Assessment of bone turnover and bone quality in type 2 diabetic bone disease: current concepts and future directions

Abstract

Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due to altered bone properties in diabetes. Circulating biochemical markers of bone turnover have been found to be decreased in type 2 diabetes (T2D) and may be predictive of fractures independently of bone mineral density (BMD). Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Bone imaging technologies, including trabecular bone score (TBS) and quantitative CT testing have revealed differences in diabetic bone as compared to non-diabetic individuals. Specifically, high resolution peripheral quantitative CT (HRpQCT) imaging has demonstrated increased cortical porosity in diabetic postmenopausal women. Other factors such as bone marrow fat saturation and advanced glycation endproduct (AGE) accumulation might also relate to bone cell function and fracture risk in diabetes. These data have increased our understanding of how T2D adversely impacts both bone metabolism and fracture risk.

References

[1] IDF Diabetes Atlas 2014. Available at http://www.idf.org/diabetesatlas/update-2014.

[2] Leslie WD, Rubin MR, Schwartz AV et al Type 2 diabetes and bone. J Bone Miner Res, 2012, 27: 2231-2237

[3] Schwartz AV, Sellmeyer DE, Ensrud KE et al Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab, 2001, 86: 32-38

[4] Bonds DE, Larson JC, Schwartz AV et al Risk of fracture in women with type 2 diabetes: the Women's Health Initiative Observational Study. J Clin Endocrinol Metab, 2006, 91: 3404-3410

[5] Janghorbani M, Van Dam RM, Willett WC et al Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol, 2007, 166: 495-505

[6] Leslie WD, Lix LM, Prior HJ et al Biphasic fracture risk in diabetes: a population-based study. Bone, 2007, 40: 1595-1601

[7] de Liefde II, van der Klift M, de Laet CE et al Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam study. Osteoporos Int, 2005, 16: 1713-1720

[8] 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: 427-444

[9] Giangregorio LM, Leslie WD, Lix LM et al FRAX underestimates fracture risk in patients with diabetes. J Bone Miner Res, 2012, 27: 301-308

[10] Leslie WD, Morin SN, Lix LM et al Does diabetes modify the effect of FRAX risk factors for predicting major osteoporotic and hip fracture? Osteoporos Int, 2014, 25: 2817-2824

[11] Schwartz AV, Hillier TA, Sellmeyer DE et al Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care, 2002, 25: 1749-1754

[12] Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ, 2009, 180: 32-39

[13] Dobnig H, Piswanger-Solkner JC, Roth M et al Type 2 diabetes mellitus in nursing home patients: effects on bone turnover, bone mass, and fracture risk. J Clin Endocrinol Metab, 2006, 91: 3355-3363

[14] Ardawi MS, Akhbar DH, Alshaikh A et al Increased serum sclerostin and decreased serum IGF-1 are associated with vertebral fractures among postmenopausal women with type-2 diabetes. Bone, 2013, 56: 355-362

[15] Yamamoto M, Yamaguchi T, Nawata K et al Decreased PTH levels accompanied by low-bone formation are associated with vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab, 2012, 97: 1277-1284

[16] Gaudio A, Privitera F, Battaglia K et al Sclerostin levels associated with inhibition of the WNT/beta-catenin signaling and reduced bone turnover in type 2 diabetes mellitus. J Clin Endocrinol Metab, 2012, 97: 3744-3750

[17] Krakauer JC, McKenna MJ, Buderer NF et al Bone loss and bone turnover in diabetes. Diabetes, 1995, 44: 775-782

[18] Manavalan JS, Cremers S, Dempster DW et al Circulating osteogenic precursor cells in type 2 diabetes mellitus. J Clin Endocrinol Metab, 2012, 97: 3240-3250

[19] Kanazawa I, Yamaguchi T, Sugimoto T. Serum insulin-like growth factor-I is a marker for assessing the severity of vertebral fractures in postmenopausal women with type 2 diabetes mellitus. Osteoporos Int, 2011, 22: 1191-1198

