a systematic review

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
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Sponsored by Eli Lilly and Company. MS is an employee of Eli Lilly Japan K.K.. RTB is an employee of Eli
Lilly and Company. FCD, AB and AW provided consulting services to Eli Lilly and Company

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