Higher Serum Uric Acid is a Risk Factor of Vertebral Fractures in Postmenopausal Women with Type 2 Diabetes Mellitus

Abstract

Purpose Serum uric acid (UA) level may affect bone metabolism because it has an anti-oxidative effect. However, whether serum UA level is associated with a fracture risk in type 2 diabetes mellitus (T2DM) is unclear. We thus aimed to clarify the association between serum UA and bone parameters in T2DM.

Methods We conducted a cross-sectional study to investigate the association of serum UA with bone mineral density (BMD) at lumbar spine (LS) and femoral neck (FN), bone turnover markers such as osteocalcin and urine type I collagen cross-linked N-telopeptide (uNTX), and the prevalence of vertebral fractures (VF) in 356 postmenopausal women and 512 men with T2DM.

Results Multiple regression analyses adjusted for age, duration of diabetes, hemoglobin A1c, body mass index and log (serum creatinine) showed that serum UA level was significantly and negatively associated with uNTX in postmenopausal women with T2DM, whereas it was not associated with osteocalcin or BMD at each site. In men, serum UA was not associated with BMD or bone turnover markers. Because postmenopausal women with VF were significantly older and had longer duration of diabetes, higher serum creatinine level and lower BMD than those without it, logistic regression analyses adjusted for these confounding factors were performed. Higher serum UA level was significantly associated with the presence of VF.

Conclusions The present study showed that higher serum UA is a risk factor for VF independently of BMD in postmenopausal women with T2DM.

Keywords

uric acid - hyperuricemia - vertebral fracture - bone - diabetes mellitus

• References

• 1 Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010; 87: 4-14
• 2 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: 495-505
• 3 Fan Y, Wei F, Lang Y, Liu Y. Diabetes mellitus and risk of hip fractures: A meta-analysis. Osteoporos Int 2016; 27: 219-228
• 4 Miyake H, Kanazawa I, Sugimoto T. Association of Bone Mineral Density, Bone Turnover Markers, and Vertebral Fractures with All-Cause Mortality in Type 2 Diabetes Mellitus. Calcif Tissue Int 2018; 102: 1-13
• 5 Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. Uric acid and oxidative stress. Curr Pharm Des 2005; 11: 4145-4151
• 6 Lippi G, Montagnana M, Franchini M. et al. The paradoxical relationship between serum uric acid and cardiovascular disease. Clin Chim Acta 2008; 392: 1-7
• 7 Verdecchia P, Schillaci G, Reboldi G. et al. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension 2000; 36: 1072-1078
• 8 Johnson RJ, Kang DH, Feig D. et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?. Hypertension 2003; 41: 1183-1190
• 9 Nabipour I, Sambrook PN, Blyth FM. et al. Serum uric acid is associated with bone health in older men: A cross-sectional population-based study. J Bone Miner Res 2011; 26: 955-964
• 10 Makovey J, Macara M, Chen JS. et al. Serum uric acid plays a protective role for bone loss in peri- and postmenopausal women: A longitudinal study. Bone 2013; 52: 400-406
• 11 Ishii S, Miyao M, Mizuno Y. et al. Association between serum uric acid and lumbar spine bone mineral density in peri- and postmenopausal Japanese women. Osteoporos Int 2014; 25: 1099-1105
• 12 Lane NE, Parimi N, Lui LY. et al. Osteoporotic Fractures in Men Study Group. Association of serum uric acid and incident nonspine fractures in elderly men: The Osteoporotic Fractures in Men (MrOS) study. J Bone Miner Res 2014; 29: 1701-1707
• 13 Zhang D, Bobulescu IA, Maalouf NM. et al. Relationship between serum uric Acid and bone mineral density in the general population and in rats with experimental hyperuricemia. J Bone Miner Res 2015; 30: 992-999
• 14 Mehta T, Bůžková P, Sarnak MJ. et al. Serum urate levels and the risk of hip fractures: Data from the Cardiovascular Health Study. Metabolism 2015; 64: 438-446
• 15 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
• 16 Napoli N, Chandran M, Pierroz DD. et al. IOF Bone and Diabetes Working Group. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol 2017; 13: 208-219
• 17 Kanazawa I, Yamaguchi T, Sugimoto T. Serum insulin-like growth factor-I is amarker for assessing the severity of vertebral fractures in postmenopausal women with type 2 diabetes mellitus. Osteoporos Int 2011; 22: 1191-1198
• 18 Kanazawa I, Yamamoto M, Yamaguchi T, Sugimoto T. Effects of metformin and pioglitazone on serum pentosidine levels in type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2011; 119: 362-365
• 19 Genant HK, Jergas M, Palermo L. et al. Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis The Study of Osteoporotic Fractures Research Group. J Bone Miner Res 1996; 11: 984-996
• 20 Hygum K, Starup-Linde J, Harsløf T. et al. Mechanisms in Endocrinology: Diabetes mellitus, a state of low bone turnover - A systematic review and meta-analysis. Eur J Endocrinol 2017; 176: R137-R157
• 21 Kunutsor SK, Apekey TA, Laukkanen JA. Association of serum total osteocalcin with type 2 diabetes and intermediate metabolic phenotypes: Systematic review and meta-analysis of observational evidence. Eur J Epidemiol 2015; 30: 599-614
• 22 Yamamoto M, Yamaguchi T, Yamauchi M, Kaji H, Sugimoto T. Diabetic patients have an increased risk of vertebral fractures independent of bone mineral density or diabetic complications. J Bone Miner Res 2009; 24: 702-709
• 23 Yan P, Zhang Z, Wan Q. et al. Association of serum uric acid with bone mineral density and clinical fractures in Chinese type 2 diabetes mellitus patients: A cross-sectional study. Clin Chim Acta 2018; 486: 76-85
• 24 Zhao DD, Jiao PL, Yu JJ. et al. Higher Serum Uric Acid Is Associated with Higher Bone Mineral Density in Chinese Men with Type 2 Diabetes Mellitus. Int J Endocrinol 2016; 2016: 2528956
• 25 Kang DH, Han L, Ouyang X. et al. Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter. Am J Nephrol 2005; 25: 425-433
• 26 Baldwin W, McRae S, Marek G. et al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes 2011; 60: 1258-1269
• 27 Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: Implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol 2005; 16: 3553-3562
• 28 Ahn SH, Lee SH, Kim BJ. et al. Higher serum uric acid is associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in healthy postmenopausal women. Osteoporos Int 2013; 24: 2961-2970
• 29 Lean JM, Davies JT, Fuller K. et al. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest 2003; 112: 915-923
• 30 Han W, Bai X, Wang N. et al. Association between lumbar bone mineral density and serum uric acid in postmenopausal women: A cross-sectional study of healthy Chinese population. Arch Osteoporos 2017; 12: 50
• 31 Takiue Y, Hosoyamada M, Kimura M, Saito H. The effect of female hormones upon urate transport systems in the mouse kidney. Nucleosides Nucleotides Nucleic Acids 2011; 30: 113-119
• 32 Shinaki M. Critical appraisal of physical rehabilitation measures after osteoporotic vertebral fracture. Osteoporos Int 2003; 14: 773-779
• 33 Majumdar SR, Leslie WD, Lix LM. et al. Longer duration of diabetes strongly impacts fracture risk assessment: The Manitoba BMD Cohort. J Clin Endocrinol Metab 2016; 101: 4489-4496