[20] Eghbali-Fatourechi GZ, Modder UI, Charatcharoenwitthaya N et al Characterization of circulating osteoblast lineage cells in humans. Bone, 2007, 40: 1370-1377

[21] Rubin MR, Manavalan JS, Dempster DW et al Parathyroid hormone stimulates circulating osteogenic cells in hypoparathyroidism. J Clin Endocrinol Metab, 2011, 96: 176-186

[22] Ardawi M, Akbar D, Rouzi A et al. Elevated sphingosine 1-phosphate levels are associated with vertebral fractures in patients with type 2 diabetes mellitus. J Bone Miner Res 2014; 29 Suppl 1. Available at http://www.asbmr.org/education/AbstractDetail?aid=51ef5a65-8072-4369-b2b7-c1381053da59. 11 December 2014.

[23] Saito M, Fujii K, Mori Y et al 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: 1514-1523

[24] Khosravi R, Sodek KL, Faibish M et al Collagen advanced glycation inhibits its discoidin domain receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts. Bone, 2014, 58: 33-41

[25] Canalis E. Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. Nat Rev Endocrinol, 2013, 9: 575-583

[26] Garcia-Martin A, Rozas-Moreno P, Reyes-Garcia R et al Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab, 2012, 97: 234-241

[27] Gennari L, Merlotti D, Valenti R et al Circulating sclerostin levels and bone turnover in type 1 and type 2 diabetes. J Clin Endocrinol Metab, 2012, 97: 1737-1744

[28] Yamamoto M, Yamauchi M, Sugimoto T. Elevated sclerostin levels are associated with vertebral fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab, 2013, 98: 4030-4037

[29] Heilmeier U, Carpenter DR, Patsch JM et al Volumetric femoral BMD, bone geometry, and serum sclerostin levels differ between type 2 diabetic postmenopausal women with and without fragility fractures. Osteoporos Int, 2015, 26: 1283-1293

[30] Tang SY, Allen MR, Phipps R et al Changes in non-enzymatic glycation and its association with altered mechanical properties following 1-year treatment with risedronate or alendronate. Osteoporos Int, 2009, 20: 887-894

[31] Morales-Santana S, Garcia-Fontana B, Garcia-Martin A et al Atherosclerotic disease in type 2 diabetes is associated with an increase in sclerostin levels. Diabetes Care, 2013, 36: 1667-1674

[32] Frye EB, Degenhardt TP, Thorpe SR et al Role of the Maillard reaction in aging of tissue proteins. Advanced glycation end product-dependent increase in imidazolium cross-links in human lens proteins. J Biol Chem, 1998, 273: 18714-18719

[33] Monnier VM, Sell DR, Genuth S. Glycation products as markers and predictors of the progression of diabetic complications. Ann NY Acad Sci, 2005, 1043: 567-581

[34] Thornalley PJ, Langborg A, Minhas HS. Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J, 1999, 344 Pt 1 109-116

[35] Makita Z, Radoff S, Rayfield EJ et al Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med, 1991, 325: 836-842

[36] Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med, 1988, 318: 1315-1321

[37] Vashishth D. The role of the collagen matrix in skeletal fragility. Curr Osteoporos Rep, 2007, 5: 62-66

[38] Schwartz AV, Garnero P, Hillier TA et al Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab, 2009, 94: 2380-2386

[39] Sanguineti R, Storace D, Monacelli F et al Pentosidine effects on human osteoblasts in vitro. Ann NY Acad Sci, 2008, 1126: 166-172

[40] McCarthy AD, Uemura T, Etcheverry SB et al Advanced glycation endproducts interefere with integrin-mediated osteoblastic attachment to a type-I collagen matrix. Int J Biochem Cell Biol, 2004, 36: 840-848

[41] McCarthy AD, Etcheverry SB, Cortizo AM. Effect of advanced glycation endproducts on the secretion of insulin-like growth factor-I and its binding proteins: role in osteoblast development. Acta Diabetol, 2001, 38: 113-122

