Skip to main content
main-content
Top

04-22-2017 | Osteoporosis | Review | Article

Diabetes, bone and glucose-lowering agents: basic biology

Journal: Diabetologia

Author: Beata Lecka-Czernik

Publisher: Springer Berlin Heidelberg

share
SHARE

Abstract

Skeletal fragility often accompanies diabetes and does not appear to correlate with low bone mass or trauma severity in individuals with diabetes. Instead (and in contrast to those with osteoporotic bone disease), bone remodelling and bone turnover are compromised in both type 1 and type 2 diabetes, contributing to defective bone material quality. This review is one of a pair discussing the relationship between diabetes, bone and glucose-lowering agents; an accompanying review is provided in this issue of Diabetologia by Ann Schwartz (DOI: 10.​1007/​s00125-017-4283-6). This review presents basic science evidence that, alongside other organs, bone is affected in diabetes via impairments in glucose metabolism, toxic effects of glucose oxidative derivatives (advance glycation end-products [AGEs]), and via impairments in bone microvascular function and muscle endocrine function. The cellular and molecular basis for the effects of diabetes on bone are discussed, as is the impact of diabetes on the stem cell niche and fracture healing. Furthermore, the safety of clinically approved glucose-lowering therapies and the possibility of developing a single therapy that would be beneficial for both insulin sensitisation and diabetes bone syndrome are outlined.
Literature
1.
Schwartz AV (2017) Diabetes, bone and glucose-lowering agents: clinical outcomes. Diabetologia. doi: 10.​1007/​s00125-017-4283-6
2.
Starup-Linde J, Frost M, Vestergaard P, Abrahamsen B (2017) Epidemiology of fractures in diabetes. Calcif Tissue Int 100:109–121 CrossRefPubMed
3.
Farr JN, Drake MT, Amin S, Melton LJ 3rd, McCready LK, Khosla S (2014) In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res 29:787–795 CrossRefPubMedPubMedCentral
4.
Lecka-Czernik B, Rosen CJ (2015) Energy excess, glucose utilization, and skeletal remodeling: new insights. J Bone Miner Res 30:1356–1361 CrossRefPubMed
5.
Krakauer JC, McKenna MJ, Buderer NF, Rao DS, Whitehouse FW, Parfitt AM (1995) Bone loss and bone turnover in diabetes. Diabetes 44:775–782 CrossRefPubMed
6.
Rubin MR (2015) Bone cells and bone turnover in diabetes mellitus. Curr Osteoporos Rep 13:186–191 CrossRefPubMed
7.
Patsch JM, Burghardt AJ, Yap SP et al (2013) Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures. J Bone Miner Res 28:313–324 CrossRefPubMedPubMedCentral
8.
Nilsson AG, Sundh D, Johansson L et al (2016) Type 2 diabetes mellitus is associated with better bone microarchitecture but lower bone material strength and poorer physical function in elderly women: a population-based study. J Bone Miner Res. doi: 10.​1002/​jbmr.​3057
9.
Wei J, Shimazu J, Makinistoglu MP et al (2015) Glucose uptake and Runx2 synergize to orchestrate osteoblast differentiation and bone formation. Cell 161:1576–1591 CrossRefPubMedPubMedCentral
10.
Clemens TL, Karsenty G (2011) The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Miner Res 26:677–680 CrossRefPubMed
11.
Ferron M, Wei J, Yoshizawa T et al (2010) Insulin signalling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142:296–308 CrossRefPubMedPubMedCentral
12.
Kondegowda NG, Fenutria R, Pollack IR et al (2015) Osteoprotegerin and denosumab stimulate human beta cell proliferation through inhibition of the receptor activator of NF-kappaB ligand pathway. Cell Metab 22:77–85 CrossRefPubMedPubMedCentral
13.
Fulzele K, Riddle RC, Digirolamo DJ et al (2010) Insulin receptor signalling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142:309–319 CrossRefPubMedPubMedCentral
