J Clin Endocrinol Metab, Sep 2006, 91(9):

Introductions Thiazolidinediones (TZDS) - Effective treatment for diabetes and frequently prescribed - Potential prevention treatment at high risk of diabetes - Effect of TZDs on bone mass is unclear ; Bone loss with rosiglitazone in mouse models

Thiazolidinediones (TZDs) - Little information on effects of TZDs on bone in humans ; In a small study of troglitazone use  Reduction in markers of bone turnover (7-18%) - Not aware of published reports on the effects of pioglitazone or rosiglitazone on BMD or bone markers

Thiazolidinediones (TZDs) 1) Increase insulin sensitivity through PPAR – r 2) Increase in bone marrow adiposity Decrease in osteoblastogenesis  Resulting in reduced bone formation 3) Decrease estrogen production by aromatase pathway  Possibly increase in bone resorption

The aim of this study - 4 yrs follow-up data from the Health, Aging and Body Composition (Health ABC) cohort study Thiazolidinediones Changes in BMD In older adults with Diabetes

Subjects and Methods Health ABC participants - Changes in body composition ; As common pathway by which multiple disease contribute to disability men and women, aged yr

Subjects and Methods Diabetes - Interview about presence of diabetes at annual follow up visits - Ask about hypoglycemic medication during the study - OGTT was performed at baseline participants had diabetes at baseline or during follow-up

Subjects and Methods Bone density measurements - Measurement at the proximal femur and whole body - Dual energy x-ray absorptiometry (DXA; QDR 4500A) - Obtained every 2 yr at baseline, yr 2, and yr participants had at least two BMD measurements  Included in these analysis Covariates - Weight change during follow-up period - Use of osteoporosis drugs, oral steroids, calcium supplements, thiazide diuretics, and oral estrogen

Subjects and Methods Laboratory measurements - Measurement of plasma glucose at baseline, yr 1, and yr 3 - OGTT - Hemglobin A1c at baseline, yr 3, and yr 5 - Glomerular filtration rate Statistical analysis - The association of repeated measures of change in BMD with duration of use of TZDs

Results

* Use of Insulin 28 % Use of sulfonylurea 72 % Use of metformin 41 %

Change in BMD among those using TZDs for at least 2 consecutive years 15 participants with use of TZD at both yr 2 and yr 4 visits Average annual bone loss ( yr 2 – 4 ) Total hip % Lumbar spine % Whole body %

Discussion This study suggest - TZD use is associated with additional bone loss in women among older adults with diabetes ; % per year for whole body with a year of TZD use 3 % average bone loss over 5 yr for women using TZDs - Average whole body bone loss among diabetic women without TZD use in health ABC cohort ; % per year

Limitation - Not designed to distinguish possible mechanisms by which TZDs may impact bone metabolism - From rodent models ; TZDs  Increase in bone marrow adiposity Decrease in osteoblastogenesis  Inhibit aromatase pathway Decrease testosterone levels in women with PCS

DXA measurement - Increases in body weight, common side effect of TZD ; Artifactual increases in BMD - Increase in tissue thickness, resulting from weight gain ; Artifactual increase in DXA measurements  Underestimation the actual bone loss Potential confounders - Adjusted for higher A1C levels, longer duration of DM, and use of other hypoglycemic medications ; Vulnerable to bias from unmeasured confounders

Conclusions TZD use is associated with bone loss at the whole body, lumbar spine and trochanter in older womn with type 2 diabetes. - Older women with type 2 diabetes are at increased risk of fracture. - Further study of the impact of TZDs on bone density and fracture risk is needed.