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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2013, Vol. 7 Issue (1) : 81-90
Impact of diabetes and its treatments on skeletal diseases
Wenbo Yan1, Xin Li2()
1. Department of Biology and Chemistry, Nyack College, Room B001, 361 Broadway, New York, NY 10013, USA; 2. Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, Room 901D Dental Center, 345 E. 24th St., New York, NY 10010, USA
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Diabetes mellitus is an enormous menace to public health globally. This chronic disease of metabolism will adversely affect the skeleton if not controlled. Both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are associated with an increased risk of osteoporosis and fragility fractures. Bone mineral density is reduced in T1DM, whereas patients with T2DM have normal or slightly higher bone density, suggesting impaired bone quality is involved. Detrimental effects of T1DM on the skeleton are more severe than T2DM, probably because of the lack of osteo-anabolic effects of insulin and other pancreatic hormones. In both T1DM and T2DM, low bone quality could be caused by various means, including but not limited to hyperglycemia, accumulation of advanced glycosylation end products (AGEs), decreased serum levels of osteocalcin and parathyroid hormone. Risk for osteoarthritis is also elevated in diabetic population. How diabetes accelerates the deterioration of cartilage remains largely unknown. Hyperglycemia and glucose derived AGEs could contribute to the development of osteoarthritis. Moreover, it is recognized that oral antidiabetic medicines affect bone metabolism and turnover as well. Insulin is shown to have anabolic effects on bone and hyperinsulinemia may help to explain the slightly higher bone density in patients with T2DM. Thiazolidinediones can promote bone loss and osteoporotic fractures by suppressing osteoblastogenesis and enhancing osteoclastogenesis. Metformin favors bone formation by stimulating osteoblast differentiation and protecting them against diabetic conditions such as hyperglycemia. Better knowledge of how diabetic conditions and its treatments influence skeletal tissues is in great need in view of the growing and aging population of patients with diabetes mellitus.

Keywords diabetes      bone      osteoporosis      osteoarthritis     
Corresponding Author(s): Li Xin,   
Issue Date: 05 March 2013
 Cite this article:   
Wenbo Yan,Xin Li. Impact of diabetes and its treatments on skeletal diseases[J]. Front Med, 2013, 7(1): 81-90.
Fig.1  Possible mechanisms through which diabetic conditions increase the risk of osteoporotic fractures. Diabetic conditions common among both T1DM and T2DM patients can exert detrimental effects on skeletal tissues which will compromise bone quality. The impaired bone quality will reduce bone strength and therefore increase osteoporotic fracture risk. In addition to the above depicted factors, the lack of insulin and other bone anabolic hormones from the pancreas also contribute to impaired osteogenesis and decreased bone mass observed in T1DM patients. AGEs, advanced glycosylation end products; PTH, parathyroid hormone; MSC, mesenchymal stem cell; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
Fig.1  Possible mechanisms through which diabetic conditions increase the risk of osteoporotic fractures. Diabetic conditions common among both T1DM and T2DM patients can exert detrimental effects on skeletal tissues which will compromise bone quality. The impaired bone quality will reduce bone strength and therefore increase osteoporotic fracture risk. In addition to the above depicted factors, the lack of insulin and other bone anabolic hormones from the pancreas also contribute to impaired osteogenesis and decreased bone mass observed in T1DM patients. AGEs, advanced glycosylation end products; PTH, parathyroid hormone; MSC, mesenchymal stem cell; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
Fig.2  Diabetic conditions increase the risk of osteoarthritis. Diabetic conditions such as elevated blood glucose and blood AGEs levels have been suggested to compromise not only the quantity but also the quality of the cartilage tissues. This will increase the risk of developing osteoarthritis. DM, diabetes mellitus; AGEs, advanced glycosylation end products.
Fig.2  Diabetic conditions increase the risk of osteoarthritis. Diabetic conditions such as elevated blood glucose and blood AGEs levels have been suggested to compromise not only the quantity but also the quality of the cartilage tissues. This will increase the risk of developing osteoarthritis. DM, diabetes mellitus; AGEs, advanced glycosylation end products.
