Dr Eisman served as a consultant, received corporate appointments and research support from Aventis, Eli Lilly and Company, MSD, NPS Pharmaceuticals, Novartis, Organon, Roche, and Servier. Dr Little has a patent licensing arrangement from Novartis. All other authors have no conflict of interest
Transient Disturbance in Physeal Morphology Is Associated With Long-Term Effects of Nitrogen-Containing Bisphosphonates in Growing Rabbits
Article first published online: 13 JUN 2005
Copyright © 2005 ASBMR
Journal of Bone and Mineral Research
Volume 20, Issue 10, pages 1731–1741, October 2005
How to Cite
Smith, E. J., Little, D. G., Briody, J. N., McEvoy, A., Smith, N. C., Eisman, J. A. and Gardiner, E. M. (2005), Transient Disturbance in Physeal Morphology Is Associated With Long-Term Effects of Nitrogen-Containing Bisphosphonates in Growing Rabbits. J Bone Miner Res, 20: 1731–1741. doi: 10.1359/JBMR.050604
- Issue published online: 4 DEC 2009
- Article first published online: 13 JUN 2005
- Manuscript Accepted: 10 JUN 2005
- Manuscript Revised: 14 MAR 2005
- Manuscript Received: 8 NOV 2004
- nitrogen-containing bisphosphonates;
- physeal morphology;
- tibial length;
- endochondral cartilage;
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.
Introduction: 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 (ZA1) or 8 and 10 weeks of age (ZA2) 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.
Results: Tibial length was 3% less at 14 weeks of age in the ZA2-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 ZA2-treated than saline animals (p < 0.05). Rate of weight gain from 8 to 10 weeks of age was 76% less in ZA2 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.
Conclusions: 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.