Bone resorption and renal calcium reabsorption in renal cell carcinoma-bearing mice: The effects of bisphosphonate

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. MATERIALS AND 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 ≈100 mm3 and 500 mm3, and the mice were monitored for ≈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 mm3 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 mm3 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. © 2007 The Authors. Chemicals / CAS: calcium, 7440-70-2; olpadronic acid, 63132-39-8; parathyroid hormone, 12584-96-2, 68893-82-3, 9002-64-6; phosphate, 14066-19-4, 14265-44-2; sodium chloride, 7647-14-5; Bone Density Conservation Agents; Calcium, 7440-70-2; Diphosphonates; olpadronic acid, 63132-39-8