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Mathematical modeling of postmenopausal osteoporosis and its treatment by the anti-catabolic drug denosumab.

Scheiner S, Pivonka P, Smith DW, Dunstan CR, Hellmich C - Int J Numer Method Biomed Eng (2013)

Bottom Line: The therapeutic effect of denosumab rests on its ability to inhibit osteoclast differentiation.Simulation results also suggest that denosumab may trigger a short-term bone volume gain, which is, however, followed by constant or decreasing bone volume.This evolution is accompanied by a dramatic decrease of the bone turnover rate by more than one order of magnitude.

View Article: PubMed Central - PubMed

Affiliation: Institute for Mechanics of Materials and Structures, Vienna University of Technology, Austria.

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Simulation results obtained for administration regimes involving one administration of denosumab: (a)–(d) phase diagrams (in logarithmic scales) for the simulated doses, (a) Dden = 0, (b) mg/kg, (c) mg/kg, and (d) mg/kg, with the temporal progress indicated by respective markers (days, ⋄…5 days, ○ …182.5 days, ▽ …185 days, △ …190 days, days, ▹…700 days, and days after onset of postmenopausal osteoporosis), and (e) the corresponding temporal evolutions of the volume fractions of the extravascular bone matrix, fbm, as postmenopausal osteoporosis progresses.
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fig05: Simulation results obtained for administration regimes involving one administration of denosumab: (a)–(d) phase diagrams (in logarithmic scales) for the simulated doses, (a) Dden = 0, (b) mg/kg, (c) mg/kg, and (d) mg/kg, with the temporal progress indicated by respective markers (days, ⋄…5 days, ○ …182.5 days, ▽ …185 days, △ …190 days, days, ▹…700 days, and days after onset of postmenopausal osteoporosis), and (e) the corresponding temporal evolutions of the volume fractions of the extravascular bone matrix, fbm, as postmenopausal osteoporosis progresses.

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).


Mathematical modeling of postmenopausal osteoporosis and its treatment by the anti-catabolic drug denosumab.

Scheiner S, Pivonka P, Smith DW, Dunstan CR, Hellmich C - Int J Numer Method Biomed Eng (2013)

Simulation results obtained for administration regimes involving one administration of denosumab: (a)–(d) phase diagrams (in logarithmic scales) for the simulated doses, (a) Dden = 0, (b) mg/kg, (c) mg/kg, and (d) mg/kg, with the temporal progress indicated by respective markers (days, ⋄…5 days, ○ …182.5 days, ▽ …185 days, △ …190 days, days, ▹…700 days, and days after onset of postmenopausal osteoporosis), and (e) the corresponding temporal evolutions of the volume fractions of the extravascular bone matrix, fbm, as postmenopausal osteoporosis progresses.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4291103&req=5

fig05: Simulation results obtained for administration regimes involving one administration of denosumab: (a)–(d) phase diagrams (in logarithmic scales) for the simulated doses, (a) Dden = 0, (b) mg/kg, (c) mg/kg, and (d) mg/kg, with the temporal progress indicated by respective markers (days, ⋄…5 days, ○ …182.5 days, ▽ …185 days, △ …190 days, days, ▹…700 days, and days after onset of postmenopausal osteoporosis), and (e) the corresponding temporal evolutions of the volume fractions of the extravascular bone matrix, fbm, as postmenopausal osteoporosis progresses.
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).

Bottom Line: The therapeutic effect of denosumab rests on its ability to inhibit osteoclast differentiation.Simulation results also suggest that denosumab may trigger a short-term bone volume gain, which is, however, followed by constant or decreasing bone volume.This evolution is accompanied by a dramatic decrease of the bone turnover rate by more than one order of magnitude.

View Article: PubMed Central - PubMed

Affiliation: Institute for Mechanics of Materials and Structures, Vienna University of Technology, Austria.

Show MeSH
Related in: MedlinePlus