title: Bone resorption and renal calcium reabsorption in renal cell carcinoma-bearing mice: the effects of bisphosphonate.
abstract: OBJECTIVE
  To examine the contribution of the skeleton and the kidney to the development of humoral hypercalcaemia of malignancy (HHM) in a mouse model of HHM treated with a potent bisphosphonate.
  
  
  METHODS
  Mice bearing the human RCC cell line RC-9 were treated with bisphosphonate (subcutaneous, 0.25 mg/kg body weight olpadronate) or saline solution. Treatment was initiated at a tumour volume (TV) of approximately 100 mm(3) and 500 mm(3), and the mice were monitored for approximately 4 weeks. Serum calcium and phosphate concentrations and trabecular bone volume (TBV) were assessed during and/or after treatment.
  
  
  RESULTS
  Athymic mice implanted with the RCC RC-9, developed severe hypercalcaemia and bone resorption. During tumour growth the mean (sd) serum calcium concentration increased to 4.1 (0.3) mmol/L, and phosphate decreased to 1.6 (0.3) mmol/L, vs 2.3 (0.1) and 2.9 (0.4) mmol/L in controls, respectively. TBV decreased from 8.7 (1.8)% in mice with no tumour, to 5.3 (2.7)% in RC-9-bearing mice. Olpadronate initiated at a Tv of 100 mm(3) prevented the loss of bone induced by RCC RC-9 cells, with a TBV of 12.8 (2.1)%, but the development of hypercalcaemia was unaffected. Olpadronate treatment at a TV of 500 mm(3) did not influence the development of hypercalcaemia and did not protect against bone resorption. Kinetic monitoring showed an identical rate of tumour growth in the presence or absence of bisphosphonate, while under both conditions there was a tumour load-dependent increase in calcium concentration.
  
  
  CONCLUSIONS
  Bisphosphonate can prevent parathyroid hormone-related peptide (PTHrP)-mediated bone resorption when administered during the early phase of renal tumour growth, but has no effect on the tumour-induced development of hypercalcaemia, indicating a primary role for renal tubular reabsorption of calcium in the kidney by PTHrP in HHM.
authors.affiliation: Department of Urology, University Medical Center, Leiden, The Netherlands. weissgla@kg.nl
authors.forename: Max
authors.initials: M
authors.lastname: Weissglas
authors.forename: Clemens
authors.initials: C
authors.lastname: Löwik
authors.forename: Denis
authors.initials: D
authors.lastname: Schamhart
authors.forename: Harry
authors.initials: H
authors.lastname: Theuns
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Kurth
authors.forename: Socrates
authors.initials: S
authors.lastname: Papapoulos
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001862:Bone Resorption / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000150:complications* / Q000378:metabolism; D004164:Diphosphonates / Q000627:therapeutic use*; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000150:complications* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C055774:olpadronic acid; D002118:Calcium