Evidence of skeletal effects with TZD use

Potential effects on fracture risk should be considered when prescribing thiazolidinediones.

Issue: November 2008

ByJames R. Taylor, PharmD, CDE

The thiazolidinediones, pioglitazone and rosiglitazone, are two commonly prescribed drugs for the treatment of type 2 diabetes and account for 21% of the oral antidiabetic drugs used in the Unites States.

Most patients tolerate them well, with weight gain and edema being the most common adverse effects. However, there is mounting evidence that these agents may impose undesirable effects on bone.

Researchers of the ADOPT trial reported that more women who received rosiglitazone experienced fractures as compared with women administered other antidiabetic drugs. This was not a component of the planned analysis of this study, but increased the concern for this potential unwanted effect. The proportion of women who received rosiglitazone and reported a fracture was 9.3% as compared with 5.1% for metformin use and 3.5% for glyburide use. The resulting RR for fracture was 2.18 (95% CI, 1.52-3.13) for rosiglitazone as compared with the other agents combined. Fracture rates in men were not different among the various treatments.

Studies in review

James R. Taylor

Schwartz et al performed post hoc analysis from a large observational study to assess the effects of TZDs on bone mineral density. The population consisted of 666 patients with type 2 diabetes aged 70 to 79 years. Sixty-nine (10.4%) patients were administered a TZD. The women who received a TZD had a 0.67% decrease in whole body, 1.14% decrease in lumbar spine and 0.65% decrease in hip trochanter BMD per year of use. All of these results were statistically significant. The BMD changes for women not receiving a TZD were –0.41% at the whole body, 1.11% at the spine and –0.35% at the hip. TZD use was associated with a 2.5-fold increase in bone loss for women.

Grey et al studied the effects of rosiglitazone on bone in nondiabetic, postmenopausal women. Twenty-five women received rosiglitazone 8 mg daily and 25 received placebo, all for 14 weeks. The bone formation markers osteocalcin decreased by 8%, procollagen type I N-terminal propeptide by 13% and total alkaline phosphatase decreased by 17% in patients receiving rosiglitazone. Total hip BMD decreased by 1.9% in rosiglitazone-treated patients as compared with 0.2% of those who received placebo. All results were statistically significant.

Yaturu et al retrospectively evaluated the effect of rosiglitazone on BMD in men with type 2 diabetes. The analysis included 32 patients during a four-year period who received rosiglitazone 4 mg twice daily. The control group consisted of 128 men. The BMD decreased 1.19% at the hip and 1.22% at the femoral neck in those receiving rosiglitazone, whereas controls only had decreases of 0.137% and 0.20%.

Meier et al conducted a nested case-control analysis using information from the U.K. General Practice Research Database. These researchers reviewed patients receiving a variety of antidiabetic drugs and determined the OR of having a fracture associated with use of rosiglitazone, pioglitazone, other oral antidiabetic drugs or insulin. In the study population, they identified 1,020 case patients with a fracture and 3,728 matched controls. The results indicated that the OR for those receiving a TZD for about 12 to 18 months was 2.43 as compared with nonuse. More specifically, the OR for pioglitazone was 2.59 (95% CI, 0.96-7.01) and for rosiglitazone it was 2.38 (95% CI, 1.39-4.09). ORs for fractures in those patients receiving sulfonylureas, metformin or insulin were not significantly altered.

Results from numerous studies now indicate that the TZDs may adversely affect bone, resulting in reduced osteoblastic activity and increased bone loss. This in turn may increase fracture risk by two to threefold. These effects occur in men and women and may be independent of BMI, duration of diabetes and use of other oral antidiabetic drugs. The data in men are less robust but there is some evidence. The mechanism behind this appears to be inhibition of bone formation by peroxisome proliferator activated receptor gamma mediated diversion of mesenchymal precursor cells into adipogenic lineages.

Although the above studies have their limitations, sufficient evidence exists supporting this potential decrease in bone density and increased fracture risk. These potential effects on fracture risk should be taken into consideration when prescribing a TZD for an individual. There are no specific recommendations for universal osteoporosis screening or BMD in patients being administered a TZD. Further randomized, controlled trials designed to assess this outcome are needed to clarify those who may be at greatest risk.

James R. Taylor, PharmD, CDE, is a Clinical Associate Professor in the Department of Pharmacy Practice at the University of Florida.

For more information:

Grey A, Bolland M, Gamble G, et al. The peroxisome proliferator-activated receptor-γ agonist rosig-litazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab. 2007;92:1305-1310.

Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-2443.

Meier C, Kraenzlin ME, Bodmer M, et al. Use of thiazolidinediones and fracture risk. Arch Intern Med. 2008;168:820-825.

Grey A, Bolland M, Gamble G, et al. The peroxisome proliferator-activated receptor-γ agonist rosig-litazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab. 2007;92:1305-1310.

Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-2443.

Meier C, Kraenzlin ME, Bodmer M, et al. Use of thiazolidinediones and fracture risk. Arch Intern Med. 2008;168:820-825.

Schwartz AV, Sellmeyer DE, Vittinghoff E, et al. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab. 2006;91:3349-3354.

Yaturu S, Bryant B, Jain SK. Thiazolidinediones treatment decreases bone mineral density in type 2 diabetic men. Diabetes Care. 2007;30:1574-1576.

Yki-Järvinen H. The PROactive study: some answers, many questions. Lancet. 2005;366:1241-1242.