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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article discusses both the linkages between glucose and bone metabolism that are actively being researched, as well as the effects of glucose-lowering agents on bones.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EMetabolic Bone Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EThe Linkages Between Glucose and Bone Metabolism are an Active Area of Research\u003C\/h2\u003E\n         \u003Cp id=\u0022p-2\u0022\u003EBone itself has an effect on glucose metabolism through osteocalcin, a hormone that enhances insulin secretion and sensitivity, increasing \u03b2-cell mass and energy expenditure. \u003Cem\u003EEsp\u003C\/em\u003E, an osteoblast-specific gene, inhibits osteocalcin function by favoring its carboxylation into the inactive form, blunting glucose handling [Lee NK et al. \u003Cem\u003ECell\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EInsulin receptors in osteoblasts are substrates of \u003Cem\u003EEsp.\u003C\/em\u003E In a series of animal studies, it was determined that inactivating insulin receptors in osteoblasts affects whole-body glucose metabolism. Indeed, insulin signaling in osteoblasts enhances bone resorption, and the acid pH that is generated by bone resorption activates osteocalcin via its decarboxylation. This regulatory mechanism controls whole-body glucose homeostasis in mice and humans [Ferron et al. \u003Cem\u003ECell\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EThe associations between glucose and bone metabolism likely contribute to the increased risk of bone fractures that is associated with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) [Vestergaard P. \u003Cem\u003EOsteoporosis Int\u003C\/em\u003E 2007; Vestergaard P et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2005]. However, the mechanisms of this increased risk appear to differ somewhat from the risk factors for osteoporosis and fracture in the general population.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EFor instance, patients with T1DM have far less bone density than would be expected in their bones and hips, while patients with T2DM have greater bone density than would be expected for their age [Vestergaard P. \u003Cem\u003EOsteoporosis Int\u003C\/em\u003E 2007]. Yet, rather than the 20% to 25% reduced fracture risk that might be expected in T2DM, the actual risk is 70% higher. Alternatively, rather than the 42% increased risk of fracture that might be expected in patients with T1DM, the actual risk is increased nearly 6-fold [Janghorbani M et al. \u003Cem\u003EAm J Epidemiol\u003C\/em\u003E 2007]. This suggests that bone quality, not just bone density, is related to the fracture risk in diabetes. Indeed, diabetes is a disease of low bone turnover [Hamada Y et al. \u003Cem\u003EBone\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EDirect effects of diabetes that contribute to the higher incidence of fracture and lower bone turnover include hyperglycemia, with marked declines in serum markers of bone resorption and bone turnover occurring within 2 hours of ingesting glucose during an oral glucose tolerance test (OGTT) [Clowes JA et al. \u003Cem\u003EJ Clin Endocrinol Metab\u003C\/em\u003E 2003].\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EIncreased calcium excretion (hypercalciuria) is observed early in the disease in patients with T1DM. These levels eventually moderate and return to normal, which could be related to improved control of hyperglycemia [McNair P et al. \u003Cem\u003EActa Endocrinol (Copenh)\u003C\/em\u003E 1979]. This is also reflected in fracture risk, which appears to be higher early in the disease [Vestergaard P et al. \u003Cem\u003ECalcif Tissue Int\u003C\/em\u003E 2009]. The reduction in calcium levels typically results in higher levels of parathyroid (PTH) hormone. However, although PTH levels rise in patients with diabetes, the peak is far lower than in individuals without diabetes [Schwarz P et al. \u003Cem\u003EActa Endocrinol\u003C\/em\u003E 1992].\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EHigh blood glucose levels also affect the bone matrix, leading to the formation of advanced glycated end-products (AGEs), such as pentosidine, which results in lower bone biomechanical competence [Saito M et al. \u003Cem\u003EOsteoporosis Int\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EMore indirect effects of diabetes on bone are related to high blood pressure. Studies in nondiabetic patients find results in greater urinary calcium excretion and bone loss; neuropathy, likely related to reduced physical activity; and macrovascular complications that reduce blood flow to bone [Cappuccio FP et al. \u003Cem\u003ELancet\u003C\/em\u003E 1999; Rix M et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 1999; Vogt MT et al. \u003Cem\u003EJ Bone Miner Res\u003C\/em\u003E 1997]. Body mass index (BMI) is important in both diabetic and nondiabetic patients. The leaner body mass of patients with T1DM may help explain their lower bone density compared with those with T2DM, who tend to be heavier [Vestergaard P. \u003Cem\u003EOsteoporosis Int\u003C\/em\u003E 2007]. Finally, increased PPAR-\u03b3 levels that result from chronic hyperglycemia, which suppresses osteoblast differentiation, promotes an adipocyte-like phenotype that results in less bone formation [Botolin S et al. \u003Cem\u003EJ Cell Biochem\u003C\/em\u003E 2006].