TreatmentsEffects on bone
Insulin (+)Stabilization of BMD and decrease in bone resorption;Prevention of osteopenia/osteoporosis
Thiazolidinediones (–)Suppressed bone formation (inhibited oesteoblastogenesis)Elevated bone resorption (enhanced osteoclastogenesis)
Metformin (+)Elevated bone formation (enhanced oesteoblastogenesis)Suppressed bone resorption (inhibited osteoclastogenesis)Protection of osteoblasts against hyperglycemia
Tab.1  Effects of diabetic treatments on bones
1 Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F, Khang YH, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 2011; 378(9785): 31-40 21705069
doi: 10.1016/S0140-6736(11)60679-X
2 Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem 2010; 285(33): 25103-25108
doi: 10.1074/jbc.R109.041087 pmid:20501658
3 Eriksen EF. Cellular mechanisms of bone remodeling. Rev Endocr Metab Disord 2010; 11(4): 219-227
doi: 10.1007/s11154-010-9153-1 pmid:21188536
4 Feng X, McDonald JM. Disorders of bone remodeling. Annu Rev Pathol 2011; 6(1): 121-145
doi: 10.1146/annurev-pathol-011110-130203 pmid:20936937
5 Bonewald LF. The amazing osteocyte. J Bone Miner Res 2011; 26(2): 229-238
doi: 10.1002/jbmr.320 pmid:21254230
6 Avrunin AS, Tikhilov RM. Osteocytic bone remodeling: history of the problem, morphological markers. Morfologiia 2011; 139(1): 86-94
7 Rochefort GY, Pallu S, Benhamou CL. Osteocyte: the unrecognized side of bone tissue. Osteoporos Int 2010; 21(9): 1457-1469
doi: 10.1007/s00198-010-1194-5 pmid:20204595
8 Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006; 17(12): 1726-1733
doi: 10.1007/s00198-006-0172-4 pmid:16983459
9 Botushanov NP, Orbetzova MM. Bone mineral density and fracture risk in patients with type 1 and type 2 diabetes mellitus. Folia Med (Plovdiv) 2009; 51(4): 12-17
10 Vestergaard P, Rejnmark L, Mosekilde L. Diabetes and its complications and their relationship with risk of fractures in type 1 and 2 diabetes. Calcif Tissue Int 2009; 84(1): 45-55
doi: 10.1007/s00223-008-9195-5 pmid:19067021
11 Ahmed LA, Joakimsen RM, Berntsen GK, F?nneb? V, Schirmer H. Diabetes mellitus and the risk of non-vertebral fractures: the Troms? study. Osteoporos Int 2006; 17(4): 495-500
doi: 10.1007/s00198-005-0013-x pmid:16283065
12 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(5): 495-505
doi: 10.1093/aje/kwm106 pmid:17575306
13 Nicodemus KK, Folsom AR. Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 2001; 24(7): 1192-1197
doi: 10.2337/diacare.24.7.1192 pmid:11423501
14 Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in patients with diabetes mellitus. J Bone Miner Res 2007; 22(9): 1317-1328
doi: 10.1359/jbmr.070510 pmid:17501667
15 Hamann C, Kirschner S, Günther KP, Hofbauer LC. Bone, sweet bone-osteoporotic fractures in diabetes mellitus.Nat Rev Endocrinol 2012; 8(5): 297-305
doi: 10.1038/nrendo.2011.23322249517
16 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(4): 427-444
doi: 10.1007/s00198-006-0253-4 pmid:17068657
17 Donnelly E. Methods for assessing bone quality: a review. Clin Orthop Relat Res 2011; 469(8): 2128-2138
doi: 10.1007/s11999-010-1702-0 pmid:21116752
18 Patel S, Hyer S, Tweed K, Kerry S, Allan K, Rodin A, Barron J. Risk factors for fractures and falls in older women with type 2 diabetes mellitus. Calcif Tissue Int 2008; 82(2): 87-91
doi: 10.1007/s00223-007-9082-5 pmid:18175036
