Bone mineral density and mortality in end-stage renal disease patients

Abstract

Osteoporosis characterized by low bone mineral density (BMD) as assessed by dual-energy X-ray absorptiometry (DXA) is common among end-stage renal disease (ESRD) patients and associates with high fracture incidence and high all-cause mortality. This is because chronic kidney disease-mineral bone disorders (CKD-MBDs) promote not only bone disease (osteoporosis and renal dystrophy) but also vascular calcification and cardiovascular disease. The disturbed bone metabolism in ESRD leads to 'loss of cortical bone' with increased cortical porosity and thinning of cortical bone rather than to loss of trabecular bone. Low BMD, especially at cortical-rich bone sites, is closely linked to CKD-MBD, vascular calcification and poor cardiovascular outcomes. These effects appear to be largely mediated by shared mechanistic pathways via the 'bone-vascular axis' through which impaired bone status associates with changes in the vascular wall. Thus, bone is more than just the scaffolding that holds the body together and protects organs from external forces but is-in addition to its physical supportive function-also an active endocrine organ that interacts with the vasculature by paracrine and endocrine factors through pathways including Wnt signalling, osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand system and the Galectin-3/receptor of advanced glycation end products axis. The insight that osteogenesis and vascular calcification share many similarities-and the knowledge that vascular calcification is a cell-mediated active rather than a passive mineralization process-suggest that low BMD and vascular calcification ('vascular ossification') to a large extent represent two sides of the same coin. Here, we briefly review changes of BMD in ESRD as observed using different DXA methods (central and whole-body DXA) at different bone sites for BMD measurements, and summarize recent knowledge regarding the relationships between 'low BMD' and 'fracture incidence, vascular calcification and increased mortality' in ESRD patients, as well as potential 'molecular mechanisms' underlying these associations.

Keywords: bone mineral density; bone–vascular axis; end-stage renal disease; mortality; osteoporosis; vascular calcification.

FIGURE 1

Low BMD as assessed by whole-body DXA at cortical-rich sites such as head and pelvis associates with increased mortality. The figure shows distribution of head BMD and restricted cubic spline curve with multivariable-adjusted sub-distribution hazard ratio (sHR) (95% CI) for all-cause mortality across values of head BMD (as continuous variable) in ESRD patients at initiation of dialysis therapy. Median value of head BMD was taken as reference. The results are adapted from a previous study [17] which concluded that cortical BMD appeared to have stronger association to survival in ESRD than trabecular BMD.

FIGURE 2

Association between tertiles of BMD head and total BMD (assessed by whole-body DXA; median and 10–90th percentiles) and Framingham’s cardiovascular risk score (adapted from a previous study [17]). Comparisons between tertiles were assessed with non-parametric ANOVA Kruskal–Wallis test followed by Dunn’s test for continuous variables. The figure illustrates that a possible reason why a cortical-rich bone site like the head appears to be suitable for analysing relations with survival in ESRD is that it associates with cardiovascular risk factors.

FIGURE 3

Associations between BMD by central DXA and histological findings by bone biopsy as reported in previous studies [40, 89].

FIGURE 4

Possible mechanisms of bone–vascular interplay in ESRD. CKD-MBDs involve activation of shared molecular signalling pathways that concomitantly may promote impaired bone status with loss of bone mass and vascular calcification.