The document discusses diabetes mellitus and fracture risk. It notes that type 2 diabetes affects over 700,000 people in the Netherlands and is associated with higher bone mineral density but also more rapid bone loss over time. While type 2 diabetes is initially linked to higher bone density due to factors like higher body weight, studies have shown those with type 2 diabetes have a 1.7 times higher risk of hip fractures and 1.2 times higher risk of any fracture after adjusting for characteristics like age, body mass index and bone mineral density. The increased fracture risk in type 2 diabetes may be due to factors beyond bone mineral density, such as changes in bone microarchitecture, turnover and material properties from excess glucose.
2. Prevalence
of
Diabetes
in
the
Netherlands
• 800.000
pa8ents
– 700.000
DM
type
2
– 100.000
DM
type
1
• Yearly
incidence:
81.000
(>1.500
/
week)
0
2
4
6
8
10
12
14
16
18
20
0 10 20 30 40 50 60 70 80 90
mannen vrouwen
incidentie (per 1.000)
leeftijd (jaren)
Copyright
Dr. J.P.W. van
den
Bergh
3. DM
type
1
• Modest
reduc8on
in
BMD
– LS
Z-‐score:
-‐0.22
– TH
Z-‐score:
-‐0.37
• Hip
fracture
RR:
6.9
(3.2-‐14.9)
• Lack
of
data
for
other
fracture
sites
Vestergaard
2007
Copyright
Dr. J.P.W. van
den
Bergh
4. DM
type
2
• Average
higher
BMD
– LS
Z-‐score:
+0.41
– TH
Z-‐score
+0.27
• Overweight
• Expected
lower
fracture
risk
Vestergaard
2007
Copyright
Dr. J.P.W. van
den
Bergh
5. Associa8on
between
bone
mineral
density
and
type
2
diabetes
mellitus
Ma
et
al.
Eur
J
Epidemiol
(2012)
27:319–332
Copyright
Dr. J.P.W. van
den
Bergh
6. Meta-‐regression
• Posi8ve
associa8on
with
higher
BMD
levels
in
diabe8cs
– younger
age
– male
gender
– higher
body
mass
index
– higher
HbA1C
Copyright
Dr. J.P.W. van
den
Bergh
7. Longitudinal
BMD
changes:
more
rapid
bone
loss
in
DM
type
2
Fracture
Interven8on
Trial
(total
hip)
Copyright
Dr. J.P.W. van
den
Bergh
8. More
rapid
bone
loss
in
DM
type
2
• At
the
hip:
– FIT
Keegan
at
al.
2004
– Health
ABC
Schwartz
et
al.
2005
– MrOS
Strotmeyer
et
al.
2008
– SOF
Schwartz
et
al.
2013
• No
differences
at
the
radius
– Krakauer
et
al.
1995
– Schwartz
et
al.
2013
Copyright
Dr. J.P.W. van
den
Bergh
9. DM
type
2:
hip
fracture
risk
• Age
adjusted
RR
=
1.4
(1.2
–
1.5)
• Mul8variable
adjusted
(age,
BMI,
BMD)
RR
=
1.7
(1.3
–
2.2)
Vestergaard
2007
Janghorbani
2007
Copyright
Dr. J.P.W. van
den
Bergh
10. DM
type
2:
any
fracture
risk
• Age
adjusted
RR
=
1.0
(0.6
–
1.6)
• Mul8variable
adjusted
(age,
BMI,
BMD)
RR
=
1.2
(1.01
–
1.5)
Vestergaard
2007
Janghorbani
2007
Copyright
Dr. J.P.W. van
den
Bergh
11. Fracture
predic8on
in
DM
type
2
Schwartz
et
al.
JAMA
2011:
2184-‐2192
Copyright
Dr. J.P.W. van
den
Bergh
12. Schwartz
et
al.
JAMA
2011:
2184-‐2192
Copyright
Dr. J.P.W. van
den
Bergh
13. Schwartz
et
al.
