Original Full Length ArticleAltered material properties are responsible for bone fragility in rats with chronic kidney injury☆
Introduction
Chronic kidney disease (CKD) is associated with abnormalities in systemic mineral metabolism, which is termed CKD-related mineral and bone disease (CKD-MBD) [1]. Abnormal bone metabolism is one of the major manifestations of CKD-MBD. In fact, abnormal bone turnover and/or bone mineralization derived from abnormal systemic mineral metabolism are commonly found among CKD patients [2], [3].
CKD is also associated with an increased risk of fragility fractures. Predialysis patients with an estimated glomerular filtration rate of < 45 ml/min/1.73 m2 have twice the risk of hip fractures compared with healthy individuals [4]. Moreover, dialysis patients have a several times higher risk of hip fractures than the general population [5], [6].
Bone mass is a partial predictor of fracture [7], even among CKD patients [8], [9]. The determinants of bone strength other than bone mass are collectively referred to as bone quality. Bone quality relies on many factors including bone turnover, mineralization, microarchitecture, collagen crosslinking, and matrix composition [7].
Abnormalities in systemic mineral metabolism could alter both bone mass and bone quality in CKD patients. In particular, abnormal bone turnover and bone mineralization are predominantly caused by abnormal parathyroid and/or mineral metabolisms in this disease condition [10]. Thus, CKD-MBD may account for the increased risk of fragility fractures among CKD patients, at least in part.
However, reduced bone mass and abnormal systemic mineral metabolism, namely CKD-MBD, may not be the only cause of the increased bone fragility in CKD patients. This is because the material properties, including the chemical composition, relative amounts, and distributions of mineral and matrix, govern the mechanical properties of bone [11]. We previously reported that the mineral and matrix composition in the femoral diaphysis showed specific alterations in uremic rats without secondary hyperparathyroidism, and those material changes were tightly associated with bone mechanical deterioration [12], [13]. Moreover, such alterations in bone material composition and mechanical properties were at least partially rescued by administration of an oral adsorbent that reduced the circulating uremic toxin levels [13]. Thus, we hypothesized that the accumulation of uremic toxins is another possible candidate for the increased bone fragility.
Nevertheless, we did not intend to negate the role of CKD-MBD in the increased bone fragility in the CKD condition. Both abnormal systemic mineral metabolism and uremic toxins are possible candidates for the pathogenesis of the increased bone fragility in the uremic condition. Thus, we performed an in vivo experimental study using rats with chronic kidney injury and various degrees of parathyroid function. The aim of this study was to evaluate the roles of uremia and abnormal mineral/parathyroid metabolism in the development of bone abnormalities in the uremic condition.
Section snippets
Materials and methods
All experiments, including animal handling and testing, were approved by the Animal Care and Use Committee of the Biomedical Research Laboratories, Kureha Chemical Industry Co. Ltd., Japan.
Renal function and bone histomorphometry
Uremia determined by decreased levels of creatinine clearance was successfully created by the Nx procedure in both the LTB-Nx and HTB-Nx groups. Although the circulating PTH levels were increased in the HTB-Nx group, they stayed within comparable levels to the control LTB-Nx group (Table 1).
Cancellous bone histomorphometric analyses were conducted to confirm bone turnover using tibial samples at the end of the experiment (16 weeks). The dynamic parameters showed that bone turnover was higher in
Discussion
In this study, we examined the bone mechanical properties using DMA in two groups of uremic rats with quite different bone metabolism. Despite their different bone turnovers, both uremic groups showed reduced bone elastic mechanical properties. As shown in Table 1 and Fig. 3, the bone storage modulus and tan delta in the HTB-Nx group were attenuated along with the severity of renal injury. We could not find any evident differences in the magnitude of elastic mechanical property deterioration
Acknowledgments
We wish to thank Kiyoshi Miyashita for the technical advice on Raman spectroscopy. We also thank Mikio Sugano and Mieko Kuwahara for their technical assistance. This work was supported in part by a grant-in-aid from the Japanese Society for the Promotion of Science (no. 23591223 to YI and no. 123591215 to JJK) and from the Kidney Foundation Japan (no. JKFB10-21 to YI).
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Funding information
This work was supported in part by Grants-in-Aid from the Japanese Society for the Promotion of Science (No. 23591223 to YI and No. 123591215 to JJK) and the Kidney Foundation, Japan (No. JKFB10-21 to YI).