1
Supplementary tables
Biochemical markers of bone turnover in diabetes patients- a meta-analysis, and a methodological study on the
effects of glucose on bone markers.
Osteoporosis International
Jakob Starup-Linde1,2, Stine Aistrup Eriksen1, Simon Lykkeboe3, Aase Handberg3, Peter Vestergaard1,4
(1) Clinical Institute, Aalborg University, Fredrik Bajers vej 7, 9220 Aalborg
(2) Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital THG, Aarhus,
Denmark
(3) Department of Clinical Biochemistry, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg
(4) Department of Endocrinology, Aalborg University Hospital, Molleparkvej 4, 9000 Aalborg
Corresponding Author:
Jakob Starup-Linde
Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital
Tage Hansens Gade 2
8000 Aarhus C
Denmark
Phone: 0045 78467682
Fax: 0045 78467684
Mail: jakolind@rm.dk
2
Table 1. Studies included in the meta-analysis. T1D type 1 diabetes, T2D type 2 diabetes.
Study
Participants
How to determine
diabetes?
Comments
Samples
taken in
fasting
condition
Renal
Disease
Newcastle
Ottawa
Scale (010)
Garcia-Martin
et al. 2012 [1]
74 T2D, 50
controls.
No group differences.
F
E
9
Gennari et al.
2012 [2]
43 T1D, 40 T2D,
21 young healthy
volunteers as
controls to T1D
and 62 older men
and
postmenopausal
women as controls
to T2D.
25 postmenopausal
T2D, 25
postmenopausal
controls.
Diagnosis of diabetes
according to American
Diabetes Association
criteria.
Referred to the
Diabetes Unit.
T1D significantly older than
their controls.
F
E
9
T2D was defined as
the presence of a
fasting plasma glucose
>126 mg/dl and use of
an antiglycemic
medication. As well as
exclusion of T1D.
R
E
9
47 young T1D, 30
sex and aged
matched healthy
controls.
36 T1D, 15 healthy
controls.
Outpatient clinic.
F
E
6
F
E
8
128 T1D, 77
controls.
78 T2D, 55
controls from an
osteoporosis
screening program.
60 children and
adolescents with
T1D, 40 healthy
children and
adolescents
matched in age,
gender, BMI and
pubertal staging as
controls.
890
postmenopausal
T2D, 689
postmenopausal
controls.
75 T1D females,
Outpatient clinic.
R
E
7
The T2D was significantly
older and more obese by
BMI.
F
E
8
Patients known to take
medication that affect bone
metabolism was excluded
e.g. (Ca, vitamin -D or
steroids). Thus, patients are
unlikely to have renal
disease (also in regard of
their young age)
R
-
5
R
E
8
R
E
7
Crosssectional
Shu et al. 2012
[3]
Abd El Dayem
et al. 2011 [4]
Hamed et al.
2011[5]
Neumann et
al. 2011[6]
Reyes-Garcia
et al. 2011[7]
Aboelasrar et
al. 2010 [8]
Zhou et al. et
al. 2010[9]
Danielson et
Outpatient clinic.
Diabetes diagnosis
according to American
Diabetes Association
criteria.
Diabetes clinic.
The controls tended to be
younger than the T1D
(P=0.081)
In- and out- patients at
a hospital.
Diabetes registry.
The T1D drank significantly
3
al. 2009[10]
75 matched female
controls.
Cutrim et al.
2007 [11]
20 poor metabolic
controlled T2D, 22
good metabolic
controlled T2D, 24
controls.
583 female T2D,
1081 female
controls.
Dobnig et al.
2006 [12]
Oz et al. 2006
[13]
52 T2D, 48
controls of similar
age, sex and BM.
Achemlal et
al. 2005 [14]
Galluzzi et al.
2005 [15]
35 male T2D, 35
male controls.
26 prepubertal
T1D, 45 age, sex
and body sized
controls.
74 female
diabetics, 1058
female controls.
Gerdhem et al.
2005 [16]
Valerio et al.
2002 [17]
less alcohol and more
caffeine than the controls.
The T1D also had
experienced significantly
more events of
hypothyroidism.
Outpatient clinic.
Patients were classified
as T2D if they had a
diagnosis of DM in
their medical chart,
had anti diabetic drugs
prescribed, or were
found with a HbA1c
level of more than
5.9%.
Diabetes diagnosis
according to American
Diabetes Association
criteria.
Internal medicine
department.
T1DM was defined by
the National Diabetes
Data Group. Recruited
at a hospital.
Questionnaire.
The participants were
females aged 70 or more in
nursing homes. The T2D
were significantly younger
and had a significantly
higher BMI.
