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Sevelamer Restores Bone Volume and Improves Bone Microarchitecture and Strength in Aged Ovariectomized Rats

Genzyme Corporation (T.K. S., S.M., N.B., A.B.), Framingham, Massachusetts 01701; and Laboratory for Mineralized Tissues (P.S., N.D., V.K., A.T., S.V.), Medical School, University of Zagreb, Faculty of Mechanical Engineering and Naval Architecture (D.S.), and Faculty of Food Technology and Biotechnology (M.B.), HR-10000 Zagreb, Croatia

Address all correspondence and requests for reprints to: T. Kuber Sampath, Ph.D., Genzyme Corporation, One Mountain Road, Framingham, Massachusetts 01701. E-mail: kuber.sampath{at}genzyme.com; or Slobodan Vukicevic, M.D., Ph.D., Department of Anatomy, School of Medicine, University of Zagreb, Trg marala Tita 14, HR-10000 Zagreb, Croatia. E-mail: vukicev{at}mef.hr.

Sevelamer hydrochloride, a noncalcium phosphate binder, has been shown to reduce coronary artery and aortic calcification, and to improve trabecular bone mineral density in hemodialysis patients with chronic kidney disease. Here, we examined whether sevelamer given orally for 12 wk with normal food could restore bone volume (BV) and strength in aged ovariectomized (OVX) rats starting at 4 wk after OVX. Dual-energy x-ray absorptiometry, microcomputerized tomography, and bone histomorphometry analyses showed that OVX animals receiving sevelamer had increased trabecular BV (51%), trabecular number (43%), trabecular thickness (9%), cortical thickness (16%), mineral apposition rate (103%), bone formation rate (25%), and enhanced cortical and trabecular bone mechanical strength as compared with OVX rats. Sevelamer decreased collagen C telopeptide, increased osteocalcin levels, and decreased phosphate and magnesium levels without affecting calcium levels in the blood. Although sevelamer was not absorbed systemically, it stimulated osteoblast differentiation in BM-derived mesenchymal stem cell cultures, as evaluated by alkaline phosphatase positive colony-forming units, and inhibited recombinant human soluble receptor activator of nuclear factor-B ligand-induced osteoclast differentiation, as evaluated by tartrate-resistant acid phosphatase positive cells in bone mineral-hematopoietic stem cell cultures. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry analysis revealed that 69 proteins were differently expressed after OVX, of which 30% (20 of 69) were reversed to sham activity after sevelamer intake. PTH, fibroblast growth factor-23, and cytokine profile in serum were not significantly changed. Together, these results suggest that sevelamer in food increases the BV and improves biomechanical properties of bone in OVX rats.