Abstract
ABSTRACTA main obstacle to diagnose and manage renal osteodystrophy (ROD) is the identification of intracortical bone turnover type (low, normal, high). The gold standard, tetracycline‐labeled transiliac crest bone biopsy, is impractical to obtain in most patients. The Kidney Disease Improving Global Outcomes Guidelines recommend PTH and bone‐specific alkaline phosphatase (BSAP) for the diagnosis of turnover type. However, PTH and BSAP have insufficient diagnostic accuracy to differentiate low from non‐low turnover and were validated for trabecular turnover. We hypothesized that four circulating microRNAs (miRNAs) that regulate osteoblast (miRNA‐30b, 30c, 125b) and osteoclast development (miRNA‐155) would provide superior discrimination of low from non‐low turnover than biomarkers in clinical use. In 23 patients with CKD 3‐5D, we obtained tetracycline‐labeled transiliac crest bone biopsy and measured circulating levels of intact PTH, BSAP, and miRNA‐30b, 30c, 125b, and 155. Spearman correlations assessed relationships between miRNAs and histomorphometry and PTH and BSAP. Diagnostic test characteristics for discriminating low from non‐low intracortical turnover were determined by receiver operator curve analysis; areas under the curve (AUC) were compared by χ2 test. In CKD rat models of low and high turnover ROD, we performed histomorphometry and determined the expression of bone tissue miRNAs. Circulating miRNAs moderately correlated with bone formation rate and adjusted apposition rate at the endo‐ and intracortical envelopes (ρ = 0.43 to 0.51; p < 0.05). Discrimination of low versus non‐low turnover was 0.866, 0.813, 0.813, and 0.723 for miRNA‐30b, 30c, 125b, and 155, respectively, and 0.509 and 0.589 for PTH and BSAP, respectively. For all four miRNAs combined, the AUC was 0.929, which was superior to that of PTH and BSAP alone and together (p < 0.05). In CKD rats, bone tissue levels of the four miRNAs reflected the findings in human serum. These data suggest that a panel of circulating miRNAs provide accurate noninvasive identification of bone turnover in ROD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
Renal osteodystrophy (ROD) is a progressive disease of cortical bone.[1,2,3,4,5] In ROD, cortical density, geometry, microarchitecture, and strength undergo progressive deterioration caused by the combined actions of high circulating levels of PTH and elevated bone remodeling rates.[1,2,6] In contrast, ROD is associated with trabecular hypertrophy rather than the trabecular dropout and disconnectivity that is associated with postmenopausal and glucocorticoid-induced osteoporosis.[2]. CKD patients are at increased risk of cortical-type bone fractures; since 1992 there has been a doubling of 1 of 10 n peripheral fracture incidence in patients with end-stage kidney disease on dialysis.[7,8]
Cortical bone is critical to the pathogenesis of ROD, trabecular rather than cortical remodeling rates are used to determine ROD type and to inform ROD treatment decisions.[3,9,10,11,12] the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines defined ROD by bone turnover, mineralization, and volume in trabecular bone based on quantitative histomorphometry of tetracycline double-labeled transiliac crest bone biopsy.[9] the primary goal of ROD treatment is to reduce high bone turnover with calcitriol and its analogues and/or calcimimetics, at the same time as avoiding the development of low turnover through excessive use of these same agents
Because widespread use of bone biopsy in the clinic for either diagnosis or treatment monitoring of ROD is impractical, KDIGO recommended that clinical use of agents used to treat ROD are guided by the biomarkers PTH and bone-specific alkaline phosphatase (BSAP) based on their ability to discriminate low turnover in trabecular bone.[13] large-scale multinational bone biopsy studies in dialysis patients demonstrated that PTH and BSAP were poor guides for ROD treatment because of their suboptimal discrimination for low turnover ROD.[3,10] we assume that relationships between the cortical, endocortical, and trabecular bone compartments and bone turnover, bone turnover markers (BTMs), and ROD treatments are similar, there are no comparative studies of these relationships
Summary
Renal osteodystrophy (ROD) is a progressive disease of cortical bone.[1,2,3,4,5] In ROD, cortical density, geometry, microarchitecture, and strength undergo progressive deterioration caused by the combined actions of high circulating levels of PTH and elevated bone remodeling rates.[1,2,6] In contrast, ROD is associated with trabecular hypertrophy rather than the trabecular dropout and disconnectivity that is associated with postmenopausal and glucocorticoid-induced osteoporosis.[2] CKD patients are at increased risk of cortical-type bone fractures; since 1992 there has been a doubling of 1 of 10 n peripheral fracture incidence in patients with end-stage kidney disease on dialysis.[7,8]. We hypothesized that (i) circulating miRNAs reported in previous investigations to regulate osteoblast (miRNA-30b, 30c, 125b(15,28–30)) and osteoclast (miRNA-155(31,32)) development are associated with low turnover in all bone compartments; (ii) PTH, BSAP, and circulating BTMs used in clinical practice reflect turnover within cortical and endocortical bone; and (iii) the turnover within all three bone compartments are highly correlated.
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