Blood samples were taken
early in the morning.
All were 75 years old.
Diabetics were significantly
heavier (5kg) than nondiabetics. Yet BMI was not
assessed.
F
E
8
R
E
9
F
E
8
R
E
7
F
E
8
R
Creatinine:
82±42 μmol/l
for diabetes
and 77±18
μmol/l for
non diabetes
controls.
6
F
E
9
R
E
8
F
E
8
27 adolescents with
T1D, 43 healthy
controls
31 T1D, 21 T2D,
20 controls. All are
premenopausal.
60 NIDD in good
metabolic control,
50 NIDD in poor
metabolic control,
50 controls
matched for age,
sex and BMI.
87 T1D children,
49 healthy children
as controls.
Diabetes Unit,
Department of
paediatrics.
Diabetics selected
from a diabetic clinic
database.
No patient had ever
been treated with
insulin; all had been
under oral
hypoglycaemic
therapy.
Hospital.
No assessment of BMI or
weight.
F
E
7
Longitudinal
Mastrandea et
al. 2008 [21]
63 T1D females,
83 female controls.
Diabetes centre and
endocrinology
practices.
R
E
7
Miazgowski
54 IDD, 25 healthy
Followed through 2 years.
The T1D younger than 20
years smoked significantly
more than the controls.
Followed through 2 months.
F
E
5
Hampson et al.
1998 [18]
Gregorio et al.
1994 [19]
Leon et al.
1989 [20]
-
BMI was significantly
higher among T2D than the
other groups.
4
and Czekalski
aged matched
1998 [22]
controls.
F: Blood samples taken after fasting, R: Blood samples taken at random or non fasting E: Individuals with renal disease,
nephropathy, poor renal function, other chronic disease, or conditions that affect bone metabolism, have been excluded.
Table 2. Additional studies included in meta-regression. T1D type 1 diabetes, T2D type 2 diabetes.
Study
Participants
How to determine
diabetes?
Comments
Samples
taken in
fasting
condition
Renal
function
NOS (0-9)
Diabetics had a
significantly higher BMI
and lower duration in
hemodialysis than nondiabetics.
52 patients with
polyneuropathy
R
All in
hemodialy
sis
6
F
E
7
Outpatient clinic
F
E
9
Hospital
F
E
7
76 with a diagnosed
vertebral fracture
Did not present results for
control group.
F
E
6
F
E
6
Assessed leptin, adiponectin
and BMD in T2D.
Diabetics with IDD had
significantly longer diabetes
duration and significantly
lower BMI than NIDD.
Assessed BMD in IDD and
also bone markers.
F
E
7
F
E
7
F
E
8
R
E
7
The study does not count
participants but
measurements, thus the
some of the measurements
have been conducted on the
same individual.
F
E
6
Followed 6 months to
determine the relationship
between bone markers and
athereosclerosis.
Follow up after 1 year. At
follow up it was only DXA,
which was conducted.
F
E
6
F
E
7
Cross-sectional
Okuno et al. 2012
[23]
189 hemodialysis
patients, 96 of
those with
diabetes.
-
Rasul et al.[24]
2012[25]
Rasul et al. 2012
120 patients with
T2D
80 patients with
T2D
289 patients with
T2D
248 male patienst
with T2D
22 children and
adolescents with
T1D, 22 healthy
controls.
40 T2D.
Outpatient clinic
Kanazawa et al.
2011[26]
Kanazawa et al.
2009[27]
Brandao et al
2007 [28]
Tamura et al.
2007 [29]
Christensen and
Svendsen 1999
[30]
Hospital
Center for diabetes and
endocrinology.
Hospital.
32 female NIDD,
53 female IDD
Outpatient clinic.
Munoz-Torres et
al. 1996 [31]
94 IDD
Pedrazzoni et al.
1989 [32]
42 IDD, 64
NIDD, 198
controls
217 T2D
measurements,
416 control
measurements.
IDD is defined in
accordance with the
criteria of the World
Health Organization.
-
Levy et al 1986
[33]
Longitudinal
Kanazawa et al.
2011[34]
Kanazawa et al.
2010 [35]
Ambulatory diabetic
patients.
50 T2D
32 T2D.
-
Hospital.
5
Kanazawa et al.
2009[36]
Capoglu et al.
2008 [37]
50 T2D
Hospital
35 T2D.
Diabetes diagnosis
according to American
Diabetes Association
criteria.
Campos Pastor et
al. 2000 [38]
57 T1D.
Inaba et al. 1999
[39]
9 T2D.
Rosato et al. 1998
[40]
20 NIDD, 20
healthy controls
T1D is defined in
accordance with the
criteria of the World
Health Organization.
