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Pharmaceuticals
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The Pharmacology of Bisphosphonates: New Advances
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The Pharmacology of Bisphosphonates: New Advances

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 25 May 2025 | Viewed by 2544

Special Issue Editors

Dr. Ewa Chmielewska

E-Mail Website
Guest Editor
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, Wrocław, Poland
Interests: bisphosphonates; synthesis of bisphosphonic acids; reaction mechanism of the synthesis of bisphosphonates; biological activity of bisphosphonates in vivo and in vitro; osteoporosis; medicinal chemistry
Prof. Dr. Paweł Kafarski

E-Mail Website
Guest Editor
Chair of Chemistry, Department of Agriculture and Forestry, University of Warmia and Mazury, Olsztyn, Poland
Interests: medicinal chemistry; organic synthesis; biotransformations; enzyme inhibitors; organophosphonates; peptide mimetics; natural products in food
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bisphosphonates (BPs) were first discovered in 1894 by the pharmacist Theodor Salzer. At that time, they were mainly used in industrial processes (in the textile, fertilizer, and oil industries) as corrosion inhibitors or as complexing agents. Bisphosphonates (BPs) are a class of compounds which are receiving growing interest in the pharmaceutical industry. Their therapeutic properties in bone-related disorders (e.g., osteoporosis, Paget′s disease, or bone metastases) makes them the focus of several research studies as well as the main component of numerous pharmaceutical formulations. Their antiresorptive action is related to their high affinity for hydroxyapatite, the main inorganic substituent of bone. On the other hand, the phosphonate groups on their backbone make them excellent ligands for metal ions. The combination of these properties finds potential application in the utilization of such systems as controlled drug release systems (CRSs). Thus, bisphosphonates are currently the target of intensive research, from basic pre-formulation studies to more advanced stages of clinical practice. In addition to such important medicinal use, they display a variety of physiologic activities, which also make them promising anti-cancer, antiprotozoal, antibacterial, and antiviral agents.

It is my great pleasure to invite experts in the field of bisphosphonates to submit manuscripts in the form of short communications, full-length papers, and reviews to this Special Issue. Potential topics include, but are not limited to, the following: innovative synthetic approaches for the preparation of bioactive bisphosphonates, the bioactivity screening of bisphosphonic acids, repurposing and newly discovered biological effects of known compounds, as well as molecular modeling and structure–activity relationship studies. All types of research are encouraged, from in silico studies, through all varieties of in vitro and in vivo research to epidemiological, prospective, and retrospective clinical studies.

I look forward to your valuable contributions.

Dr. Ewa Chmielewska
Prof. Dr. Paweł Kafarski
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • bisphosphonates
  • bisphosphonic acids
  • pharmacology of bisphosphonates
  • pharmacokinetics
  • pharmacodynamics
  • hypocalcemia
  • osteonecrosis
  • gastrointestinal disturbances
  • delivery systems of bisphosphonates
  • bisphosphonate prodrugs
  • osteoporosis
  • breast cancer
  • prostate cancer
  • hypercalcemia
  • antiresorptive properties
  • antibacterial properties
  • anti-cancer properties
  • antiparasitic activity
  • antiprotozoal properties
  • antiviral properties
  • effects of drugs on the metabolism and biomechanical properties of bone tissue
  • properties and effects of bisphosphonates in in vitro and/or in vivo experimental models of bone disorders
  • different bisphosphonates in an in vitro experimental model of bone disease

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Published Papers (3 papers)

