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3. Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using competing inert hydroxymethylene diphosphonate.

Author

Okawa, Hiroko, Kondo, Takeru, Hokugo, Akishige, Cherian, Philip, Campagna, Jesus J, Lentini, Nicholas A, Sung, Eric C, Chiang, Samantha, Lin, Yi-Ling, Ebetino, Frank H, John, Varghese, Sun, Shuting, McKenna, Charles E, and Nishimura, Ichiro

Subjects
Animals, Humans, Mice, Nitrogen, Diphosphonates, Liposomes, Bisphosphonate-Associated Osteonecrosis of the Jaw, Zoledronic Acid, biochemistry, bisphosphonate, chemical biology, immunology, inflammation, mouse, oral barrier inflammation, osteonecrosis of the jaw, therapeutic, Clinical Research, Dental/Oral and Craniofacial Disease, Aetiology, 2.1 Biological and endogenous factors, Mouse, Biochemistry and Cell Biology
Abstract

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) presents as a morbid jawbone lesion in patients exposed to a nitrogen-containing bisphosphonate (N-BP). Although it is rare, BRONJ has caused apprehension among patients and healthcare providers and decreased acceptance of this antiresorptive drug class to treat osteoporosis and metastatic osteolysis. We report here a novel method to elucidate the pathological mechanism of BRONJ by the selective removal of legacy N-BP from the jawbone using an intra-oral application of hydroxymethylene diphosphonate (HMDP) formulated in liposome-based deformable nanoscale vesicles (DNV). After maxillary tooth extraction, zoledronate-treated mice developed delayed gingival wound closure, delayed tooth extraction socket healing and increased jawbone osteonecrosis consistent with human BRONJ lesions. Single cell RNA sequencing of mouse gingival cells revealed oral barrier immune dysregulation and unresolved proinflammatory reaction. HMDP-DNV topical applications to nascent mouse BRONJ lesions resulted in accelerated gingival wound closure and bone socket healing as well as attenuation of osteonecrosis development. The gingival single cell RNA sequencing demonstrated resolution of chronic inflammation by increased anti-inflammatory signature gene expression of lymphocytes and myeloid-derived suppressor cells. This study suggests that BRONJ pathology is related to N-BP levels in jawbones and demonstrates the potential of HMDP-DNV as an effective BRONJ therapy.

Published
2022

5. Rescue bisphosphonate treatment of alveolar bone improves extraction socket healing and reduces osteonecrosis in zoledronate-treated mice

Author

Hokugo, Akishige, Kanayama, Keiichi, Sun, Shuting, Morinaga, Kenzo, Sun, Yujie, Wu, QingQing, Sasaki, Hodaka, Okawa, Hiroko, Evans, Courtney, Ebetino, Frank H, Lundy, Mark W, Sadrerafi, Keivan, McKenna, Charles E, and Nishimura, Ichiro

Subjects
Biomedical and Clinical Sciences, Dentistry, Dental/Oral and Craniofacial Disease, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Musculoskeletal, Administration, Intravenous, Animals, Bone Density Conservation Agents, Diphosphonates, Female, Mice, Mice, Inbred C57BL, Osteonecrosis, Wound Healing, Zoledronic Acid, Bisphosphonates, Osteonecrosis of the jaw, BRONJ, MRONJ, Drug displacement, Prophylaxis, Biological Sciences, Engineering, Medical and Health Sciences, Endocrinology & Metabolism, Clinical sciences
Abstract

