Bad to the Bones: Diabetes and Thiazolidinediones 9/9/2010. Steven Ing, MD, MSCE Assistant Professor Division of Endocrinology, Diabetes & Metabolism

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1 Bad to the Bones: Diabetes and Thiazolidinediones 9/9/2010 Steven Ing, MD, MSCE Assistant Professor Division of Endocrinology, Diabetes & Metabolism

2 Any reduction of bone mass in diabetics that is revealed by sophisticated analysis is of no medical or economic importance Further extensive studies of bone metabolism in diabetics are unlikely to yield positive results of practical importance Heath NEJM 1980

3 Effects of DM on Bone T1DM T2DM Pathology Insulin deficiency Insulin resistance/ hyperinsulinemia Age of onset Younger age affects peak bone mass Older age after peak bone mass achieved BMI Often low Often high: loading, padding, more E2 Mechanism Hyperglycemia increases urinary calcium loss and inhibits bone formation Low bone turnover AGE Hyperglycemia increases urinary calcium loss and inhibits bone formation Low bone turnover AGE BMD May be lower May be higher

4 Potential Factors Affecting Fracture Risk in Diabetes T2DM have increased BMD Increased loading from obesity Anabolic effect of hyperinsulinemia Obesity associated with lower fracture risk Cushioning during falls Lower bone turnover Lower PTH levels Hypercalciuria Lower 25 OH Vitamin D Lower IGF 1 (anabolic for bone) AGE s Inflammation DM nephropathy Fall risk greater: retinopathy, neuropathy, foot problems, cerebrovascular disease, hypoglycemia

5 Metanalysis: Effect of DM on Fracture & BMD Fracture Site T1DM T2DM Hip 6.94* ( ) 1.38* ( ) Wrist 1.19* ( ) Spine 0.93 ( ) Any Fracture 1.19* ( ) Spine Z score 0.22* ± * ± 0.01 Hip Z score 0.37* ± * ±0.01 Vestergaard, Osteoporos Int 2007;18:427

6 Women s Health Initiative RR (95% CI) in RR (95% CI) in Multivariate Multivariate without BMD with BMD Any fracture 1.20 (1.11, 1.30) 1.24 (0.96, 1.63) Hip/pelvis/upper leg 1.46 (1.17, 1.83) 1.82 (0.90, 3.64) Lower leg/ankle/knee 1.13 (0.95, 1.34) 1.31 (0.76, 2.24) Foot 1.32 (1.07, 1.62) 1.27 (0.61, 2.64) Upper arm/shoulder/elbow 1.13 (0.90, 1.41) 0.90 (0.39, 2.07) Lower arm/wrist/hand 1.02 (0.85, 1.22) 1.27 (0.71, 2.25) Spine/tailbone 1.27 (1.00, 1.61) 1.57 (0.72, 3.44) Bonds, JCEM 2006;91(9):3404

7 Health Aging and Body Composition: TZDs associated with bone loss in women 2006: No published data of BMD in clinical trials of ROSI and PIO Prospective cohort community dwelling, 3075 men and women, yrs 69 TZD users among 666 diabetics Annualized % Change in BMD per Year of TZD Use in Women % Change 95% CI P value Whole body , 0.30 < Lumbar spine , Total hip , Femoral neck , Trochanter , Schwartz, JCEM 2006; 91;3349

8 A Diabetes Outcome Progression Trial (ADOPT) and Fractures December, 2006 Kahn, SE, et al.nejm 2006;355(23):

9 Dear Doctor February, 2007 February, 2007: GlaxoSmithKline (Avandia) reports the increased fracture risk in women in upper arm, hand, or foot Based on 4360 subjects in ADOPT (1840 women) Fracture incidence in ROSI treated = 2.74 per 100 patient years Fracture incidence in MET treated = 1.54 per 100 patient years Fracture incidence in GLY treated = 1.29 per 100 patient years

10 Dear Doctor March, 2007 Analysis of Takeda (Actos) clinical trials database N=8100 PIO treated; N=7400 comparator treated No increase in fracture risk in men In women, there was higher incidence of fracture Distal upper limb (forearm, hand, wrist) Distal lower limb (foot, ankle, fibula, tibia) Fracture incidence PIO: 1.9 fractures per 100 pt yrs CON: 1.1 fractures per 100 pt yrs

