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.