Bisphosphonate (BP)-related osteonecrosis of the jaw, previously known as BRONJ, now referred to more broadly as medication-related osteonecrosis of the jaw (MRONJ), is a morbid condition that represents a significant risk for oncology patients who have received high dose intravenous (IV) infusion of a potent nitrogen containing BP (N-BP) drug. At present, no clinical procedure is available to prevent or effectively treat MRONJ. Although the pathophysiological basis is not yet fully understood, legacy adsorbed N-BP in jawbone has been proposed to be associated with BRONJ by one or more mechanisms. We hypothesized that removal of the pre-adsorbed N-BP drug common to these pathological mechanisms from alveolar bone could be an effective preventative/therapeutic strategy. This study demonstrates that fluorescently labeled BP pre-adsorbed on the surface of murine maxillo-cranial bone in vivo can be displaced by subsequent application of other BPs. We previously described rodent BRONJ models involving the combination of N-BP treatment such as zoledronate (ZOL) and dental initiating factors such as tooth extraction. We further refined our mouse model by using gel food during the first 7 days of the tooth extraction wound healing period, which decreased confounding food pellet impaction problems in the open boney socket. This refined mouse model does not manifest BRONJ-like severe jawbone exposure, but development of osteonecrosis around the extraction socket and chronic gingival inflammation are clearly exhibited. In this study, we examined the effect of benign BP displacement of legacy N-BP on tooth extraction wound healing in the in vivo model. Systemic IV administration of a low potency BP (lpBP: defined as inactive at 100 μM in a standard protein anti-prenylation assay) did not significantly attenuate jawbone osteonecrosis. We then developed an intra-oral formulation of lpBP, which when injected into the gingiva adjacent to the tooth prior to extraction, dramatically reduced the osteocyte necrosis area. Furthermore, the tooth extraction wound healing pattern was normalized, as evidenced by timely closure of oral soft tissue without epithelial hyperplasia, significantly reduced gingival inflammation and increased new bone filling in the extraction socket. Our results are consistent with the hypothesis that local application of a rescue BP prior to dental surgery can decrease the amount of a legacy N-BP drug in proximate jawbone surfaces below the threshold that promotes osteocyte necrosis. This observation should provide a conceptual basis for a novel strategy to improve socket healing in patients treated with BPs while preserving therapeutic benefit from anti-resorptive N-BP drug in vertebral and appendicular bones.

Published
2019

7. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

Author

McDonald, Michelle M., Khoo, Weng Hua, Ng, Pei Ying, Xiao, Ya, Zamerli, Jad, Thatcher, Peter, Kyaw, Wunna, Pathmanandavel, Karrnan, Grootveld, Abigail K., Moran, Imogen, Butt, Danyal, Nguyen, Akira, Corr, Alexander, Warren, Sean, Biro, Maté, Butterfield, Natalie C., Guilfoyle, Siobhan E., Komla-Ebri, Davide, Dack, Michael R.G., Dewhurst, Hannah F., Logan, John G., Li, Yongxiao, Mohanty, Sindhu T., Byrne, Niall, Terry, Rachael L., Simic, Marija K., Chai, Ryan, Quinn, Julian M.W., Youlten, Scott E., Pettitt, Jessica A., Abi-Hanna, David, Jain, Rohit, Weninger, Wolfgang, Lundberg, Mischa, Sun, Shuting, Ebetino, Frank H., Timpson, Paul, Lee, Woei Ming, Baldock, Paul A., Rogers, Michael J., Brink, Robert, Williams, Graham R., Bassett, J.H. Duncan, Kemp, John P., Pavlos, Nathan J., Croucher, Peter I., and Phan, Tri Giang

Published
2021
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9. Real-Time Impedance-Based Monitoring of the Growth and Inhibition of Osteomyelitis Biofilm Pathogen Staphylococcus aureus Treated with Novel Bisphosphonate-Fluoroquinolone Antimicrobial Conjugates

Author

Sedghizadeh, Parish P., primary, Cherian, Philip, additional, Roshandel, Sahar, additional, Tjokro, Natalia, additional, Chen, Casey, additional, Junka, Adam F., additional, Hu, Eric, additional, Neighbors, Jeffrey, additional, Pawlak, Jacek, additional, Russell, R. Graham G., additional, McKenna, Charles E., additional, Ebetino, Frank H., additional, Sun, Shuting, additional, and Sodagar, Esmat, additional

Published
2023
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11. Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using competing inert hydroxymethylene diphosphonate

Author

Okawa, Hiroko, primary, Kondo, Takeru, primary, Hokugo, Akishige, additional, Cherian, Philip, additional, Campagna, Jesus J, additional, Lentini, Nicholas A, additional, Sung, Eric C, additional, Chiang, Samantha, additional, Lin, Yi-Ling, additional, Ebetino, Frank H, additional, John, Varghese, additional, Sun, Shuting, additional, McKenna, Charles E, additional, and Nishimura, Ichiro, additional

Published
2022
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12. Efficacy of Bisphosphonate-Conjugated Sitafloxacin in a Murine Model of S. aureus Osteomyelitis: Evidence of “Target & Release” Kinetics and Killing of Bacteria Within Canaliculi