14.
Wei J, Ferron M, Clarke CJ et al (2014) Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. J Clin Invest 124:1–13 CrossRefPubMed
15.
Doucette CR, Horowitz MC, Berry R et al (2015) A high fat diet increases bone marrow adipose tissue (MAT) but does not alter trabecular or cortical bone mass in C57BL/6J mice. J Cell Physiol 230:2032–2037 CrossRefPubMedPubMedCentral
16.
Lecka-Czernik B, Stechschulte LA, Czernik PJ, Dowling AR (2015) High bone mass in adult mice with diet-induced obesity results from a combination of initial increase in bone mass followed by attenuation in bone formation; implications for high bone mass and decreased bone quality in obesity. Mol Cell Endocrinol 410:35–41 CrossRefPubMed
17.
Stechschulte LA, Czernik PJ, Rotter ZC et al (2016) PPARG post-translational modifications regulate bone formation and bone resorption. EBioMedicine 10:174–184 CrossRefPubMedPubMedCentral
18.
Lecka-Czernik B (2010) PPARs in bone: the role in bone cell differentiation and regulation of energy metabolism. Curr Osteoporos Rep 8:84–90 CrossRefPubMed
19.
Ge C, Cawthorn WP, Li Y, Zhao G, MacDougald OA, Franceschi RT (2016) Reciprocal control of osteogenic and adipogenic differentiation by ERK/MAP kinase phosphorylation of Runx2 and PPARgamma transcription factors. J Cell Physiol 231:587–596 CrossRefPubMedPubMedCentral
20.
Stechschulte LA, Ge C, Hinds TD Jr, Sanchez ER, Franceschi RT, Lecka-Czernik B (2016) Protein phosphatase PP5 controls bone mass and the negative effects of rosiglitazone on bone through reciprocal regulation of PPARgamma (peroxisome proliferator-activated receptor gamma) and RUNX2 (runt-related transcription factor 2). J Biol Chem 291:24475–24486 CrossRefPubMed
21.
Wei W, Wang X, Yang M, Smith LC, Dechow PC, Wan Y (2010) PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss. Cell Metab 11:503–516 CrossRefPubMedPubMedCentral
22.
Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B (2007) Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology 148:2669–2680 CrossRefPubMedPubMedCentral
23.
Abdallah BM, Ditzel N, Laborda J, Karsenty G, Kassem M (2015) DLK1 regulates whole-body glucose metabolism: a negative feedback regulation of the osteocalcin-insulin loop. Diabetes 64:3069–3080 CrossRefPubMed
24.
Tevlin R, Seo EY, Marecic O et al (2017) Pharmacological rescue of diabetic skeletal stem cell niches. Sci Transl Med 9:eaag2809 CrossRefPubMed
25.
Creecy A, Uppuganti S, Merkel AR et al (2016) Changes in the fracture resistance of bone with the progression of type 2 diabetes in the ZDSD rat. Calcif Tissue Int 99:289–301 CrossRefPubMed
26.
Aikawa E, Fujita R, Asai M, Kaneda Y, Tamai K (2016) Receptor for advanced glycation end products-mediated signalling impairs the maintenance of bone marrow mesenchymal stromal cells in diabetic model mice. Stem Cells Dev 25:1721–1732 CrossRefPubMed
27.
Ding KH, Wang ZZ, Hamrick MW et al (2006) Disordered osteoclast formation in RAGE-deficient mouse establishes an essential role for RAGE in diabetes related bone loss. Biochem Biophys Res Commun 340:1091–1097 CrossRefPubMed
28.
Schwartz AV, Garnero P, Hillier TA et al (2009) Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab 94:2380–2386 CrossRefPubMedPubMedCentral
29.
Lafage-Proust MH, Roche B, Langer M et al (2015) Assessment of bone vascularization and its role in bone remodeling. Bonekey Rep 4:662 CrossRefPubMedPubMedCentral
30.
Weber DR, Haynes K, Leonard MB, Willi SM, Denburg MR (2015) Type 1 diabetes is associated with an increased risk of fracture across the life span: a population-based cohort study using the health improvement network (THIN). Diabetes Care 38:1913–1920 CrossRefPubMedPubMedCentral
