title: The effect of nitrogen containing bisphosphonates, zoledronate and alendronate, on the production of pro-angiogenic factors by osteoblastic cells.
abstract: Bisphosphonates (BPs) have been shown to influence angiogenesis. This may contribute to BP-associated side-effects such as osteonecrosis of the jaw (ONJ) or atypical femoral fractures (AFF). The effect of BPs on the production of angiogenic factors by osteoblasts is unclear. The aims were to investigate the effect of (1) alendronate on circulating angiogenic factors; vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) in vivo and (2) zoledronate and alendronate on the production of VEGF and ANG-1 by osteoblasts in vitro. We studied 18 post-menopausal women with T score⩽-2 randomized to calcium/vitamin D only (control arm, n=8) or calcium/vitamin D and alendronate 70mg weekly (treatment arm, n=10). Circulating concentrations of VEGF and ANG-1 were measured at baseline, 3, 6 and 12months. Two human osteoblastic cell lines (MG-63 and HCC1) and a murine osteocytic cell line (MLO-Y4) were treated with zoledronate or alendronate at concentrations of 10(-12)-10(-6)M. VEGF and ANG-1 were measured in the cell culture supernatant. We observed a trend towards a decline in VEGF and ANG-1 at 6 and 12months following treatment with alendronate (p=0.08). Production of VEGF and ANG-1 by the MG-63 and HCC1 cells decreased significantly by 34-39% (p<0.01) following treatment with zoledronate (10(-9)-10(-6)M). Treatment of the MG-63 cells with alendronate (10(-7) and 10(-6)) led to a smaller decrease (25-28%) in VEGF (p<0.05). Zoledronate (10(-10)-10(-)(6)M) suppressed the production of ANG-1 by MG-63 cells with a decrease of 43-49% (p<0.01). Co-treatment with calcitriol (10(-8)M) partially reversed this zoledronate-induced inhibition. BPs suppress osteoblastic production of angiogenic factors. This may explain, in part, the pathogenesis of the BP-associated side-effects.
authors.affiliation: Department of Chemical Pathology, St Thomas' Hospital, London SE1 7EH, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ishtiaq
authors.affiliation: Osteoporosis Unit, Guy's Hospital, London SE19RT, UK.
authors.forename: S
authors.initials: S
authors.lastname: Edwards
authors.affiliation: Department of Chemical Pathology, St Thomas' Hospital, London SE1 7EH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Sankaralingam
authors.affiliation: Institute of Molecular and Experimental Medicine, Cardiff University, CF14 4XN Wales, UK.
authors.forename: B A J
authors.initials: BA
authors.lastname: Evans
authors.affiliation: Institute of Molecular and Experimental Medicine, Cardiff University, CF14 4XN Wales, UK.
authors.forename: C
authors.initials: C
authors.lastname: Elford
authors.affiliation: Osteoporosis Unit, Guy's Hospital, London SE19RT, UK.
authors.forename: M L
authors.initials: ML
authors.lastname: Frost
authors.affiliation: Osteoporosis Unit, Guy's Hospital, London SE19RT, UK.
authors.forename: I
authors.initials: I
authors.lastname: Fogelman
authors.affiliation: Department of Chemical Pathology, St Thomas' Hospital, London SE1 7EH, UK; Osteoporosis Unit, Guy's Hospital, London SE19RT, UK. Electronic address: Geeta.hampson@kcl.ac.uk.
authors.forename: G
authors.initials: G
authors.lastname: Hampson
mesh_terms: D019386:Alendronate / Q000494:pharmacology* / Q000627:therapeutic use; D042683:Angiopoietin-1 / Q000097:blood / Q000378:metabolism*; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000188:drug therapy; D002117:Calcitriol / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008875:Middle Aged; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000188:drug therapy; D010446:Peptide Fragments / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000077211:Zoledronic Acid
chemical_list: D042683:Angiopoietin-1; D050071:Bone Density Conservation Agents; D017077:Culture Media, Conditioned; D004164:Diphosphonates; D007093:Imidazoles; D010446:Peptide Fragments; D011347:Procollagen; D042461:Vascular Endothelial Growth Factor A; C047202:procollagen Type I N-terminal peptide; D000077211:Zoledronic Acid; D002117:Calcitriol; D019386:Alendronate
keywords: Angiogenesis; Angiopoietin-1; Bisphosphonates; Osteoblasts; VEGF