Type 2 diabetes mellitus and bone

Type 2 diabetes (T2DM) is a rapidly growing public health problem. It is associated with an increased risk of fracture, particularly of the hip, despite normal or high bone mineral density. Longer duration of disease and poor glycaemic control are both associated with higher fracture risk. The factors underlying increased fracture risk have not been clearly established, but increased falls risk, obesity, sarcopenia and co‐morbidities are likely to contribute. The basis for reduced bone strength despite higher bone mineral density remains to be fully elucidated. Bone turnover is reduced in individuals with T2DM, with evidence of impaired bone formation. Most studies indicate normal or superior trabecular bone structure although reduced lumbar spine trabecular bone score (TBS) has been reported. Deficits in cortical bone structure have been demonstrated in some, but not all, studies whilst reduced bone material strength index (BMSi), as assessed by microindentation, has been a consistent finding. Accumulation of advanced glycation end products in bone may also contribute to reduced bone strength. The use of FRAX in individuals with T2DM underestimates fracture probability. Clinical management should focus on falls prevention strategies, avoidance of known risk factors, maintenance of good glycaemic control and bone protective intervention in individuals at high risk of fracture. Dietary and surgical strategies to reduce weight have beneficial effects on diabetes but may have adverse effects on skeletal health. Future research priorities include better definition of the mechanisms underlying increased fracture risk in T2DM and optimal strategies for identifying and treating those at high risk.

[1]  M. Frost,et al.  Compromised cortical bone compartment in type 2 diabetes mellitus patients with microvascular disease. , 2015, European journal of endocrinology.

[2]  P. Ungprasert,et al.  Sodium‐glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: A meta‐analysis , 2017, Diabetes/metabolism research and reviews.

[3]  Chung-Yi Li,et al.  Increased Risks of Hip Fracture in Diabetic Patients of Taiwan , 2008, Diabetes Care.

[4]  R. Nuti,et al.  Circulating sclerostin levels and bone turnover in type 1 and type 2 diabetes. , 2012, The Journal of clinical endocrinology and metabolism.

[5]  J. Kanis,et al.  FRAX underestimates fracture risk in patients with diabetes , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[6]  T. Svensson,et al.  Obesity in orthopedic patients. , 2009, Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery.

[7]  S. Derksen,et al.  Biphasic fracture risk in diabetes: a population-based study. , 2007, Bone.

[8]  A. Hofman,et al.  Hyperinsulinemia and bone mineral density in an elderly population: The Rotterdam Study. , 1996, Bone.

[9]  S. Mori,et al.  Risk factors associated with falls in elderly patients with type 2 diabetes. , 2015, Journal of diabetes and its complications.

[10]  C. Coleman,et al.  Impact of Diabetes Mellitus on Bone Health , 2019, International journal of molecular sciences.

[11]  W. Tan,et al.  A United Kingdom perspective on the relationship between body mass index (BMI) and bone health: a cross sectional analysis of data from the Nottingham Fracture Liaison Service. , 2014, Bone.

[12]  A. Alshaikh,et al.  Increased serum sclerostin and decreased serum IGF-1 are associated with vertebral fractures among postmenopausal women with type-2 diabetes. , 2013, Bone.

[13]  Yu Gu,et al.  Are falls prevention programs effective at reducing the risk factors for falls in people with type-2 diabetes mellitus and peripheral neuropathy: A systematic review with narrative synthesis. , 2017, Journal of diabetes and its complications.

[14]  H. Choi,et al.  Trabecular bone score as an indicator for skeletal deterioration in diabetes. , 2015, The Journal of clinical endocrinology and metabolism.

[15]  M. Lorentzon,et al.  A High Amount of Local Adipose Tissue Is Associated With High Cortical Porosity and Low Bone Material Strength in Older Women , 2016, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[16]  L. Kuller,et al.  Excessive Loss of Skeletal Muscle Mass in Older Adults With Type 2 Diabetes , 2009, Diabetes Care.

[17]  P. Vestergaard,et al.  Biochemical bone turnover markers in diabetes mellitus - A systematic review. , 2016, Bone.

[18]  Luigi Ferrucci,et al.  Age-related and disease-related muscle loss: the effect of diabetes, obesity, and other diseases. , 2014, The lancet. Diabetes & endocrinology.

