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Application of a Systems Pharmacology-Based Placebo Population Model to Analyze Long-Term Data of Postmenopausal Osteoporosis.

Berkhout J, Stone JA, Verhamme KM, Stricker BH, Sturkenboom MC, Danhof M, Post TM - CPT Pharmacometrics Syst Pharmacol (2015)

Bottom Line: Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk.Second, we applied the model to all 470 women.Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Informatics, Erasmus Medical Centre Rotterdam, The Netherlands ; Leiden Academic Centre for Drug Research, Division of Pharmacology Leiden, The Netherlands.

ABSTRACT
Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed disease systems analysis model for osteoporosis could describe disease progression in a placebo-treated population from the Early Postmenopausal Intervention Cohort (EPIC) study. First, we qualified the model using a subset from the placebo arm of the EPIC study of 222 women who had similar demographic characteristics as the 149 women from the placebo arm of the original population. Second, we applied the model to all 470 women. Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population. This updated disease systems analysis placebo model describes the dynamics of all biomarkers in the corresponding datasets to a very good approximation; a good description of an individual placebo response will be valuable for evaluating treatments for osteoporosis.

No MeSH data available.


Related in: MedlinePlus

Comparison of zeroth-order and indirect response model for BMD dynamics. (a) Changes in the net bone cell activity (S = z/y) vs. time for the zeroth-order process (ZO, solid line) and the indirect response model (IR, dashed line). The arrows indicate the start and end of the placebo treatment in the two studies. (b). Changes in LS-BMD (gray lines) and TH-BMD (black lines) for the zeroth-order process (solid line) and the indirect response model (dashed line). Scatterplot showing the change between baseline and the latest observation available for LS-BMD (c) and TH-BMD (d) vs. years since menopause.
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fig04: Comparison of zeroth-order and indirect response model for BMD dynamics. (a) Changes in the net bone cell activity (S = z/y) vs. time for the zeroth-order process (ZO, solid line) and the indirect response model (IR, dashed line). The arrows indicate the start and end of the placebo treatment in the two studies. (b). Changes in LS-BMD (gray lines) and TH-BMD (black lines) for the zeroth-order process (solid line) and the indirect response model (dashed line). Scatterplot showing the change between baseline and the latest observation available for LS-BMD (c) and TH-BMD (d) vs. years since menopause.

Mentions: Simulations with both types of BMD equations were performed in order to compare the effect on the dynamics. The parameter values as shown in Table2 were used for these simulations. For both equations the change of BMD is determined by the balance between the relative changes in y and z (i.e., S = z/y). In Figure4a it is shown how these relative quantities evolve as a result of the placebo treatment. Both models evolve towards a similar maximal value of S. The underlying dynamics for both models is different, however: the zeroth-order model has reached this maximal value already after 2 years, whereas the indirect response model reached this value only after 4 years. Note that S represents the ratio of relative osteoclast activity over relative osteoblast activity. Therefore, there is net bone loss if this ratio is bigger than 1 and net bone formation when it is smaller than 1. This can also be seen in Figure4b, where the change of LS-BMD (gray lines) and TH-BMD (black lines) over time is plotted and decreases as a result of disease progression. The difference in the two BMD equations can be seen from this plot: the zeroth-order response function (solid lines) has a concave shape, whereas the indirect response model (dashed lines) has a convex shape. This implies that right after onset of disease progression (e.g., beginning of the menopause) the change in BMD is largest. In addition, this change is bigger for LS-BMD compared to TH-BMD. These model predictions were compared to the available observations. So, for every individual we calculated the difference between baseline value and the latest available measurement for LS- and TH-BMD and plotted this difference vs. YSM. As shown in Figure4c,d, we also found the biggest change (i.e., decrease) in BMD at the LS and TH shortly after onset of menopause, and the absolute mean change was ∼25% higher in BMD at the lumbar spine compared to the total hip.


