen H, Ambrosius WT, Sood A, Josse RG, Bonds DE. et al. Effects of TZD Use and Discontinuation on Fracture Rates in ACCORD Bone Study. J Clin Endocrinol Metab 2015; 100 (11) 4059-4066.
  • 52 Schwartz AV. Diabetes, bone and glucose-lowering agents: clinical outcomes. Diabetologia 2017; 60 (07) 1170-1179.
  • 53 Yamada C, Yamada Y, Tsukiyama K, Yamada K, Udagawa N, Takahashi N. et al. The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 2008; 149 (02) 574-579.
  • 54 Walsh JS, Henriksen DB. Feeding and bone. Arch Biochem Biophys 2010; 503 (01) 11-19.
  • 55 Henriksen DB, Alexandersen P, Byrjalsen I, Hartmann B, Bone HG, Christiansen C. et al. Reduction of nocturnal rise in bone resorption by subcutaneous GLP-2. Bone 2004; 34 (01) 140-147.
  • 56 Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG. et al. Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women. Bone 2007; 40 (03) 723-729.
  • 57 Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG. et al. Four-month treatment with GLP-2 significantly increases hip BMD: a randomized, placebo-controlled, doseranging study in postmenopausal women with low BMD. Bone 2009; 45 (05) 833-842.
  • 58 Nuche-Berenguer B, Portal-Nunez S, Moreno P, Gonzalez N, Acitores A, Lopez-Herradon A. et al. Presence of a functional receptor for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor. J Cell Physiol 2010; 225 (02) 585-592.
  • 59 Kim JY, Lee SK, Jo KJ, Song DY, Lim DM, Park KY. et al. Exendin-4 increases bone mineral density in type 2 diabetic OLETF rats potentially through the down-regulation of SOST/sclerostin in osteocytes. Life Sci 2013; 92 (10) 533-540.
  • 60 Nuche-Berenguer B, Lozano D, Gutierrez-Rojas I, Moreno P, Marinoso ML, Esbrit P. et al. GLP-1 and exendin-4 can reverse hyperlipidic-related osteopenia. J Endocrinol 2011; 209 (02) 203-210.
  • 61 Ma X, Meng J, Jia M, Bi L, Zhou Y, Wang Y. et al. 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 2013; 28 (07) 1641-1652.
  • 62 Lu N, Sun H, Yu J, Wang X, Liu D, Zhao L. et al. Glucagon-like peptide-1 receptor agonist Liraglutide has anabolic bone effects in ovariectomized rats without diabetes. PLoS One 2015; 10 (07) e0132744.
  • 63 Nuche-Berenguer B, Moreno P, Esbrit P, Dapia S, Caeiro JR, Cancelas J. et al. Effect of GLP-1 treatment on bone turnover in normal, type 2 diabetic, and insulin-resistant states. Calcif Tissue Int 2009; 84 (06) 453-461.
  • 64 http://www.scanco.ch/en/systems-solutions/clinical-microct/xtremect.html
  • 65 Raun K, von Voss P, Gotfredsen CF, Golozoubova V, Rolin B, Knudsen LB. Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 2007; 56 (01) 8-15.
  • 66 Bunck MC, Eliasson B, Corner A, Heine RJ, Shaginian RM, Taskinen MR. et al. Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes. Diabetes Obes Metab 2011; 13 (04) 374-377.
  • 67 Gilbert MP, Marre M, Holst JJ, Garber A, Baeres FM, Thomsen H. et al. Comparison of the Long-Term Effects of Liraglutide and Glimepiride Monotherapy on Bone Mineral Density in Patients with Type 2 Diabetes. Endocr Pract 2016; 22 (04) 406-411.
  • 68 Su B, Sheng H, Zhang M, Bu L, Yang P, Li L. et al. Risk of bone fractures associated with glucagonlike peptide-1 receptor agonists’ treatment: a metaanalysis of randomized controlled trials. Endocrine 2015; 48 (01) 107-115.
