Minimally effective concentration of zoledronic acid to suppress osteoclasts in vitro

Zoledronic acid is regarded as the most potent bisphosphonate and is widely used in patients with osteoporosis; however, its side effects, including acute-phase reactions, gastrointestinal complaints, renal dysfunction and bisphosphonate-associated osteonecrosis impair the safety and quality of life of patients. The present study was designed to determine the minimal effective concentration of zoledronic acid through testing the dose-dependent effects of zoledronic acid on osteoclast suppression. A primary culture of bone marrow mononuclear cells obtained from C57 mice (age, 6 weeks) was established and induced to form osteoclasts. The number of multinuclear cells was determined by tartrate-resistant acid phosphatase staining and compared among cultured marrow cells treated with different concentrations of zoledronic acid. Furthermore, the cellular properties, including adhesion, migration and bone resorption, were compared at the minimal effective concentration. At a concentration of 1×10−6 mol/l, zoledronic acid significantly inhibited the formation of osteoclasts. This inhibitory effect was further enhanced at the concentration of 1×10−5 mol/l. However, the inhibitory effect of zoledronic acid tapered at the concentration of 1×10−4 mol/l and there was no further dose-dependent increase. In addition, the concentration of 1×10−6 mol/l was sufficient to alter cellular functions, including cell adhesion, migration and bone resorption. In conclusion, zoledronic acid was effective in reducing osteoclast formation and suppressing cellular functions. The minimal effective concentration of zoledronic acid in vitro was 1 µmol/l. Based on these results, a comparable dosage should be explored in clinical applications.

[1]  N. Raje,et al.  Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. , 2018, The Lancet. Oncology.

[2]  S. Schurman,et al.  Zoledronic acid for neonatal subcutaneous fat necrosis , 2017, Clinical case reports.

[3]  J. Byun,et al.  The Efficacy of Bisphosphonates for Prevention of Osteoporotic Fracture: An Update Meta-analysis , 2017, Journal of bone metabolism.

[4]  John D. Roberts,et al.  Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial , 2017, JAMA.

[5]  A. Agrawal,et al.  Effect of zoledronic acid on fracture healing in osteoporotic patients with intertrochanteric fractures , 2017, International journal of applied & basic medical research.

[6]  A. Schindeler,et al.  Combination sclerostin antibody and zoledronic acid treatment outperforms either treatment alone in a mouse model of osteogenesis imperfecta. , 2015, Bone.

[7]  C. Shivaprasad,et al.  Preoperative zoledronic acid therapy prevent hungry bone syndrome in patients with primary hyperparathyroidism , 2017, Indian journal of endocrinology and metabolism.

[8]  R. Laing,et al.  Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial , 2016, The Lancet.

[9]  M. Shingyoji,et al.  An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol , 2016, SpringerPlus.

[10]  C. Poznak,et al.  Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: A meta-analysis of randomised trials , 2016 .

[11]  J. Olson,et al.  Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy: a 5-year follow-up , 2016, Supportive Care in Cancer.

[12]  T. Rosol,et al.  Combined zoledronic acid and meloxicam reduced bone loss and tumour growth in an orthotopic mouse model of bone-invasive oral squamous cell carcinoma. , 2015, Veterinary and comparative oncology.

[13]  L. Mascarenhas,et al.  Zoledronic Acid for the Treatment of Children With Refractory Central Giant Cell Granuloma , 2015, Journal of pediatric hematology/oncology.

[14]  Meral Günaldı,et al.  Effect of the cumulative dose of zoledronic acid on the pathogenesis of osteonecrosis of the jaws. , 2015, Oncology letters.

[15]  Junkang Shen,et al.  Effect of zoledronic acid on vertebral marrow adiposity in postmenopausal osteoporosis assessed by MR spectroscopy , 2015, Skeletal Radiology.

[16]  E. Yonemochi,et al.  Zoledronic acid enhances antitumor efficacy of liposomal doxorubicin. , 2015, International journal of oncology.

[17]  J. Tisdale,et al.  Influence of Zoledronic Acid on Atrial Electrophysiological Parameters and Electrocardiographic Measurements , 2015, Cardiovascular Electrophysiology.

[18]  S. Polyzos,et al.  Denosumab versus zoledronic acid in patients previously treated with zoledronic acid , 2015, Osteoporosis International.

[19]  Wei-Ming Chen,et al.  Zoledronic acid-loaded bone cement as a local adjuvant therapy for giant cell tumor of the sacrum after intralesional curettage , 2015, European Spine Journal.

[20]  E. Yonemochi,et al.  Evaluation of antitumor effect of zoledronic acid entrapped in folate-linked liposome for targeting to tumor-associated macrophages , 2015, Journal of liposome research.

[21]  A. Berdal,et al.  Skeletal consequences of RANKL-blocking antibody (IK22-5) injections during growth: mouse strain disparities and synergic effect with zoledronic acid. , 2015, Bone.

