The Utility of Circulating Markers to Predict Bone Loss across the CKD Spectrum

Abstract

Patients with CKD are at increased risk of bone loss and fractures. Prospective observational studies have shown that the severity of kidney disease is directly associated with the amount of bone loss (1-4). In CKD, fractures are 2-to 14-fold more common than in the general population (5,6). The frequency of fractures increases as renal disease worsens (7,8), and the incidence of fractures has increased over the past 20 years (9,10). Compared with those without fractures, patients with CKD with fractures experience a 16% (9) to 270% (11) increased risk of mortality. The increasing numbers of fractures together with the high mortality rates have focused attention on methods to improve the diagnosis, risk stratification, and treatment of renal osteodystrophy in order to prevent fractures. The tetracycline double-labeled transiliac crest bone biopsy with histomorphometry is the gold standard for diagnosing and classifying renal osteodystrophy and these biopsy results form the basis on which treatment decisions are made. However, bone biopsy is not practical in all patients all of the time. Bone biopsy is invasive, expensive, and not widely available, and physicians performing this procedure require specialized training (12)(13)(14). The pragmatic limitations of biopsy have fueled interest in the use of noninvasive imaging and biochemical methods to assess the type of renal osteodystrophy, classify risk of bone loss and fractures, and inform therapeutic decisions. Although the utility of noninvasive methods to improve patient-related outcomes remains to be proven in clinical trials, they have elucidated both mechanisms of bone fragility and potential targets for fracture prevention strategies in CKD populations.Traditionally, the role of dual energy x-ray absorptiometry (DXA) to classify fracture risk in CKD was controversial. This is because the pathogenesis of renal osteodystrophy is not uniform, may be the result of either single or overlapping causes (e.g., hypogonadal, glucocorticoid-induced, hyperparathyroidism, low or high turnover bone disease, poorly mineralized osteoid, mixed), and is fluid (e.g., may change from low to high turnover and vice versa). In addition, the type of renal osteodystrophy does not correlate with low, high, or normal bone mineral density (BMD). Furthermore, elevated parathyroid hormone (PTH) levels, which are common in CKD, may be anabolic for trabecular bone and catabolic for cortical bone. Given the inability of DXA to separate these components, DXA may be limited in its use as a marker of bone strength. However, despite these limitations of DXA, recent prospective trials in patients with predialysis CKD (15), ESRD on hemodialysis (16), and after kidney transplantation (17) indicate that low areal BMD measured by DXA at the forearm and hip predicts future fracture. These new data will influence the updated recommendations on the screening and management of bone disease from the Kidney Disease Improving Global Outcomes Guidelines Committee.Measurement of PTH and bone turnover marker...

Impact of serum magnesium and bone mineral density on systemic fractures in chronic hemodialysis patients

“…The usefulness of DXA to classify fracture risk in CKD patients has been controversial because the pathogenesis of renal osteodystrophy is not uniform and may be the result of multiple causes, and BMD measured by DXA does not provide information about the type of renal osteodystrophy [ 22 ]. Some past studies with small sample sizes showed that BMD measured by DXA could not be used to identify the fracture risk in hemodialysis patients [ 23 , 24 ].…”

Rethinking Bone Disease in Kidney Disease

“…However, progressive CKD is generally associated with increased levels of PTH, fibroblast growth factor 23 (FGF‐23), osteoprotegerin, sclerostin, and Dickkopf‐related protein 1 (DKK1) and reductions in α‐Klotho, serum 25‐hydroxyvitamin D [25(OH)D], and [1,25(OH) 2 D] . The expression of bone turnover such as bone‐specific alkaline phosphatase (BSAP), procollagen type 1 N‐terminal (P1NP), C‐terminal telopeptide of type 1 collagen (CTX), and tartrate‐resistant acid phosphatase (TRAP‐5b) is more variable and dependent not only on the degree of renal impairment but also bone turnover . Together, these changes impact bone formation, resorption, and mineralization through their effects on osteoblast and osteocyte function.…”

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease

“…Several other recent papers have shown that low BMD actually predicts fracture in dialysis and renal transplant patients 90, 91. The use of micro‐computerized tomography might also be a useful tool for the estimation of bone loss and micro‐architectural changes; however, they need further evaluation in CKD 92. Overall, although there have been uncertainties concerning the utility of BMD in CKD,93 BMD measure may become useful in this population.…”

“…90,91 The use of micro-computerized tomography might also be a useful tool for the estimation of bone loss and micro-architectural changes; however, they need further evaluation in CKD. 92 Overall, although there have been uncertainties concerning the utility of BMD in CKD, 93 BMD measure may become useful in this population. This issue is currently under review, 94 and it is likely that BMD testing could be suggested in CKD patients with evidence of CKD-MBD and/or risk factors for osteoporosis, if results may affect treatment decisions.…”