title: Disease modifying and anti-nociceptive effects of the bisphosphonate, zoledronic acid in a model of bone cancer pain.
abstract: Inoculation of syngeneic MRMT-1 mammary tumour cells into one tibia of female rats produced tumour growth within the bone associated with a reduction in bone mineral density (BMD) and bone mineral content (BMC), severe radiological signs of bone destruction, together with the development of behavioural mechanical allodynia and hyperalgesia. Histological and radiological examination showed that chronic treatment with the bisphosphonate, zoledronic acid (30 microg/kg, s.c.), for 19 days significantly inhibited tumour proliferation and preserved the cortical and trabecular bone structure. In addition, BMD and BMC were preserved and a dramatic reduction of tartrate resistant acid phosphatase-positive polykaryocytes (osteoclasts) was observed. In behavioural tests, chronic treatment with zoledronic acid but not the significantly less effective bisphosphonate, pamidronate, or the selective COX-2 inhibitor, celebrex, attenuated mechanical allodynia and hyperalgesia in the affected hind paw. Zoledronic acid also attenuated mechanical hyperalgesia associated with chronic peripheral neuropathy and inflammation in the rat. In contrast, pamidronate or clodronate did not have any anti-hyperalgesic effect on mechanical hyperalgesia in the neuropathic and inflammatory pain models. We conclude that zoledronic acid, in addition to, or independent from, its anti-metastatic and bone preserving therapeutic effects, is an anti-nociceptive agent in a rat model of metastatic cancer pain. This unique property of zoledronic acid amongst the bisphosphonate class of compounds could make this drug a preferred choice for the treatment of painful bone metastases in the clinic.
authors.affiliation: Purdue Biopharma LP, 201 College Road East, Princeton, NJ 08540, USA Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BN, UK W. Harvey Research Institute, St Bartholomew's and Royal London School of Medicine, Charterhouse Square, London, UK Novartis Pharma AG, Basel, Switzerland.
authors.forename: Katharine
authors.initials: K
authors.lastname: Walker
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Medhurst
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Kidd
authors.forename: Markus
authors.initials: M
authors.lastname: Glatt
authors.forename: Mick
authors.initials: M
authors.lastname: Bowes
authors.forename: Sadhana
authors.initials: S
authors.lastname: Patel
authors.forename: Kara
authors.initials: K
authors.lastname: McNair
authors.forename: Adam
authors.initials: A
authors.lastname: Kesingland
authors.forename: Jonathan
authors.initials: J
authors.lastname: Green
authors.forename: Otto
authors.initials: O
authors.lastname: Chan
authors.forename: Alyson J
authors.initials: AJ
authors.lastname: Fox
authors.forename: Laszlo A
authors.initials: LA
authors.lastname: Urban
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001859:Bone Neoplasms / Q000150:complications* / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D004002:Clodronic Acid / Q000008:administration & dosage; D004164:Diphosphonates / Q000008:administration & dosage*; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D006941:Hyperesthesia / Q000188:drug therapy / Q000209:etiology; D007093:Imidazoles / Q000008:administration & dosage*; D023421:Models, Animal; D009368:Neoplasm Transplantation; D015588:Observer Variation; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D000077268:Pamidronate; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013977:Tibia / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D014110:Touch / Q000187:drug effects; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D004002:Clodronic Acid; D000077211:Zoledronic Acid; D000077268:Pamidronate