[22]  A. Rody,et al.  Lack of difference in acute nephrotoxicity of intravenous bisphosphonates zoledronic acid and ibandronate in women with breast cancer and bone metastases. , 2015, Anticancer research.

[23]  M. Imamura,et al.  The effects of bisphosphonate zoledronic acid in hepatocellular carcinoma, depending on mevalonate pathway , 2015, Journal of gastroenterology and hepatology.

[24]  Yukihiko Hiroshima,et al.  Selective efficacy of zoledronic acid on metastasis in a patient‐derived orthotopic xenograph (PDOX) nude‐mouse model of human pancreatic cancer , 2015, Journal of surgical oncology.

[25]  R. Greil,et al.  Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[26]  A. Evdokiou,et al.  The combined use of Camellia sinensis and metronomic zoledronic acid in a breast cancer-induced osteolysis mouse model , 2015, Journal of Cancer Research and Clinical Oncology.

[27]  H. Guan,et al.  Continuous effect with long-term safety in zoledronic acid therapy for polyostotic fibrous dysplasia with severe bone destruction , 2015, Rheumatology International.

[28]  A. Cataldi,et al.  Zoledronic acid at subtoxic dose extends osteoblastic stage span of primary human osteoblasts , 2014, Clinical Oral Investigations.

[29]  F. O'Brien,et al.  A collagen-hydroxyapatite scaffold allows for binding and co-delivery of recombinant bone morphogenetic proteins and bisphosphonates. , 2014, Acta biomaterialia.

[30]  P. Edwards,et al.  Upregulation of endogenous farnesyl diphosphate synthase overcomes the inhibitory effect of bisphosphonate on protein prenylation in Hela cells. , 2014, Biochimica et biophysica acta.

[31]  F. O'Brien,et al.  Effects of ageing, prolonged estrogen deficiency and zoledronate on bone tissue mineral distribution. , 2014, Journal of the mechanical behavior of biomedical materials.

[32]  U. Albert,et al.  Effects of zoledronic acid versus placebo on bone mineral density and bone texture analysis assessed by the trabecular bone score in premenopausal women with breast cancer treatment-induced bone loss: results of the ProBONE II substudy , 2014, Osteoporosis International.

[33]  C. Gialeli,et al.  Preclinical evaluation of zoledronate using an in vitro mimetic cellular model for breast cancer metastatic bone disease. , 2013, Biochimica et biophysica acta.

[34]  T. Kuroishi,et al.  In vitro cytotoxicity of zoledronate (nitrogen-containing bisphosphonate: NBP) and/or etidronate (non-NBP) in tumour cells and periodontal cells. , 2013, Archives of oral biology.

[35]  R. Taichman,et al.  The effects of zoledronic acid in the bone and vasculature support of hematopoietic stem cell niches , 2013, Journal of cellular biochemistry.

[36]  A. Russo,et al.  Analysis of molecular mechanisms and anti-tumoural effects of zoledronic acid in breast cancer cells , 2012, Journal of cellular and molecular medicine.

[37]  S. Polyzos,et al.  High Circulating Sclerostin is Present in Patients with Thalassemia-associated Osteoporosis and Correlates with Bone Mineral Density , 2012, Hormone and Metabolic Research.

[38]  D. Ota,et al.  A case of femoral diaphyseal fracture after long-term treatment with zoledronic acid , 2011, Breast Cancer.

[39]  T. Ikebe,et al.  Zoledronic acid inhibits RANK expression and migration of osteoclast precursors during osteoclastogenesis , 2011, Naunyn-Schmiedeberg's Archives of Pharmacology.

[40]  A. Salama,et al.  A novel bioassay model to determine clinically significant bisphosphonate levels , 2009, Supportive Care in Cancer.

[41]  K. Kavanagh,et al.  Bisphosphonates , 2007, Annals of the New York Academy of Sciences.

[42]  I. Holen,et al.  Zoledronic acid-induced IPP/ApppI production in vivo. , 2007, Life sciences.

[43]  Hannu-Ville Leskelä,et al.  In vitro comparison of clodronate, pamidronate and zoledronic acid effects on rat osteoclasts and human stem cell-derived osteoblasts. , 2005, Basic & clinical pharmacology & toxicology.

[44]  E. Kleinerman,et al.  Zoledronic acid inhibits primary bone tumor growth in Ewing sarcoma , 2005, Cancer.

[45]  A. Evdokiou,et al.  Induction of cell death of human osteogenic sarcoma cells by zoledronic acid resembles anoikis. , 2003, Bone.

[46]  J. Soria,et al.  New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects , 2003, British Journal of Cancer.

[47]  P. LoRusso,et al.  Pharmacokinetics and Pharmacodynamics of Zoledronic Acid in Cancer Patients with Bone Metastases , 2002, Journal of clinical pharmacology.