Preventing Periodontitis or Controlling its …...Medication-Related Osteonecrosis of the Jaw...
Transcript of Preventing Periodontitis or Controlling its …...Medication-Related Osteonecrosis of the Jaw...
EJ Castillo1, JG Messer1, JM Jiron1, AM Abraham1, SM Thomas1, JF Yarrow2, DB Kimmel1, JI Aguirre1
1University of Florida, Department of Physiological Sciences Gainesville, FL, USA2VA Medical Center, Research Service, VA Medical Center, Gainesville, FL
Preventing Periodontitis or Controlling its Progression Reduces the Development of Medication-Related Osteonecrosis of the
Jaw (MRONJ) in Rice Rats (Oryzomys Palustris)
This research was supported by NIH grant RO1DE023783-01A National Institute of Dental and Craniofacial Research (NIDCR)
MRONJ
• >8 wk without healing• Systemic medications
• Powerful anti-resorptives [(pARS) eg. Bisphosphonates (Zoledronic acid, ZOL) or anti-RANKL inhibitors]
• Anti – angiogenics (eg. anti- vascular endothelial growth factors.
• No history of radiation therapy or apparent metastases to head and neck
• Local oral risk factors• Recent tooth extractions• Periodontitis (PD), periapical infection• Mucosal trauma
Necrotic bone
H&E
Bacterial colonies
• Exposed necrotic bone in the oral cavity
• Elimination/Reduction of oral and dental risk factors
Preventative Measures can reduce MRONJ
Tooth Extraction
Unfitting Removable Denture
Peri-implantitis
Periodontitis
STD rodent chow
Rice rat (O. palustris) M1
M2
M3
hard palate
soft palate
Food-impaction induced localized PD (FILP) lesions
(Messer et al 2017)
+Zoledronicacid (ZOL)+
MRONJ-like lesionmaxillae
M2M3
alveolar bone
alveolar bone
necrotic bone
Oral cavity
Preclinical Model of PD and MRONJ
(Messer et al 2018)
60-80% rice rats develop FILP lesions at 16-34 wks of age
Around 94% of FILP lesions occur in the maxilla
A dietary modification or mechanical dental cleaning in rice rats will prevent or control PD, and hence will reduce the prevalence of MRONJ
Determine the efficacy of preventing or controlling PD in the development of MRONJ by:
1) Oral mechanical cleaning of Lesions
2) Diet modification
Hypothesis
STD diet
VEH
ZOL 80μg/Kg
ZOL 80μg/Kg +Dental cleaning (DC)
Necropsy
In vivo oral exams under ISO anesthesia (q2wks)
High Soluble Fiber (HSF) (7.5% inulin and 10% fructo-oligosaccharides)
SF diet
OUTCOMES: • In vivo analysis of the jaws• High Resolution Photographs of Jaws
(necropsy = 24 wks). Gross Quadrant Grade (GQG)
• MicroCT• Histopathology
• decalcified, serially sectioned, and H&E stained
• Immunohistochemical TRAP staining
Materials and Methods
VEH
IV q4wks
ZOL 80μg/Kg
n=15/ groupPD lesions
n=15/ groupNo PD lesions
Rice rat (O.Palustris)
In Vivo Analysis of Maxillary Quadrants
0102030405060708090
100
0 5 10 15 20 25
Prev
alen
ce (%
)
Treatment Duration (wks)
Prevalence of Maxillary Gross Oral Lesions
STD+VEH STD+ZOL STD+ZOL+DC
SF+VEH SF+ZOL
• SF+VEH and SF+ ZOL rats had significantly lower prevalence of oral lesions than STD rats
• STD+ZOL rats that received dental cleanings had significantly reduced severity of PD lesions.
0
1
2
3
0 5 10 15 20 25Gro
ss Q
uadr
ant
Gra
de (G
QG
)
Treatment Duration (wks)
Maxillary Lesion severity
STD+VEH STD+ZOL STD+ZOL+DC
✢* ✢*✢*
SFSF+VEH
M1
SF+ZOL
M1
Ex-Vivo Gross Analysis of Oral Lesions
M1
3D reconstruction of MicroCT slices
M1
STD+VEH STD+ZOL
M1
STD+ZOL+DC
M1
STD
M1M1 M1
STD
STD+VEH STD+ZOL STD+ZOL+DC
M1 M1
SFSF+VEH SF+ZOL
High Resolution Photographs
0
1
2
3
4
Gross Lesion Severity based on Maxillary Quadrants
Gro
ss Q
uadr
ant G
rade
STD+VEH STD+ZOL STD+ZOL+DC
** P <0.05
0
2
4
6
8
10
12
14
16
18
20
STD+VEH STD+ZOL STD+ZOL+DC PD
Area
%
Lesion area/Total area(Ex Vivo)
P =0.004**
0
200
400
600
800
1000
1200Maxillary ABL M2M3
CEJ
-ABC
dis
tanc
e(u
m)
no PD PD no PD ONJ no PD PD no PD no PD
STD+VEH STD+ZOLSTD+ ZOL+DC SF+VEH SF+ZOL
Alveolar Bone Loss
ZOL, ONJ
M3M2M1
ABC
ABC
CEJ
500 µm * *
500 µm
STD+VEH no PD
M1M2 M3
CEJ
ABC
ABC
STD+VEH PD
M1M2 M3CEJ
ABC
ABC
500 µm
STD+ZOL+DC PD
M2M1 M3
CEJ
ABC
ABC
500µm
SF+VEH no PDM1
M3
M2
CEJ
ABCABC
500 µm
SF+ZOL no PDM1
M2M3CEJ
ABCABC
Immunohistochemical staining of TRAP+ Cells
0
2
4
6
8 TRAP+ cells/B.Pm
#/m
m2
No PD PD No PD No PD No PD No PDONJ PD
STD+VEH STD+ZOL STD+ZOL+DC SF+VEH SF+ZOL
STD +VEH STD+ZOL STD+ZOL+DC
STD
SFSF+ZOL no PDSF+VEH no PD
Immunohistochemical TRAP stained sections. Red arrow indicates TRAP+ osteoclast
Quantification of osteoclast number/mm2
0
1
2
3
4
5
Maxillary Histological PD Scores at 24 weeks (M2M3)
STD VEH STD ZOL STD ZOL+DC SF VEH SF ZOL
PD s
core
Histopathologic Assessment
ONJ
0
20
40
60
80
100 Empty Osteocyte Lacunae
Perc
ent
STD+VEH PD STD+ZOL MRONJ STD+ZOL+DC PD
*Epi
bone
*
200 µm
*M2
M3
50 µm
*
*
bone• Exposed necrotic bone• Lack of overlying gingival epithelium• ≥10 confluent empty osteocyte lacunae
0
20
40
60
80
STD+VEH STD+ZOL STD+ZOL+DC SF+VEH SF+ZOL
Prev
alen
ce (%
)
Treatment
* **
*
MRONJ Prevalence
Conclusions
• Dental cleaning reduces gross severity and extension but does not resolve PD lesions in rice rats.
• Preventing progression of PD reduces occurrence of MRONJ.
• SF diet prevented the development of PD and MRONJ regardless of treatment
• These findings provide direct preclinical evidence to support current guidelines2 concerning maintenance of good oral hygiene in pAR patients.