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Diabetes	
  Mellitus	
  and	
  Fracture	
  Risk	
  
Copyright
Dr. J.P.W. van
den
Bergh
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
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
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
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
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
Longitudinal	
  BMD	
  changes:	
  
more	
  rapid	
  bone	
  loss	
  in	
  DM	
  type	
  2	
  
Fracture	
  Interven8on	
  Trial	
  (total	
  hip)	
  
Copyright
Dr. J.P.W. van
den
Bergh
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
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
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
Fracture	
  predic8on	
  in	
  DM	
  type	
  2	
  
Schwartz	
  et	
  al.	
  JAMA	
  2011:	
  2184-­‐2192	
  
Copyright
Dr. J.P.W. van
den
Bergh
Schwartz	
  et	
  al.	
  JAMA	
  2011:	
  2184-­‐2192	
  
Copyright
Dr. J.P.W. van
den
Bergh
Schwartz	
  et	
  al.	
  JAMA	
  2011:	
  2184-­‐2192	
  
Copyright
Dr. J.P.W. van
den
Bergh
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
Leslie	
  et	
  al.	
  JBMR	
  2012:	
  2231-­‐2237	
  
Copyright
Dr. J.P.W. van
den
Bergh
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
Copyright
Dr. J.P.W. van
den
Bergh
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
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
Bone	
  turnover	
  
Copyright
Dr. J.P.W. van
den
Bergh
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
Microarchitecture:	
  HR-­‐pQCT	
  distal	
  radius	
  
Patsch	
  et	
  al.	
  JBMR	
  2013:	
  313	
  
Copyright
Dr. J.P.W. van
den
Bergh
DMFx	
  had	
  4.7-­‐fold	
  greater	
  porosity	
  than	
  DM	
  
Patsch	
  et	
  al.	
  JBMR	
  2013:	
  313	
  
Copyright
Dr. J.P.W. van
den
Bergh
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
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
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
Glycemic	
  control	
  and	
  fractures	
  
Schneider	
  et	
  al.	
  Diabetes	
  Care	
  2013:1153	
  
Copyright
Dr. J.P.W. van
den
Bergh
Glycemic	
  control	
  and	
  fractures	
  
Schneider	
  et	
  al.	
  Diabetes	
  Care	
  2013:1153	
  
Copyright
Dr. J.P.W. van
den
Bergh
Oei	
  et	
  al.	
  Diabetes	
  Care	
  2013:1619	
  
Copyright
Dr. J.P.W. van
den
Bergh
Oei	
  et	
  al.	
  Diabetes	
  Care	
  2013:1619	
  
Schneider	
  et	
  al.	
  Diabetes	
  Care	
  2013:1153	
  
Copyright
Dr. J.P.W. van
den
Bergh
HSA	
  =	
  hip	
  structural	
  analysis	
  (on	
  DXA)	
  	
  
Oei	
  et	
  al.	
  Diabetes	
  Care	
  2013:1619	
  
Copyright
Dr. J.P.W. van
den
Bergh
Oei	
  et	
  al.	
  Diabetes	
  Care	
  2013:1619	
  
Copyright
Dr. J.P.W. van
den
Bergh
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
Effect	
  of	
  treatment	
  on	
  hip	
  fracture	
  
HbA1C 	
   	
  Odds	
  ra8o	
  
Copyright
Dr. J.P.W. van
den
Bergh
Related	
  to	
  hypoglycemia	
  /	
  fall	
  incidents	
  
HbA1C 	
   	
  Odds	
  ra8o	
  
Copyright
Dr. J.P.W. van
den
Bergh
Copyright
Dr. J.P.W. van
den
Bergh
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
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
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
Insulin	
  
Copyright
Dr. J.P.W. van
den
Bergh
DPP-­‐4	
  inhibitors:	
  Meta-­‐analysis	
  (SAEs)	
  
Moname	
  et	
  al.	
  Diabetes	
  Care	
  2011:2474	
  	
  
Copyright
Dr. J.P.W. van
den
Bergh
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
Specific	
  an8-­‐osteoporosis	
  therapy	
  in	
  DM	
  type	
  2	
  
Copyright
Dr. J.P.W. van
den
Bergh
Copyright
Dr. J.P.W. van
den
Bergh
Copyright
Dr. J.P.W. van
den
Bergh
Copyright
Dr. J.P.W. van
den
Bergh
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
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
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

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Diabetes and fracture risk iwo 18-09-13

  • 1. Diabetes  Mellitus  and  Fracture  Risk   Copyright Dr. J.P.W. van den Bergh
  • 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
  • 20. Bone  turnover   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
  • 22. Microarchitecture:  HR-­‐pQCT  distal  radius   Patsch  et  al.  JBMR  2013:  313   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
  • 35. Related  to  hypoglycemia  /  fall  incidents   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
  • 41. DPP-­‐4  inhibitors:  Meta-­‐analysis  (SAEs)   Moname  et  al.  Diabetes  Care  2011:2474     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
  • 43. Specific  an8-­‐osteoporosis  therapy  in  DM  type  2   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