Author

Ren, Youliang, primary, Xue, Thomas, additional, Rainbolt, Joshua, additional, Bentley, Karen L. de Mesy, additional, Galloway, Chad A., additional, Liu, Yuting, additional, Cherian, Philip, additional, Neighbors, Jeffrey, additional, Hofstee, Marloes I., additional, Ebetino, Frank H., additional, Moriarty, Thomas Fintan, additional, Sun, Shuting, additional, Schwarz, Edward M., additional, and Xie, Chao, additional

Published
2022
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15. Bone‐Targeted Bortezomib Inhibits Bortezomib‐Resistant Multiple Myeloma in Mice by Providing Higher Levels of Bortezomib in Bone

Author

Tao, Jianguo, primary, Srinivasan, Venkat, additional, Yi, Xiangjiao, additional, Zhao, Yingchun, additional, Zhang, Hengwei, additional, Lin, Xi, additional, Zhou, Xichao, additional, Boyce, Brendan F, additional, Villalta, Peter W, additional, Ebetino, Frank H, additional, Ho, Koc Kan, additional, Boeckman, Robert K, additional, and Xing, Lianping, additional

Published
2022
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16. Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages

Author

Munoz, Marcia A, primary, Fletcher, Emma K, additional, Skinner, Oliver P, additional, Jurczyluk, Julie, additional, Kristianto, Esther, additional, Hodson, Mark P, additional, Sun, Shuting, additional, Ebetino, Frank H, additional, Croucher, David R, additional, Hansbro, Philip M, additional, Center, Jacqueline R, additional, and Rogers, Michael J, additional

Published
2021
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18. Targeting Notch Inhibitors to the Myeloma Bone Marrow Niche Decreases Tumor Growth and Bone Destruction without Gut Toxicity

Author

Sabol, Hayley M., primary, Ferrari, Adam J., additional, Adhikari, Manish, additional, Amorim, Tânia, additional, McAndrews, Kevin, additional, Anderson, Judith, additional, Vigolo, Michele, additional, Lehal, Rajwinder, additional, Cregor, Meloney, additional, Khan, Sharmin, additional, Cuevas, Pedro L., additional, Helms, Jill A., additional, Kurihara, Noriyoshi, additional, Srinivasan, Venkat, additional, Ebetino, Frank H., additional, Boeckman, Robert K., additional, Roodman, G. David, additional, Bellido, Teresita, additional, and Delgado-Calle, Jesus, additional

Published
2021
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19. Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid

Author

Adjei-Sowah, Emmanuela, primary, Peng, Yue, additional, Weeks, Jason, additional, Jonason, Jennifer H., additional, de Mesy Bentley, Karen L., additional, Masters, Elysia, additional, Morita, Yugo, additional, Muthukrishnan, Gowrishankar, additional, Cherian, Philip, additional, Hu, X. Eric, additional, McKenna, Charles E., additional, Ebetino, Frank H., additional, Sun, Shuting, additional, Schwarz, Edward M., additional, and Xie, Chao, additional

Published
2021
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22. Bisphosphonates for delivering drugs to bone

Author

Sun, Shuting, primary, Tao, Jianguo, additional, Sedghizadeh, Parish P., additional, Cherian, Philip, additional, Junka, Adam F., additional, Sodagar, Esmat, additional, Xing, Lianping, additional, Boeckman, Robert K., additional, Srinivasan, Venkatesan, additional, Yao, Zhenqiang, additional, Boyce, Brendan F., additional, Lipe, Brea, additional, Neighbors, Jeffrey D., additional, Russell, R. Graham G., additional, McKenna, Charles E., additional, and Ebetino, Frank H., additional

Published
2021
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28. Targeting Bortezomib to Bone Increases Its Bone Anabolic Activity and Reduces Systemic Adverse Effects in Mice.

