Abstract
Bisphosphonates are widely used as anti-resorptive agents for the treatment of various bone and joint diseases, including advanced osteoporosis, multiple myeloma, bone metastatic cancers, Paget’s disease of bone, and rheumatoid arthritis. Bisphosphonates act as an anti-osteoclast via the induction of osteoclast apoptosis, resulting in a decreased rate of bone resorption. Unfortunately, there is much evidence to demonstrate that the long-term use of bisphosphonates is associated with osteonecrosis. The pathogenesis of osteonecrosis includes the death of osteoblasts, osteoclasts, and osteocytes. In addition, the functions of endothelial cells, epithelial cells, and fibroblasts are impaired in osteonecrosis, leading to disruptive angiogenesis, and delayed wound healing. Osteonecrosis is most commonly found in the jawbone and the term medication-related osteonecrosis of the jaw (MRONJ) has become the condition of greatest clinical concern among patients receiving bisphosphonates. Although surgical treatment is an effective strategy for the treatment of MRONJ, several non-surgical interventions for the attenuation of MRONJ have also been investigated. With the aim of increasing understanding around MRONJ, we set out to summarize and discuss the holistic effects of bisphosphonates on the bone and its surrounding tissues. In addition, non-surgical interventions for the attenuation of bisphosphonate-induced osteonecrosis were reviewed and discussed.
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Abbreviations
- µM:
-
Micromolar
- µmol:
-
Micromole
- Akt:
-
Protein kinase B
- Al:
-
Alendronate
- ALP:
-
Alkaline phosphatase
- ATP:
-
Adenosine triphosphate
- Bad:
-
BCL2-associated agonist of cell death
- Bak:
-
BCL2 homologous antagonist killer
- BAX:
-
BCL2-associated X protein
- BCL2:
-
B-cell lymphoma 2
- BMP2:
-
Bone morphogenetic protein 2
- BMSCs:
-
Bone marrow stromal cells
- BPs:
-
Bisphosphonates
- BRONJ:
-
Bisphosphonate-related osteonecrosis of the jaw
- BSP:
-
Bone sialoprotein
- CCL:
-
Chemokine ligand
- CD:
-
Cluster of differentiation
- Cl:
-
Clodronate
- COL1A1:
-
Collagen type I alpha 1 chain
- COL1A2:
-
Collagen type I alpha 2 chain
- CTR:
-
Calcitonin receptor
- CTX:
-
C-terminal cross-linking telopeptide of type I collagen
- d:
-
Day(s)
- DAPI:
-
4′,6-Diamidino-2-phenylindole
- DNA:
-
Deoxyribonucleic acid
- Dno:
-
Denosumab
- DPSCs:
-
Human dental pulp stem cells
- EGF:
-
Epidermal growth factor
- EGFR:
-
Epidermal growth factor receptor
- eNOS:
-
Endothelial nitric oxide synthase
- ERK:
-
Extracellular signal-regulated kinase
- Fn:
-
Fusobacterium nucleatum
- G-CSF:
-
Granulocyte colony-stimulating factor
- GFs:
-
Gingival fibroblasts
- h:
-
Hour(s)
- HA:
-
Hydroxyapatite
- HOKs:
-
Human oral keratinocytes
- IAP:
-
Inhibitor of apoptosis
- Ib:
-
Ibandronate
- IFN-α:
-
Interferon alpha
- IkB-α:
-
Inhibitor kappa B-alpha
- IL:
-
Interleukin
- iNOS:
-
Inducible nitric oxide synthase
- iPTH:
-
Intact parathyroid hormone
- IV:
-
Intravenous
- J/cm2 :
-
Joules per square centimeter
- KC:
-
Keratinocyte-derived chemokine
- KGF:
-
Keratinocyte growth factor
- L:
-
Liter(s)
- LC3β-II:
-
Light chain 3 beta 2
- LC3β:
-