31.
Shanbhogue VV, Hansen S, Frost M et al (2016) Compromised cortical bone compartment in type 2 diabetes mellitus patients with microvascular disease. Eur J Endocrinol 174:115–124 CrossRefPubMed
32.
Tanikawa T, Okada Y, Tanikawa R, Tanaka Y (2009) Advanced glycation end products induce calcification of vascular smooth muscle cells through RAGE/p38 MAPK. J Vasc Res 46:572–580 CrossRefPubMed
33.
Gohin S, Carriero A, Chenu C, Pitsillides AA, Arnett TR, Marenzana M (2016) The anabolic action of intermittent parathyroid hormone on cortical bone depends partly on its ability to induce nitric oxide-mediated vasorelaxation in BALB/c mice. Cell Biochem Funct 34:52–62 CrossRefPubMedPubMedCentral
34.
Eckardt K, Gorgens SW, Raschke S, Eckel J (2014) Myokines in insulin resistance and type 2 diabetes. Diabetologia 57:1087–1099 CrossRefPubMed
35.
Yang X, Ricciardi BF, Hernandez-Soria A, Shi Y, Pleshko Camacho N, Bostrom MP (2007) Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice. Bone 41:928–936 CrossRefPubMedPubMedCentral
36.
Mera P, Laue K, Ferron M et al (2016) Osteocalcin signalling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metab 23:1078–1092 CrossRefPubMed
37.
Colaianni G, Cuscito C, Mongelli T et al (2015) The myokine irisin increases cortical bone mass. Proc Natl Acad Sci U S A 112:12157–12162 CrossRefPubMedPubMedCentral
38.
Hampp C, Borders-Hemphill V, Moeny DG, Wysowski DK (2014) Use of antidiabetic drugs in the U.S., 2003–2012. Diabetes Care 37:1367–1374 CrossRefPubMed
39.
Jang WG, Kim EJ, Bae IH et al (2011) Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone 48:885–893 CrossRefPubMed
40.
Chen SC, Brooks R, Houskeeper J et al (2017) Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. Mol Cell Endocrinol 440:57–68 CrossRefPubMedPubMedCentral
41.
Zhou Z, Tang Y, Jin X et al (2016) Metformin inhibits advanced glycation end products-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFkappaB pathway suppression. J Diabetes Res 2016:4847812 PubMedPubMedCentral
42.
Yu JW, Deng YP, Han X, Ren GF, Cai J, Jiang GJ (2016) Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice. Cardiovasc Diabetol 15:88 CrossRefPubMedPubMedCentral
43.
Mai QG, Zhang ZM, Xu S et al (2011) Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 112:2902–2909 CrossRefPubMed
44.
Ma P, Gu B, Xiong W et al (2014) Glimepiride promotes osteogenic differentiation in rat osteoblasts via the PI3K/Akt/eNOS pathway in a high glucose microenvironment. PLoS One 9:e112243 CrossRefPubMedPubMedCentral
45.
Fronczek-Sokol J, Pytlik M (2014) Effect of glimepiride on the skeletal system of ovariectomized and non-ovariectomized rats. Pharmacol Rep 66:412–417 CrossRefPubMed
46.
Pereira M, Jeyabalan J, Jorgensen CS et al (2015) Chronic administration of glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice. Bone 81:459–467 CrossRefPubMed
47.
Thrailkill KM, Nyman JS, Bunn RC et al (2016) The impact of SGLT2 inhibitors, compared with insulin, on diabetic bone disease in a mouse model of type 1 diabetes. Bone 82:101–107 CrossRefPubMed
48.
Lecka-Czernik B (2010) Bone loss in diabetes: use of anti-diabetic thiazolidinediones and secondary osteoporosis. Curr Osteoporosis Rep 8:178–184
49.
Mieczkowska A, Basle MF, Chappard D, Mabilleau G (2012) Thiazolidinediones induce osteocyte apoptosis by a G protein-coupled receptor 40-dependent mechanism. J Biol Chem 287:23517–23526 CrossRefPubMedPubMedCentral

New additions to the Adis Journal Club

A selection of topical peer-reviewed articles from the Adis journals, curated by the editors.

GLP-1 receptor agonists

Browse the latest news, clinical trial updates, and expert commentary.