T2D is defined in
accordance with the
criteria of the World
Health Organization.
Outpatient clinic.
Follow up after 1 month of
glycemic control
Followed through 12
months. They were treated
with oral anti diabetics and
assessed for metabolic
control every month.
Followed through 7 years of
intensive insulin therapy
(three insulin injections or
more pr. day).
Followed through 1 week
with Vitamin D stimulation.
F
E
8
F
E
9
F
E
7
F
E
7
Followed through 2 years.
Participants underwent
glycemic control by diet,
counseling and medication.
F
E
8
F: Blood samples taken after fasting, R: Blood samples taken at random or non fasting E: Individuals with renal disease,
nephropathy, poor renal function, other chronic disease, or conditions that affect bone metabolism, have been excluded.
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Sieberer C, Fahrleitner-Pammer A (2006) Type 2 diabetes mellitus in nursing home patients: Effects on bone turnover,
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mass in patients with type-2 diabetes mellitus. J Natl Med Assoc 98:1598-604
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metabolism in male patients with type 2 diabetes. Clin Rheumatol 24:493-6
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levels in children with type 1 diabetes: a potential modulating role in bone status. Eur J Endocrinol 153:879-85
16. Gerdhem P, Isaksson A, Akesson K, Obrant KJ (2005) Increased bone density and decreased bone turnover, but no
evident alteration of fracture susceptibility in elderly women with diabetes mellitus. Osteoporos Int 16:1506-12
17. Valerio G, del Puente A, Esposito-del Puente A, Buono P, Mozzillo E, Franzese A (2002) The lumbar bone mineral
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41:1314-20
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type 1 diabetes have lower bone mineral density that persists over time. Diabetes Care 31:1729-35
22. Miazgowski T, Czekalski S (1998) A 2-year follow-up study on bone mineral density and markers of bone turnover
in patients with long-standing insulin-dependent diabetes mellitus. Osteoporosis Int 8:399-403
23. Okuno S, Ishimura E, Tsuboniwa N, Norimine K, Yamakawa K, Yamakawa T, Shoji S, Mori K, Nishizawa Y,
Inaba M (2012) Significant inverse relationship between serum undercarboxylated osteocalcin and glycemic control in
maintenance hemodialysis patients. Osteoporosis Int :1-8
24. Rasul S, Ilhan A, Reiter MH, Todoric J, Farhan S, Esterbauer H, Kautzky-Willer A (2012) Levels of fetuin-A relate
to the levels of bone turnover biomarkers in male and female patients with type 2 diabetes. Clin Endocrinol 76:499-505
7
25. Rasul S, Ilhan A, Wagner L, Luger A, Kautzky-Willer A (2012) Diabetic polyneuropathy relates to bone
metabolism and markers of bone turnover in elderly patients with type 2 diabetes: Greater effects in male patients.
Gender Med 9:187-96
26. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T (2011) Serum
undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes
mellitus. Osteoporosis Int 22:187-94
27. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Yano S, Sugimoto T (2009) Serum osteocalcin/bonespecific alkaline phosphatase ratio is a predictor for the presence of vertebral fractures in men with type 2 diabetes.
Calcif Tissue Int 85:228-34
28. Brandao FR, Vicente EJ, Daltro CH, Sacramento M, Moreira A, Adan L (2007) Bone metabolism is linked to
disease duration and metabolic control in type 1 diabetes mellitus. Diabetes Res Clin Pract 78:334-9
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adiponectin are positively associated with bone mineral density at the distal radius in patients with type 2 diabetes
mellitus. Metabolism 56:623-8
30. Christensen JO, Svendsen OL (1999) Bone mineral in pre- and postmenopausal women with insulin-dependent and
non-insulin-dependent diabetes mellitus. Osteoporosis Int 10:307-11
31. Munoz-Torres M, Jodar E, Escobar-Jimenez F, Lopez-Ibarra PJ, Luna JD (1996) Bone mineral density measured by
dual X-ray absorptiometry in Spanish patients with insulin-dependent diabetes mellitus. Calcif Tissue Int 58:316-9
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diabetic subjects. Calcif Tissue Int 45:331-6
33. Levy L, Stern Z, Gutman A (1986) Plasma calcium and phosphate levels in an adult noninsulin-dependent diabetic
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34. Kanazawa I, Yamaguchi T, Sugimoto T (2011) Relationship between bone biochemical markers versus
glucose/lipid metabolism and atherosclerosis; a longitudinal study in type 2 diabetes mellitus. Diabetes Res Clin Pract
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94:3031-7
37. Capoglu I, Ozkan A, Ozkan B, Umudum Z (2008) Bone turnover markers in patients with type 2 diabetes and their
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38. Campos Pastor MM, Lopez-Ibarra PJ, Escobar-Jimenez F, Serrano Pardo MD, Garcia-Cervigon AG (2000)
Intensive insulin therapy and bone mineral density in type 1 diabetes mellitus: a prospective study. Osteoporos Int
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(1999) Poor glycemic control impairs the response of biochemical parameters of bone formation and resorption to
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8
9
Table 3. Number of methods used in the pooled analysis and meta-regression to assess bone marker levels
Bone Marker
Number of methods used in assessing the marker
CICP
2
OC (pooled analysis)
12
OC (meta-regression)
7
BAP
3
CTX
5
NTX
4
DPD
2
10
Table 4. Metaregression results for calcium, phosphate, 25OHD, PTH, osteocalcin, bone specific alkaline phosphatase
and CTX. All variables are mutually adjusted by each other with except creatinin and diabetes duration and some
markers for the specific diabetestypes, which in for some markers were performed alone.