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Research

14 pages, 4383 KiB  
Article
Bisphosphonate-Conjugated Sitafloxacin for Treatment of Staphylococcus aureus Infection Associated with Cortical Bone Screws: Case Series in Sheep Model
by Niels Vanvelk, James Tapia-Dean, Stephan Zeiter, Karen de Mesy Bentley, Chao Xie, Frank Hal Ebetino, Shuting Sun, Jeffrey Neighbors, Edward M. Schwarz and Thomas Fintan Moriarty
Pharmaceuticals 2025, 18(5), 675; https://doi.org/10.3390/ph18050675 - 1 May 2025
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Abstract
Background/Objectives: Hydroxybisphosphonate-conjugated sitafloxacin (HBCS) was developed to achieve higher antibiotic concentrations within infected bone. Small animal studies supported further development, but the feasibility of HBCS treatment in a more clinically relevant and larger animal model is unknown. Methods: In this study, [...] Read more.
Background/Objectives: Hydroxybisphosphonate-conjugated sitafloxacin (HBCS) was developed to achieve higher antibiotic concentrations within infected bone. Small animal studies supported further development, but the feasibility of HBCS treatment in a more clinically relevant and larger animal model is unknown. Methods: In this study, we present case reports on four sheep, each receiving four MRSA-contaminated tibial screws treated with different regimens of intravenous antibiotics. The first two sheep received two screws contaminated with 103 CFU and two screws contaminated with 105 CFU. Sheep 1 only received vancomycin, starting on day two. Sheep 2 received vancomycin, starting on day 2, but also received 7 doses of HBCS (2 mg/kg/48 h). The protocol for the final two sheep was revised, and both received four screws contaminated with 103 CFU, and vancomycin was started preoperatively. Sheep 3 and 4 received 7 doses (starting on day 6) and 9 doses (starting on day 2) of HBCS (4 mg/kg/48 h), respectively. Bacteriology was performed on three screws per animal. Longitudinal radiography and histology (n = 1 screw) were assessed for signs of osteolysis and reactive bone formation. Electron microscopy (EM) was performed in the first two sheep to evaluate antibiotic-induced bacterial damage. Results: All sheep tolerated HBCS infusion without clinical signs of discomfort. In addition to a high bacterial load (~104 CFU on all screws), Sheep 1 displayed extensive radiographic and histologic evidence of peri-implant osteolysis and reactive bone formation. Despite having a high bacterial load (~104 CFU on all screws), Sheep 2 displayed only mild radiographic and histologic evidence of peri-implant osteolysis and periosteal reactive bone formation. Bacteriology in Sheep 3 and 4 demonstrated near MRSA eradication (<100 CFU on 2 screws). Both sheep displayed no evidence of osteolysis or new bone formation adjacent to the screw head. EM confirmed the presence of bacteria resorbing bone and replicating in biofilm in Sheep 1, while antibiotic-killed bacteria with ruptured septal planes were seen in Sheep 2. Conclusions: This study demonstrates the feasibility of HBCS therapy in a clinically relevant animal model and provides guidance on future efficacy studies, such as the use of an inoculum of 103 CFU per screw, the initiation of antibiotic treatment commencing at the time of surgery, and the usability of antibiotic-killed bacteria within altered glycocalyx observed by TEM as a potential biomarker for HBCS efficacy. Full article
(This article belongs to the Special Issue The Pharmacology of Bisphosphonates: New Advances)
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14 pages, 2090 KiB  
Article
Prolonged Impact of Bisphosphonates and Glucocorticoids on Bone Mechanical Properties
by Alaa Mansour, Zaher Jabbour, Ammar Alsheghri, Amir Elhadad, Karla R. Berridi, Hanan Moussa, Jose Luis Ramirez-Garcialuna, Iskandar Tamimi, Sailer Santos dos Santos, Janet Henderson, Jun Song and Faleh Tamimi
Pharmaceuticals 2025, 18(2), 164; https://doi.org/10.3390/ph18020164 - 26 Jan 2025
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Abstract
Background: This study aimed at investigating the prolonged effects of glucocorticoids and bisphosphonates on bone. Methods: Six-to-eight-month-old skeletally mature male Sprague Dawley rats were randomized to receive a cancer therapy combination of zoledronic acid (ZA = 0.13 mg/kg) and dexamethasone (DX = 3.8 [...] Read more.