19 Schwartz AV, Hillier TA, Sellmeyer DE, Resnick HE, Gregg E, Ensrud KE, Schreiner PJ, Margolis KL, Cauley JA, Nevitt MC, Black DM, Cummings SR. Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care 2002; 25(10): 1749-1754
doi: 10.2337/diacare.25.10.1749 pmid:12351472
20 Pijpers E, Ferreira I, de Jongh RT, Deeg DJ, Lips P, Stehouwer CD, Nieuwenhuijzen Kruseman AC. Older individuals with diabetes have an increased risk of recurrent falls: analysis of potential mediating factors: the Longitudinal Ageing Study Amsterdam. Age Ageing 2012; 41(3): 358-365
doi: 10.1093/ageing/afr145 pmid:22156559
21 Volpato S, Leveille SG, Blaum C, Fried LP, Guralnik JM. Risk factors for falls in older disabled women with diabetes: the women’s health and aging study. J Gerontol A Biol Sci Med Sci 2005; 60(12): 1539-1545
doi: 10.1093/gerona/60.12.1539 pmid:16424285
22 Azidah AK, Hasniza H, Zunaina E. Prevalence of Falls and Its Associated Factors among Elderly Diabetes in a Tertiary Center, Malaysia. Curr Gerontol Geriatr Res 2012; 2012: 539073
doi: 10.1155/2012/539073 pmid:22693496
23 Thrailkill KM, Lumpkin CK Jr, Bunn RC, Kemp SF, Fowlkes JL. Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab 2005; 289(5): E735-E745
doi: 10.1152/ajpendo.00159.2005 pmid:16215165
24 Barbagallo I, Vanella A, Peterson SJ, Kim DH, Tibullo D, Giallongo C, Vanella L, Parrinello N, Palumbo GA, Di Raimondo F, Abraham NG, Asprinio D. Overexpression of heme oxygenase-1 increases human osteoblast stem cell differentiation. J Bone Miner Metab 2010; 28(3): 276-288
doi: 10.1007/s00774-009-0134-y pmid:19924377
25 Keats E, Khan ZA. Unique responses of stem cell-derived vascular endothelial and mesenchymal cells to high levels of glucose. PLoS ONE 2012; 7(6): e38752
doi: 10.1371/journal.pone.0038752 pmid:22701703
26 Stolzing A, Colley H, Scutt A. Effect of age and diabetes on the response of mesenchymal progenitor cells to fibrin matrices. Int J Biomater 2011; 2011: 378034
doi: 10.1155/2011/378034 pmid:22194749
27 Kawahito S, Kitahata H, Oshita S. Problems associated with glucose toxicity: role of hyperglycemia-induced oxidative stress. World J Gastroenterol 2009; 15(33): 4137-4142
doi: 10.3748/wjg.15.4137 pmid:19725147
28 Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol 2006; 212(2): 167-178
doi: 10.1016/j.taap.2006.01.003 pmid:16490224
29 King GL, Loeken MR. Hyperglycemia-induced oxidative stress in diabetic complications. Histochem Cell Biol 2004; 122(4): 333-338
doi: 10.1007/s00418-004-0678-9 pmid:15257460
30 Grassi F, Tell G, Robbie-Ryan M, Gao Y, Terauchi M, Yang X, Romanello M, Jones DP, Weitzmann MN, Pacifici R. Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation. Proc Natl Acad Sci USA 2007; 104(38): 15087-15092
doi: 10.1073/pnas.0703610104 pmid:17848519
31 Manolagas SC. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev 2010; 31(3): 266-300
doi: 10.1210/er.2009-0024 pmid:20051526
32 Saito M, Fujii K, Mori Y, Marumo K. Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int 2006; 17(10): 1514-1523
doi: 10.1007/s00198-006-0155-5 pmid:16770520
33 Sanguineti R, Storace D, Monacelli F, Federici A, Odetti P. Pentosidine effects on human osteoblasts in vitro. Ann N Y Acad Sci 2008; 1126(1): 166-172
doi: 10.1196/annals.1433.044 pmid:18448811
34 Schwartz AV, Garnero P, Hillier TA, Sellmeyer DE, Strotmeyer ES, Feingold KR, Resnick HE, Tylavsky FA, Black DM, Cummings SR, Harris TB, Bauer DC ; Health, Aging, and Body Composition Study. Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab 2009; 94(7): 2380-2386
