Diabetes and fracture risk iwo 18-09-13
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Diabetes Mellitus and Fracture Risk Copyright Dr. J.P.W. van den Bergh
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Tenslotte zal Prof. Dr. Joop van den Bergh het fractuurrisico bij patiënten met DM type 1 en 2 bespreken: hoe relevant is het verhoogde fractuurrisico bij jonge patiënten met DM type 1? Zijn adipeuze patiënten met DM type 2 beschermd tegen osteoporose? Welke determinanten spelen een rol bij het fractuurrisico bij DM type 2?
Transcript of Diabetes and fracture risk iwo 18-09-13
Diabetes Mellitus and Fracture Risk
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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)
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0 10 20 30 40 50 60 70 80 90 mannen vrouwen
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leeftijd (jaren)
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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
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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
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Associa8on between bone mineral density and type 2 diabetes mellitus
Ma et al. Eur J Epidemiol (2012) 27:319–332
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Meta-‐regression
• Posi8ve associa8on with higher BMD levels in diabe8cs – younger age – male gender – higher body mass index
– higher HbA1C
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Dr. J.P.W. van den Bergh
Longitudinal BMD changes: more rapid bone loss in DM type 2
Fracture Interven8on Trial (total hip)
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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
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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
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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
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Fracture predic8on in DM type 2
Schwartz et al. JAMA 2011: 2184-‐2192
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Schwartz et al. JAMA 2011: 2184-‐2192
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Schwartz et al. JAMA 2011: 2184-‐2192
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The FRAX score tends to underes8mate risk in pa8ents with DM type 2
Schwartz et al. JAMA 2011: 2184-‐2192
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Leslie et al. JBMR 2012: 2231-‐2237
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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
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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
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Diabe8c bone fragility possible contribu8ng factors
• Bone turnover • Microarchitecture • Geometry
• Material proper8es • Rela8onship with glycemic control (HbA1C)
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Bone turnover
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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
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Microarchitecture: HR-‐pQCT distal radius
Patsch et al. JBMR 2013: 313
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DMFx had 4.7-‐fold greater porosity than DM
Patsch et al. JBMR 2013: 313
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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
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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
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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
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Glycemic control and fractures
Schneider et al. Diabetes Care 2013:1153
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Glycemic control and fractures
Schneider et al. Diabetes Care 2013:1153
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Oei et al. Diabetes Care 2013:1619
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Oei et al. Diabetes Care 2013:1619
Schneider et al. Diabetes Care 2013:1153
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HSA = hip structural analysis (on DXA)
Oei et al. Diabetes Care 2013:1619
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Oei et al. Diabetes Care 2013:1619
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Possible contributors to bone fragility in DM type 2
• Deficits in:
– Geometry
– Cor8cal microarchitecture (porosity) – Material proper8es
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Effect of treatment on hip fracture
HbA1C Odds ra8o
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Related to hypoglycemia / fall incidents
HbA1C Odds ra8o
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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
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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
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Insulin
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DPP-‐4 inhibitors: Meta-‐analysis (SAEs)
Moname et al. Diabetes Care 2011:2474
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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?
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Specific an8-‐osteoporosis therapy in DM type 2
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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
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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
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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 Copyrig
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