Abstract 2369: Elevated Levels of the Wnt Antagonist DKK1 and RANKL in the Bone Marrow Environment Link Chronic Heart Failure With Osteoporosis
Background: Chronic heart failure is associated with a profoundly increased risk of osteoporotic fractures. However, a pathophysiological link between chronic heart failure (CHF) and osteoporosis has not been found so far. Therefore, we investigated secreted mediators of bone remodeling directly within the bone marrow (BM) environment by measuring BM plasma levels.
Methods: BM plasma levels of the bone formation inhibiting soluble Wnt-antagonist DKK-1, the bone resorbing RANKL (receptor activator of nuclear factor kappa B ligand), and the bone forming OPG (osteoprotegerin) were measured in a total of 154 subjects: 96 patients (pts) with a documented history of CHF; 20 pts with documented coronary artery disease (CAD), but preserved systolic function and absence of diastolic heart failure; and 32 healthy control subjects and 6 post-menopausal woman. In addition, in 61 patients, we measured systemic serum levels of serum C - telopeptide of type I collagen (CTX), a sensitive circulating biochemical marker of bone turnover.
Results: Pts with CHF had significantly (p<0.001) elevated BM plasma levels of the bone resorption promoting DKK-1 and RANKL, which are not counteracted by similar increases in the bone forming OPG. The ratio of RANKL/OPG in the BM plasma was significantly increased in pts with CHF (12.98±10.89) compared to pts with CAD, but normal LV function (5.42±4.85; p<0.0001 vs. CHF) and compared to healthy control subjects (3.96±4.77; p<0.0001 vs. CHF). RANKL BM plasma levels were closely correlated with NT-pro-BNP serum levels (r=0.62; p<0.0001) as well as with reduced LV function (r=−0.32; p=0.037) and increased NYHA class (r=0.541; p=0.014), whereas DKK-1 BM plasma levels were significantly (r=0.510; p<0.0001) correlated with the duration of CHF. Finally, BM plasma levels of RANKL were closely correlated (r=0.502; p<0.0001; n=45) with systemic serum levels of CTX as an objective marker of bone resorption. Male pts with CHF had CTX serum levels comparable to post-menopausal women.
Conclusion: Within the BM environment, CHF is associated with an imbalance of the cytokines mediating bone remodeling that favors bone resorption over bone formation disclosing a plausible pathophysiological link between osteoporosis and CHF.