Light chain 3 beta
- LLLT:
-
Low-level laser therapy
- LPS:
-
Lipopolysaccharide
- Ly6C:
-
Lymphocyte antigen 6C
- mg:
-
Milligram(s)
- MIP:
-
Macrophage inflammatory proteins
- MIP-2:
-
Macrophage inflammatory proteins 2
- mL:
-
Milliliter(s)
- mM:
-
Millimolar(s)
- MMP:
-
Matrix metalloproteinases
- mRNA:
-
Messenger ribonucleic acid
- MRONJ:
-
Medication-related osteonecrosis of the jaw
- mTOR:
-
Mammalian target of rapamycin
- MTT:
-
Thiazolyl blue tetrazolium bromide
- NFAT:
-
Nuclear factor of activated T cells
- NO:
-
Nitric oxide
- NOS:
-
Nitric oxide synthase
- ONJ:
-
Osteonecrosis of jaw
- OPG:
-
Osteoprotegerin
- OCN:
-
Osteocalcin
- p-:
-
Phosphorylated
- P1NP:
-
Procollagen type I N-terminal propeptide
- Pa:
-
Pamidronate
- PAS:
-
Periodic acid–Schiff
- PCNA:
-
Proliferating cell nuclear antigen
- PDGF-BB:
-
Platelet-derived growth factor-BB
- Pg:
-
Porphyromonas gingivalis
- PGE2:
-
Prostaglandin E2
- PI3K:
-
Phosphoinositide 3-kinase
- PMA:
-
Phorbol-12-myrisate-13-acetate
- PTH:
-
Parathyroid hormone
- RANKL:
-
Receptor activator of NF-kappaB ligand
- rER:
-
Rough endoplasmic reticulum
- RHOB:
-
Ras homologue gene family member B
- RNA:
-
Ribonucleic acid
- RUNX2:
-
Runt-related transcription factor 2
- s:
-
Second(s)
- SOCS:
-
Suppressor of cytokine signaling
- SPP1:
-
Secreted phosphoprotein 1
- SQSTM:
-
Sequestosome
- SQSTM1:
-
Sequestosome 1
- Tcirg1:
-
T-cell immune regulator 1
- TNF:
-
Tumor necrosis factor
- TNFa:
-
Tumor necrosis factor alpha
- TRAcP5b:
-
Tartrate-resistant acid phosphatase 5b
- TRAF:
-
Tumor necrosis factor receptor-associated factors
- TRAP:
-
Tartrate-resistant acid phosphatase
- VEGF:
-
Vascular endothelial growth factor
- VEGF-A:
-
Vascular endothelial growth factor A
- VEGF-C:
-
Vascular endothelial growth factor C
- VEGFR2:
-
Vascular endothelial growth factor receptor 2
- VitD:
-
Vitamin D
- vWF:
-
Von Willebrand factor
- wk:
-
Week(s)
- Zo:
-
Zoledronate
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Acknowledgements
This article was supported by the CMU Presidential Scholarships for the 2021 Academic Year from Chiang Mai University (B.S.); a Research Grant for New Scholars from Thailand Science Research and Innovation (C.T.); a Senior Research Scholar grant from the National Research Council of Thailand (S.C.C.); the NSTDA Research Chair Grant from the National Science and Technology Development Agency Thailand (N.C.); a Chiang Mai University Center of Excellence Award (N. C.).
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SCC and BS conceived the presented idea. CT and BS drafted the tables and figures and wrote the manuscript. SCC, NC, and CT supervised the review and revised it critically for important intellectual content. SCC approved the final version for submission.
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Srivichit, B., Thonusin, C., Chattipakorn, N. et al. Impacts of bisphosphonates on the bone and its surrounding tissues: mechanistic insights into medication-related osteonecrosis of the jaw. Arch Toxicol 96, 1227–1255 (2022). https://doi.org/10.1007/s00204-021-03220-y
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DOI: https://doi.org/10.1007/s00204-021-03220-y