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EThe Effects of Glucose-Lowering Agents on Bone\u003C\/h2\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EIn addition to the mechanisms described above, certain glucose-lowering drugs can impact bone. Among the most studied are the thiazolidinediones rosiglitazone and pioglitazone. Both are independently associated with an increased risk of bone fracture in men and women with T2DM, with a doubling of the risk in women (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Kahn SE et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2008; Aubert RE et al. \u003Cem\u003EDiabetes Obes Metab\u003C\/em\u003E 2010; Home PD et al. \u003Cem\u003ELancet\u003C\/em\u003E 2009].\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/9\/31\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Rosiglitazone and Bone Fracture Risk in Women with T2DM.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1082849033\u0022 data-figure-caption=\u0022Rosiglitazone and Bone Fracture Risk in Women with T2DM.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/9\/31\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/9\/31\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/9\/31\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11557\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003ERosiglitazone and Bone Fracture Risk in Women with T2DM.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReprinted from \u003Cem\u003EThe Lancet\u003C\/em\u003E. Volume 373, Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicenter, randomized, open-label trial, RECORD Study Group, pages 2125\u20132135, Copyright 2009, with permission from Elsevier.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EThis increased risk may be related to increased osteoclast activity rather than decreased osteoblast activity [Zinman B et al. \u003Cem\u003ELancet\u003C\/em\u003E 2010]. Animal and human studies suggest that these drugs may suppress osteoblast differentiation, decreasing osteoblastogenesis in human mesenchymal stem cells [Ali AA et al. \u003Cem\u003EEndocrinology\u003C\/em\u003E 2005; Benvenuti S et al. \u003Cem\u003EJ Endocrinol Invest\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EWhile a large case-control study of 2000 patients with T2DM who were followed for 4 years found a significant increase in bone fracture in patients who were using insulin, there was no reduction in bone mineral density [Monami M et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2008; Stolk RP et al. \u003Cem\u003EBone\u003C\/em\u003E 1996]. The mechanism may be related more to the higher rate of hypoglycemia that occurs with insulin therapy, increasing the risk of falls [Schwartz AV et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2002; Adami S. \u003Cem\u003ECurr Med Res Opin\u003C\/em\u003E 2009].\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EAlthough hypoglycemia can also be induced by secretagogues, the risk is much lower than that observed with insulin, which may explain why insulin secretagogues are not associated with an increased risk of bone fracture [Vestergaard P et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2005; Monami M et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2008]. Metformin also appears to have neutral effects on bone [Vestergaard P et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2005; Monami M et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2008].\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EMeanwhile, the incretin-based therapies may exert some favorable effects on bone metabolism. Bone has receptors for glucagon-like peptide-1 (GLP-1). In animal models, GLP-1 receptor knockout mice exhibited higher osteoblast activity than wild-type mice, while even short-term treatment with the GLP-1 agonist exenatide stimulated the deposition of new bone in animal models of T2DM and insulin resistance [Nuche-Berenguer B et al. \u003Cem\u003ERegul Pept\u003C\/em\u003E 2010]. Responsible mechanisms may be the ability of GLP-1 to prevent the differentiation of mesenchymal stem cells into adipocytes or stimulate thyroid C-cells, in turn stimulating increased calcitonin release and C-cell proliferation [Knudsen BL et al. \u003Cem\u003EEndocrinology\u003C\/em\u003E 2010; Sanz C et al. \u003Cem\u003EAm J Physiol Endocrinol Metab\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EThe dipeptidyl peptidase-4 (DPP4) inhibitors could affect bone both by increasing circulating GLP-1 levels and by increasing gastric inhibitory polypeptide, thus having a favorable effect on osteogenesis while decreasing bone resorption [Baggio LL et al. \u003Cem\u003EGastroenterology\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EIn conclusion, the low bone turnover in patients with diabetes may have implications for the treatment of osteoporosis in this population. The traditional therapy for osteoporosis is antiresorptive agents. However, this may contribute to further reductions in bone turnover. In addition, there seems to be a discrepancy between bone mineral density, as measured by dual-energy x-ray absorptiometry (DXA) scans, and bone biomechanical competence, especially in T2DM. Thus, it is unclear how DXA scans should be interpreted in diabetes. Finally, bone fractures should be considered among the treatment outcomes when choosing antidiabetic medications.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2010 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/10\/9\/31.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzmo4d\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmo4d\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}