A PHYSIOLOGICALLY-BASED, MULTISCALE MODEL USED TO PREDICT PROGRESSIVE BONE MINERAL DENSITY LOSS DUE TO CHRONIC RENAL DISEASE

Purpose: Extend an existing physiologically-based model of calcium and bone homeostasis to enable prediction of changes in bone mineral density (BMD) observed during the progression of renal failure. Methods: The underlying physiologic model has been published and is described in Bone 46 (2010) 49‐63. 1 Clinical data (plasma calcium, phosphate, parathyroid hormone (PTH), calcitriol, bone remodeling markers and bone mineral density (BMD)) measured at various degrees of renal function were digitized from Rix et al. (Kidney Int 56 (1999) 1084‐93). 2 A mathematical expression describing progressive renal function loss as an exponential decrease in glomerular filtration rate (GFR) from a baseline of 100 mL/min to approximately 16 mL/min 10 years later was constructed and invoked in the model as: GFR = 10 + 90*exp(-0.27*time(yrs)). The model appropriately predicts the evolution of secondary hyperparathyroidism (HPT) caused by diminished renal phosphate clearance and increased plasma phosphate associated with GFR loss. Since an important sequelae of HPT is marked elevations in bone resorption and loss of BMD, a differential equation linking the prior description of bone remodeling markers was developed to predict longitudinal BMD changes during chronic worsening renal function. Results: A differential equation model linked bone remodeling markers to elimination and formation rates of BMD. BMD was described with first order elimination (0.000145 h 1 ) and formation and elimination rates scaled by percentage of resorption and formation markers. The composite model predicted lumbar spine BMD losses from baseline at Month 28 (GFR = 58 mL/min), 50 (GFR = 39 mL/min) and 120 (GFR = 16 mL/min) of approximately ‐0.98%, ‐3.0%, and ‐6.5%, respectively, compared to the observed BMD values in corresponding renal function groups, scaled to a baseline of 100 mL/min, of ‐0.5%, ‐4.0%, ‐8.1%, respectively. Conclusions: The extended multiscale model is able to predict changes in BMD during the progression of renal impairment. This model provides a platform for evaluating therapeutics and interventions targeted at underlying causal mechanisms, as well as symptomatic treatments.