Doses effects of zoledronic acid on mineral apatite and collagen quality of newly-formed bone in the rat's calvaria defect
Résumé
Due to their inhibitory effects on resorption, bisphosphonates are widely used in the treatment of diseases associated to an extensive bone loss. Yet, little is known about bisphosphonates effects on newly-formed bone quality. In the present study, adult male Sprague-Dawley rats (n = 80) with a bone defect calvaria area were used and short-term effects of zoledronic acid (ZA) were studied on the healing bone area. Three ZA treatments were tested by using either: 1°) a low single dose (120 μg ZA/kg, n = 10; equivalent to human osteoporosis treatment), 2°) a low fractionated doses (20 μg ZA/kg daily for 6 days either a total of 120 μg/kg, n = 15), and 3°) a high fractionated doses, (100 μg ZA/kg weekly for 6 weeks, n = 15; equivalent to 6 months of human bone metastasis treatment). For each treatment, a control "vehicle" treatment was performed (with an identical number of rats). After ZA administration, the intrinsic bone material properties were evaluated by quantitative backscattered electron imaging (qBEI) and Raman microspectroscopy. Neither single nor fractionated low ZA doses modify the intrinsic bone material properties of the newly-formed bone compared to their respective control animals. On the opposite, the high ZA treatment resulted in a significant decrease of the crystallinity (-25%, P b 0.05) and of the hydroxyproline-to-proline ratio (-30%, P b 0.05) in newly-formed bones. Moreover, with the high ZA treatment, the crystallinity was positively correlated with the hydroxyproline-to-proline ratio (ρ = 0.78, P b 0.0001). The present data highlight new properties for ZA on bone formation in a craniofacial defect model. As such, ZA at high doses disrupted the apatite crystal organization. In addition, we report here for the first time that high ZA doses decreased the hydroxyproline-to-proline ratio suggesting that ZA may affect the early collagen organization during the bone healing.
Mots clés
Bisphosphonate Bone quality Collagen Mineral Raman microspectroscopy Rat BE
back-scattered electrons BMDD
bone mineralization density distribution BP
bisphosphonate CTL
control GAG
glycosaminoglycan PMMA
polymethyl methacrylate qBEI
quantitative backscattered electron imaging ROI
region of interest ZA
zoledronic acid
back-scattered electrons
BMDD
bone mineralization density distribution
BP
bisphosphonate
CTL
control
GAG
glycosaminoglycan
PMMA
polymethyl methacrylate
qBEI
quantitative backscattered electron imaging
ROI
region of interest
ZA