[19]  W. Leslie,et al.  DXA-Based Measurements in Diabetes: Can They Predict Fracture Risk? , 2017, Calcified Tissue International.

[20]  I. Idris,et al.  DPP-4 inhibitor therapy and bone fractures in people with Type 2 diabetes - A systematic review and meta-analysis. , 2016, Diabetes research and clinical practice.

[21]  H. Leufkens,et al.  Long‐term use of dipeptidyl peptidase‐4 inhibitors and risk of fracture: A retrospective population‐based cohort study , 2017, Diabetes, obesity & metabolism.

[22]  C. Browning,et al.  Exercise interventions for the improvement of falls-related outcomes among older adults with diabetes mellitus: A systematic review and meta-analyses. , 2017, Journal of diabetes and its complications.

[23]  M. Monami,et al.  Dipeptidyl Peptidase-4 Inhibitors and Bone Fractures , 2011, Diabetes Care.

[24]  Jennifer M. Harris,et al.  Teriparatide in patients with osteoporosis and type 2 diabetes. , 2016, Bone.

[25]  J. Pérez-Castrillón,et al.  Type 2 Diabetes Mellitus as a Risk Factor for Hip Fracture , 2004, Journal of the American Geriatrics Society.

[26]  Ahmed H. YoussefAgha,et al.  Attenuated PTH responsiveness to vitamin D deficiency among patients with type 2 diabetes and chronic hyperglycemia. , 2017, Diabetes research and clinical practice.

[27]  T. Keaveny,et al.  Trabecular microfracture and the influence of pyridinium and non-enzymatic glycation-mediated collagen cross-links. , 2005, Bone.

[28]  V. Beral,et al.  Body mass index and physical activity in relation to the incidence of hip fracture in postmenopausal women , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[29]  M. Rubin,et al.  Advanced Glycation Endproducts and Bone Material Strength in Type 2 Diabetes. , 2016, The Journal of clinical endocrinology and metabolism.

[30]  A. LaCroix,et al.  Effect of co-morbidities on fracture risk: findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW). , 2012, Bone.

[31]  B. Carleton,et al.  Thiazolidinediones and fractures in men and women. , 2009, Archives of internal medicine.

[32]  E. Eriksen,et al.  Reduced Bone Material Strength is Associated with Increased Risk and Severity of Osteoporotic Fractures. An Impact Microindentation Study , 2017, Calcified Tissue International.

[33]  S. Cremers,et al.  Bone structure and turnover in type 2 diabetes mellitus , 2012, Osteoporosis International.

[34]  J. Cauley,et al.  Adipokines and the risk of fracture in older adults , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  S. Satterfield,et al.  Insulin Resistance Is Associated With Decreased Quadriceps Muscle Strength in Nondiabetic Adults Aged ≥70 Years , 2009, Diabetes Care.

[36]  I. Reid,et al.  Fat mass is an important predictor of parathyroid hormone levels in postmenopausal women. , 2006, Bone.

[37]  S. Cummings,et al.  Older women with diabetes have an increased risk of fracture: a prospective study. , 2001, The Journal of clinical endocrinology and metabolism.

[38]  A. Díez-Pérez,et al.  The association between fracture and obesity is site‐dependent: A population‐based study in postmenopausal women , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[39]  P. Vestergaard,et al.  Are Antiresorptive Drugs Effective Against Fractures in Patients with Diabetes? , 2011, Calcified Tissue International.

[40]  A. Tiran,et al.  Type 2 diabetes mellitus in nursing home patients: effects on bone turnover, bone mass, and fracture risk. , 2006, The Journal of clinical endocrinology and metabolism.

[41]  J. A. Garcia-Salcedo,et al.  Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. , 2012, The Journal of clinical endocrinology and metabolism.

[42]  Yangang Wang,et al.  Increased risk of vertebral fracture in patients with diabetes: a meta-analysis of cohort studies , 2016, International Orthopaedics.

[43]  S. Mittelman,et al.  Reciprocal relations of subcutaneous and visceral fat to bone structure and strength. , 2009, The Journal of clinical endocrinology and metabolism.