[42] Kume S, Kato S, Yamagishi S et al Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into adipose tissue, cartilage, and bone. J Bone Miner Res, 2005, 20: 1647-1658

[43] Valcourt U, Merle B, Gineyts E et al Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation. J Biol Chem, 2007, 282: 5691-5703

[44] Zhang L, Chen B, Tang L. Metabolic memory: mechanisms and implications for diabetic retinopathy. Diabetes Res Clin Pract, 2012, 96: 286-293

[45] Genuth S, Sun W, Cleary P et al Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes, 2005, 54: 3103-3111

[46] Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet, 2002, 359: 1929-1936

[47] Link TM. Osteoporosis imaging: state of the art and advanced imaging. Radiology, 2012, 263: 3-17

[48] Schwartz AV, Vittinghoff E, Bauer DC et al Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA, 2011, 305: 2184-2192

[49] Pothuaud L, Carceller P, Hans D. Correlations between grey-level variations in 2D projection images (TBS) and 3D microarchitecture: applications in the study of human trabecular bone microarchitecture. Bone, 2008, 42: 775-787

[50] Harvey NC, Gluer CC, Binkley N et al Trabecular bone score (TBS) as a new complementary approach for osteoporosis evaluation in clinical practice. Bone, 2015, 78: 216-224

[51] Leslie WD, Aubry-Rozier B, Lamy O et al TBS (trabecular bone score) and diabetes-related fracture risk. J Clin Endocrinol Metab, 2013, 98: 602-609

[52] Dhaliwal R, Cibula D, Ghosh C et al Bone quality assessment in type 2 diabetes mellitus. Osteoporos Int, 2014, 25: 1969-1973

[53] Kim JH, Choi HJ, Ku EJ et al Trabecular bone score as an indicator for skeletal deterioration in diabetes. J Clin Endocrinol Metab, 2015, 100: 475-482

[54] Shepherd JA, Schousboe JT, Broy SB et al Executive summary of the 2015 ISCD position development conference on advanced measures from DXA and QCT: fracture prediction beyond BMD. J Clin Densitom, 2015, 18: 274-286

[55] Melton LJ 3rd, Riggs BL, Leibson CL et al A bone structural basis for fracture risk in diabetes. J Clin Endocrinol Metab, 2008, 93: 4804-4809

[56] Patsch JM, Burghardt AJ, Kazakia G et al Noninvasive imaging of bone microarchitecture. Ann NY Acad Sci, 2011, 1240: 77-87

[57] NIH Consensus Development Panel on Osteoporosis Prevention D, Therapy Osteoporosis prevention, diagnosis, and therapy. JAMA, 2001, 285: 785-795

[58] Parfitt AM, Drezner MK, Glorieux FH et al Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Mineral Res, 1987, 2: 595-610

[59] Hildebrand T, Ruegsegger P. A new method for the model-independent assessment of thickness in three-dimensional images. J Microsc, 1997, 185: 67-75

[60] Laib A, Hauselmann HJ, Ruegsegger P. In vivo high resolution 3D-QCT of the human forearm. Technol Health Care, 1998, 6: 329-337

[61] Manske SL, Zhu Y, Sandino C et al Human trabecular bone microarchitecture can be assessed independently of density with second generation HR-pQCT. Bone, 2015, 79: 213-221

[62] Burghardt AJ, Issever AS, Schwartz AV et al High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab, 2010, 95: 5045-5055

[63] Shu A, Yin MT, Stein E et al Bone structure and turnover in type 2 diabetes mellitus. Osteoporos Int, 2011, 23: 635-641

[64] Patsch JM, Burghardt AJ, Yap SP et al Increased cortical porosity in type-2 diabetic postmenopausal women with fragility fractures. J Bone Mineral Res, 2012, 28: 313-324

[65] Yu EW, Putman MS, Derrico N et al Defects in cortical microarchitecture among African-American women with type 2 diabetes. Osteoporos Int, 2014, 26: 673-679

[66] Petit MA, Paudel ML, Taylor BC et al Bone mass and strength in older men with type 2 diabetes: the osteoporotic fractures in men study. J Bone Miner Res, 2010, 25: 285-291

