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This version published online on October 29, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-0572
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Submitted on March 16, 2009
Accepted on October 2, 2009

Effect of Rosiglitazone, Metformin, and Glyburide on Bone Biomarkers in Patients with Type 2 Diabetes

Bernard Zinman, Steven M. Haffner, William H. Herman, Rury R. Holman, John M. Lachin, Barbara G. Kravitz, Gitanjali Paul, Nigel P. Jones, R. Paul Aftring, Giancarlo Viberti, Steven E. Kahn*, and the A Diabetes Outcome Progression Trial Study Group

Samuel Lunenfeld Research Institute (B.Z.), Mount Sinai Hospital and University of Toronto, Ontario, Canada MT5 3L9; University of Texas Health Science Center at San Antonio (S.M.H.), San Antonio, Texas 78229; Departments of Internal Medicine and Epidemiology (W.H.H.), University of Michigan, Ann Arbor, Michigan 48109; Diabetes Trials Unit (R.R.H.), Oxford Centre for Diabetes, Endocrinology, and Metabolism, Oxford OX3 7LJ, United Kingdom; Biostatistics Center (J.M.L.), George Washington University, Rockville, Maryland 20852; GlaxoSmithKline (B.G.K., G.P., R.P.A.), King of Prussia, Pennsylvania 19406; GlaxoSmithKline (N.P.J.), Harlow CM19 5AW, United Kingdom; King's College London School of Medicine (G.V.), London SE5 9RS, United Kingdom; and Division of Metabolism, Endocrinology, and Nutrition (S.E.K.), Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108

* To whom correspondence should be addressed. E-mail: skahn{at}u.washington.edu.

Context: An increase in bone fractures has been observed in women taking thiazolidinediones.

Objective: The objective of the study was to examine whether changes in circulating bone biomarkers provide insight into the underlying mechanisms responsible for the increase in bone fractures in female participants randomized to rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT).

Research Design and Methods: Paired stored baseline and 12-month serum samples were available from 1605 participants (689 women, 916 men) in ADOPT, a long-term clinical trial comparing the effects of rosiglitazone, glyburide, and metformin on glycemic control in patients with type 2 diabetes.

Results: This subset was well matched to the total ADOPT study population. In women a marker of osteoclast activity, C-terminal telopeptide (for type 1 collagen), increased by 6.1% with rosiglitazone compared with reductions of 1.3% (P = 0.03 vs. rosiglitazone) and 3.3% (P = 0.002 vs. rosiglitazone) with metformin and glyburide, respectively. In men, C-terminal telopeptide was unchanged on rosiglitazone (-1.0%) and fell on metformin (-12.7%; P < 0.001) and glyburide (-4.3%, P = NS). Markers of osteoblast activity, procollagen type 1 N-propeptide (P1NP) and bone alkaline phosphatase, were reduced for women and men in almost all treatment groups, with the greatest changes in the metformin group (P1NP in females, -14.4%; P1NP in males, -19.3%), intermediate for rosiglitazone (P1NP in females, -4.4%; P1NP in males, -14.4%), and smallest for glyburide (P1NP in males, +0.2%; bone alkaline phosphatase in females, -11.6%).

Conclusions: Commonly measured bone biomarkers suggest that changes in bone resorption may be partly responsible for the increased risk of fracture in women taking thiazolidinediones.






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