  • 69 Driessen JH, Henry RM, van Onzenoort HA, Lalmohamed A, Burden AM, Prieto-Alhambra D. et al. Bone fracture risk is not associated with the use of glucagon-like peptide-1 receptor agonists: a population-based cohort analysis. Calcif Tissue Int 2015; 97 (02) 104-112.
  • 70 Driessen JH, van Onzenoort HA, Starup-Linde J, Henry R, Burden AM, Neef C. et al. Use of Glucagon-Like-Peptide 1 Receptor Agonists and Risk of Fracture as Compared to Use of Other Anti-hyperglycemic Drugs. Calcif Tissue Int 2015; 97 (05) 506-515.
  • 71 Sbaraglini ML, Molinuevo MS, Sedlinsky C, Schurman L, McCarthy AD. Saxagliptin affects long-bone microarchitecture and decreases the osteogenic potential of bone marrow stromal cells. Eur J Pharmacol 2014; 727: 8-14.
  • 72 Gallagher EJ, Sun H, Kornhauser C, Tobin-Hess A, Epstein S, Yakar S. et al. The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes. Diabetes Metab Res Rev 2014; 30 (03) 191-200.
  • 73 Glorie L, Behets GJ, Baerts L, De Meester I, D’Haese PC, Verhulst A. DPP4 inhibitor treatment attenuates bone loss and improves mechanical bone strength in male diabetic rats. Am J Physiol Endocrinol Metab. 2014
  • 74 Dombrowski S, Kostev K, Jacob L. Use of dipeptidyl peptidase-4 inhibitors and risk of bone fracture: in patients with type 2 diabetes in Germany-A retrospective analysis of real-world data. Osteoporos Int 2017; 28 (08) 2421-2428.
  • 75 Majumdar SR, Josse RG, Lin M, Eurich DT. Does Sitagliptin Affect the Rate of Osteoporotic Fractures in Type 2 Diabetes? Population-Based Cohort Study. J Clin Endocrinol Metab 2016; 101 (05) 1963-1969.
  • 76 Monami M, Dicembrini I, Antenore A, Mannucci E. Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care 2011; 34 (11) 2474-2476.
  • 77 Fu J, Zhu J, Hao Y, Guo C, Zhou Z. Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials. Scientific reports 2016; 06: 29104.
  • 78 Mamza J, Marlin C, Wang C, Chokkalingam K, Idris I. DPP-4 inhibitor therapy and bone fractures in people with Type 2 diabetes – A systematic review and meta-analysis. Diabetes Res Clin Pract 2016; 116: 288-298.
  • 79 Harada N, Inagaki N. Role of sodium-glucose transporters in glucose uptake of the intestine and kidney. Journal of diabetes investigation 2012; 03 (04) 352-353.
  • 80 Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. The lancet Diabetes & endocrinology 2015; 03 (01) 8-10.
  • 81 Scheen AJ. SGLT2 Inhibitors: Benefit/Risk Balance. Curr Diab Rep 2016; 16 (10) 92.
  • 82 Ljunggren O, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjostrom CD. et al. 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 2012; 14 (11) 990-999.
  • 83 Bolinder J, Ljunggren O, Johansson L, Wilding J, Langkilde AM, Sjostrom CD. et al. 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 2014; 16 (02) 159-169.
  • 84 Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D. et al. Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With Canagliflozin. J Clin Endocrinol Metab 2016; 101 (01) 44-51.
  • 85 Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G. et al. Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. J Clin Endocrinol Metab 2016; 101 (01) 157-166.
  • 86 Kohan DE, Fioretto P, Tang W, List JF. 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 2014; 85 (04) 962-971.
  • 87 Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S. et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373 (22) 2117-2128.
  • 88 Ruanpeng D, Ungprasert P, Sangtian J, Harindhanavudhi T. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: A meta-analysis. Diabetes Metab Res Rev. 2017 33. 06.