[67] Majumdar S, Genant HK, Grampp S et al Correlation of trabecular bone structure with age, bone mineral density, and osteoporotic status: in vivo studies in the distal radius using high resolution magnetic resonance imaging. J Bone Miner Res, 1997, 12: 111-118

[68] Majumdar S, Link TM, Augat P et al Trabecular bone architecture in the distal radius using magnetic resonance imaging in subjects with fractures of the proximal femur. Osteoporosis Int, 1999, 10: 231-239

[69] Link TM, Majumdar S, Augat P et al In vivo high resolution MRI of the calcaneus: differences in trabecular structure in osteoporosis patients. J Bone Mineral Res, 1998, 13: 1175-1182

[70] Benito M, Gomberg B, Wehrli FW et al Deterioration of trabecular architecture in hypogonadal men. J Clin Endocrinol Metab, 2003, 88: 1497-1502

[71] Techawiboonwong A, Song HK, Leonard MB et al Cortical bone water: in vivo quantification with ultrashort echo-time MR imaging. Radiology, 2008, 248: 824-833

[72] Benito M, Vasilic B, Wehrli FW et al Effect of testosterone replacement on trabecular architecture in hypogonadal men. J Bone Mineral Res, 2005, 20: 1785-1791

[73] Chesnut CH 3rd, Majumdar S, Newitt DC et al Effects of salmon calcitonin on trabecular microarchitecture as determined by magnetic resonance imaging: results from the QUEST study. J Bone Mineral Res, 2005, 20: 1548-1561

[74] Pritchard JM, Giangregorio LM, Atkinson SA et al Association of larger holes in the trabecular bone at the distal radius in postmenopausal women with type 2 diabetes mellitus compared to controls. Arthritis Care Res (Hoboken), 2012, 64: 944

[75] Griffith JF, Yeung DK, Tsang PH et al Compromised bone marrow perfusion in osteoporosis. J Bone Mineral Res, 2008, 23: 1068-1075

[76] Paccou J, Hardouin P, Cotten A et al The role of bone marrow fat in skeletal health: usefulness and perspectives for clinicians. J Clin Endocrinol Metab, 2015, 100: 3613-3621

[77] Patsch JM, Li X, Baum T et al Bone marrow fat composition as a novel imaging biomarker in postmenopausal women with prevalent fragility fractures. J Bone Miner Res, 2013, 28: 1721-1728

[78] Farina EK, Kiel DP, Roubenoff R et al Protective effects of fish intake and interactive effects of long-chain polyunsaturated fatty acid intakes on hip bone mineral density in older adults: the Framingham Osteoporosis study. Am J Clin Nutr, 2011, 93: 1142-1151

[79] Jarvinen R, Tuppurainen M, Erkkila AT et al Associations of dietary polyunsaturated fatty acids with bone mineral density in elderly women. Eur J Clin Nutr, 2012, 66: 496-503

[80] Weiss LA, Barrett-Connor E, von Muhlen D. Ratio of n-6 to n-3 fatty acids and bone mineral density in older adults: the Rancho Bernardo study. Am J Clin Nutr, 2005, 81: 934-938

[81] Farina EK, Kiel DP, Roubenoff R et al Dietary intakes of arachidonic acid and alpha-linolenic acid are associated with reduced risk of hip fracture in older adults. J Nutr, 2011, 141: 1146-1153

[82] Griel AE, Kris-Etherton PM, Hilpert KF et al An increase in dietary n-3 fatty acids decreases a marker of bone resorption in humans. Nutr J, 2007, 6: 2

[83] Watkins BA, Li Y, Seifert MF. Dietary ratio of n-6/n-3 PUFAs and docosahexaenoic acid: actions on bone mineral and serum biomarkers in ovariectomized rats. J Nutr Biochem, 2006, 17: 282-289

[84] Coetzer H, Claassen N, van Papendorp DH et al Calcium transport by isolated brush border and basolateral membrane vesicles: role of essential fatty acid supplementation. Prostaglandins Leukot Essen Fatty Acids, 1994, 50: 257-266

