P2, N=60, Completed, Columbia University | Recruiting --> Completed

P=N/A, N=500, Recruiting, Fudan University

In bone, ZOL prevented osteoporotic changes and tumour cell invasion produced a significant decrease in RANK and an increase in OPG expressions, alongside improved bone mineral density in CT scans. ZOL could be a promising preventive therapy against colitis-induced cancer and associated OP via modulation expression of SNHG16, miRNA-146a, and TRAF6.

P3, N=318, Active, not recruiting, UNICANCER | Trial completion date: Dec 2025 --> Dec 2026

Our findings suggest that ALN augments TLR2 ligand-induced proinflammatory cytokine production via the upregulation of MyD88 expression, and this augmentation is accompanied by the activation of NF-κB and AP-1 in RAW-ASC cells.

P4, N=89, Completed, Centre Hospitalier Universitaire de Nice | Unknown status --> Completed | N=350 --> 89

Following 14-days ex vivo expansion with zoledronic acid and interleukin (IL)-2, exercise mobilized γδ T-cells had surface phenotypes and transcriptomic profiles associated with enhanced effector functions, and demonstrated superior cytotoxic activity against multiple hematologic tumors in vitro, and in vivo in leukemia bearing xenogeneic mice...Antibody blocking of DNAM-1 on expanded γδ T-cells, as well as the DNAM-1 ligands PVR and Nectin-2 on leukemic targets, abolished the enhanced anti-leukemic effects of exercise. These findings provide a mechanistic link between exercise, β2-AR activation, and the manufacture of superior γδ T-cell products for adoptive cell therapy against hematological malignancies.

Here, we demonstrated that next-generation immunomodulators called cereblon E3 ligase modulators (CELMoDs), as well as lenalidomide and pomalidomide, expanded Th1-like Vδ2+ γδ T cells from PBMCs in the presence of zoledronic acid (ZA). ZA but not these immunomodulatory drugs upregulated BTN3A1 in monocytes. These results suggest that immunomodulatory drugs and ZA have cooperative roles in expansion of Th1-like Vδ2+ γδ T cells, and provide the important knowledge for clinical application of human Vδ2+ γδ T cells as effector cells.

P4, N=300, Recruiting, Lene Bergendal Solberg | Trial completion date: Dec 2025 --> Mar 2026 | Trial primary completion date: Dec 2025 --> Mar 2026

Compared with DMSO treatment, CEE markedly inhibited RANK, TNF receptor associated factor 6 (TRAF6), Proto-oncogene c-Fos (c-Fos), Nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) expressions, and Extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK), NF-kappa B-p65 (p65) phosphorylation in osteoclasts. In conclusion, CEE significantly inhibits OVX-induced osteoporosis and RANKL-induced osteoclastogenesis, potentially through modulating the Estrogen Receptor (ER)/RANK/NFATc1 signaling pathway.

Notably, bone metastasis progression of NSCLC was inhibited by moderate exercise, and combinations with zoledronic acid had additive effects. Moreover, exercise preconditioning effectively suppressed bone metastasis progression. This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression.

Echinacoside improved angiogenesis and osteogenesis and inhibited osteoclast formation to promote fracture healing.

P2, N=80, Recruiting, AUVA Traumazentrum Vienna Site UKH Meidling | Trial completion date: Jul 2025 --> Dec 2030

This study demonstrated that ADMSCs inhibit osteoclast differentiation through TSG-6 under osteoclastogenic conditions.

The use of bisphosphonates in the therapeutic strategy for JO should be further explored, as should the role of bone resorption in the pathophysiology of the disease.

P=N/A, N=60, Not yet recruiting, Cairo University

P4, N=64, Recruiting, Chinese University of Hong Kong | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Oct 2023 --> Oct 2025

ZA in a dose-dependent manner prevented the pathological effect of CCl4 in the lung by targeting mevalonate pathway. It could be promising therapy against PCPF.

Zoledronic acid combined with chemotherapy can effectively treat bone metastases of NSCLC and improve pain stress and bone metabolic status, which has value that can be promoted and applied in clinical treatment.

P2, N=40, Completed, Oslo University Hospital | Active, not recruiting --> Completed

Overall, 1 % (95 % CI 0.75-1.15) of patients experienced osteonecrosis of jaw related to zoledronic acid. Compared to the Early Breast Cancer Trialist's Collaborative Group meta-analysis, benefit from adjuvant bisphosphonates is lower in recent trials especially in higher risk patients receiving contemporary chemotherapy. The balance between benefits and risks of adjuvant bisphosphonates should be considered in individual patients.

P=N/A, N=20, Active, not recruiting, Lithuanian University of Health Sciences | Recruiting --> Active, not recruiting

Ibandronate sodium demonstrates a protective effect on articular chondrocytes and exhibits the potential to decelerate the pathological progression of knee osteoarthritis (KOA) in rats. This mechanism is likely achieved through the inhibition of the TLRs/MyD88/NF-κB signaling pathway.

In addition, galectin-3 reduced the effector memory compartment of zoledronate-activated Vδ2 T cells. Therefore, our data suggest that an activation of Vδ1 T-cell proliferation as part of a T-cell-based immunotherapy can be of advantage.

