Changes in chemical composition of cortical bone associated with bone fragility in rat model with chronic kidney disease

Bone fragility is a complication of chronic kidney disease (CKD). Patients on dialysis have higher risk of fracture than the general population, but the reason remains obscure. Bone strength is determined by bone mass and bone quality. Although factors affecting bone quality include microarchitecture, remodeling activity, mineral content, and collagen composition, it remains unclear which factor is critically important for bone strength in CKD. We conducted an in vivo study to elucidate the factors that reduce bone mechanical property in CKD. Rats underwent thyroparathyroidectomy and progressive partial nephrectomy (TPTx–Nx). Bone mechanical property, bone mineral density (BMD), and cortical bone chemical composition (all in femur) as well as histomorphometry (in tibia) were determined. The storage modulus, which is a mechanical factor, was reduced in CKD model rats compared with controls that underwent thyroparathyroidectomy alone (TPTx). There were no differences in BMD and histomorphometric parameters between groups. However, cortical bone chemical composition differed: mineral to matrix ratio and carbonate substitution increased whereas crystallinity decreased in TPTx–Nx. In addition, enzymatic crosslinks ratio and pentosidine to matrix ratio also increased. These changes were significant in TPTx–Nx rats with most impaired renal function. Stepwise multiple regression analysis identified mature to immature crosslink ratio and crystallinity as independent contributors to storage modulus. Deteriorated bone mechanical properties in CKD may be caused by changes in chemical composition of the cortical bone, and is independent of BMD or cancellous bone microarchitecture.

Research Highlights
► Mechanical property of cortical bone was decreased in chronic kidney disease (CKD).
► This deterioration was not associated with bone mineral density.
► Decreasing bone strength in CKD was associated with the changes of chemical composition.
► Altered material properties are likely to be major pathogenesis of fragility in CKD.