[85] Ortiz-Alvarado O, Miyaoka R, Kriedberg C et al Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid in the management of hypercalciuric stone formers. Urology, 2012, 79: 282-286

[86] Orchard TS, Cauley JA, Frank GC et al Fatty acid consumption and risk of fracture in the Women's Health Initiative. Am J Clin Nutr, 2010, 92: 1452-1460

[87] Kirkland JL, Tchkonia T, Pirtskhalava T et al Adipogenesis and aging: does aging make fat go MAD? Exp Gerontol, 2002, 37: 757-767

[88] Monickaraj F, Aravind S, Gokulakrishnan K et al Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes. Mol Cell Biochem, 2012, 365: 343-350

[89] de Heredia FP, Larque E, Portillo MP et al Age-related changes in fatty acids from different adipose depots in rat and their association with adiposity and insulin. Nutrition, 2008, 24: 1013-1022

[90] Morley JE. Diabetes and aging: epidemiologic overview. Clin Geriatr Med, 2008, 24: 395-405

[91] Ma YH, Schwartz AV, Sigurdsson S et al Circulating sclerostin associated with vertebral bone marrow fat in older men but not women. J Clin Endocrinol Metab, 2014, 99: E2584-E2590

[92] Compston JE, Watts NB, Chapurlat R et al Obesity is not protective against fracture in postmenopausal women: GLOW. Am J Med, 2011, 124: 1043-1050

[93] Nielson CM, Marshall LM, Adams AL et al BMI and fracture risk in older men: the osteoporotic fractures in men study (MrOS). J Bone Miner Res, 2011, 26: 496-502

[94] Johansson H, Kanis JA, Oden A et al A meta-analysis of the association of fracture risk and body mass index in women. J Bone Miner Res, 2014, 29: 223-233

[95] Sornay-Rendu E, Boutroy S, Vilayphiou N et al In obese postmenopausal women, bone microarchitecture and strength are not commensurate to greater body weight: the Os des Femmes de Lyon (OFELY) study. J Bone Miner Res, 2013, 28: 1679-1687

[96] Gerdhem P, Isaksson A, Akesson K et al Increased bone density and decreased bone turnover, but no evident alteration of fracture susceptibility in elderly women with diabetes mellitus. Osteoporos Int, 2005, 16: 1506-1512

[97] Weyer C, Funahashi T, Tanaka S et al Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab, 2001, 86: 1930-1935

[98] Bredella MA, Torriani M, Ghomi RH et al Determinants of bone mineral density in obese premenopausal women. Bone, 2011, 48: 748-754

[99] Gilsanz V, Chalfant J, Mo AO et al Reciprocal relations of subcutaneous and visceral fat to bone structure and strength. J Clin Endocrinol Metab, 2009, 94: 3387-3393

[100] Cohen A, Dempster DW, Recker RR et al Abdominal fat is associated with lower bone formation and inferior bone quality in healthy premenopausal women: a transiliac bone biopsy study. J Clin Endocrinol Metab, 2013, 98: 2562-2572

[101] Amrein K, Amrein S, Drexler C et al Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults. J Clin Endocrinol Metab, 2012, 97: 148-154

[102] Bridges D, Randall C, Hansma PK. A new device for performing reference point indentation without a reference probe. Rev Sci Instrum, 2012, 83: 044301

[103] Randall C, Bridges D, Guerri R et al Applications of a new handheld reference point indentation instrument measuring bone material strength. J Med Dev, 2013, 7: 410051-410056

[104] Farr JN, Drake MT, Amin S et al In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res, 2013, 29: 787-795

[105] Diez-Perez A, Guerri R, Nogues X et al Microindentation for in vivo measurement of bone tissue mechanical properties in humans. J Bone Miner Res, 2010, 25: 1877-1885

[106] Guerri-Fernandez RC, Nogues X, Quesada Gomez JM et al Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls. J Bone Miner Res, 2013, 28: 162-168