[44]  A. LaCroix,et al.  World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO 2014): Oral Communication Abstracts , 2014, Osteoporosis International.

[45]  Robert R. Henry,et al.  Type 2 diabetes mellitus , 2015, Nature Reviews Disease Primers.

[46]  Y. Lang,et al.  Diabetes mellitus and risk of hip fractures: a meta-analysis , 2015, Osteoporosis International.

[47]  J. Kanis,et al.  Longer Duration of Diabetes Strongly Impacts Fracture Risk Assessment: The Manitoba BMD Cohort , 2016, The Journal of clinical endocrinology and metabolism.

[48]  S. Cummings,et al.  Risk factors for nonvertebral fracture in obese older women. , 2011, The Journal of clinical endocrinology and metabolism.

[49]  Qiang Zhang,et al.  Diabetes mellitus and risk of falls in older adults: a systematic review and meta-analysis. , 2016, Age and ageing.

[50]  E. Friedman,et al.  Advanced glycosylation end products in patients with diabetic nephropathy. , 1991, The New England journal of medicine.

[51]  J. Cauley,et al.  Effects of Raloxifene on Fracture Risk in Postmenopausal Women: The Raloxifene Use for The Heart Trial , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[52]  S. Kirkland,et al.  Associations Among Disease Conditions, Bone Mineral Density, and Prevalent Vertebral Deformities in Men and Women 50 Years of Age and Older: Cross‐Sectional Results From the Canadian Multicentre Osteoporosis Study , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[53]  S. Zhai,et al.  Lack of evidence for a harmful effect of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta‐analysis of randomized controlled trials , 2016, Diabetes, obesity & metabolism.

[54]  M. Bouxsein,et al.  A bone structural basis for fracture risk in diabetes. , 2008, The Journal of clinical endocrinology and metabolism.

[55]  A. Hofman,et al.  Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. , 2005, Osteoporosis International.

[56]  C. Qualls,et al.  Exercise training in obese older adults prevents increase in bone turnover and attenuates decrease in hip bone mineral density induced by weight loss despite decline in bone‐active hormones , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[57]  L. Forsén,et al.  Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trøndelag Health Survey , 1999, Diabetologia.

[58]  A. LaCroix,et al.  Increase in Fracture Risk Following Unintentional Weight Loss in Postmenopausal Women: The Global Longitudinal Study of Osteoporosis in Women , 2016, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[59]  R. Scragg,et al.  Vitamin D and Type 2 Diabetes , 2009 .

[60]  G. Hawker,et al.  The Risk of Hip Fractures in Older Individuals With Diabetes , 2007, Diabetes Care.

[61]  A. Folsom,et al.  Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. , 2001, Diabetes care.

[62]  P. Vestergaard,et al.  Use of glucose-lowering drugs and risk of fracture in patients with type 2 diabetes. , 2017, Bone.

[63]  A. Cerami,et al.  Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. , 1988, The New England journal of medicine.

[64]  C. Earthman,et al.  The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications , 2012, International Journal of Obesity.

[65]  M. Bouxsein,et al.  Defects in cortical microarchitecture among African-American women with type 2 diabetes , 2015, Osteoporosis International.

[66]  D. Carpenter,et al.  Association between ankle fractures and obesity. , 2012, The Journal of foot and ankle surgery : official publication of the American College of Foot and Ankle Surgeons.

[67]  Thomas Baum,et al.  Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[68]  P. Vestergaard,et al.  The use of incretins and fractures – a meta‐analysis on population‐based real life data , 2017, British journal of clinical pharmacology.

[69]  S. Gnudi,et al.  Relationship of body mass index with main limb fragility fractures in postmenopausal women , 2009, Journal of Bone and Mineral Metabolism.

[70]  L. Jacob,et al.  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 , 2017, Osteoporosis International.

[71]  P. Gamache,et al.  Change in fracture risk and fracture pattern after bariatric surgery: nested case-control study , 2016, British Medical Journal.

[72]  M. E. Leite Duarte,et al.  [Histomorphometric analysis of the bone tissue in patients with non-insulin-dependent diabetes (DMNID)]. , 1996, Revista do Hospital das Clinicas.

