Zoledronic acid decreases bone formation without causing
osteocyte death in mice
S.S. Huja
a,b,
*
, S.A. Fernandez
c
, Christina Phillips
a
,Y.Li
c
a
Division of Orthodontics, College of Dentistry, The Ohio State University, 305 W. 12th St., Columbus, OH 43210, USA
b
Oral Biology, College of Dentistry, The Ohio State University, 305 W. 12th St., Columbus, OH 43210, USA
c
Center for Biostatistics, The Ohio State University, 320 W. 10th Ave., Columbus, OH 43210, USA
1. Introduction
There is limited information on the effect of bisphosphonate
on the jaw bones. In contrast, the effect of a variety of
bisphosphonates on non-craniofacial bones has been exten-
sively investigated.
1–6
As a result, the effect of bisphosphonate
on very basic parameters of bone formation and resorption in
the jaw bones is not clearly understood. The purpose of this
study was to obtain information on the effects of zoledronic
acid, a commonly used bisphosphonate on the jaw bone in a
mouse model. Zoledronic acid is a nitrogen containing, highly
potent bisphosphonate and is commonly used to provide
supportive treatment for cancer patients and is now approved
in a single dose/year for the treatment of postmenopausal
osteoporosis. This drug along with other oral and i.v. bispho-
sphonates
7,8
are associated with osteonecrosis (ONJ) of the
jaw
9–12
which currently seems to be an uncommon but serious
complication of drug therapy. ONJ is limited to the craniofacial
region and the pathophysiology of bisphosphonate related
ONJ is unknown. It has been suggested the bone remodelling
suppression may be related to development of ONJ.
11
Others
suggest that high doses of bisphosphonate are directly
archives of oral biology 54 (2009) 851–856
article info
Article history:
Accepted 2 June 2009
Keywords:
Bisphosphonate
Osteocyte
Bone labels
Viability
Osteonecrosis
abstract
Bisphosphonates have been associated with osteonecrosis of the jaw. The purpose of this
study was to examine the effect of a potent bisphosphonate, zoledronic acid (ZA) on
osteocyte viability and bone formation. Ten experimental C57BL/6 mice were administered
ZA (0.1 mg/kg-i.p.) weekly for 9 weeks while four control mice did not receive the drug. A pair
of calcein (30 mg/kg) labels was administered 10 and 3 days prior to sacrifice of the 34-week-
old mice. Fresh mandibular and femoral sections were obtained to evaluate osteocyte
viability using a lactate dehydrogenase (LDH) assay. In addition, sections from the femur,
mandible and maxilla were prepared for standard histomorphometry. The operator was
blinded for data collection to eliminate bias. Data on necrotic area/total bone area from the
LDH sections were collected. In addition, standard histomorphometric variables including
bone formation rate were calculated. Mixed models were used to analyse data. The
osteocytes were overwhelmingly viable and no necrotic areas were detected in the mandible
and femur of both groups. ZA was not directly cytotoxic to the mouse osteocytes. There was
suppression in indices of bone formation at all skeletal sites of the ZA group compared to the
control group. While ZA administration in mice does not produce necrotic osteocytes, it
severely suppresses bone formation. Such reductions can have a profound effect on bone
healing.
# 2009 Elsevier Ltd. All rights reserved.
* Corresponding author at: Division of Orthodontics, College of Dentistry, The Ohio State University, 4088 E Postle Hall, 305W. 12th Ave.,
Columbus, OH 43210, USA. Tel.: +1 614 247 6889; fax: +1 614 688 3077.
E-mail address: huja.1@osu.edu (S.S. Huja).
available at www.sciencedirect.com
journal homepage: www.intl.elsevierhealth.com/journals/arob
0003–9969/$ – see front matter # 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.archoralbio.2009.06.002