Author

Wang, Hua, Zhang, Hengwei, Srinivasan, Venkat, Tao, Jianguo, Sun, Wen, Lin, Xi, Wu, Tao, Boyce, Brendan F, Ebetino, Frank H, Boeckman, Robert K, and Xing, Lianping

Abstract

Bortezomib (Btz) is a proteasome inhibitor approved by the FDA to treat multiple myeloma. It also increases bone volume by promoting osteoblast differentiation and inhibiting osteoclastogenesis in mice. However, Btz has severe systemic adverse effects, which would limit its use as a bone anabolic agent. Here, we designed and synthesized a bone‐targeted form of Btz by conjugating it to a bisphosphonate (BP) with no antiresorptive activity. We report that BP‐Btz inhibited osteoclast formation and bone resorption and stimulated osteoblast differentiation in vitro similar to Btz. In vivo, BP‐Btz increased bone volume more effectively than Btz in three mouse models: untreated wild‐type mice, mice with ovariectomy, and aged mice with tibial factures. Importantly, BP‐Btz had significantly less systemic side effects than Btz, including less thymic cell death, sympathetic nerve damage, and thrombocytopenia, and it improved survival rates in aged mice. Thus, BP‐Btz represents a novel anabolic agent to treat conditions, such as postmenopausal and age‐related bone loss. Bone targeting is an attractive approach to repurpose approved drugs to treat skeletal diseases. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Published
2020
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29. The Pharmacological Profile of a Novel Highly Potent Bisphosphonate, OX14 (1-Fluoro-2-(Imidazo-[1,2-α]Pyridin-3-yl)-Ethyl-Bisphosphonate)

Author

Lawson, Michelle A, primary, Ebetino, Frank H, additional, Mazur, Adam, additional, Chantry, Andrew D, additional, Paton-Hough, Julia, additional, Evans, Holly R, additional, Lath, Darren, additional, Tsoumpra, Maria K, additional, Lundy, Mark W, additional, Dobson, Roy LM, additional, Quijano, Michael, additional, Kwaasi, Aaron A, additional, Dunford, James E, additional, Duan, Xuchen, additional, Triffitt, James T, additional, Jeans, Gwyn, additional, and Russell, R Graham G, additional

Published
2017
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30. Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureusinfection with osseointegration in murine models of implant-associated osteomyelitis

Author

Ren, Youliang, Weeks, Jason, Xue, Thomas, Rainbolt, Joshua, de Mesy Bentley, Karen L., Shu, Ye, Liu, Yuting, Masters, Elysia, Cherian, Philip, McKenna, Charles E., Neighbors, Jeffrey, Ebetino, Frank H., Schwarz, Edward M., Sun, Shuting, and Xie, Chao

Abstract

Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve “target-and-release” drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (hydroxybisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.

Published
2023
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32. Cancer-induced bone loss and associated pain-related behavior is reduced by risedronate but not its phosphonocarboxylate analog NE-10790

Author

Hald, Andreas, Hansen, Rikke Rie, Thomsen, Mette W, Ding, Ming, Croucher, Peter I, Gallagher, Orla, Ebetino, Frank H, Kassem, Moustapha, Heegaard, Anne-Marie, Hald, Andreas, Hansen, Rikke Rie, Thomsen, Mette W, Ding, Ming, Croucher, Peter I, Gallagher, Orla, Ebetino, Frank H, Kassem, Moustapha, and Heegaard, Anne-Marie

Abstract

Udgivelsesdato: 2009-Sep-1, Prostate, breast and lung cancers readily develop bone metastases which lead to fractures, hypercalcemia and pain. Malignant growth in the bones depends on osteoclast-mediated bone resorption and in this regard bisphosphonate compounds, which have high-bone affinity and inhibit osteoclast activity, have been found to alleviate bone cancer symptoms. In this study, the bisphosphonate risedronate and its phosphonocarboxylate derivative NE-10790 was tested in a murine bone cancer pain model. Risedronate decreased bone cancer-related bone destruction and pain-related behavior and decreased the spinal expression of glial fibrillary acidic protein, whereas NE-10790 had no effect on these parameters. Furthermore, risedronate but not NE-10790 induced dose-dependent toxicity in NCTC-2472 cells in vitro. Furthermore, the direct toxic effect of risedronate on tumor cells observed in vitro opens the possibility that a direct toxic effect on tumor cells may also be present in vivo and be related to the efficacy of bisphosphonate compounds. In conclusion, these results suggest that risedronate treatment may lead to an increased life quality, in patient suffering from bone cancer, in terms of decreased osteolysis and pain, and merits further study.