[73]  R. Cumming,et al.  Diabetes and risk of fracture: The Blue Mountains Eye Study. , 2001, Diabetes care.

[74]  S. Papapoulos,et al.  Bone material strength index as measured by impact microindentation is low in patients with fractures irrespective of fracture site , 2017, Osteoporosis International.

[75]  Manna Zhang,et al.  Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists’ treatment: a meta-analysis of randomized controlled trials , 2015, Endocrine.

[76]  M. Bredella,et al.  Vertebral Bone Marrow Fat Is Positively Associated With Visceral Fat and Inversely Associated With IGF‐1 in Obese Women , 2011, Obesity.

[77]  Walter C Willett,et al.  Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. , 2007, American journal of epidemiology.

[78]  Toru Yamaguchi,et al.  Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. , 2015, Biochemical and biophysical research communications.

[79]  Jianhong Zhu,et al.  Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials , 2016, Scientific Reports.

[80]  T. Sugimoto,et al.  Decreased PTH levels accompanied by low bone formation are associated with vertebral fractures in postmenopausal women with type 2 diabetes. , 2012, The Journal of clinical endocrinology and metabolism.

[81]  S. Cummings,et al.  Pentosidine and increased fracture risk in older adults with type 2 diabetes. , 2009, The Journal of clinical endocrinology and metabolism.

[82]  Song Xu,et al.  Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats , 2011, Journal of cellular biochemistry.

[83]  R. Harnish,et al.  Volumetric femoral BMD, bone geometry, and serum sclerostin levels differ between type 2 diabetic postmenopausal women with and without fragility fractures , 2015, Osteoporosis International.

[84]  J. Lehmann,et al.  Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells. , 1996, Molecular pharmacology.

[85]  W. Leslie,et al.  Trabecular Bone Score , 2018, Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism.

[86]  Avis J. Thomas,et al.  Roux-en-Y gastric bypass for diabetes (the Diabetes Surgery Study): 2-year outcomes of a 5-year, randomised, controlled trial. , 2015, The lancet. Diabetes & endocrinology.

[87]  S. Cummings,et al.  Endogenous testosterone levels, physical performance, and fall risk in older men. , 2006, Archives of internal medicine.

[88]  S. Wild,et al.  Contemporary Risk of Hip Fracture in Type 1 and Type 2 Diabetes: A National Registry Study From Scotland† , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[89]  C. Cooper,et al.  Risk of fracture after bariatric surgery in the United Kingdom: population based, retrospective cohort study , 2012, BMJ : British Medical Journal.

[90]  T. Sugimoto,et al.  Advanced Glycation End Products, Diabetes, and Bone Strength , 2016, Current Osteoporosis Reports.

[91]  Jian-Min Yuan,et al.  Diabetes and Risk of Hip Fracture in the Singapore Chinese Health Study , 2010, Diabetes Care.

[92]  J. Cauley,et al.  Bone Mass and Strength in Older Men With Type 2 Diabetes: The Osteoporotic Fractures in Men Study , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[93]  Jasmine A. Nirody,et al.  Cortical bone laminar analysis reveals increased midcortical and periosteal porosity in type 2 diabetic postmenopausal women with history of fragility fractures compared to fracture-free diabetics , 2016, Osteoporosis International.

[94]  D. Rao,et al.  Bone Loss and Bone Turnover in Diabetes , 1995, Diabetes.

[95]  Stephanie Boutroy,et al.  Fracture Risk Prediction by Non-BMD DXA Measures: the 2015 ISCD Official Positions Part 2: Trabecular Bone Score. , 2015, Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry.

[96]  P. J. Bowman,et al.  Intentional and Unintentional Weight Loss Increase Bone Loss and Hip Fracture Risk in Older Women , 2003, Journal of the American Geriatrics Society.

[97]  Julie Flahive,et al.  Obesity is not protective against fracture in postmenopausal women: GLOW. , 2011, The American journal of medicine.

[98]  K. Jáuregui-Renaud,et al.  Influence of the body mass index on the occurrence of falls in patients with type 2 diabetes mellitus. , 2015, Obesity research & clinical practice.

[99]  L. Kuller,et al.  Accelerated Loss of Skeletal Muscle Strength in Older Adults With Type 2 Diabetes , 2007, Diabetes Care.

