Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using competing inerthydroxymethylene diphosphonate
- Weintraub Center for Reconstructive Biotechnology, Division of Regenerative & Reconstructive Sciences, University of California, Los Angeles School of Dentistry, United States
- Division of Molecular & Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Japan
- Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, United States
- BioVinc, LLC, United States
- Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, United States
- Department of Chemistry, University of Southern California, United States
- Division of Oral & Systemic Health Sciences, University of California, Los Angeles School of Dentistry, United States
- Section of Oral & Maxillofacial Pathology, University of California, Los Angeles School of Dentistry, United States
Figures
Figure 1
Competitive equilibrium-based dissociation of N-BP by low potency BP (lpBP).
(A) Chemical structures (shown as the tetraacids) of N-BP, zoledronate (ZOL) and hydroxymethylene diphosphonate (HMDP). (B) ZOL but not HMDP affects mouse femur trabecular bone architecture. Mice …
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Figure 1—source data 1
Source data of Figure 1C.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig1-data1-v2.pdf
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Figure 1—source data 2
Source data of Figure 1D.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig1-data2-v2.pdf
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Figure 1—source data 3
Source data of Figure 1E.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig1-data3-v2.pdf
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Figure 1—source data 4
Source data of Figure 1F.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig1-data4-v2.pdf
Figure 2
Manufacturing and trans-oral mucosal penetration evaluation of hydroxymethylene diphosphonate (HMDP)-DNV and AF647-ZOL-DNV.
(A) Diagram of deformable nanoscale vesicles (DNV), a liposome derivative. (B) Flow diagram of micro-fluidics based DNV synthesis. (C) Confocal laser scanning microscopy of AF647-ZOL-DNV. …
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Figure 2—source data 1
Source data of Figure 2F.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig2-data1-v2.pdf
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Figure 2—source data 2
Source data of Figure 2G.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig2-data2-v2.pdf
Figure 3 with 2 supplements
Disease phenotypes of mouse and human BRONJ lesion.
(A) Experimental protocol for inducing a bisphosphonate-related osteonecrosis of the jaw (BRONJ) lesion in mice. Mice received a bolus IV injection of zoledronate (ZOL) (40 nmol, 500 µg/kg) or …
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Figure 3—source data 1
Source data of Figure 3I.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig3-data1-v2.pdf
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Figure 3—source data 2
Source data of Figure 3J.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig3-data2-v2.pdf
Figure 3—figure supplement 1
Mouse BRONJ model.
(A) Time course protocol to develop bisphosphonate-related osteonecrosis of the jaw (BRONJ) in the mouse. Mice received a bolus IV injection of zoledronate (ZOL) (500 µg/kg) or vehicle saline …
Figure 3—figure supplement 2
Single intra-oral topical application of hydroxymethylene diphosphonate (HMDP)-deformable nanoscale vesicles (DNV) to zoledronate (ZOL)-treated mice prior to tooth extraction did not prevent development of a BRONJ lesion.
(A) Time course experimental diagram. All mice received a ZOL IV injection. HMDP-DNV (5 nmol, 3 μl of 1.67 mM), Empty-DNV or HMDP in saline solution (HMDP alone, 5 nmol, 3 μl of 1.67 mM) was …
Figure 4
Hydroxymethylene diphosphonate (HMDP)-deformable nanoscale vesicles (DNV) topical application to the established BRONJ lesion in mice accelerated the disease resolution.
(A) The time course experimental protocol. After zoledronate (ZOL) IV injection and tooth extraction, a BRONJ lesion developed, which was treated by two topical applications of HMDP-DNV in MQW at a …
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Figure 4—source data 1
Source data of Figure 4C.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig4-data1-v2.pdf
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Figure 4—source data 2
Source data of Figure 4D.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig4-data2-v2.pdf
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Figure 4—source data 3
Source data of Figure 4E.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig4-data3-v2.pdf
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Figure 4—source data 4
Source data of Figure 4F.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig4-data4-v2.pdf
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Figure 4—source data 5
Source data of Figure 4G.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig4-data5-v2.pdf
Figure 5
Hydroxymethylene diphosphonate (HMDP)-deformable nanoscale vesicles (DNV) topical application normalized tooth extraction wound healing of zoledronate (ZOL)-pretreated mice.
(A) Histological evaluation depicted BRONJ lesion at the tooth extraction site of the untreated ZOL-injected mice (No Tx) exhibiting that the abnormal epithelial hyperplasia (E. Hyp) extending to …
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Figure 5—source data 1
Source data of Figure 5D.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig5-data1-v2.pdf
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Figure 5—source data 2
Source data of Figure 5E.
- https://cdn.elifesciences.org/articles/76207/elife-76207-fig5-data2-v2.pdf
Figure 6
Single-cell RNA sequencing of gingival cells of untreated and hydroxymethylene diphosphonate (HMDP)-deformable nanoscale vesicles (DNV)-treated zoledronate (ZOL)-injected mice.
(A) Two weeks after tooth extraction, gingival tissue adjacent to the tooth extraction site was harvested for cell dissociation followed by single cell RNA-sequencing. (B) Using signature gene …
Figure 7
Characterization of myeloid immune cells.
(A) The myeloid cell fraction of scRNA-seq was further divided into neutrophils and macrophages. (B) Myeloid immune cells identified by Trem1 demonstrated a significant decrease of neutrophils by …
Tables
Table 1
Estimated MRONJ case numbers in the US based on MRONJ incidence for the major underlying diseases*.
| Underlying diseases | New cases in the US (Year) | MRONJ incidence | Estimated MRONJ cases (Year)* |
|---|---|---|---|
| Multiple myeloma | 34,920† | 5.16% (Rugani et al., 2016) | 1,802 |
| Breast cancer | 330,840‡ | 2.09% (Rugani et al., 2016) | 6,915 |
| Prostate cancer | 248,530† | 3.80% (Rugani et al., 2016) | 9,444 |
| Osteoporosis/Low bone mass | 53,500,000§ | 0.01% (Khan et al., 2017) | 5,350 |
| Estimated annual incidents of MRONJ | 23,511 | ||
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MRONJ: Medication-related osteonecrosis in the jawbone.
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*
Based on an assumption that all these patients were treated by antiresorptive medications.
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†
American Cancer Society. Cancer Facts & Figures 2021. Atlanta, Ga: American Cancer Society; 2021.
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‡
Invasive breast cancer and ductal carcinoma: American Cancer Society. How Common Is Breast Cancer? Jan. 2020. Available at: https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html.
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§
Center for Disease Control and Prevention at: https://www.cdc.gov/nchs/products/databriefs/db405htm.
