Multifaceted skeletal effects of sevelamer carbonate in a secondary hyperparathyroidism model

Hyperphosphatemia leads to abnormal mineralization of bones and soft tissues in patients with chronic kidney disease-induced secondary hyperparathyroidism (CKD-SHPT). Sevelamer lowers phosphate levels by binding to dietary phosphate in the gastrointestinal system, forming new bone and reducing the risk of renal osteodystrophy and fracture. However, the influence of sevelamer carbonate (SevC) on bone microarchitecture, material qualities, and mechanical behavior is unknown in CKD-SHPT conditions.

We utilized a rat model of CKD-induced hyperphosphatemia by feeding a 1.8% high-phosphate diet to 5/6 nephrectomized rats to test the effects of SevC on skeletal quality and strength, employing microCT, Fourier transform infrared spectroscopy (FTIR), 3-point bending, nanoindentation, and compression tests.

SevC preserved mineral homeostasis and reduced PTH, and FGF-23 levels in CKD-SHPT rats. SevC mitigated the serum renal parameters, pyrophosphate levels, and indole acetic acid. In CKD-SHPT rats, SevC reduced hyperphosphatemia, improved the mineralization defect, and upregulated mineralization-promoting genes like ankyrin-1, ectonucleotide-pyrophosphatase/phosphodiesterase-1, tissue non-specific alkaline phosphatase, phosphate-regulating endopeptidase X-linked, dentin matrix protein-1, and matrix extracellular phosphoglycoprotein. In the cortical bones of CKD-SHPT rats, SevC increased cortical mass and thickness, decreased porosity by likely decreasing cortical bone remodeling induced by high PTH, and increased osteocyte preservation. SevC mitigated all of the alterations in the mineral and matrix composition of CKD-SHPT rats, including decreased collagen-maturity, mineral-to-matrix ratio, and increased carbonate substitution of hydroxyapatite crystals. SevC enhanced bone strength and mechanical behavior in CKD-SHPT rats at a macro (three-point bending) and nano (nanoindentation) scales.

These findings in CKD-SHPT rats suggest that SevC improves bone mechanical properties at various levels by decreasing serum pyrophosphate, empty lacunae, and enhancing renal clearance of indole acetic acid, organized mineral-matrix deposition, and osteocyte number by suppressing cortical remodeling.