Excess Accumulation of Bone Drug in Rats With Compromised Kidneys

A drug used to treat osteoporosis accumulates excessively in the bones of rats with chronic kidney disease, (CKD), according to a study presented at Kidney Week.

Bisphosphonates are currently not recommended in patients with CKD—despite the elevated risk of osteoporosis—because of potential safety concerns. The drug is cleared by the kidney, so in patients with impaired kidney function there is a concern about excess accumulation of the drug, said Mohammad Walid Aref, an MD/PhD candidate at the Indiana University-Purdue University-Indianapolis School of Medicine. But other experts point to the risk of more brittle bone rather than reduced excretion.

“The main concern about using these drugs is that they cause very low bone formation (adynamic bone), which could eventually result in more brittle bone,” said bone disease specialist Susan Ott, MD, a professor of medicine at the University of Washington in Seattle.

Limited data are available on the use of this class of drugs in CKD because patients with the condition were excluded from clinical trials (Ott S. Intl Soc Nephrol 2012; 82:833–835). Some studies, however, have documented a risk of acute kidney injury in patients without kidney disease who are taking intravenous bisphosphonates. Others have suggested a potential benefit for patients with stage 3 disease, but no clear benefit has been shown for patients with later stages of disease (Ott SM. Semin Dial 2015; 28:363–369).

To better understand the dynamics of these drugs, Aref and his colleagues administered fluorescently labeled zolendronate to 25-week-old rats with CKD or without. Blood flow to the bones was measured using an injection of fluorescent microspheres. The rats were later euthanized, some 24 hours later, others 5 weeks out from the treatment. The animals’ radius/ulna, distal femur, tibia, and 3rd lumbar vertebra were then examined using whole bone fluorescence imaging.

The animals with CKD had levels of blood urea nitrogen twice as high as the normal animals. The kidney-impaired animals also had higher levels of zolendronate in their bones at 24 hours and 5-weeks posttreatment. The authors also found nonsignificant differences in blood flow in the CKD animals compared with the normal controls. The results suggest that the accumulation of bisphosphonate may be caused by more blood flow and more bone surface, Aref said.

“It may be due to increased turnover and increased blood flow rather than a damaged kidney that can’t filter them out,” he noted.

The results add to the preclinical evidence on the dynamics of bisphosphonate in the setting of kidney disease, said Ott.

“This [finding] is consistent with the previous studies and has used a different technique which is interesting, and studied a different bisphosphonate that is known to have a stronger binding to the bone mineral,” Ott wrote.

Ott noted that there are many more questions to be answered including how kidney disease affects skeletal uptake and whether worsening kidney disease impacts blood flow or whether the zolendronate itself may affect blood flow. She also questioned whether parathyroid hormone also may play a role since zolendronic acid would be expected to increase the hormone.

Aref and his colleagues are currently studying whether lower doses or different patterns of administering zolendronate change its accumulation in rats with CKD.

The study doesn’t yet have implications for clinical care, Ott cautioned. “We still don’t have any studies that show any benefit with these drugs in late stages of CKD on fractures,” Ott said.

“Bisphosphonate Skeletal Accumulation is Increased in Early and Mid-Stage CKD” (Poster 0897)

December 2017 (Vol. 9, Number 12)