title: Strontium potently inhibits mineralisation in bone-forming primary rat osteoblast cultures and reduces numbers of osteoclasts in mouse marrow cultures.
abstract: CONCLUSIONS
  The basic mechanisms by which strontium ranelate acts on bone are still unclear. We show that an important action of strontium salts is to block calcification in cultures of osteoblasts, the bone-forming cells. These results suggest that strontium treatment could have previously overlooked effects on bone.
  
  
  BACKGROUND
  The basic mechanisms of action of strontium ranelate (SrR) on bone have remained unclear. We studied the direct actions of Sr(2+) salts in functional cultures of osteoblasts and osteoclasts.
  
  
  METHODS
  Cultures of primary osteoblasts from rat calvariae and osteoclast-forming mouse marrow cells were treated continuously with either SrR or strontium chloride (SrCl2).
  
  
  RESULTS
  Abundant, discretely mineralised 'trabecular' bone structures formed in control osteoblast cultures after 14 days. SrR at 0.01, 0.1 and 1 mM inhibited mineralisation to 59, 98 and 100 % (all p < 0.001) of control values, respectively. SrCl2 at the same concentrations caused similar inhibitions. Osteoblast cell numbers and alkaline phosphatase activity were unaltered. SrR dose-dependently reduced the formation of multinucleated osteoclasts from marrow mononuclear cells cultured on dentine for 8 days in the presence of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL), with a 50 % inhibition occurring at 1 mM; SrCl2 was slightly less effective, eliciting a maximal 30 % inhibition. Corresponding decreases in total resorption pit formation were observed, suggesting Sr(2+) salts affect osteoclast formation rather than resorptive activity.
  
  
  CONCLUSIONS
  Our findings are consistent with the documented physicochemical inhibitory action of Sr(2+) on mineralisation but contrast with reports that Sr(2+) increases osteoblast activity and number in vitro. Our results suggest that rather than acting as an agent that 'uncouples' bone formation and resorption, Sr(2+) acts as a global inhibitor of bone cell function, with particularly marked effects on mineralisation. The potential effects of long-term Sr(2+) on secondary mineralisation in bone deserve investigation.
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: D P
authors.initials: DP
authors.lastname: Wornham
authors.forename: M O
authors.initials: MO
authors.lastname: Hajjawi
authors.forename: I R
authors.initials: IR
authors.lastname: Orriss
authors.forename: T R
authors.initials: TR
authors.lastname: Arnett
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002113:Calcification, Physiologic / Q000187:drug effects*; D002452:Cell Count; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D010006:Osteoblasts / Q000187:drug effects* / Q000502:physiology; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology; D017207:Rats, Sprague-Dawley; D013324:Strontium / Q000494:pharmacology; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D050071:Bone Density Conservation Agents; D013876:Thiophenes; C081587:strontium ranelate; D000469:Alkaline Phosphatase; C025700:strontium chloride; D013324:Strontium