Application of a Systems Pharmacology-Based Placebo Population Model to Analyze Long-Term Data of Postmenopausal Osteoporosis.

Berkhout J, Stone JA, Verhamme KM, Stricker BH, Sturkenboom MC, Danhof M, Post TM - CPT Pharmacometrics Syst Pharmacol (2015)

Comparison of zeroth-order and indirect response model for BMD dynamics. (a) Changes in the net bone cell activity (S = z/y) vs. time for the zeroth-order process (ZO, solid line) and the indirect response model (IR, dashed line). The arrows indicate the start and end of the placebo treatment in the two studies. (b). Changes in LS-BMD (gray lines) and TH-BMD (black lines) for the zeroth-order process (solid line) and the indirect response model (dashed line). Scatterplot showing the change between baseline and the latest observation available for LS-BMD (c) and TH-BMD (d) vs. years since menopause.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592531&req=5

fig04: Comparison of zeroth-order and indirect response model for BMD dynamics. (a) Changes in the net bone cell activity (S = z/y) vs. time for the zeroth-order process (ZO, solid line) and the indirect response model (IR, dashed line). The arrows indicate the start and end of the placebo treatment in the two studies. (b). Changes in LS-BMD (gray lines) and TH-BMD (black lines) for the zeroth-order process (solid line) and the indirect response model (dashed line). Scatterplot showing the change between baseline and the latest observation available for LS-BMD (c) and TH-BMD (d) vs. years since menopause.
Mentions: Simulations with both types of BMD equations were performed in order to compare the effect on the dynamics. The parameter values as shown in Table2 were used for these simulations. For both equations the change of BMD is determined by the balance between the relative changes in y and z (i.e., S = z/y). In Figure4a it is shown how these relative quantities evolve as a result of the placebo treatment. Both models evolve towards a similar maximal value of S. The underlying dynamics for both models is different, however: the zeroth-order model has reached this maximal value already after 2 years, whereas the indirect response model reached this value only after 4 years. Note that S represents the ratio of relative osteoclast activity over relative osteoblast activity. Therefore, there is net bone loss if this ratio is bigger than 1 and net bone formation when it is smaller than 1. This can also be seen in Figure4b, where the change of LS-BMD (gray lines) and TH-BMD (black lines) over time is plotted and decreases as a result of disease progression. The difference in the two BMD equations can be seen from this plot: the zeroth-order response function (solid lines) has a concave shape, whereas the indirect response model (dashed lines) has a convex shape. This implies that right after onset of disease progression (e.g., beginning of the menopause) the change in BMD is largest. In addition, this change is bigger for LS-BMD compared to TH-BMD. These model predictions were compared to the available observations. So, for every individual we calculated the difference between baseline value and the latest available measurement for LS- and TH-BMD and plotted this difference vs. YSM. As shown in Figure4c,d, we also found the biggest change (i.e., decrease) in BMD at the LS and TH shortly after onset of menopause, and the absolute mean change was ∼25% higher in BMD at the lumbar spine compared to the total hip.

Bottom Line: Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk.Second, we applied the model to all 470 women.Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Informatics, Erasmus Medical Centre Rotterdam, The Netherlands ; Leiden Academic Centre for Drug Research, Division of Pharmacology Leiden, The Netherlands.

ABSTRACT
Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed disease systems analysis model for osteoporosis could describe disease progression in a placebo-treated population from the Early Postmenopausal Intervention Cohort (EPIC) study. First, we qualified the model using a subset from the placebo arm of the EPIC study of 222 women who had similar demographic characteristics as the 149 women from the placebo arm of the original population. Second, we applied the model to all 470 women. Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population. This updated disease systems analysis placebo model describes the dynamics of all biomarkers in the corresponding datasets to a very good approximation; a good description of an individual placebo response will be valuable for evaluating treatments for osteoporosis.

No MeSH data available.


Related in: MedlinePlus