Variable
Calcium
Phosphate
25 OHD
PTH
Osteocalcin
BAP
CTX
NTX
Diabetestype
0.1 (-0.8,
0.5 (-0.5,1.4)
49.2 (-19.6,
1.1 (-36.7,
16.9 (-26.5,
9.32 (-22.1, 40.8)
0.1 (-0.9,1.1)
-
118.0)
38.9)
60.4)
-1.2 (-3.8, 1.4)
0.4 (-1.0, 1.8)
-0.7 (-2.8,
-0.2 (-1.7, 1.4)
-0. 1 (-0.4,
-4.9 (-8.8, -
0.1)
1.0)
0.2 (-1.2, 1.5)
43.3 (-55.7,
0.9)
Age
-0.1 (-0.1,
-0.1 (-0.1, 0.
0.1)
1)
Gender
0.1 (-0.2,
0.8 (-0.1, 1.6)
(female vs
0.3)
1.4)
-11.6 (-67.0,
11.4 (-19.0,
-5.2 (-23.4,
43.7)
41.8)
13.1)
5.08 (-7.7,17.8)
-1.4 (-10.3,
-2.4 (-7.0,
7.5)
2.3)
-1.4 (-5.1, 2.3)
-0.7 (-1.6,
1.3 (-9.9, 12.5)
142.3)
male)
HbA1c
-0.1 (-0.1,
0.1 (-0.1,0.1)
0.1)
BMI
0.1 (-0.1,
-0.1 (-0.2,0.1)
1.3 (-4.2, 6.7)
0.1)
Fasting
0.3 (-0.1,
7.7 (2.1, 13.2)
-0.1 (-1.0, 1.0)
0.2)
0.7 (0.1, 1.4)
0.5)
-1.9 (-76.4,
4.8 (-21.6,
-27.9 (-97.0,
72.7)
31.2)
41.2)
-1.5 (-4.2, 1.2)
1.9 (-3.4, 7.2)
-0.1 (-1.1,
5.4 (-6.2,
1.0)
17.0)
-0.1 (-0.2,
0.7 (-4.3, 5.7)
0.1)
-9.6 (-34.0, 14.8)
-0.1 (-1.0,
-59.1 (-146.8,
0.7)
28.7)
0.1 (-0.1, 0.1)
-5.8 (-9.2, -
*
2.3)
Diabetes
0.1 (-0.1,
-0.1 (-0.1,
-4.4 (-20.3,
duration
0.1)
0.1) *
11.5)*
Creatinin
0.4 (0.1,
-2.3 (-4.5, -
-495.5 (-1330.7,
-16,0 (-103,7,
-87.0 (--
-38.8 (-66.5, -
0.3 (-1.0,
-56.0 (-
(mg/dl)
0.8)*
0.1)*
339.6)*
71.8)*
281.6, 107.5)
11.0)*
1.5)**
1044.4,
-2.7 (-5.1, -0.4)*
932.4)
Type 1 diabetes
Variable
Calcium
Phosphate
25 OHD
PTH
Osteocalcin
BAP
CTX
NTX
Age
-0.1 (-0.1,
-0.1 (-0.2,
0.1 (-1.0, 1.0)
7.0 (-6.6,
0.5 (0.1,1.0)
-4.6 (-8.6, -0.6)*
0.1 (-0.2,
-
0.1)
0.1)
Gender
-0.1(-0.3,
-0.2 (-2.2,
6.0 (-56.1,
48.1 (-63.4,
9.8 (-5.4,
(female vs
0.1)*
1.8)
68.0)*
159.7)
25.0)
-0.1 (-0.2,
0.1 (-0.5, 0.7)
4.1 (-25.9,
-
20.7)
0.2)*
-
-
-
8.5 (-4.0,
87.5 (-0.1,
0.1 (-1.9,
-
21.0)
175.1)*
2.1)*
39.7 (2.1, 77.3)*
-
-
-
-0.1 (-0.5,
-
male)
HbA1c
0.1)***
BMI
Fasting
34.1)*
-0.1 (-0.1,
-0.1 (-0.8,
-1.2 (-10.7,
-26.8 (-71.9,
-2.2 (-8.4,
0.1)*
0.8)
8.3)*
18.4)
4.0)
0.1 (-0.2,
0.1 (-2.0, 2.3)
5.4 (-28.1, 38.9)
58.2 (-81.4,