JAMA
2011:
2184-‐2192
Copyright
Dr. J.P.W. van
den
Bergh
14. The
FRAX
score
tends
to
underes8mate
risk
in
pa8ents
with
DM
type
2
Schwartz
et
al.
JAMA
2011:
2184-‐2192
Copyright
Dr. J.P.W. van
den
Bergh
15. Leslie
et
al.
JBMR
2012:
2231-‐2237
Copyright
Dr. J.P.W. van
den
Bergh
16. DM
type
2
more
likely
to
fracture
at
given
BMD
• Cause?
– More
frequent
falls
– Diabe8c
bone
fragility
– Aspects
of
bone
strength
not
captured
by
BMD/DXA
Copyright
Dr. J.P.W. van
den
Bergh
18. Falls:
not
the
whole
story
• DM2
is
s8ll
associated
with
higher
fracture
risk
ajer
adjustment
for
fall
frequency
– WHI
Bonds
et
al.
2006
– Rolerdam
study
de
Liefde
et
al.
2005
– Health,
Ageing
Study
Strotmeyer
et
al.
2005
– SOF
Schwartz
et
al.
2001
Copyright
Dr. J.P.W. van
den
Bergh
19. Diabe8c
bone
fragility
possible
contribu8ng
factors
• Bone
turnover
• Microarchitecture
• Geometry
• Material
proper8es
• Rela8onship
with
glycemic
control
(HbA1C)
Copyright
Dr. J.P.W. van
den
Bergh
21. Bone
turnover
• Reduced
bone
forma8on
– Bone
biopsy:
lower
bone
forma8on
rate
– Compared
with
controls:
postmenopausal
women
(n=
5
vs
4)
Manavalan
et
al.
JCEM
2012:
3240
Copyright
Dr. J.P.W. van
den
Bergh
23. DMFx
had
4.7-‐fold
greater
porosity
than
DM
Patsch
et
al.
JBMR
2013:
313
Copyright
Dr. J.P.W. van
den
Bergh
24. Geometry:
(p)QCT
in
DM
type
2
• Higher
volumetric
BMD,
especially
trabecular
BMD
• Modest
reduc8on
in
cross
sec8onal
area
• Load
to
strength
ra8o
– Similar
for
hip,
spine
– Reduced
in
radius
and
8bia
– In
spite
of
higher
BMD
Melton
et
al.
2008
and
Patsch
et
al.
JBMR
2013:
313
Copyright
Dr. J.P.W. van
den
Bergh
25. Material
proper8es:
AGEs
• Advanced
Glyca8on
End
products
(AGEs)
– Formed
by
nonenzyma8c
reac8on
between
glucose
and
protein
– Accumulate
in
collagen
(and
other
structures)
– Form
cross-‐links
that
increase
s8ffness
of
collagen
and
reduce
osteoblast
func8on
Wang
et
al.
2002
and
Willet
et
al.
2013
Copyright
Dr. J.P.W. van
den
Bergh
26. Advanced
Glyca8on
End
products
(AGEs)
AGEs
form
on
different
molecules
as
collagen,
laminin
and
elas8n.
This
alters
the
physiological
proper8es
of
the
matrix
and
increases
its
s8ffness
Hegab
et
al.
World
J
Cardiol
2012;
90–102
Copyright
Dr. J.P.W. van
den
Bergh
27. Glycemic
control
and
fractures
Schneider
et
al.
Diabetes
Care
2013:1153
Copyright
Dr. J.P.W. van
den
Bergh
28. Glycemic
control
and
fractures
Schneider
et
al.
Diabetes
Care
2013:1153
Copyright
Dr. J.P.W. van
den
Bergh
29. Oei
et
al.
Diabetes
Care
2013:1619
Copyright
Dr. J.P.W. van
den
Bergh
30. Oei
et
al.
Diabetes
Care
2013:1619
Schneider
et
al.
