EXPERIMENTAL
Radiation-Induced Craniofacial Bone Growth
Inhibition: Acute and Long-Term Effects on Bone
Histopathology with and without Cytoprotection
David A. O’Donovan,
F.R.C.S.(I.), F.R.C.S.(Plast.)
Giorgio C. La Scala,
F.M.H.(C.H.)
Iona Leong, F.R.C.D.(C.)
Maria Mendes, M.S.H.
Marianne Rogers, M.S.H.
Kenneth H. Pritzker,
F.R.C.P.(C.)
Ivan Yeung, Ph.D.
Cho Y. Pang, Ph.D.
Peter C. Neligan,
F.R.C.S.(I.), F.R.C.S.(C.)
Christopher R. Forrest,
F.R.C.S.(C.)
Toronto, Ontario, Canada; Geneva,
Switzerland; and Seattle, Wash.
Background: The authors previously established an animal model of radiation-
induced craniofacial bone growth inhibition and demonstrated the effectiveness of
cytoprotection in preserving growth using amifostine, but the mechanism is un-
clear. The objective of this study was to investigate the acute and long-term histo-
pathologic effects of single-dose orthovoltage irradiation on craniofacial bone with
and without cytoprotection.
Methods: Sixty infant New Zealand White rabbits (7-week-old) were random-
ized into three groups (n = 20 per group): group 1, 0-Gy, sham irradiation;
group 2, 35-Gy single-dose orthovoltage irradiation; and group 3, cytoprotection
with amifostine before irradiation. Orbitozygomatic complex bone was har-
vested from animals 12 hours after irradiation and at skeletal maturity (21 weeks
of age). Histologic parameters measured included native bone cell (osteoblast,
osteoclast, and osteocyte) populations, periosteal proliferation indices (MIB-1
stains), bone turnover rates [triple fluorochromes: tetracycline administered at
7 weeks of age (before irradiation), alizarin complexone at 12 weeks, and calcein
at 16 weeks of age], and endosteal space fibrosis levels.
Results: Orthovoltage irradiation significantly (p 0.05) reduced osteoblast and
osteoclast counts 12 hours after irradiation (age, 7 weeks) with or without pre-
treatment with amifostine but had no effect on osteocyte populations. Long-term
analysis at age 21 weeks demonstrated significantly (p 0.05) increased osteoblast
counts, reduced endosteal space fibrosis, reduced periosteal proliferation indices,
and improved bone turnover (fluorochrome stains) in amifostine-treated animals.
Conclusion: This study suggests that amifostine cytoprotection is mediated
through a combination of reduced cellular injury with enhanced promotion of
cellular bone rebuilding potential. (Plast. Reconstr. Surg. 129: 636e, 2012.)
P
ediatric soft-tissue sarcomas represent ap-
proximately 7 percent of all childhood can-
cers and involve the head and neck in 40
percent of cases.
1–4
Combination radiotherapy-
chemotherapy regimens are effective in the their
management, with 3-year relapse-free survival rates
of 70 percent.
2,5–7
However, up to 100 percent of
survivors of pediatric head and neck cancers sustain
radiation-induced craniofacial growth inhibition,
with significant cosmetic and functional deformities
and devastating psychosocial implications.
8 –15
Ade-
quate surgical correction of these deformities rep-
resents a tremendous challenge because of trophic
changes in the bone and overlying soft tissue, radi-
From the Division of Plastic Surgery, The Hospital for Sick
Children Center for Craniofacial Care and Research, The Hos-
pital for Sick Children Research Institute, University of Toronto,
the Department of Pathology, Mount Sinai Hospital, the De-
partment of Clinical Physics, Ontario Cancer Institute, Princess
Margaret Hospital, the Pediatric Surgery Clinic, University of
Geneva Children’s Hospital, and the Department of Surgery,
Center for Reconstructive Surgery, University of Washington.
Received for publication June 7, 2011; accepted October 19,
2011.
Presented in part at the 45th Annual Meeting of the Plastic
Surgery Research Council, in Seattle, Washington, May 17
through 20, 2000.
Copyright ©2012 by the American Society of Plastic Surgeons
DOI: 10.1097/PRS.0b013e31824421b6
Disclosure: The authors have no financial interest
to declare in relation to the content of this article.
This work was supported by
THE PLASTIC SURGERY FOUNDATION.
www.PRSJournal.com 636e