Abstract: SA-PO897

Bisphosphonate Skeletal Accumulation Is Increased in Early and Mid-Stage CKD

Session Information

  • Mineral Disease: CKD-Bone
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Mineral Disease

  • 1203 Mineral Disease: CKD-Bone

Authors

  • Aref, Mohammad Walid, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Swallow, Elizabeth A, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Chen, Neal X., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Allen, Matthew R., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Bisphosphonates represent the gold standard pharmacological treatment for skeletal disease. Despite limited data, this class of drugs is contraindicated in patients with chronic kidney disease (CKD) due to concerns of compromised excretion and thus increased skeletal accumulation. The goal of this study was to use an animal model of progressive chronic kidney disease (Cy/+ rat) to study bisphosphonate distribution in the setting of reduced kidney function.

Methods

At 25 weeks of age, CKD and normal (NL) animals were administered a single bolus of fluorescently labelled zoledronic acid (Fam-ZOL). Animals were euthanized either 24 hours or 5 weeks later (30 weeks of age) and radius/ulna, distal femur, tibia, and 3rd lumbar vertebra (L3) were collected. Bulk levels of FAM-ZOL accumulation were estimated using whole bone fluorescence imaging (NightOwl LB981). Skeletal perfusion, to estimate blood flow and thus FAM-ZOL delivery, was measured prior to euthanasia via intra-cardiac injection of fluorescent microspheres.

Results

CKD animals had blood urea nitrogen (BUN) levels 2x higher than NL. At 24-hours post-dose, total bone fluorescence was higher in CKD radius (+134%, p<0.05), distal femur (+105%, NS), L3 body (+26%, NS) and tibia (+51%, p<0.05) compared to NL. Five-weeks post-dose, levels of drug in bone were significantly higher in all four bone sites of CKD animals relative to NL. Levels of drug in the bone at 5 weeks were indistinguishable from levels at 24-hrs post dose in both treatment groups. Skeletal perfusion was non-significantly higher in CKD relative to NL at 25 weeks of age. By 30 weeks (~20% NL GFR), perfusion was higher in CKD humeri (+155%, p<0.05), distal femur (+138%, NS) and L4 body (+142%, NS) compared to NL.

Conclusion

Based on these data we conclude that animals with reduced kidney function have altered dynamics of zoledronate accumulation in the skeleton, but such accumulation might be driven by factors other than compromised kidney excretion and may be due to altered blood flow.

Funding

  • NIDDK Support