Diabetes
Care
2013:1153
Copyright
Dr. J.P.W. van
den
Bergh
31. HSA
=
hip
structural
analysis
(on
DXA)
Oei
et
al.
Diabetes
Care
2013:1619
Copyright
Dr. J.P.W. van
den
Bergh
32. Oei
et
al.
Diabetes
Care
2013:1619
Copyright
Dr. J.P.W. van
den
Bergh
33. Possible
contributors
to
bone
fragility
in
DM
type
2
• Deficits
in:
– Geometry
– Cor8cal
microarchitecture
(porosity)
– Material
proper8es
Copyright
Dr. J.P.W. van
den
Bergh
34. Effect
of
treatment
on
hip
fracture
HbA1C
Odds
ra8o
Copyright
Dr. J.P.W. van
den
Bergh
37. Diabetes
Medica8on:
Effect
on
bone
• Meqormin
One
RCT
(meq
&
SU)
• Sulfonylureas
• Insulin
Observa8onal
• TZD
RCT
(fracture
as
AE)
• Incre8n
based
RCT
(fracture
as
SAE)
– DPP-‐4
inhibitors
– GLP-‐1
agonists
• SGLT2
inhibitors
Lack
of
data
Copyright
Dr. J.P.W. van
den
Bergh
38. ADOPT
trial:
Increased
risk
in
women
(not
men)
treated
with
rosiglitazone
Kahn
et
al.
Diabetes
Care
2008:845–851
Copyright
Dr. J.P.W. van
den
Bergh
39. TZDs
and
fractures
Meta-‐analysis
of
5
RCTs
• Women
OR
2.2
(1.6-‐3.0)
• Men
OR
1.0
(0.7-‐1.4)
• Dura8on
1-‐4
years
Loke
et
al.
2009
Copyright
Dr. J.P.W. van
den
Bergh
42. Effect
of
diabetes
treatments
on
bone
• Poten8al
(indirect)
effect
of
insulin
• TZDs
should
be
avoided
in
women
at
higher
risk
of
fracture
• Poten8al
posi8ve
effect
of
DPP4-‐inhibitors?
Copyright
Dr. J.P.W. van
den
Bergh
47. Observa8onal
studies
• Diabetes
does
not
seem
to
affect
the
fracture-‐preven8ve
poten8al
of
bisphosphonates
and
raloxifene.
• The
low-‐turnover
state
of
diabetes
thus
does
not
seem
to
be
a
hindrance
to
the
effect
of
bisphosphonates
and
raloxifene.
• Pa8ents
with
diabetes
should
receive
an8-‐osteoporo8c
treatment
in
the
same
way
as
non-‐diabe8c
pa8ents
Vestergaard
et
al.
Calcif
Tissue
Int
2011:209
Copyright
Dr. J.P.W. van
den
Bergh
48. Summary
• DM
type
1
and
2
associated
with
higher
risk
of
fracture
• At
the
same
BMD,
DM2
are
at
higher
risk
• DXA
T-‐score
and
FRAX
predict
fracture
in
DM
type
2,
but
underes8mate
the
risk
• More
frequent
falls
(hypoglycemia?)
and
poorer
bone
quality
probably
contribute
to
higher
fracture
risk
• Bone
proper8es
are
altered
in
DM
type
2
– decreased
diameter
– increased
cor8cal
thickness
and
porosity
– lower
bone
forma8on
– Effect
on
cross-‐links
of
higher
AGEs
Copyright
Dr. J.P.W. van
den
Bergh
49. Summary
• Fracture
risk
is
higher
with
increased
HbA1C
• Intensive
control
does
not
increase
fractures
– (except
one
study)
• Diabetes
medica8on
can
affect
bone
– TZD:
increased
fracture
risk
in
women
– Insulin?
• Limited
data
on
efficacy
and
safety
of
an8-‐osteoporosis
therapy
in
DM
type
2
– Alendronate:
1
BMD
study
– Raloxifene:
decrease
of
VF
incidence
Copyright
Dr. J.P.W. van
den
Bergh