doi: 10.1210/jc.2008-2498 pmid:19383780
35 Clemens TL, Karsenty G. The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Miner Res 2011; 26(4): 677-680
doi: 10.1002/jbmr.321 pmid:21433069
36 Karsenty G, Oury F. The central regulation of bone mass, the first link between bone remodeling and energy metabolism. J Clin Endocrinol Metab 2010; 95(11): 4795-4801
doi: 10.1210/jc.2010-1030 pmid:21051575
37 Karsenty G, Oury F. Biology without walls: the novel endocrinology of bone. Annu Rev Physiol 2012; 74(1): 87-105
doi: 10.1146/annurev-physiol-020911-153233 pmid:22077214
38 Karsenty G. Bone endocrine regulation of energy metabolism and male reproduction. C R Biol 2011; 334(10): 720-724
doi: 10.1016/j.crvi.2011.07.007 pmid:21943521
39 Lee NK, Karsenty G. Reciprocal regulation of bone and energy metabolism. Trends Endocrinol Metab 2008; 19(5): 161-166
doi: 10.1016/j.tem.2008.02.006 pmid:18407515
40 Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G. Endocrine regulation of energy metabolism by the skeleton. Cell 2007; 130(3): 456-469
doi: 10.1016/j.cell.2007.05.047 pmid:17693256
41 Karsenty G. The mutual dependence between bone and gonads. J Endocrinol 2012; 213(2): 107-114
doi: 10.1530/JOE-11-0452 pmid:22407998
42 Movahed A, Larijani B, Nabipour I, Kalantarhormozi M, Asadipooya K, Vahdat K, Akbarzadeh S, Farrokhnia M, Assadi M, Amirinejad R, Bargahi A, Sanjdideh Z. Reduced serum osteocalcin concentrations are associated with type 2 diabetes mellitus and the metabolic syndrome components in postmenopausal women: the crosstalk between bone and energy metabolism. J Bone Miner Metab 2012; 30(6): 683-691
doi: 10.1007/s00774-012-0367-z
43 Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T. Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus. Osteoporos Int 2011; 22(1): 187-194
doi: 10.1007/s00198-010-1184-7 pmid:20165834
44 Bao YQ, Zhou M, Zhou J, Lu W, Gao YC, Pan XP, Tang JL, Lu HJ, Jia WP. Relationship between serum osteocalcin and glycaemic variability in Type 2 diabetes. Clin Exp Pharmacol Physiol 2011; 38(1): 50-54
doi: 10.1111/j.1440-1681.2010.05463.x pmid:21083700
45 Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Yano S, Sugimoto T. Serum osteocalcin/bone-specific alkaline phosphatase ratio is a predictor for the presence of vertebral fractures in men with type 2 diabetes. Calcif Tissue Int 2009; 85(3): 228-234
doi: 10.1007/s00223-009-9272-4 pmid:19641839
46 NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001; 285(6): 785-795
doi: 10.1001/jama.285.6.785 pmid:11176917
47 Polymeris AD, Doumouchtsis KK, Giagourta I, Karga H. Effect of an oral glucose load on PTH, 250HD3, calcium, and phosphorus homeostasis in postmenopausal women. Endocr Res 2011; 36(2): 45-52
doi: 10.3109/07435800.2010.496761 pmid:21539443
48 Inaba M, Nagasue K, Okuno S, Ueda M, Kumeda Y, Imanishi Y, Shoji T, Ishimura E, Ohta T, Nakatani T, Kim M, Nishizawa Y. Impaired secretion of parathyroid hormone, but not refractoriness of osteoblast, is a major mechanism of low bone turnover in hemodialyzed patients with diabetes mellitus. Am J Kidney Dis 2002; 39(6): 1261-1269
doi: 10.1053/ajkd.2002.33400 pmid:12046040
49 Inaba M, Okuno S, Kumeda Y, Yamakawa T, Ishimura E, Nishizawa Y. Increased incidence of vertebral fracture in older female hemodialyzed patients with type 2 diabetes mellitus. Calcif Tissue Int 2005; 76(4): 256-260
doi: 10.1007/s00223-004-0094-0 pmid:15692725
