Hyperlipidemia impairs osteoanabolic effects of PTH.

Epidemiological and in vitro studies have suggested that hyperlipidemia/oxidized phospholipids adversely affect bone. We recently found that oxidized phospholipids attenuate PTH-induced cAMP and immediate-early gene (IEG) expression in MC3T3-E1 cells, raising concerns that clinical hyperlipidemia may attenuate osteoanabolic effects of PTH in vivo. Thus, we studied whether intermittent PTH treatment has differential osteoanabolic effects in wildtype (C57BL/6) and hyperlipidemic (LDLR(-/-)) mice. Consistent with our previous in vitro studies, induction of IEGs in calvarial tissue, 45 min after a single dose of recombinant hPTH(1-34), was attenuated in LDLR(-/-) mice compared with C57BL/6 mice. Daily hPTH(1-34) injections for 5 wk significantly increased total and cortical BMD and BMC, assessed by pQCT, in C57BL/6 mice. However, this induction was completely abrogated in LDLR(-/-) mice. Similarly, PTH(1-34) failed to increase BMD in another hyperlipidemic mouse model, ApoE(-/-) mice. Histomorphometric analysis showed that trabecular bone of both mice responded similarly to PTH(1-34). Structural parameters improved significantly in response to PTH(1-34) in both mouse strains, although to a lesser degree in LDLR(-/-) mice. With PTH(1-34) treatment, osteoblast surface trended toward an increase in C57BL/6 mice and increased significantly in LDLR(-/-) mice. PTH(1-34) did not alter resorption parameters significantly, except for the eroded surface (ES/BS), which was reduced in the C57BL/6 but not in the LDLR(-/-) mice. These results show that PTH(1-34) has adverse effects on cortical bones of the hyperlipidemic mice, suggesting that the therapeutic effects of PTH may be compromised in the presence of hyperlipidemia.