Kidney Week

Abstract: FR-PO518

Multiple Lower Doses of Zoledronate Reduces Skeletal Accumulation in the Setting of CKD

Session Information

• Bone and Mineral Metabolism: Basic
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 401 Bone and Mineral Metabolism: Basic

Authors

• Swallow, Elizabeth A., Indiana University, Indianapolis, Indiana, United States

Elizabeth A. Swallow,

• Aref, Mohammad Walid, IU School of Medicine, Indianapolis, Indiana, United States

Mohammad Walid Aref,

• Sacks, Spencer, Marian University, Indianapolis, Indiana, United States

Spencer Sacks,

• Lehmkuhler, Demi R., Indiana University, Indianapolis, Indiana, United States

Demi R. Lehmkuhler,

• Chen, Neal X., Indiana University School of Medicine, Indianapolis, Indiana, United States

Neal X. Chen,

• Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States

Sharon M. Moe,

• Allen, Matthew R., Indiana University School of Medicine, Indianapolis, Indiana, United States

Matthew R. Allen,

Background

Chronic Kidney Disease (CKD) results in a dramatic increase in skeletal fracture risk. Bisphosphates (BP) are an effective and common treatment for reducing fracture risk but they are not recommended in advanced CKD. We have recently shown higher skeletal accumulation of zoledronate (ZOL) in the setting of CKD. This study aimed to test the hypothesis that more frequent, lower dose administration of ZOL would alter skeletal accumulation profiles in CKD.

Methods

At 25 weeks of age, normal (NL) and CKD (Cy/+) rats were divided into control groups (no dosing), a single dose of a fluorescent-tagged ZOL (FAM-ZOL), or ten weekly doses of FAM-ZOL each at 1/10^th the dose of the single dose group. A subset of CKD animals were provided 3% calcium (Ca) in drinking water to lower PTH and bone remodelling. At 35 weeks of age, serum, tibia, ulna, radius, vertebra, femora, and mandible were collected. Bulk fluorescence levels were assessed using Spectral CT and data compared using 2-way ANOVA.

Results

At 35 weeks of age, all CKD groups had significantly higher blood urea nitrogen (BUN) compared to NL. Parathyroid hormone (PTH) levels were 10-fold greater in CKD animals compared to NL; Ca supplementation normalized PTH levels to those of NL. At all skeletal sites assessed CKD and CKD+Ca animals had higher FAM-ZOL levels compared to NL (+89 to +167%). The vertebra, radius, and ulna all showed significant dosing effects with the multiple dosed animals accumulating 20-32% less FAM-ZOL than those given a single dose. At the distal femur, there was a significant interaction between factors, with CKD+Ca animals having a 40% reduction in FAM-ZOL retention with multiple FAM-ZOL doses versus a single dose.

Conclusion

More frequent, lower dose administration result in significantly less zoledronic acid accumulation compared to a single dose at multiple skeletal sites.

Funding

• Veterans Affairs Support