50 Dobnig H, Piswanger-S?lkner JC, Roth M, Obermayer-Pietsch B, Tiran A, Strele A, Maier E, Maritschnegg P, Sieberer C, Fahrleitner-Pammer A. Type 2 diabetes mellitus in nursing home patients: effects on bone turnover, bone mass, and fracture risk. J Clin Endocrinol Metab 2006; 91(9): 3355-3363
doi: 10.1210/jc.2006-0460 pmid:16735485
51 Picton ML, Moore PR, Mawer EB, Houghton D, Freemont AJ, Hutchison AJ, Gokal R, Hoyland JA. Down-regulation of human osteoblast PTH/PTHrP receptor mRNA in end-stage renal failure. Kidney Int 2000; 58(4): 1440-1449
doi: 10.1046/j.1523-1755.2000.00306.x pmid:11012879
52 Kuchler U, Spilka T, Baron K, Tangl S, Watzek G, Gruber R. Intermittent parathyroid hormone fails to stimulate osseointegration in diabetic rats. Clin Oral Implants Res 2011; 22(5): 518-523
doi: 10.1111/j.1600-0501.2010.02047.x pmid:21251075
53 Murphy L, Helmick CG. The impact of osteoarthritis in the United States: a population-health perspective. Am J Nurs 2012; 112(3 Suppl 1): S13-S19
doi: 10.1097/01.NAJ.0000412646.80054.21 pmid:22373741
54 Berenbaum F. Diabetes-induced osteoarthritis: from a new paradigm to a new phenotype. Postgrad Med J 2012; 88(1038): 240-242
doi: 10.1136/pgmj.2010.146399rep pmid:22441236
55 Cheng YJ, Imperatore G, Caspersen CJ, Gregg EW, Albright AL, Helmick CG. Prevalence of diagnosed arthritis and arthritis-attributable activity limitation among adults with and without diagnosed diabetes: United States, 2008-2010. Diabetes Care 2012; 35(8): 1686-1691
doi: 10.2337/dc12-0046
56 Kayal RA, Alblowi J, McKenzie E, Krothapalli N, Silkman L, Gerstenfeld L, Einhorn TA, Graves DT. Diabetes causes the accelerated loss of cartilage during fracture repair which is reversed by insulin treatment. Bone 2009; 44(2): 357-363
doi: 10.1016/j.bone.2008.10.042 pmid:19010456
57 Rosa SC, Rufino AT, Judas FM, Tenreiro CM, Lopes MC, Mendes AF. Role of glucose as a modulator of anabolic and catabolic gene expression in normal and osteoarthritic human chondrocytes. J Cell Biochem 2011; 112(10): 2813-2824
doi: 10.1002/jcb.23196 pmid:21608018
58 Davies-Tuck ML, Wang Y, Wluka AE, Berry PA, Giles GG, English DR, Cicuttini FM. Increased fasting serum glucose concentration is associated with adverse knee structural changes in adults with no knee symptoms and diabetes.Maturitas 2012; 72(4): 373-378
doi: 10.1016/j.maturitas.2012.05.013
59 Verzijl N, DeGroot J, Ben ZC, Brau-Benjamin O, Maroudas A, Bank RA, Mizrahi J, Schalkwijk CG, Thorpe SR, Baynes JW, Bijlsma JW, Lafeber FP, TeKoppele JM. Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis. Arthritis Rheum 2002; 46(1): 114-123
doi: 10.1002/1529-0131(200201)46:1<114::AID-ART10025>3.0.CO;2-P pmid:11822407
60 DeGroot J, Verzijl N, Jacobs KM, Budde M, Bank RA, Bijlsma JW, TeKoppele JM, Lafeber FP. Accumulation of advanced glycation endproducts reduces chondrocyte-mediated extracellular matrix turnover in human articular cartilage. Osteoarthritis Cartilage 2001; 9(8): 720-726
doi: 10.1053/joca.2001.0469 pmid:11795991
61 DeGroot J, Verzijl N, Wenting-van Wijk MJ, Jacobs KM, Van El B, Van Roermund PM, Bank RA, Bijlsma JW, TeKoppele JM, Lafeber FP. Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum 2004; 50(4): 1207-1215
doi: 10.1002/art.20170 pmid:15077303
62 Yammani RR, Carlson CS, Bresnick AR, Loeser RF. Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: Role of the receptor for advanced glycation end products. Arthritis Rheum 2006; 54(9): 2901-2911
