Dietary Fiber Inulin Is Additive to PTH-Lowering Therapies to Improve Bone Quantity in a Rat Model of CKD-MBD

Background: Bone fractures progressively increase as CKD worsens compared to the general population. Fracture risk is increased at extremes of both low and high PTH demonstrating renal osteodystrophy (ROD) is more than just abnormal PTH. We previously demonstrated that the dietary fiber inulin slows progression of CKD-MBD and improves bone in a rat model of CKD by reducing circulating uremic toxins such as indoxyl sulfate. We hypothesized that combined treatment of inulin and PTH lowering drugs will have an additive effect to improve bone in CKD. Methods: We treated the Cy/+ (CKD) rats with inulin (lower indoxyl sulfate) or cellulose diet beginning at 22 weeks for 10 weeks with three interventions 1) no PTH lowering treatment (high PTH), 2) calcimimetics (KP-2326 at 0.6mg/kg, i.p. 3x/week to generate pulsatile high-low PTH), or 3) 2% calcium gluconate in drinking water to continuously suppress PTH in a 2 x 3 design. CKD-MBD end points of biochemistry and bone structural parameters were assessed; p < 0.05 was significant. Results: The results showed equivalent decline of kidney function in all groups. In CKD rats, inulin (compared to cellulose diet) further lowered serum levels of PTH when combined with KP-2326 or 2% calcium. Micro-CT showed that 2% calcium treated rats had higher trabecular bone volume and this effect was greater when combined with inulin. In contrast, KP-2326 had no effect on trabecular bone volume. 2% calcium water treated groups had higher cortical bone area, but all treatments had lower cortical porosity than untreated CKD. Corresponding bone turnover markers showed a reduction of TRAP5b serum levels with both KP2326 and 2% calcium, and this was amplified in the presence of inulin vs. cellulose. Conclusion: In conclusion, the dietary fiber inulin, together with both KP2326 and 2% calcium, led to additive beneficial effects to reduce serum PTH, but only the calcium treatment with inulin improved bone quantity. This suggests that optimization of bone outcomes requires the reduction of indoxyl sulfate in addition to lowering PTH. Future biomechanical studies will determine if this combination improves bone quality, as lowering PTH alone in this model does not. Funding: NIDDK Support