Mathematical modeling of postmenopausal osteoporosis and its treatment by the anti-catabolic drug denosumab.
Bottom Line: The therapeutic effect of denosumab rests on its ability to inhibit osteoclast differentiation.Here, we present a computational approach on the basis of coupling a pharmacokinetics model of denosumab with a pharmacodynamics model for quantifying the effect of denosumab on bone remodeling.This evolution is accompanied by a dramatic decrease of the bone turnover rate by more than one order of magnitude.
Affiliation: Institute for Mechanics of Materials and Structures, Vienna University of Technology, Austria.Show MeSH
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Mentions: For t < 6 months (prior to administration of denosumab), all graphs (representing doses , , and , as well as the zero dose) obviously coincide, see the paths between the square-shaped and the circle-shaped markers in Figures 5(a)–(d). For months, the presence of denosumab entails inhibition of the differentiation of osteoclast precursor cells to active osteoclasts, consequently leading to fast decrease of , see the paths in Figures 5(b)–(d) after passing the circle-shaped markers. At the same time, a temporary increase of is observed, leading to a short but steep increase of fbm following denosumab administration, see Figure 5(e). This increase, indicated by the phase diagram paths crossing the balanced turnover-representing diagonal lines in Figures 5(b)–(d), stems from how the action of TGF- β is considered in our model. On the one hand, TGF- β inhibits differentiation of osteoblast precursor cells to active osteoblasts. Administration of denosumab leads to downregulation of the concentration of active osteoclasts, entailing a reduced release of TGF- β, and in further consequence an increase, due to reduced differentiation inhibition, of the concentration of active osteoblasts. Moreover, the presence of TGF- β is required for maintaining differentiation of osteoblast progenitor cells to osteoblast precursor cells. This means that reduction of the concentration of TGF- β leads to downregulation of the aforementioned differentiation process, and thus, with a certain time delay, to downregulation of the concentration of active osteoblasts, completing the “anabolic loops” observed in Figures 5(b)–(d).
Affiliation: Institute for Mechanics of Materials and Structures, Vienna University of Technology, Austria.