Meta-analysis: analysis:

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1 1 Diabetes and TZDs: Risk Factors for Fracture Ann Schwartz, PhD Dept. of Epidemiology and Biostatistics University of California San Francisco July 2010 Osteoporosis CME Presenter Disclosure Information ANN V. SCHWARTZ Research support: Amgen, GlaxoSmithKline, Merck Consultant: GlaxoSmithKline, Merck Type 1 Diabetes Modest reduction in BMD Higher fracture risk Meta-analysis: analysis: Hip RR = 6.9 ( ) Not entirely accounted for by lower BMD RR expected from BMD = 1.4 Vestergaard 2007

2 2 Type 2 Diabetes T2 Diabetes and Hip Fracture Risk Meta-analysisanalysis Average or higher BMD Overweight Hip RR = 1.38 ( ) 1.53) Meta-analysis. analysis. Age-adjusted. Higher risk of fractures Vestergaard 2007 T2DM and Fracture Risk WHI Skeletal site RR (95% CI) Hip 1.41 (1.17, 1.70) Proximal humerus 1.30 (1.07, 1.56) Foot 1.44 (1.21, 1.71) Ankle 1.34 (1.16, 1.55) Clinical spine 1.28 (1.04, 1.56) Forearm 0.98 (0.84, 1.15) Bonds, et al. 2006

3 3 Risk Factors for Fracture in T2DM Lower BMD More frequent falls Reduced balance, gait, strength Stroke Reduced peripheral sensation (monofilament) Insulin therapy TZDs BMD (g/cm 2 ) Higher BMD in T2DM Older Women 0.3 Insulin Tx Femoral Neck Non-Insulin Tx Calcanea Non-Diabetic Adjusted for age, BMI l Distal Radius All p <0.01 for Non-ins tx vs. not DM. All NS for Insulin tx vs. non-insulin-tx. Schwartz et al T2DM, T-score and Hip Fracture Risk Women 75 y.o. T2DM, FRAX Score & Hip Fracture Risk Women T-score gap of 0.5 in DM women FRAX underestimates risk in DM Study of Osteoporotic Fractures Schwartz et al. ADA 2009 Study of Osteoporotic Fractures

4 4 Fracture Prediction in T2DM Lower BMD predicts fractures, but at higher threshold for similar fracture risk FRAX predicts fractures, but current algorithm under- estimates risk in T2DM Effect of Alendronate on BMD in Diabetic Women Fracture Intervention Trial Raloxifene and Vertebral Fracture MORE Trial Change in BMD (%) Total Hip PBO Month Keegan et al ALN Change in BMD (%) Lumbar Spine Month Nondiabetic ALN Diabetic ALN Nondiabetic placebo Diabetic placebo ALN PBO (p for interaction = 0.04) 0.13 (0.03, 0.55) Diabetes No diabetes Overall, 60 mg/day Overall, 120 mg/day 0.59 (0.49, 0.71) 0.70 (0.50, 0.80) 0.50 (0.40, 0.70) Johnell et al RR (95% CI)

5 5 Risk of More Frequent Falls Health, Aging and Body Composition Study OR* (95% CI) Nml 1.00 Reference Impaired glucose 0.95 (0.82, 1.11) metabolism T2DM 1.42 (1.20, 1.68) Falls: 0, 1, 2-3, 4-5, 6+ in past year * Adjusted for age, race, gender Risk Factors for Falls in T2DM Older adults - Health ABC Peripheral neuropathy Impaired renal function Poorer vision Reduced balance, gait, strength Low A1C with insulin use Fall Risk: A1C and Insulin Use Schwartz et al. 2008

6 6 Summary: Fall Prevention Important for Older T2DM Patients Fracture Prevention: T1 and T2 DM Increased risk of falls Standard fall prevention measures Reducing complications through glycemic control likely to prevent falls Intensive control safe with oral meds, but caution with insulin use and low A1C Include when assessing overall risk for fracture Fall prevention Lifestyle modifications Diet Exercise Limited evidence that bisphosphonates and raloxifene effective in T2. No data for T1. TZDs 3 TZDs prescribed: Troglitazone Rezulin Rosiglitazone [RSG] Avandia Pioglitazone [PIO] Actos GSK Parke-Davis Takeda and Lilly

7 7 TZDS and Bone Loss: Summary More rapid bone loss: Rodent evidence Small clinical trials in women Mechanisms: Reduced bone formation and increased resorption Observational studies in men with conflicting results RSG: Increased fracture risk in women compared with metformin or glyburide Incidence per 100 person yrs: RSG 2.74 Met 1.54 Gly 1.29 Increase in peripheral, not hip or spine, fx Kahn et al ADOPT No Increased Fracture Risk in Men TZD and Fracture: Women Meta-analysis analysis RCTs. 111 TZD/76 ctrl fractures (AEs). Odds Ratio (95% CI) Favors treatment Favors control Dormandy et al. Kahn et al. Nissen et al. Seufert et al. (a) Seufert et al. (b) Overall Loke et al (1.65, 3.01)

8 8 TZD and Fracture: Men Meta-analysis analysis RCTs. 64 TZD/95 ctrl fractures (AEs). Dormandy et al. Kahn et al. Nissen et al. Seufert et al. (a) Seufert et al. (b) Overall Odds Ratio (95% CI) Favors treatment Favors control (0.73, 1.39) TZD Use and Fracture Risk: UK General Practice Research Database (UKGPRD) Observational study Type 2 diabetic patients (N=66,696) Cases: First low trauma fracture (N=1,020) Controls: Matched on age, sex, general practice attended, index date (N=3,728) Age: 58% > 70 y.o. at index date 68% Women 6% of cases used a TZD (PIO and RSG) Meier et al., Arch Intern Med 2008 TZDs and Fracture Risk by Skeletal Sites Increased Fracture Risk in Men All Fx Sites Hip / Femur No Rx 1-7 Rx 8-14 > > Fracture Risk: Current TZD Use of 8+ Prescriptions versus Non Use OR 95% CI Women 2.56 ( ) 4.58) Men 2.50 ( ) Too few vertebral or rib fractures to include Adjusted OR

9 9 TZDS and Fracture: Summary EVIDENCE: RCTs. AEs. Consistent findings; Plausibility TZDs and bone loss CLASS EFFECT: Both pio- and rosiglitazone. FRACTURE SITES: Appendicular sites. Probably hip. GENDER: In RCTs, increased fracture risk in women, but not men. Observational study with older ages suggests increased risk in men. Clinical Implications Assess fracture risk if considering TZD WHO/FRAX fracture risk calculator but underestimates risk in T2DM Clinical Implications In those with higher fracture risk, consider other hypoglycemic therapy. If using a TZD, consider therapy to prevent TZD-induced osteoporosis. Therapies effective for steroid-induced induced osteoporosis. However, no data on efficacy of osteoporosis therapies given with a TZD.