Transient disturbance in physeal morphology is associated with long-term effects of nitrogen-containing bisphosphonates in growing rabbits

Smith, Elisabeth J., Little, David G., Briody, Julie N., McEvoy, Anthony, Smith, Nicholas C., Eisman, John A. and Gardiner, Edith M. (2005) Transient disturbance in physeal morphology is associated with long-term effects of nitrogen-containing bisphosphonates in growing rabbits. Journal of Bone and Mineral Research, 20 10: 1731-1741. doi:10.1359/JBMR.050604

Author Smith, Elisabeth J.
Little, David G.
Briody, Julie N.
McEvoy, Anthony
Smith, Nicholas C.
Eisman, John A.
Gardiner, Edith M.
Title Transient disturbance in physeal morphology is associated with long-term effects of nitrogen-containing bisphosphonates in growing rabbits
Journal name Journal of Bone and Mineral Research   Check publisher's open access policy
ISSN 0884-0431
Publication date 2005-10
Sub-type Article (original research)
DOI 10.1359/JBMR.050604
Volume 20
Issue 10
Start page 1731
End page 1741
Total pages 11
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell Publishing
Language eng
Subject 11 Medical and Health Sciences
Formatted abstract
Bisphosphonates have clinical benefit in children with severe osteogenesis imperfecta or osteoporosis and potential benefit in children with Perthes disease or undergoing distraction osteogenesis. However, there is concern about the effects of bisphosphonates on the physis and bone length. In 44 growing rabbits, zoledronic acid caused a transient disruption of physeal morphology, retention of cartilaginous matrix in trabeculae and cortical bone of the metaphysis, and a minor decrement in tibial bone length at maturity.


Data from growing animal models suggest that bisphosphonates cause retention of longitudinal cartilaginous septa at the chondro-osseous junction, extension of trabeculae to the metaphyseal-diaphyseal junction, and varying dose-dependent effects on longitudinal growth. However, there is a lack of data regarding effects of intermittent use of nitrogen-containing bisphosphonates on the physis and on tibial length in models reaching maturity.

Materials and Methods:
Contralateral tibias of juvenile rabbits were examined after right tibial distraction osteogenesis from two previous studies. Animals were randomized to receive 0.1 mg/kg zoledronic acid (ZA) IV at 8 weeks of age (ZA*1) or 8 and 10 weeks of age (ZA*2) or saline. Body mass was analyzed from 5 to 44 weeks of age; tibial length and proximal physeal-metaphyseal histology and histomorphometry were analyzed at 8-52 weeks of age.

Tibial length was 3% less at 14 weeks of age in the ZA*2-treated versus saline group (p < 0.05) in both studies, and this difference persisted at maturity in the long-term study group (26 weeks of age, p < 0.05). Total body mass gain from 5 to 26 weeks of age was 14% less in ZA*2-treated than saline animals (p < 0.05). Rate of weight gain from 8 to 10 weeks of age was 76% less in ZA*2 compared with saline animals (P < 0.05). Radiographs showed radiodense lines in the metaphyses of ZA-treated bones, corresponding to the number of doses. Histologically, lines resulting from the first dose of ZA contained longitudinal cartilaginous matrix cores surrounded by bone, whereas those from the second dose contained spherical cores of matrix caused by transient disruption of physeal morphology after the first dose of ZA. Resorption of these lines at later times was radiographically and histologically evident, but remnants of cartilaginous matrix remained in the cortical bone of ZA-treated animals.

ZA treatment within the final 13.5% of the rabbit tibial growth period caused a transient disruption in physeal morphology and resorption associated with retention of cartilaginous matrix and coinciding with a persistent 3% decrement in tibial length. Disruption of physeal morphology and potential loss of bone length should be considered when administering nitrogen-containing bisphosphonates to children before closure of the major physes.
Keyword Endochondral cartilage
Nitrogen-containing bisphosphonates
Physeal morphology
Tibial length
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ
Additional Notes Article first published online: 13 June 2005

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 11 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 25 Jan 2008, 16:39:49 EST