Poster Topical Area: Aging and Chronic Disease
Poster Board Number: 53
Objectives: To develop a dynamic (non-steady-state) mathematical model of calcium metabolism in young growing rats and to quantify the effect of bone resorption inhibitor (osteoprotegerin; OPG) and stimulant (receptor activator of nuclear factor kappa-Β ligand; RANKL) on calcium release from bone.
Methods: In this kinetic analysis, we analyzed data collected from Sprague Dawley male rats (n = 162) dosed intraperitoneally with 50 μCi of 45Ca at 4 weeks of age and, at 10.5 weeks, treated with OPG (20 mg/kg; n = 54), RANKL (1 mg/kg for 4 consecutive days; n = 54), or vehicle control (0.3 mL phosphate-buffered saline; n = 54). Total calcium and 45Ca levels measured in serum and 24-h urine samples collected periodically for 45 days after treatment were analyzed by compartmental modeling and WinSAAM software. Parameters denoting bone resorption and formation were estimated by iterative weighted nonlinear regression analysis and compared statistically by a Student's t-test.
Results: During the first 40 days after weaning (prior to treatment), the model included a 4-fold decrease in bone resorption and a 20-fold decrease in bone formation, consistent with previous findings of studies conducted in growing rats. During the first 4 days after treatment, rats in the RANKL group showed a 25-fold increase in bone resorption, while rats in the control group showed a 4-fold increase in bone resorption. Rats in the OPG group showed a 3-fold increase in bone formation, which lasted for 16-18 days after treatment, and a concurrent 1.5-fold increase in calcium absorption, while maintaining a constant level of serum total calcium. The total mass of bone calcium gained/lost during 10 days after treatment was significantly higher in the OPG group compared with the control group (1130 ± 51 vs. 595 ± 20 mg; P < 0.001) and significantly lower in the RANKL group compared with the control group (-98 ± 47 mg vs. 595 ± 20 mg; P < 0.001).
Conclusions: A dynamic model of calcium metabolism was successfully developed and may be used in future studies to quantify the effect of various treatments on bone resorption and formation in young growing rats.
Supported by Metabolic Disorders Research, Amgen, Inc., Thousand Oaks, CA, USA
Postdoctoral Research Associate
West Lafayette, Indiana