The complexes studied involve four compounds: cyclosporin A (CSA), amiodarone (AMI), pamidronate (APD), and valproic acid (VPA). Furthermore, distinctive behavior was observed in the presence of active and inactive compounds, particularly in the arrangement of ATP between NBDs, supporting the proposed nucleotide sandwich dimer mechanism for ATP binding. This study provides comprehensive insights into P-gp behavior with various ligands and ATP, offering implications for drug development, toxicity assessment and demonstrating the validity of the results derived from the MD simulations.

In this study, we established a protocol for ex vivo expansion of Vγ9Vδ2 T cells from healthy donors' peripheral blood mononuclear cells by culture with zoledronate and addition of IL-2, and IL-15 or IL-18 or neither...We found that in the presence of either IL-15 or IL-18, levels of caspase 3 were significantly reduced. Also, IL-15 and IL-18 stimulated cells contained cytotoxicity against cholangiocarcinoma cells, suggesting that stimulated Vγ9Vδ2 T cells may provide a feasible therapy for cholangiocarcinoma.

ZA decreased phosphorylated ERK (pERK) levels in resistant cell lines and attenuated HER-2 signaling in tamoxifen- and fulvestrant-resistant cells. Moreover, ZA inhibited the migration and invasion in the resistant cell lines, suggesting an ability to inhibit tumor metastasis. The results indicate that ZA has potential for repurposing as an adjuvant treatment for patients with endocrine-resistant breast cancer.

P2, N=44, Recruiting, University of Nebraska | Trial completion date: Dec 2024 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2027

P1, N=22, Recruiting, University of Wisconsin, Madison

Here, we express an anti-CD19 εTRuC in primary γδ T cells that were expanded using zoledronate (Zol) or concanavalin A. We show that the resulting εTRuC γδ T cells were reprogrammed to better recognize CD19-positive B cell tumors and-in case of the Zol-expanded cells-a CD19-expressing colon adenocarcinoma-derived cell line in vitro...Finally, addition of vitamin C promoted the recovery of larger γδ T cell numbers after lentiviral transduction, as used for the expression of the εTRuC. In conclusion, the generation and use of γδ εTRuC T cells might be a new approach for cancer immunotherapy.

The findings of this work highlighted ZGP's potential for intervening in the progression of breast cancer bone metastasis. Thus, this investigation served as an experimental foundation for expanding the application scope of ZGP and for advancing drug development efforts in bone metastasis treatment.

The present study demonstrated that catalpol prevents estrogen deficiency-induced osteoporosis by promoting osteoclast apoptosis via the Sirt6-ERα-FasL axis. These findings revealed a novel molecular mechanism underpinning the impact of catalpol in the progression of osteoporosis and provided novel insights into the treatment of osteoporosis.

P4, N=20, Recruiting, Aksaray University | Not yet recruiting --> Recruiting

P2, N=24, Not yet recruiting, University of California, Davis | Initiation date: Oct 2023 --> Jan 2024

We tried different electroporation procedures (X001, T007, U014, T023) and cell culture conditions (cultured in medium containing zoledronic acid (ZOL)/ IL2 for 5 days or for 10 days) to select out the optimal procedure to acquire high KO/KI efficiency and high cell proliferation rate...Interestingly, the proportion of memory phenotype (CD62L + ) in CAR-γδ T cells after being stimulated was comparable to that of CAR-γδ T cells without stimulation, indicating the potential of the great anti-tumor activity of CAR-γδ T cells after being stimulated in tumor environment (Figure 1F). Our new method successfully generated CAR-γδ T cells with a CAR expression of 20% and in a high proliferation rate, which was determined to exert effective anti-tumor effects.

P=N/A, N=287, Enrolling by invitation, University of Edinburgh | Recruiting --> Enrolling by invitation

P2, N=69, Completed, University of Aarhus | Active, not recruiting --> Completed

P4, N=20, Not yet recruiting, Aksaray University

The results showed that compounds 1-3 exhibited anti-inflammatory activities with dose-dependent manner range from 12.5 to 50 µmol/L. Furthermore, the inhibitory activities of compounds 1 and 2 on receptor activator of NF-κB ligand (RANKL) induced osteoclast formation were tested in vitro. Compounds 1 and 2  at 5 µmol/L exhibited the significant inhibitory effect on the osteoclastogenesis induced by RANKL. This work reported the anti-inflammatory and osteoclast inhibitory activities of new monoterpenoid indole hybrids, which may inspire the further light on the related traditional application research of G. elegans.

EA treatment enhanced the A2AR activity and inhibited osteoclast formation by inhibition of RANKL, RANK, TRAF6, p38α, NF-κB, and NFATc1. SCH58261 reversed the effect of EA. These results suggest that EA regulated p38α-MAPK signaling by increasing A2AR activity, which inhibited osteoclastogenesis.

MIDP, a zoledronic acid derivative, can cause the death of human colorectal cancer cells by increasing the level of intracellular reactive oxygen species (ROS)...This study revealed for the first time a possible mechanism of bisphosphonate-induced increase of ROS in malignant tumor cells. This is helpful for the development of new molecular therapeutic targets and can provide new ideas for the combined therapy of bisphosphonates in tumors.