Abstract
Objectives
Quantifying the long-term effects of nutritional or drug treatments on bone is challenging due to the delay in time between treatment and changes in bone mass. The objective of this study was to develop a dynamic (non-steady state) mathematical model of calcium metabolism in young growing rats as an analogue for human adolescents and to use that model to predict the effects of treatments on calcium mass in bone.
Methods
A dynamic model of calcium metabolism was developed using kinetic data collected from Sprague-Dawley male rats (n = 54) dosed intraperitoneally with 50 μCi of 45Ca at 4 wk of age. Total calcium and 45Ca levels measured in serum and 24-h urine samples collected periodically for 45 d after treatment were analyzed by compartmental modeling using WinSAAM software. Concurrently, tracer (45Ca) and tracee (total calcium) models, together called the ‘dynamic model’, were developed. Growth of the rats was modeled using a formula based on body weight. Calcium absorption was decreased by about 50% at wk 6 to account for the reduction in bone mineral accretion in late puberty. During the first 40 d after weaning, 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. Data were fitted by iterative least squares regression analysis. To mimic the effects of dietary and drug interventions during adolescence, the absorption efficiency was manipulated in terms of degree, timing, and duration and the subsequent changes in bone mass were quantified.
Results
The dynamic model predicted that, if absorption decreased by 25% instead of 50% during growth, the rate of bone accretion would be 32% higher and the bone mineral mass at d 50 would be 24% larger, suggesting that a dietary or drug intervention that minimizes the drop in absorption, would result in a higher bone mineral mass.
Conclusions
A dynamic model of calcium metabolism during growth was developed and used to predict the effect of interventions on bone mass. These predictions would be tested in future studies.
Funding Sources
Purdue University Graduate School and Amgen, Inc., Thousand Oaks, CA.
A Dynamic Model of Calcium Metabolism for Predicting the Effects of Treatments on Bone Mineral Mass in Young Growing Rats (P24-046-19)
