title: Increased bone resorption in HD patients: is it caused by elevated RANKL synthesis?
abstract: BACKGROUND
  The receptor activator of nuclear factor kappaB ligand (RANKL), produced by osteoblasts/stromal cells, is a member of the RANK/RANKL/OPG system, which regulates bone resorption by osteoclasts. Since RANKL and osteoprotegerin (OPG) production in bone is influenced by parathyroid hormone (PTH), we measured serum RANKL and OPG concentrations in haemodialysis (HD) patients, who commonly hypersecrete PTH. We aimed to determine if clinically demonstrated PTH-enhanced bone resorption is a consequence of increased RANKL synthesis.
  
  
  METHODS
  RANKL, OPG, osteocalcin, intact PTH, bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase 5b and beta-CrossLaps (CTx) were measured in blood samples from 80 HD patients and 50 age-matched controls. HD patients were stratified to tertiles according to their serum PTH levels: 29.3-103.0, 109.7-263.0 and 262.0-1700.0 pg/ml in the first, second and third tertiles, respectively.
  
  
  RESULTS
  Mean serum RANKL levels were 1.6 times higher in HD patients than in age-matched controls (1.36+/-0.39 vs 0.83+/-0.70 pmol/l; P<0.001). All the measured bone markers significantly differed between patients and controls (P<0.001). Spearman's tests of correlation showed a statistically significant association of RANKL with PTH, osteocalcin and CTx (r=0.322, P=0.004; r=0.231, P=0.039; and r=0.230, P=0.040, respectively). Mean serum RANKL levels were significantly different between PTH tertiles (P = 0.003), but serum OPG levels were not (P=0.144). The highest RANKL levels were measured in the upper PTH tertile (1.54+/-0.39 pmol/l) and were significantly higher than in the middle or lower tertiles (1.27+/-0.42 and 1.23+/-0.26 pmol/l, respectively; P=0.003). Both of the measured bone-resorption markers, tartarate-resistant acid phosphatase 5b and CTx, as well as both bone formation markers, osteocalcin and bone-specific alkaline phosphatase were also significantly higher in the upper tertile, indicating that whole-bone remodelling is activated at high PTH and RANKL levels.
  
  
  CONCLUSIONS
  Serum RANKL levels were significantly higher in HD patients than in healthy age-matched controls. Moreover, RANKL levels were significantly higher in the upper PTH tertile, indicating enhanced RANKL synthesis in a PTH-dependent fashion. Thus, our clinical findings clearly support published in vitro studies that demonstrated a stimulating effect of PTH on RANKL synthesis. Therefore, the hypothesis that PTH increases bone resorption in HD patients through RANKL appears valid.
authors.affiliation: Department of Clinical Biochemistry, General Hospital Jesenice, Jesenice, Slovenia.
authors.forename: Ivica
authors.initials: I
authors.lastname: Avbersek-Luznik
authors.forename: Breda Pecovnik
authors.initials: BP
authors.lastname: Balon
authors.forename: Igor
authors.initials: I
authors.lastname: Rus
authors.forename: Janja
authors.initials: J
authors.lastname: Marc
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D001862:Bone Resorption / Q000097:blood / Q000209:etiology*; D002352:Carrier Proteins / Q000097:blood*; D016022:Case-Control Studies; D003094:Collagen / Q000097:blood; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D007527:Isoenzymes / Q000097:blood; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000150:complications / Q000628:therapy; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D053244:Osteoprotegerin; D010281:Parathyroid Hormone / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood*; D018124:Receptors, Tumor Necrosis Factor; D006435:Renal Dialysis; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C110762:glutamyl-lysyl-alanyl-histidyl-aspartyl-glycyl-glycyl-arginine; D015675:Osteocalcin; D003094:Collagen; D000469:Alkaline Phosphatase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase