Rosiglitazone administration results in significant bone loss.
Rosiglitazone improves insulin sensitivity through the activation of the nuclear receptor, peroxisome proliferator-activated receptor- (PPAR- ).
In addition to sensitizing cells to insulin, the PPAR- 2 isoform appears to be critical for the regulation of osteoblast and adipocyte differentiation from common mesenchymal bone marrow progenitors. We have demonstrated previously that PPAR- 2 activated with rosiglitazone acts as a dominant inhibitor of osteoblastogenesis in murine bone marrow in vitro.
It was shown that in vivo, rosiglitazone administration results in significant bone loss.
When rosiglitazone (20 µg/g body weight/day) was given to 6 mo old, non-diabetic C57BL/6 mice for seven weeks, a significant decrease in total body bone mineral density was observed. Analysis of bone microarchitecture, using micro-computed tomography, demonstrated a decrease in bone volume, trabecular width, trabecular number, and an increase in trabecular spacing. Histomorphometric analysis showed a decrease in bone formation rate, with a simultaneous increase in fat content in the bone marrow. Changes in bone morphology and structure were accompanied by changes in the expression of osteoblast and adipocyte-specific marker genes; the expression of the osteoblast-specific genes Runx2/Cbfa1, Dlx5, and 1(I)collagen were decreased, whereas the expression of the adipocyte-specific fatty acid binding protein aP2, was increased.
These in vivo data suggest that rosiglitazone therapy may pose a significant risk of adverse skeletal effects in humans. Endocrinology 2003, 10.1210/en.2003-0746)