11 ADOPT Cont d Among 2511 men, fractures were not different by tx group # subjects with Incidence fracture ROSI 32 (4.0%) 1.16/100 pt yr HR metformin 29 (3.4%) 0.98/100 pt yr NS glyburide 28 (3.4%) 1.07/100 pt yr NS Kahn, Diabetes Care 2008;31(5)845

12 ADOPT Cont d Among 1840 women, ROSI doubled fracture risk # subjects with Cumulative fracture 5 yr ROSI 60 (9.3%) 15.1% ( ) HR (95% CI) metformin 30 (5.1%) 7.3% ( ) 1.81 ( ) p= glyburide 21 (3.5%) 7.7% ( ) 2.13 ( ) p= Kahn, Diabetes Care 2008;31(5)845

13 ADOPT Cont d Increased fracture risk after 1 st yr No placebo arm Fracture not a specified endpoint (only Adverse Event reporting) No spinal x-rays Kahn, Diabetes Care 2008;31(5)845

14 ROSI Decreases BMD & Bone Formation 14 week RCT in 50 postmenopausal women without DM Grey, JCEM 2006;92(4):1305

15 PIO Decreases BMD & Alkaline Phosphatase 16 week RCT in 30 premenopausal women with PCOS PIO Pre PIO Post CON Pre CON Post ALP U/L ( ) ( ) ( ) ( ) Glintborg JCEM 2008; 93(5):1696

16 Mechanism: PPAR-γ Alter Lineage Allocation of Precursors Preadipocyt e C/EBP Adipocyt e Osteoclast Mesenchyma l Stem Cell TZD PPAR γ Preosteobla st Runx2 OSX Osteoblas t RANKL OPG Preosteoclas t Hematopoieti c Stem Cell

17 Unclear Mechanism by BTMs in ADOPT Women Men ROSI MET GLY ROSI MET GLY CTX * 3.3* * 4.3 (3.7, 8.7) (3.8, 1.2) ( 6.0, 0.6) ( 3.0, 1.0) ( 14.4, 10.9) ( 6.0, 2.5) P1NP * * 0.2* ( 6.2, 2.6) ( 16.4, 12.4) ( 7.1, 2.8) ( 15.9, 13.0) ( 20.7, 18.0) ( 1.7, 2.1) BSAP ( 15.3, 9.9) ( 17.8, 13.6) ( 14.7, 8.3) ( 15.8, 11.3) ( 18.9, 13.8) ( 9.4, 4.0) Zinman, JCEM 2010;95(1):134

18 Metanalysis: TZD and Fracture 10 RCTs, N=13,715 IGT or T2DM 1 4 years of TZD exposure TZDs increased overall fracture risk Both: OR 1.45 ( , p <0.001) Women: OR 2.23 ( , p < 0.001) Men: OR 1.00 ( , p = 0.98) Loke, CMAJ 2009;180(1):32

19 Is Fracture Risk Increased Only in Appendicular Skeleton? Underlying hip fracture risk in RCT population was low UKGPRD, 1020 cases of incident fracture, 3728 matched controls among 66,696 diabetics Adjusted OR (95% CI) 1 7 Rx Adjusted OR (95% CI) 8 Rx Hip/femur 1.40 ( ) 4.54 ( ) Humerus 0.28 ( ) 2.12 ( ) Wrist/forearm 0.74 ( ) 2.90 ( ) Meier, Arch Intern Med 2008;168(8):820

20 Is Increased Fracture Risk only in Early Menopausal Women? In UKGPRD: For men: OR 2.50 ( ) For women: OR 2.56 ( ) For < 70 years: OR 2.96 ( ) For 70 years: OR 2.57 ( ) For PIO: OR 2.59 ( ) For ROSI: 2.38 ( ) Meier, Arch Intern Med 2008;168(8):820

21 Number Needed to Harm Dormuth, Arch Intern Med 2009;169(15):1395

22 Are Men Susceptible? Annualized % Change at No ROSI N=128 ROSI N=32 P Lumbar Spine 2.3 ± ± Total Hip ± ± Femoral Neck 0.20 ± ± Yaturi, Diabetes Care 2007;30(6):1574

23 Practical Tips Be aware of potential for bone loss and increased fracture risk in T2DM patients who initiate or continue TZD treatment A doubling of fracture risk by TZD for older diabetic women % Comparable to 1 SD decrease in T score DXA in postmenopausal women 60 yrs Other fracture risk factors Age Prevalent fragility fracture Family history of fragility fracture Low body weight or BMI Cigarette smoking Corticosteroids Consider pharmacologic osteoporosis therapy in those with increased risk for fracture

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