[100]  R. Jorde,et al.  Smoking and other determinants of bone turnover , 2019, PloS one.

[101]  D. Kohan,et al.  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 , 2013, Kidney international.

[102]  C. Poiană,et al.  OSTEOPOROSIS AND FRACTURE RISK IN PATIENTS WITH TYPE 2 DIABETES MELLITUS. , 2019, Acta endocrinologica.

[103]  P. Vestergaard,et al.  MECHANISMS IN ENDOCRINOLOGY: Diabetes mellitus, a state of low bone turnover - a systematic review and meta-analysis. , 2017, European journal of endocrinology.

[104]  Hang Lee,et al.  Visceral fat is a negative predictor of bone density measures in obese adolescent girls. , 2010, The Journal of clinical endocrinology and metabolism.

[105]  L. Lix,et al.  Does diabetes modify the effect of FRAX risk factors for predicting major osteoporotic and hip fracture? , 2014, Osteoporosis International.

[106]  P. Vestergaard,et al.  Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis , 2007, Osteoporosis International.

[107]  H. Kroger,et al.  Body mass index as a predictor of fracture risk: A meta-analysis , 2005, Osteoporosis International.

[108]  T. Sugimoto,et al.  Diabetic Patients Have an Increased Risk of Vertebral Fractures Independent of BMD or Diabetic Complications , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[109]  D. Mellström,et al.  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 , 2017, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[110]  Karen C Johnson,et al.  Risk of fracture in women with type 2 diabetes: the Women's Health Initiative Observational Study. , 2006, The Journal of clinical endocrinology and metabolism.

[111]  C. Furberg,et al.  Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis , 2009, Canadian Medical Association Journal.

[112]  J. Pasco,et al.  Bone mineral density in diabetes and impaired fasting glucose , 2019, Osteoporosis International.

[113]  K. Jepsen,et al.  Biomechanical Mechanisms: Resolving the Apparent Conundrum of Why Individuals With Type II Diabetes Show Increased Fracture Incidence Despite Having Normal BMD , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[114]  Ta-Liang Chen,et al.  Increased Risk of Fracture and Postfracture Adverse Events in Patients With Diabetes: Two Nationwide Population-Based Retrospective Cohort Studies , 2014, Diabetes Care.

[115]  K. Lapane,et al.  Sulfonylureas and Risk of Falls and Fractures: A Systematic Review , 2013, Drugs & Aging.

[116]  Elizabeth Selvin,et al.  Association of Diabetes, Comorbidities, and A1C With Functional Disability in Older Adults , 2010, Diabetes Care.

[117]  Gabriëlle H S Buitendijk,et al.  High Bone Mineral Density and Fracture Risk in Type 2 Diabetes as Skeletal Complications of Inadequate Glucose Control , 2013, Diabetes Care.

[118]  Karin Kraft,et al.  [Type-2 diabetes]. , 2010, MMW Fortschritte der Medizin.

[119]  Chih-Cheng Hsu,et al.  Fracture Risk After Bariatric Surgery: A 12-Year Nationwide Cohort Study , 2015, Medicine.

[120]  M. Michalak,et al.  Type 2 diabetes and risk of low-energy fractures in postmenopausal women: meta-analysis of observational studies , 2016, Aging Clinical and Experimental Research.

[121]  Deepak Vashishth,et al.  Heterogeneous Glycation of Cancellous Bone and Its Association with Bone Quality and Fragility , 2012, PloS one.

[122]  S. Perkins,et al.  Vitamin D and hyperparathyroidism in obesity. , 2011, The Journal of clinical endocrinology and metabolism.

[123]  D. Chappard,et al.  Use of glucagon‐like peptide‐1 receptor agonists and bone fractures: A meta‐analysis of randomized clinical trials (胰高血糖素样肽‐1受体激动剂的使用与骨折的关系:一项对随机临床试验的meta分析) , 2014, Journal of diabetes.

[124]  Richard Barnett,et al.  Diabetes mellitus. , 1993, The Medical journal of Australia.

[125]  S. Majumdar,et al.  High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. , 2010, Journal of Clinical Endocrinology and Metabolism.