-8.4 (-36.2,
197.7)
19.4)
-
1.6 (0.8, 2.3)*
0.4)
Diabetes
-0.1 (-0.1,
-
-
0.4)*
-
-
-
11
duration
0.1)*
Creatinin
-0.1 (1.9,
-2.2 (-5.6,
(mg/dl)
1.7)*
1.1)*
Variable
Calcium
Phosphate
Age
0.1 (-0.1,
0.1 (-0.1, 0.1)
-
101.7 (-218.3,
1.9 (-22.2,
-
-
-
421.8)*
26.0)*
25 OHD
PTH
Osteocalcin
BAP
CTX
NTX
-2.3 (-5.8, 1.1)
-0.4 (-1.3, 0.6)
-0.8 (-3.2,
0.4 (-2.0, 2.9)
-0.1 (-0.1,
-5.0 (-8.8, -
0.1)
1.2)
0.2 (-1.2, 1.5)
53.1 (-23.9,
Type 2 diabetes
0.2)
Gender
0.1 (-0.2,
(female vs
0.2)
1.5)
0.9 (-0.1, 1.8)
-4.1 (-61,7,
3.1 (-20.0,
-5.7 (-24.4,
53.5)
26.2)
13.0)
2.3 (-11.6, 16.2)
-0.4 (-2.6, 1.7)
-2.6 (-7.8, 2-
5.4 (-18.7, 29.6)
130.1)
male)
HbA1c
0.1 (-0.2,
0.1 (-0.1, 0.1)
0.2)
BMI
Fasting
0.8 (-8.9, 10.6)
5)
0.1 (-0.1,
-0.1 (-0.2,
0.1)
0.1)
0.2 (-2.6,
0.7 (0.1, 1.4)
2.1)
Diabetes
0.1 (0.1,
duration
0.1)*
Creatinin
0.1 (-0.8,
-4.6 (-8.7, -
(mg/dl)
0.9)*
0.5)*
-
2.0 (-4.1, 8.1)
-0.1 (-2.0, 2.0)
-0.8 (-2.2,
-1.2 (-3.7, 1.3)
0.6)
-2.9 (-92.8,
10.9 (-5.4,
-30.0 (-101-4,
87.0)
27.2)
41.4)
-9.1 (-27.9,
-0.6 (-3.9,
2.1 (-3.7, 7.9)
9.8)*
2.7*
-
-23.5 (-119.6,
-93.5 (-295.7,
72.7)*
108.7)
Values are regression coefficients (95 % CI). Bold indicates significance (P<0.05).
* Analysed as only variate in the metaregression.
-0.1 (-1.1,
5.7 (-5.8,
1.0)
17.2)
-0.1 (-0.2,
0.8 (-4.2, 5.7)
0.1)
-5.8 (-35.9, 24.2)
-0.2 (-3.4, 3.0)
7.3 (-63.0, 77.6)
-0.1 (-1.0,
-50.2 (-117.7,
0.7)
17.2)
-0.1 (-0.1,
-5.7 (-9.1, -
0.1)*
2.3)
0.2 (-1.2,
-119.1 (-
1.6)*
528.5, 290.3)
12
Table 5. Multiple linear regression analysis by time and added glucose for the bone markers P1NP, osteocalcin and
CTX.
Regression Coefficient
P1NP
Osteocalcin
CTX
Time
-.416 (0.432)
-,386 (0.348)
-0.006 (0.013)
Addition of glucose
0.000 (0.065)
0.006 (0.053)
0.000 (0.002)
R2
0.031
0.041
0.007
Values are regression coefficients (standard error). Bold indicates significance (P<0.05). R 2 prediction power for the
model including time, and addition of glucose.