Date Published: September 22, 2016
Publisher: Public Library of Science
Author(s): Jarkko Jokihaara, Ilkka H. Pörsti, Harri Sievänen, Peeter Kööbi, Pekka Kannus, Onni Niemelä, Russell T. Turner, Urszula T. Iwaniec, Teppo L. N. Järvinen, Leighton R James.
Phosphate binding with sevelamer can ameliorate detrimental histomorphometric changes of bone in chronic renal insufficiency (CRI). Here we explored the effects of sevelamer-HCl treatment on bone strength and structure in experimental CRI.
Forty-eight 8-week-old rats were assigned to surgical 5/6 nephrectomy (CRI) or renal decapsulation (Sham). After 14 weeks of disease progression, the rats were allocated to untreated and sevelamer-treated (3% in chow) groups for 9 weeks. Then the animals were sacrificed, plasma samples collected, and femora excised for structural analysis (biomechanical testing, quantitative computed tomography).
Sevelamer-HCl significantly reduced blood pH, and final creatinine clearance in the CRI groups ranged 30%-50% of that in the Sham group. Final plasma phosphate increased 2.4- to 2.9-fold, and parathyroid hormone 13- to 21-fold in CRI rats, with no difference between sevelamer-treated and untreated animals. In the femoral midshaft, CRI reduced cortical bone mineral density (-3%) and breaking load (-15%) (p<0.05 for all versus Sham), while sevelamer increased bone mineral density (+2%) and prevented the deleterious changes in bone. In the femoral neck, CRI reduced bone mineral density (-11%) and breaking load (-10%), while sevelamer prevented the decrease in bone mineral density (+6%) so that breaking load did not differ from controls. In this model of stage 3–4 CRI, sevelamer-HCl treatment ameliorated the decreases in femoral midshaft and neck mineral density, and restored bone strength despite prevailing acidosis. Therefore, treatment with sevelamer can efficiently preserve mechanical competence of bone in CRI.
Efficient control of hyperphosphatemia is a cornerstone in the treatment of chronic kidney disease-mineral bone disorder (CKD-MBD) [1–5]. If dietary phosphate restriction is not sufficient, the control of hyperphosphatemia in CKD patients is often accomplished by the use of oral calcium salts as phosphate binders . However, excess calcium intake may predispose to hypercalcemia, soft-tissue calcification, and increase the risk of adynamic bone disease and bone fragility [2–4, 7]. As an alternative approach, the non-calcium containing polymer sevelamer is an effective phosphate-binder [8–13].
We explored the effects of sevelamer-HCl treatment on femoral bone strength and structure in a model of advanced CRI. To mimic the clinical situation in renal disease, the first 14 weeks comprised a progression period of renal insufficiency and hyperphosphatemia, followed by a 9-week treatment period. The study protocol was successful, since characteristic plasma chemistry of advanced CRI was observed [23–25], and increased femoral bone fragility was detected. The detrimental changes in bone were effectively ameliorated by sevelamer-HCl, although the compound induced acidosis in both uremic and control rats.