[126]  J. Kelsey,et al.  Effect of alendronate on bone mineral density and biochemical markers of bone turnover in type 2 diabetic women: the fracture intervention trial. , 2004, Diabetes care.

[127]  C. Torp-Pedersen,et al.  Hip and distal arm fracture rates in peri‐ and postmenopausal insulin‐treated diabetic females , 1994, Journal of internal medicine.

[128]  E. Yu,et al.  Fracture Risk After Bariatric Surgery: Roux‐en‐Y Gastric Bypass Versus Adjustable Gastric Banding , 2017, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[129]  A. Díez-Pérez,et al.  Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[130]  O. Johnell,et al.  Risk factors for fragility fracture in middle age. A prospective population-based study of 33,000 men and women , 2006, Osteoporosis International.

[131]  N. Watts,et al.  Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. , 2016, The Journal of clinical endocrinology and metabolism.

[132]  M. Ruffing-Rahal,et al.  Older Women , 1987, Ageing & Society.

[133]  A. Apanovitch,et al.  Safety Profile of Dapagliflozin for Type 2 Diabetes: Pooled Analysis of Clinical Studies for Overall Safety and Rare Events , 2014, Drug Safety.

[134]  D. Kiel,et al.  Diabetes and Deficits in Cortical Bone Density, Microarchitecture, and Bone Size: Framingham HR‐pQCT Study , 2018, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[135]  P. Vestergaard,et al.  Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk , 2005, Diabetologia.

[136]  Bess Dawson-Hughes,et al.  The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. , 2007, The Journal of clinical endocrinology and metabolism.

[137]  Chao Wan,et al.  Insulin Receptor Signaling in Osteoblasts Regulates Postnatal Bone Acquisition and Body Composition , 2010, Cell.

[138]  Deepak L. Bhatt,et al.  Two‐year outcomes on bone density and fracture incidence in patients with T2DM randomized to bariatric surgery versus intensive medical therapy , 2015, Obesity.

[139]  T. Therneau,et al.  Fracture Risk in Type 2 Diabetes: Update of a Population‐Based Study , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[140]  S. Yano,et al.  Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes. , 2008, The Journal of clinical endocrinology and metabolism.

[141]  A. Breggia,et al.  Determinants of bone mineral density in obese premenopausal women. , 2011, Bone.

[142]  S. Cummings,et al.  Risk Factors for Nonvertebral Fracture in Obese Older Women , 2011 .

[143]  H. Kuo,et al.  Inverse association between insulin resistance and gait speed in nondiabetic older men: results from the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2002 , 2009, BMC geriatrics.

[144]  D. Cibula,et al.  Bone quality assessment in type 2 diabetes mellitus , 2014, Osteoporosis International.

[145]  S. Costantini,et al.  Bone health in diabetes and prediabetes , 2019, World journal of diabetes.

[146]  J. Cauley,et al.  Postmenopausal weight change and incidence of fracture: post hoc findings from Women’s Health Initiative Observational Study and Clinical Trials , 2015, BMJ : British Medical Journal.

[147]  S. Cremers,et al.  Circulating osteogenic precursor cells in type 2 diabetes mellitus. , 2012, The Journal of clinical endocrinology and metabolism.

[148]  M. Amraei,et al.  Fracture risk in patients with type 2 diabetes mellitus and possible risk factors: a systematic review and meta-analysis , 2017, Therapeutics and clinical risk management.

[149]  E. Vittinghoff,et al.  Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. , 2011, JAMA.

[150]  S. Bandinelli,et al.  Role of Muscle Mass and Muscle Quality in the Association Between Diabetes and Gait Speed , 2012, Diabetes Care.

[151]  K. Lapane,et al.  Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. , 2015, Diabetes research and clinical practice.

[152]  W. Leslie,et al.  TBS (trabecular bone score) and diabetes-related fracture risk. , 2013, The Journal of clinical endocrinology and metabolism.

[153]  P. Lips,et al.  MANAGEMENT OF ENDOCRINE DISEASE: The effect of vitamin D supplementation on glycaemic control in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. , 2017, European journal of endocrinology.

[154]  S. Khosla,et al.  In Vivo Assessment of Bone Quality in Postmenopausal Women With Type 2 Diabetes , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.