title: Dose-dependent effects of strontium on bone of chronic renal failure rats.
abstract: BACKGROUND
  We previously reported on increased bone strontium (Sr) levels in dialysis patients with osteomalacia versus those presenting other types of renal osteodystrophy. A causal role of strontium in the development of osteomalacia was established in a chronic renal failure (CRF) rat model.
  
  
  METHODS
  In the present study we investigated whether the effect of Sr on bone was related to dosage. Four groups of CRF rats were studied: a control group (control-CFR; N=6) not receiving strontium and three groups of animals loaded orally with Sr during 18 weeks by adding the element as the SrCl2. H20 compound to the drinking water at concentrations of 0.03 g/100mL (Sr-30; N=6), 0.075 g/100mL (Sr-75; N=6), or 0.15 g/100mL (Sr-150; N=6) respectively. A fifth group consisting of seven animals with intact renal function (control-NRF), not receiving Sr served as controls for the effect of CRF on bone histology.
  
  
  RESULTS
  As compared to the control-NRF and control-CRF groups, Sr administration resulted in a dose-dependent increase in bone and serum Sr levels. No difference in body weight and biochemical serum and urinary parameters [i.e., calcium (Ca), phosphorus (P), and creatinine] was noted between the various CRF groups. At sacrifice, intact parathyroid hormone (iPTH) levels of CRF groups were significantly (P < 0.05) higher than the values measured in the control-NRF group indicating the development of hyperparathyroidism secondary to the installation of the CRF. This is further supported by the differences in bone histomorphometry between the control-CRF and control-NRF animals, which, respectively, showed an increased amount of osteoid (mean +/- SEM 3.4 +/- 1.2% vs. 0.37 +/- 0.14%, P < 0.05) in combination with a distinct osteoblastic activity (35 +/- 11% vs. <2%, P < 0.05) and an increased bone formation rate [(BFR), 677 +/- 177 microm 2/mm2/day vs. 130 +/- 50 microm 2/mm2/day, P < 0.05]. Bone surface area and erodic perimeter did not differ between the various study groups. In the Sr-30 group, Sr loading went along with a dramatic reduction of the BFR as indicated by the total absence of double tetracyclin labels and osteoblastic activity, which in the presence of a low to normal amount of osteoid (2.7 +/- 1.9%) points to the development of the adynamic type of renal osteodystrophy. Interestingly, compared to the control-CRF group, histodynamic and histologic parameters of the Sr-75 group did not differ significantly and a substantial osteoblastic activity (7.6 +/- 4.0%) was seen also. In the Sr-150 group, the various osteoid parameters were significantly (P < 0.05) increased vs. all other groups and were accompanied by a reduced BFR and mineral apposition rate (MAR) and an increased mineralization lag time (MLT), indicating a mineralization defect and the development of osteomalacia.
  
  
  CONCLUSIONS
  Our findings indicate that the role of Sr in the development of bone lesions in renal failure is complex and that, depending on the dose, the element may act via multiple pathways.
authors.affiliation: Department of Nephrology-Hypertension, University of Antwerp, Belgium.
authors.forename: Iris
authors.initials: I
authors.lastname: Schrooten
authors.forename: Geert J S
authors.initials: GJ
authors.lastname: Behets
authors.forename: Walter E
authors.initials: WE
authors.lastname: Cabrera
authors.forename: Sven R
authors.initials: SR
authors.lastname: Vercauteren
authors.forename: Ludwig V
authors.initials: LV
authors.lastname: Lamberts
authors.forename: Steven C
authors.initials: SC
authors.lastname: Verberckmoes
authors.forename: An J
authors.initials: AJ
authors.lastname: Bervoets
authors.forename: Geert
authors.initials: G
authors.lastname: Dams
authors.forename: William G
authors.initials: WG
authors.lastname: Goodman
authors.forename: Marc E
authors.initials: ME
authors.lastname: De Broe
authors.forename: Patrick C
authors.initials: PC
authors.lastname: D'Haese
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007676:Kidney Failure, Chronic / Q000150:complications*; D008297:Male; D009392:Nephrectomy; D010006:Osteoblasts / Q000502:physiology; D010018:Osteomalacia / Q000188:drug therapy* / Q000209:etiology*; D051381:Rats; D017208:Rats, Wistar; D013324:Strontium / Q000494:pharmacology*
chemical_list: C025700:strontium chloride; D013324:Strontium