doi: 10.1002/art.22042 pmid:16948116
63 Nah SS, Choi IY, Yoo B, Kim YG, Moon HB, Lee CK. Advanced glycation end products increases matrix metalloproteinase-1, -3, and-13, and TNF-alpha in human osteoarthritic chondrocytes. FEBS Lett 2007; 581(9): 1928-1932
doi: 10.1016/j.febslet.2007.03.090 pmid:17434489
64 Nah SS, Choi IY, Lee CK, Oh JS, Kim YG, Moon HB, Yoo B. Effects of advanced glycation end products on the expression of COX-2, PGE2 and NO in human osteoarthritic chondrocytes. Rheumatology (Oxford) 2008; 47(4): 425-431
doi: 10.1093/rheumatology/kem376 pmid:18285354
65 Rasheed Z, Akhtar N, Haqqi TM. Advanced glycation end products induce the expression of interleukin-6 and interleukin-8 by receptor for advanced glycation end product-mediated activation of mitogen-activated protein kinases and nuclear factor-kB in human osteoarthritis chondrocytes. Rheumatology (Oxford) 2011; 50(5): 838-851
doi: 10.1093/rheumatology/keq380 pmid:21172926
66 Ogata N, Chikazu D, Kubota N, Terauchi Y, Tobe K, Azuma Y, Ohta T, Kadowaki T, Nakamura K, Kawaguchi H. Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. J Clin Invest 2000; 105(7): 935-943
doi: 10.1172/JCI9017 pmid:10749573
67 Akune T, Ogata N, Hoshi K, Kubota N, Terauchi Y, Tobe K, Takagi H, Azuma Y, Kadowaki T, Nakamura K, Kawaguchi H. Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts. J Cell Biol 2002; 159(1): 147-156
doi: 10.1083/jcb.200204046 pmid:12379806
68 Kawamura N, Kugimiya F, Oshima Y, Ohba S, Ikeda T, Saito T, Shinoda Y, Kawasaki Y, Ogata N, Hoshi K, Akiyama T, Chen WS, Hay N, Tobe K, Kadowaki T, Azuma Y, Tanaka S, Nakamura K, Chung UI, Kawaguchi H. Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS ONE 2007; 2(10): e1058
doi: 10.1371/journal.pone.0001058 pmid:17957242
69 Bouillon R, Bex M, Van Herck E, Laureys J, Dooms L, Lesaffre E, Ravussin E. Influence of age, sex, and insulin on osteoblast function: osteoblast dysfunction in diabetes mellitus. J Clin Endocrinol Metab 1995; 80(4): 1194-1202
doi: 10.1210/jc.80.4.1194 pmid:7714089
70 Campos Pastor MM, López-Ibarra PJ, Escobar-Jiménez F, Serrano Pardo MD, García-Cervigón AG. Intensive insulin therapy and bone mineral density in type 1 diabetes mellitus: a prospective study. Osteoporos Int 2000; 11(5): 455-459
doi: 10.1007/s001980070114 pmid:10912849
71 Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994; 331(18): 1188-1193
doi: 10.1056/NEJM199411033311803 pmid:7935656
72 Mimura K, Umeda F, Hiramatsu S, Taniguchi S, Ono Y, Nakashima N, Kobayashi K, Masakado M, Sako Y, Nawata H. Effects of a new oral hypoglycaemic agent (CS-045) on metabolic abnormalities and insulin resistance in type 2 diabetes. Diabet Med 1994; 11(7): 685-691
doi: 10.1111/j.1464-5491.1994.tb00333.x pmid:7955995
73 Takino H, Okuno S, Uotani S, Yano M, Matsumoto K, Kawasaki E, Takao Y, Yamasaki H, Yamaguchi Y, Akazawa S, Nagataki S. Increased insulin responsiveness after CS-045 treatment in diabetes associated with Werner’s syndrome. Diabetes Res Clin Pract 1994; 24(3): 167-172
doi: 10.1016/0168-8227(94)90112-0 pmid:7988348
74 Murano K, Inoue Y, Emoto M, Kaku K, Kaneko T. CS-045, a new oral antidiabetic agent, stimulates fructose-2,6-bisphosphate production in rat hepatocytes. Eur J Pharmacol 1994; 254(3): 257-262
doi: 10.1016/0014-2999(94)90462-6 pmid:8013560
75 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(6): 2376-2384
