In Vitro and In Vivo Responses to High and Low Doses of Nitrogen-Containing Bisphosphonates Suggest Engagement of Different Mechanisms for Inhibition of Osteoclastic Bone Resorption

The effects of nitrogen-containing bisphosphonates (N-BPs) on osteoclasts (Ocs) may differ with dose and regimen. N-BPs reduce Oc bone resorption by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), an effect counteracted by geranylgeraniol (GGOH), which restores geranylgeranylation downst...

Full description

Saved in:
Bibliographic Details
Published in:Calcified tissue international 2013-06, Vol.92 (6), p.531-538
Main Authors: Fisher, John E., Rosenberg, Elizabeth, Santora, Arthur C., Reszka, Alfred A.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biochemistry
Biomedical and Life Sciences
Bone density
Bone Resorption - metabolism
Cattle
Cell Biology
Diphosphonates - administration & dosage
Diphosphonates - chemistry
Dose-Response Relationship, Drug
Drug dosages
Endocrinology
Inhibitor drugs
Life Sciences
Male
Nitrogen - administration & dosage
Original Research
Orthopedics
Osteoclasts - drug effects
Osteoporosis
Rabbits
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The effects of nitrogen-containing bisphosphonates (N-BPs) on osteoclasts (Ocs) may differ with dose and regimen. N-BPs reduce Oc bone resorption by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), an effect counteracted by geranylgeraniol (GGOH), which restores geranylgeranylation downstream of FPPS. We assessed GGOH effects on inhibition of bone resorption by the N-BPs alendronate (ALN), ibandronate (IBN), and zoledronate (ZOL) in an assay of rabbit Oc resorption of bovine cortical bone. GGOH blocked inhibition of resorption at low, but not high, N-BP concentrations, with a 14- to 20-fold increase in IC 50 values for each N-BP. In vivo, growing male rats were administered doses calculated to mimic bioavailable exposures in daily (ALN, IBN), weekly (ALN), monthly (IBN), and yearly (ZOL) clinical regimens. Tibiae were harvested at 48 h, and metaphyses were analyzed. With lower ALN and IBN doses, Oc numbers rose by 26–48 %, morphology was normal, and there was no increase in apoptotic Ocs. In contrast, with higher IBN and ZOL doses, bone-associated Ocs were generally rounded in appearance and numbers of nuclei/Oc versus vehicle increased 42 and 31 %, respectively ( P  
ISSN:0171-967X
1432-0827
DOI:10.1007/s00223-013-9711-0