METABOLIC DISORDERS, OSTEOPOROSIS AND FRACTURE RISK IN ASIA: A SYSTEMATIC REVIEW Toshitsugu Sugimoto a, Masayo Sato b, Francis C Dehle c, Alan JM Brnabic c, Adele Weston c, Russel Burge d a Shimane University Faculty of Medicine, Internal Medicine 1, Shimane, Japan; b Eli Lilly Japan K. K., Lilly Research Laboratories, Kobe, Japan; c Optum, Sydney, NSW, Australia; d Eli Lilly and Company, Global Health Outcomes, Indianapolis, IN, USA BACKGROUND Table 1: Results of BMD in patients with and without metabolic disorders • The International Osteoporosis Foundation projects that by 2050 more than 50% of all osteoporotic fractures will occur in East and South-East Asia [1]. In addition, the prevalence of lifestyle-related metabolic disorders is rapidly increasing in Asia [2,3]. • Glucose/fat metabolism and bone metabolism are linked, with diabetes found to be a risk factor for fracture in United States and European populations [4]. Publication ID (Disease) Outcome Subjects with disorder Subjects without disorder Mean (SD) Mean (SD) Choi 2009 [11] M (211) 1.012 (0.141) 1.057 (0.127) 0.060 W (117) 0.926 (0.140) 0.977 (0.119) 0.167 M (211) 0.936 (0.134) 0.967 (0.114) 0.156 W (117) 0.789 (0.136) 0.845 (0.119) 0.120 M (211) 0.797 (0.113) 0.817 (0.102) 0.295 W (117) 0.688 (0.110) 0.740 (0.099) 0.077 < 10 years PM (159) 1.57 (0.431) 1.17 (0.430) < 0.05 ≥ 10 years PM(144) 1.55 (0.458) 1.24 (0.468) < 0.05 M (218) 0.72 (0.210) 1.08 (0.260) 0.015 0.81 (0.130) 0.83 (0.080) 0.382 Men with diabetes Type 2 have lower LSBMD than men without diabetes. Not statistically significant for FNBMD 0.90 (0.160) 0.87 (0.150) 0.264 Not statistically significant FNBMD (g/cm2) 0.77 (0.110) 0.73 (0.120) 0.280 THBMD (g/cm2) 0.92 (0.130) 0.89 (0.130) 0.366 W (2475) (MetS) 0.898 (0.158) 0.914 (0.133) 0.031 hypertriglyceridemia 0.895 (0.143) 0.916 (0.131) 0.002 hyperglycemia 0.912 (0.130) 0.911 (0.141) 0.947 PreMW (1,234) 1.110 (0.140) 1.154 (0.137) 0.014 PMW (931) 1.111 (0.157) 1.147 (0.142) 0.017 PreMW (1,234) 0.885 (0.107) 0.903 (0.102) 0.0177 PMW (931) 0.870 (0.112) 0.896 (0.113) 0.016 M (1,780) 0.813 (0.150) 0.839 (0.151) 0.002 W (1,108) 0.684 (0.122) 0.721 (0.118) <0.001 M (6,659) 0.967 (0.278) 0.969 (0.129) 0.658 PreMW (4,547) 0.980 (0.507) 0.984 (0.092) 0.602 PMW (3,279) 0.800 (0.239) 0.788 (0.247) 0.056 M (6,659) 0.962 (0.278) 0.971 (0.129) 0.030 PreMW (4,547) 0.903 (0.443) 0.904 (0.092) 0.973 PMW (3,279) 0.762 (0.199) 0.759 (0.205) 0.428 M (6,659) 0.801 (0.278) 0.814 (0.129) <0.001 PreMW (4,547) 0.764 (0.443) 0.764 (0.092) 0.999 PMW (3,279) 0.615 (0.159) 0.613 (0.205) 0.555 LSBMD PMW (1,218) (% change per year) -0.606 (1.792) -0.880 (1.767) 0.029 FNBMD (% change per year) -0.899 (1.280) -1.083 (1.246) 0.041 PMW with MetS have significantly less reduction in LSBMD and FNBMD per year compared with women without MetS 1.06 (0.140) 1.01 (0.180) 0.32 Not statistically significant 0.84 (0.100) 0.81 (0.120) 0.55 LSBMD (g/cm2) THBMD (g/cm2) • The aim of this systematic review was to summarize all published studies within Asia on the association between disorders of glucose and lipid metabolism and risk of fracture and osteoporosis. FNBMD (g/cm2) Tamaki 2009 [19] IMT (mm) METHODS Chen 2013 [20] LSBMD (g/cm2) FNBMD (g/cm2) Anaforoglu 2009 [21] LSBMD (g/cm2) PMW (267) Hwang 2010 [22] Jeon 2011 a [23] LSBMD (g/cm2) LSBMD (g/cm2) FNBMD (g/cm2) Kim 2013a [25] FNBMD (g/cm2) FNBMD (g/cm2) Kim 2013b [26] Figure 1: Association between metabolic disorders and fracture 0.100 10.000 Atherosclerosis LSBMD (g/cm2) THBMD (g/cm2) Park 2010 [27] Risk estimatea (95% CI) 1.000 PMW with osteoporosis have significantly higher IMT than women without osteoporosis Metabolic syndrome [ • The literature search identified 32 observational studies for inclusion, including 28 studies conducted in East and South-East Asia and four in the Middle-East. • The majority of studies were cross-sectional study design (24 studies). • One study [6] was assessed as high quality (++) and 31 assessed as adequate (+). • There were 13 studies that included both men and women, two studies in men only and 17 studies in women only. • The most commonly controlled variables were age (29 studies), BMI or weight (22 studies) and smoking (18 studies). • Studies reporting risk of fracture are shown in Figure 1. • Studies reporting risk of osteoporosis are shown in Figure 2 and studies examining mean BMD in subjects with and without the disorder are summarized in Table 1. In addition, there were three studies reporting mean difference in BMD [30-32]. Not statistically significant Diabetes Kim 2010a [24] RESULTS P value Finding Atherosclerosis OBJECTIVES • The databases searched were EMBASE.com (includes Medline and EMBASE) and The Cochrane Library. The overall search strategy included terms for osteoporosis, BMD, fracture and the following risk factors: • Type 2 Diabetes • Hyperglycemia • Hypercholesterolemia, hyperlipidemia and dyslipidemia • Metabolic syndrome (MetS) • Atherosclerosis • Only observational studies (cohort, case-control or cross-sectional) reporting the above risk factors conducted within Asia, which reported multivariate analysis in a sample size ≥ 200 subjects, were included. • For fractures, studies reported risk estimates (odds ratio, hazard ratio or relative risk) and corresponding confidence intervals. For BMD, studies reported risk estimates for osteoporosis (i.e. BMD T-score < -2.5) or osteopenia (i.e. BMD T-score < -1 and > -2.5). In addition, studies reporting mean values of BMD and measures of variance (SEs, SDs or 95% CIs) in patients with and without metabolic disorders were included. • Studies were assessed as ++ (high quality), + (acceptable) or 0 (low quality) using checklists for cohort and case-control studies developed by the Scottish Intercollegiate Guidelines Network (SIGN). Population (N) LSBMD (g/cm2) PMW (399) FNBMD (g/cm2) Women with MetS and hypertriglyceridemia have significantly lower LSBMD than women without MetS or hypertriglyceridemia Not statistically significant for hyperglycemia Postmenopausal and premenopausal women with MetS and have significantly lower LSBMD and FNBMD than women without MetS Men and women with MetS and have significantly lower FNBMD than subjects without MetS Men with MetS and have significantly lower FNBMD and THBMD than men without MetS Not statistically significant for LSBMD Not statistically different for premenopausal or PMW Sanada 2012 [28] LSBMD (g/cm2) W (533) 0.98 (0.161) 1.03 (0.216) 0.214 Not statistically significant Tseng 2009 [29] Foot BMD (g/cm2) M (352) -1.021 (0.775) -1.014 (0.753) 0.938 Not statistically significant W (468) -1.063 (0.791) -1.105 (0.775) 0.517 Note: a SD calculated post-hoc from standard error. b SD calculated post-hoc from 95%CIs. Abbreviations: M, men; PMW, postmenopausal women; PreMW, premenopausal women; W, women; IMT, intima-media thickness of carotid bifurcation; MetS; metabolic syndrome; BMD, bone mineral density; FN, femoral neck; LS, lumbar spine; TH, total hip; CI, confidence interval; SD, standard deviation Lai 2013 [1]: A (87,748) M (46,322) W (41,426) Wada 2012 [2]: PMW (421) Diabetes • Two studies found that subjects with atherosclerosis had a significantly higher risk of fracture than subjects without atherosclerosis [1,2] (risk estimate range: 1.10 to 2.52). • All six studies examining diabetes and fracture found that subjects with diabetes had a significantly higher risk of fracture compared with subjects without diabetes [3-8] (risk estimate range: 1.26 to 4.73). • No consistent association was found between diabetes and osteoporosis or BMD, with studies reporting contrasting results [12-16,20,21,31,32]. • In men, three studies reported that MetS is likely to be associated with osteoporosis or decreased BMD [18,24,25] whereas one study reported no significant difference [29]. Studies examining this association in women produced contrasting results [18,22-29]. • There was limited evidence investigating lipid metabolism or hyperglycemia and risk of fracture or bone loss. One study found that women with high triglycerides had a significantly lower risk of fractures [10]. Chen 2008 [3]: M (454,592) W (515,229) Segal 2009 [4]: All (238) W (198) Yamamoto 2009 [5]: PM W (759) M (237) Koh 2010 [6]: All (63,154) M (27,939) W (35,215) Soong 2013 [7]: All (32,604) Tatsuno 2013 [8]: PMW (64,809) MetS Kim 2010b [9]: PMW (900) LIMITATIONS Lipids Yamaguchi 2002 [10]: PMW (214): T-C LDL-C HDL-C TG Tatsuno 2013 [8]: PMW: Dys Protective • The majority of studies included in the review were cross-sectional design. • Meta-analyses were not undertaken due to the high degree of heterogeneity in study design and patient populations. • Important confounders were not always measured and therefore not adjusted for in the analyses. Risk Note: a Studies presented either odds ratio, relative risk or hazard ratio. Logarithmic scale. Abbreviations: A, all patients; M, men; PMW, postmenopausal women; W, women; Dys, dyslipedemia; HDL-C, high-density lipoprotien cholesterol; LDL-C, low-density lipoprotien; T-C, total cholesterol; cholesterol TG, triglyceride Figure 2: Association between metabolic disorders and osteoporosis Risk estimatea (95% CI) 0.100 1.000 10.000 100.000 Atherosclerosis Choi 2009 [11]: A (328) M (211) W (117) Diabetes Li 2010 [12]: W (4,382) El-Heis2013 [13]: PMW (384) Shilbayeh 2003 [14]: W (402) Romana 2007 [15]: W (1,180) Shan 2009 [16]: PMW (1,961): LS FN TH Shaw 1993 [17]: A (398) MetS Kim 2013c [18]: A (3,108) M (1,498) PreMW (957) PMW (752) Risk Note: a All studies presented odds ratio. Logarithmic scale. Abbreviations: A, all patients; M, men; PMW, postmenopausal women; W, women; FN, femoral neck BMD; LS, lumbar spine BMD; TH, total hip BMD ISPOR • Findings from this review suggest that diabetes is a risk factor for fracture in Asian populations. • Atherosclerosis may also be associated with increased fractures in Asian populations, and MetS associated with bone loss in Asian men, however, the extent of causality in these observations is yet to be determined. • These findings highlight the importance of properly managing patients with these risk factors to minimise the risk of fractures. Further appropriately adjusted prospective cohort studies are needed to investigate the extent and mechanisms of these associations in Asian populations. References Protective 6th CONCLUSIONS Asia-Pacific Conference, Beijing, September 6 – 9, 2014 1. Lai SW, Liao KF, Lai HC, et al (2013) Risk of major osteoporotic fracture after cardiovascular disease: a population-based cohort study in Taiwan. 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