Background: This study aimed at investigating the prolonged effects of glucocorticoids and bisphosphonates on bone. Methods: Six-to-eight-month-old skeletally mature male Sprague Dawley rats were randomized to receive a cancer therapy combination of zoledronic acid (ZA = 0.13 mg/kg) and dexamethasone (DX = 3.8 mg/kg) (treatment group, n = 10) or sterile phosphate buffer saline solution (control group, n = 10). The rats received weekly intraperitoneal injections for 8 weeks, which were stopped 6 weeks before euthanasia. Mineralized bone samples were characterized by three-point bending tests, micro-CT imaging, X-ray diffraction (XRD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Bone collagen was assessed using tensile tests on the demineralized bones and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy on mineralized and demineralized bones. Results: The samples in the treatment group showed increased tibial cortical thickness, mineral crystal size, and toughness. Analyses of demineralized tibiae revealed decreased collagen tensile strength in the experimental group. The spectroscopic and TGA/DSC analyses showed that the ZA + DX treatment increased the collagen amide I 1660/1690 cm−1 area ratio and collagen denaturalization temperature, indicating a higher level of collagen cross-linking. Conclusions: Bisphosphonates and glucocorticoids led to prolonged changes in the mechanical properties of bone as a result of increased cortical thickness, increased crystal size, and the deterioration of collagen quality. Full article
(This article belongs to the Special Issue The Pharmacology of Bisphosphonates: New Advances)
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26 pages, 11275 KiB  
Article
Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis–Arbuzov or the Pudovik Reaction
by Zsuzsanna Szalai, Janka Bednárik, Boldizsár Szigfrid Tóth, Angéla Takács, Szilárd Tekula, László Kőhidai, Konstantin Karaghiosoff, László Drahos and György Keglevich
Pharmaceuticals 2025, 18(1), 91; https://doi.org/10.3390/ph18010091 - 13 Jan 2025
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Abstract
Background: Methylenebisphosphonic derivatives including hydroxy-methylenebisphosphonic species may be of potential biological activity, and a part of them is used in the treatment of bone diseases. Methods: Methylenebisphosphonates may be obtained by the Michaelis–Arbuzov reaction of suitably α-substituted methylphosphonates and trialkyl phosphites or phosphinous [...] Read more.
Background: Methylenebisphosphonic derivatives including hydroxy-methylenebisphosphonic species may be of potential biological activity, and a part of them is used in the treatment of bone diseases. Methods: Methylenebisphosphonates may be obtained by the Michaelis–Arbuzov reaction of suitably α-substituted methylphosphonates and trialkyl phosphites or phosphinous esters, while the hydroxy-methylene variations are prepared by the Pudovik reaction of α-oxophosphonates and different >P(O)H reagents, such as diethyl phosphite and diarylphosphine oxides. Results: After converting α-hydroxy-benzylphosphonates and -phosphine oxides to the α-halogeno- and α-sulfonyloxy derivatives, they were utilized in the Michaelis–Arbuzov reaction with trialkyl phosphites and ethyl diphenylphosphinite to afford the corresponding bisphosphonate, bis(phosphine oxide) and phosphonate–phosphine oxide derivatives. The Pudovik approach led to α-hydroxy-methylenebisphosphonic species and to their rearranged products. A part of the derivatives revealed a significant cytotoxic effect on pancreatic adenocarcinoma or multiple myeloma cells. Conclusions: The new families of compounds synthesized by our novel approaches may be of practical importance due to the significant cytotoxic activity on the cell cultures investigated. Compounds lacking hydroxy groups showed anti-myeloma activity or limited effect on pancreatic cancer (PANC-1) cells unless substituted with para-trifluoromethyl group. Hydroxy-containing bisphosphonates and their rearranged derivatives demonstrated varying effects depending on structural modifications. While myeloma (U266) cells indicated greater sensitivity overall, the most significant reductions in cell viability were observed in PANC-1 cancer cells, raising potential therapeutic applications of bisphosphonates beyond myeloma-associated bone disease, particularly for malignancies like pancreatic ductal adenocarcinoma. Full article
(This article belongs to the Special Issue The Pharmacology of Bisphosphonates: New Advances)
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