ECTS2016 Poster Presentations Cancer and bone: basic, translational and clinical (37 abstracts)
The pharmacological profile of a novel highly potent bisphosphonate, OX14 (1-fluoro-2-(imidazo-[1,2 alpha]pyridin-3-yl)ethyl-bisphosphonate), with reduced bone affinity, which is as effective as zoledronate in the treatment of myeloma bone disease in JJN3-NOD/SCID-γ mice
Michelle Lawson 1, , Andrew Chantry 1, , Julia Paton-Hough 1, , Holly Evans 1, , Darren Lath 1, , Maria Tsoumpra 1, , Mark Lundy 3 , Roy Dobson 4 , Michael Quijano 4 , Aaron Kwaasi 5 , James Dunford 5 , Xuchen Duan 5 , James Triffit 5 , Adam Mazur 5 , Gwyn Jeans 4 , Graham Russell 2, & Hal Ebetino 6
1Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK; 2Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffiled, UK; 3Indiana University, Purdue, Indianapolis, USA; 4Procter & Gamble, Mason, Ohio, USA; 5Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, The Oxford University Institute of Musculoskeletal Sciences, The Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK; 6University of Rochester, Rochester, New York, USA.
Bisphosphonates are used in the treatment of a variety of diseases with skeletal complications. With the development of more potent compounds, there is the potential for further improvement. One concept is to use compounds with a reduced affinity for bone, reducing their long-term retention and possible adverse events, as well as potentially enhancing their non-skeletal benefits. We hypothesise that a highly potent bisphosphonate with low bone affinity, known as OX14, will be as effective as bisphosphonates currently used in the clinic. The aim of this work was to evaluate the use of OX14 in vitro and in vivo. The binding of OX14 to hydroxyapatite and its ability to inhibit FPPS was compared to other bisphosphonates. The excretion rate and anti-resorptive potency of OX14 was assessed in a growing rat model. The effects of different doses of OX14 on bone integrity were assessed in naïve mice and its therapeutic effect was compared to ZOL in the JJN3-NSG murine model of myeloma. OX14 was more potent than ZOL at inhibiting FPPS and had a lower binding affinity to hydroxyapatite than ZOL, ALEN, IBAN or RIS. In a growing rat model, OX14 was more effective than RIS at increasing BMD. In addition, it was excreted into the urine to a greater extent than other bisphosphonates currently used clinically, indicating lower skeletal retention. In non-tumour mice, OX14 was shown to have a dose dependent effect on bone and was as effective as clinically relevant bisphosphonates. In a murine model of myeloma-induced bone disease, OX14 was shown to be as effective as ZOL at preventing the formation of osteolytic lesions. In summary, OX14 is a highly potent bisphosphonate with lower bone affinity than other bisphosphonates, and this may offer potential advantages in eventually treating patients who require bisphosphonates for their skeletal or non-skeletal benefits.
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Bone Abstracts
ISSN 2052-1219 (online)
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