Bad to the Bones: Bad to the Bones: Diabetes and Thiazolidinediones - - PowerPoint PPT Presentation
Bad to the Bones: Bad to the Bones: Diabetes and Thiazolidinediones Diabetes and Thiazolidinediones 9/9/2010 9/9/2010 Steven Ing, MD, MSCE Assistant Professor Division of Endocrinology, Diabetes & Metabolism Any reduction of bone
Heath NEJM 1980
T1DM T2DM Pathology
Insulin deficiency Insulin resistance/ hyperinsulinemia
Age of
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
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
Fracture Site T1DM T2DM Hip 6.94* (3.25‐14.78) 1.38* (1.25‐1.53) Wrist ‐‐‐ 1.19* (1.01‐1.41) Spine ‐‐‐ 0.93 (0.63‐1.37) Any Fracture ‐‐‐ 1.19* (1.11‐127) Spine Z‐score ‐0.22* ± 0.01 0.41* ± 0.01 Hip Z‐score ‐0.37* ± 0.16 0.27* ±0.01
Vestergaard, Osteoporos Int 2007;18:427
RR (95% CI) in Multivariate without BMD RR (95% CI) in Multivariate 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
2006: No published data of BMD in clinical trials of ROSI and PIO Prospective cohort community dwelling, 3075 men and women, 70‐79 yrs 69 TZD users among 666 diabetics
Schwartz, JCEM 2006; 91;3349 Annualized % Change in BMD per Year of TZD Use in Women % Change 95% CI P value Whole body ‐0.67 ‐1.03, ‐0.30 < 0.001 Lumbar spine ‐1.14 ‐1.90, ‐0.37 0.004 Total hip ‐0.38 ‐0.93, 0.17 0.178 Femoral neck ‐0.26 ‐0.86, 0.34 0.391 Trochanter ‐0.50 ‐1.02, 0.003 0.063
December, 2006
Kahn, SE, et al.NEJM 2006;355(23):2427-43
Based on 4360 subjects in ADOPT (1840
Fracture incidence in ROSI‐treated = 2.74 per
Fracture incidence in MET‐treated = 1.54 per
Fracture incidence in GLY‐treated = 1.29 per 100
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
Kahn, Diabetes Care 2008;31(5)845
# subjects with fracture Incidence HR ROSI 32 (4.0%) 1.16/100 pt‐yr 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
# subjects with fracture Cumulative Incidence @ 5 yr HR (95% CI) ROSI 60 (9.3%) 15.1% (11.2‐19.1) metformin 30 (5.1%) 7.3% (4.4‐10.1) 1.81 (1.17‐2.80) p= 0.008 glyburide 21 (3.5%) 7.7% (3.7‐11.7) 2.13 (1.30‐3.51) p=0.0029
Among 1840 women, ROSI doubled fracture risk
Kahn, Diabetes Care 2008;31(5)845 Increased fracture risk after 1st yr No placebo arm Fracture not a specified endpoint (only Adverse Event reporting) No spinal x-rays
14 week RCT in 50 postmenopausal women without DM
Grey, JCEM 2006;92(4):1305
16 week RCT in 30 premenopausal women with PCOS
Glintborg JCEM 2008; 93(5):1696
PIO Pre PIO Post CON Pre CON Post ALP U/L 186 (110‐315) 173 (104‐288) 174 (109‐280) 186 (113‐186)
Mesenchyma l Stem Cell Preadipocyt e Preosteobla st Adipocyt e Osteoblas t
Runx2 OSX PPAR‐γ C/EBP
Osteoclast Preosteoclas t
RANKL OPG
Hematopoieti c Stem Cell
TZD
Mechanism: PPAR-γ Alter Lineage Allocation of Precursors
Women Men ROSI MET GLY ROSI MET GLY
CTX 6.1 (3.7, 8.7) ‐1.3* (3.8, 1.2) ‐3.3* (‐6.0, ‐0.6) ‐1.0 (‐3.0, 1.0) ‐12.7* (‐14.4, ‐10.9) ‐4.3 (‐6.0, ‐2.5) P1NP ‐4.4 (‐6.2, ‐2.6) ‐14.4* (‐16.4, ‐12.4) ‐5.0 (‐7.1, ‐2.8) ‐14.4 (‐15.9, ‐13.0) ‐19.3* (‐20.7, ‐18.0) 0.2* (‐1.7, 2.1) BSAP ‐12.6 (‐15.3, ‐9.9) ‐15.7 (‐17.8, ‐13.6) ‐11.6 (‐14.7, ‐8.3) ‐13.6 (‐15.8, ‐11.3) ‐16.4 (‐18.9, ‐13.8) ‐6.8 (‐9.4, ‐4.0) Zinman, JCEM 2010;95(1):134
Both:
OR 1.45 (1.18‐1.79, p <0.001)
Women: OR 2.23 (1.65‐3.01, p < 0.001) Men:
OR 1.00 (0.73‐1.39, p = 0.98)
Loke, CMAJ 2009;180(1):32
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 (0.31‐6.30) 4.54 (1.28‐16.10) Humerus 0.28 (0.04‐1.92) 2.12 (0.62‐7.26) Wrist/forearm 0.74 (0.23‐2.35) 2.90 (1.19‐7.10)
Meier, Arch Intern Med 2008;168(8):820
For men: OR 2.50 (0.84‐7.41) For women: OR 2.56 (1.43‐4.58) For < 70 years: OR 2.96 (1.40‐6.25) For ≥ 70 years: OR 2.57 (1.22‐5.4) For PIO: OR 2.59 (0.96‐7.01) For ROSI: 2.38 (1.39‐4.09)
Meier, Arch Intern Med 2008;168(8):820
Dormuth, Arch Intern Med 2009;169(15):1395
Yaturi, Diabetes Care 2007;30(6):1574
Annualized % Change at No ROSI N=128 ROSI N=32 P Lumbar Spine 2.3 ± 2.9 0.69 ± 2.4 0.03 Total Hip ‐0.137 ± 1.9 ‐1.19 ± 1.8 0.006 Femoral Neck ‐0.20 ± 1.25 ‐1.22 ± 1.3 0.0001
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
4.3 8‐9% 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