doi: 10.1210/en.143.6.2376 pmid:12021203
76 Lazarenko OP, Rzonca SO, Suva LJ, Lecka-Czernik B. Netoglitazone is a PPAR-gamma ligand with selective effects on bone and fat. Bone 2006; 38(1): 74-84
doi: 10.1016/j.bone.2005.07.008 pmid:16137931
77 Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernik B. Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology 2004; 145(1): 401-406
doi: 10.1210/en.2003-0746 pmid:14500573
78 Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR, Strotmeyer ES, Resnick HE, Carbone L, Beamer BA, Park SW, Lane NE, Harris TB, Cummings SR. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 2006; 91(9): 3349-3354
doi: 10.1210/jc.2005-2226 pmid:16608888
79 Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, Kravitz BG, Yu D, Heise MA, Aftring RP, Viberti G ; Diabetes Outcome Progression Trial (ADOPT) Study Group. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 2008; 31(5): 845-851
doi: 10.2337/dc07-2270 pmid:18223031
80 Habib ZA, Havstad SL, Wells K, Divine G, Pladevall M, Williams LK. Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2010; 95(2): 592-600
doi: 10.1210/jc.2009-1385 pmid:20061432
81 Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR. 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 2007; 92(4): 1305-1310
doi: 10.1210/jc.2006-2646 pmid:17264176
82 Yaturu S, Bryant B, Jain SK. Thiazolidinedione treatment decreases bone mineral density in type 2 diabetic men. Diabetes Care 2007; 30(6): 1574-1576
doi: 10.2337/dc06-2606 pmid:17363747
83 Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung UI, Kubota N, Terauchi Y, Harada Y, Azuma Y, Nakamura K, Kadowaki T, Kawaguchi H. PPARγ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 2004; 113(6): 846-855
84 Cho SW, Yang JY, Her SJ, Choi HJ, Jung JY, Sun HJ, An JH, Cho HY, Kim SW, Park KS, Kim SY, Baek WY, Kim JE, Yim M, Shin CS. Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice. J Bone Miner Res 2011; 26(8): 1939-1952
doi: 10.1002/jbmr.366 pmid:21351141
85 Wan Y, Chong LW, Evans RM. PPAR-gamma regulates osteoclastogenesis in mice. Nat Med 2007; 13(12): 1496-1503
doi: 10.1038/nm1672 pmid:18059282
86 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(3): 1226-1235
doi: 10.1210/en.2004-0735 pmid:15591153
87 Lecka-Czernik B, Gubrij I, Moerman EJ, Kajkenova O, Lipschitz DA, Manolagas SC, Jilka RL. Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARγ2. J Cell Biochem 1999; 74(3): 357-371
doi: 10.1002/(SICI)1097-4644(19990901)74:3<357::AID-JCB5>3.0.CO;2-7 pmid:10412038
88 Zinman B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG, Paul G, Jones NP, Aftring RP, Viberti G, Kahn SE ; ADOPT Study Group. Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab 2010; 95(1): 134-142
doi: 10.1210/jc.2009-0572 pmid:19875477
89 Sorocéanu MA, Miao D, Bai XY, Su H, Goltzman D, Karaplis AC. Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis. J Endocrinol 2004; 183(1): 203-216
doi: 10.1677/joe.1.05723 pmid:15525588
90 Mabilleau G, Mieczkowska A, Edmonds ME. Thiazolidinediones induce osteocyte apoptosis and increase sclerostin expression. Diabet Med 2010; 27(8): 925-932
doi: 10.1111/j.1464-5491.2010.03048.x pmid:20653751
91 Wei W, Wan Y. Thiazolidinediones on PPARγ: the roles in bone remodeling. PPAR Res 2011; 2011: 867180
doi: 10.1155/2011/867180 pmid:22135675
92 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(7): 1292-1299
doi: 10.1007/s00125-005-1786-3 pmid:15909154