Published
2009

34. Influence of bone affinity on the skeletal distribution of fluorescently labeled bisphosphonates in vivo

Author

Roelofs, Anke J, primary, Stewart, Charlotte A, additional, Sun, Shuting, additional, Błażewska, Katarzyna M, additional, Kashemirov, Boris A, additional, McKenna, Charles E, additional, Russell, R Graham G, additional, Rogers, Michael J, additional, Lundy, Mark W, additional, Ebetino, Frank H, additional, and Coxon, Fraser P, additional

Published
2012
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35. Fluorescent risedronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivo

Author

Roelofs, Anke J, primary, Coxon, Fraser P, additional, Ebetino, Frank H, additional, Lundy, Mark W, additional, Henneman, Zachary J, additional, Nancollas, George H, additional, Sun, Shuting, additional, Blazewska, Katarzyna M, additional, Bala, Joy Lynn F, additional, Kashemirov, Boris A, additional, Khalid, Aysha B, additional, McKenna, Charles E, additional, and Rogers, Michael J, additional

Published
2010
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42. Inhibitory effects of bisphosphonates on growth of amoebae of the cellular slime mold dictyostelium discoideum

Author

Dr. Rogers, Michael J., Watts, Donald J., Russell, R. Graham G., Ji, Xiaohui, Xiong, Xiaojuan, Blackburn, G. Michael, Bayless, Allan V., and Ebetino, Frank H.

Abstract

Bisphosphonates are inhibitors of bone resorption and are used increasingly as therapeutic agents for treating clinical disorders of skeletal metabolism. Their mode of action is still not fully understood. The demonstration that methylenebisphosphonate, a simple methylene analog of pyrophosphate, inhibits the axenic growth of amoebae of the slime mold Dictyostelium discoideumand is incorporated into adenine nucleotides suggested that this organism might be useful in elucidating the cellular effects of bisphosphonates. We examined 24 bisphosphonates, including all those of clinical interest as inhibitors of osteoclast‐mediated bone resorption in vivo, for their effects on D. discoideum.All the geminal bisphosphonates inhibited growth of Dictyostelium, although the effectiveness of individual compounds varied widely. When the bisphosphonates were ranked there was a remarkable similarity between the order of potency as inhibitors of growth of Dictyosteliumand the order of potency as inhibitors of bone resorption. Thus, bisphosphonates with more complex side‐chain structures, especially those containing a nitrogen group, were more potent than simple substituted bisphosphonates, some inhibiting Dictyosteliumgrowth even at concentrations below 10 μM. It therefore appears that the mechanism by which bisphosphonates prevent Dictyosteliumgrowth could be similar to the mechanism by which these compounds affect the activity of osteoclasts. Because the mechanisms of action of bisphosphonates on osteoclasts remains unclear, Dictyosteliummay provide an additional model for studying the biochemical mode of action of bisphosphonates. Furthermore, these studies suggest that Dictyosteliummay also be a convenient organism for rapid evaluation of potentially active bisphosphonates.

Published
1994
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43. Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice.

Author

Wang, Hua, Xiao, Lifeng, Tao, Jianguo, Srinivasan, Venkat, Boyce, Brendan F., Ebetino, Frank H., Oyajobi, Babatunde O., Boeckman, Robert K., and Xing, Lianping

Subjects
BORTEZOMIB, DRUG synthesis, ANTINEOPLASTIC agents, MULTIPLE myeloma treatment, DIPHOSPHONATES, DRUG approval
Abstract

Multiple myeloma (MM) is the most common cancer affecting the bone and bone marrow and remains incurable for most patients; novel therapies are therefore needed. Bortezomib (Btz) is an FDA-approved drug for the treatment of patients with MM. However, its severe side effects require a dose reduction or the potential discontinuation of treatment. To overcome this limitation, we conjugated Btz to a bisphosphonate (BP) residue lacking anti-osteoclastic activity using a novel chemical linker and generated a new bone-targeted Btz-based (BP-Btz) proteasome inhibitor. We demonstrated that BP-Btz, but not Btz, bound to bone slices and inhibited the growth of MM cells in vitro. In a mouse model of MM, BP-Btz more effectively reduced tumor burden and bone loss with less systemic side effects than Btz. Thus, BP-Btz may represent a novel therapeutic approach to treat patients with MM. [ABSTRACT FROM AUTHOR]

Published
2018
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