93 Gao Y, Xue J, Li X, Jia Y, Hu J. Metformin regulates osteoblast and adipocyte differentiation of rat mesenchymal stem cells. J Pharm Pharmacol 2008; 60(12): 1695-1700
doi: 10.1211/jpp.60.12.0017 pmid:19000376
94 Shah M, Kola B, Bataveljic A, Arnett TR, Viollet B, Saxon L, Korbonits M, Chenu C. AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass. Bone 2010; 47(2): 309-319
doi: 10.1016/j.bone.2010.04.596 pmid:20399918
95 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
doi: 10.1016/j.ejphar.2010.02.051 pmid:20307532
96 Molinuevo MS, Schurman L, McCarthy AD, Cortizo AM, Tolosa MJ, Gangoiti MV, Arnol V, Sedlinsky C. Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J Bone Miner Res 2010; 25(2): 211-221
doi: 10.1359/jbmr.090732 pmid:19594306
97 Takatani T, Minagawa M, Takatani R, Kinoshita K, Kohno Y. AMP-activated protein kinase attenuates Wnt/β-catenin signaling in human osteoblastic Saos-2 cells. Mol Cell Endocrinol 2011; 339(1-2): 114-119
doi: 10.1016/j.mce.2011.04.003 pmid:21501658
98 Jang WG, Kim EJ, Bae IH, Lee KN, Kim YD, Kim DK, Kim SH, Lee CH, Franceschi RT, Choi HS, Koh JT. Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone 2011; 48(4): 885-893
doi: 10.1016/j.bone.2010.12.003 pmid:21147283
99 Zhen D, Chen Y, Tang X. Metformin reverses the deleterious effects of high glucose on osteoblast function. J Diabetes Complications 2010; 24(5): 334-344
doi: 10.1016/j.jdiacomp.2009.05.002 pmid:19628413
100 Schurman L, McCarthy AD, Sedlinsky C, Gangoiti MV, Arnol V, Bruzzone L, Cortizo AM. Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. Exp Clin Endocrinol Diabetes 2008; 116(6): 333-340
doi: 10.1055/s-2007-992786 pmid:18273753
101 Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Jia CH, Wen ZH, Jin DD, Bai XC. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 2011; 112(10): 2902-2909
doi: 10.1002/jcb.23206 pmid:21618594
102 Liu L, Zhang C, Hu Y, Peng B. 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 2012; 38(7): 943-947
doi: 10.1016/j.joen.2012.03.010 pmid:22703658
103 Sukala WR, Page R, Cheema BS. Exercise training in high-risk ethnic populations with type 2 diabetes: a systematic review of clinical trials. Diabetes Res Clin Pract 2012; 97(2): 206-216
doi: 10.1016/j.diabres.2012.02.001 pmid:22385831
104 Dunkley AJ, Charles K, Gray LJ, Camosso-Stefinovic J, Davies MJ, Khunti K. Effectiveness of interventions for reducing diabetes and cardiovascular disease risk in people with metabolic syndrome: systematic review and mixed treatment comparison meta-analysis. Diabetes Obes Metab 2012; 14(7): 616-625
doi: 10.1111/j.1463-1326.2012.01571.x pmid:22284386
105 Petersen JL, McGuire DK. Impaired glucose tolerance and impaired fasting glucose—a review of diagnosis, clinical implications and management. Diab Vasc Dis Res 2005; 2(1): 9-15
doi: 10.3132/dvdr.2005.007 pmid:16305067
106 Kelley GA, Kelley KS, Kohrt WM. Effects of ground and joint reaction force exercise on lumbar spine and femoral neck bone mineral density in postmenopausal women: a meta-analysis of randomized controlled trials. BMC Musculoskelet Disord 2012; 13(1): 177
doi: 10.1186/1471-2474-13-177 pmid:22992273
107 Marques EA, Mota J, Carvalho J. Exercise effects on bone mineral density in older adults: a meta-analysis of randomized controlled trials. Age (Dordr) 2012; 34(6): 1493-1515
doi: 10.1007/s11357-011-9311-8 pmid:21922251
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