Jan Berkhout (1), Teun M Post (2), Katia MC Verhamme (1), Bruno HC Stricker (1), Miriam CJM Sturkenboom (1), Meindert Danhof (3)
(1) Departments of Epidemiology and Medical Informatics, Erasmus UniversityMedical Center, Rotterdam, The Netherlands (2) Quantitative Pharmacology and Pharmacometrics (QP2), Pharmacokinetics, Pharmacodynamics & Drug Metabolism (PPDM), Merck Research Laboratories, Merck Sharp & Dohme, Oss, The Netherlands (3) Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
Objectives: Osteoporosis is a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the US alone, approximately 44 million people are affected by osteoporosis and low bone mass. Several pharmacological treatments exist for the prevention of osteoporosis such as hormone replacement therapy and bisphosphonates. However, limited data exist on the comparative effectiveness (e.g. providing evidence on the effectiveness, benefits, and harms of different treatment options) of these treatments between populations within clinical trials and under the real life circumstance. Recently, a mechanistic osteoporosis framework was developed to describe disease progression together with treatment effects. This model was applied to clinical data from post-menopausal women receiving various doses of tibolone or calcium [1]. This research project will use the mechanistic model to address the following research questions:
1. Can the existing disease system model for osteoporosis be extended to treatment with the bisphosphonate drug alendronate?
2. Use the mechanism-based model in combination with data from a cohort study in the elderly population (The Rotterdam Study, RS) to explore what part of the observed variation in bone mineral density (BMD) in the real-life population is due to treatment effect and what part by other covariates.
3. Fracture data available from the RS will be used to extend the model to predict clinical outcome.
Methods: To address the first research question the previously developed model will be applied to clinical trial data from post-menopausal women receiving the bisphosphonate alendronate and/or conjugated estrogen [2]. The disease model will be used to obtain a further mechanism-based description of the disease processes following alendronate treatment. The RS is a unique population based cohort of elderly subjects with extensive long term follow-up data that will be used to address the second and third research questions. Both questions will contribute to a more complete and mechanism-based description of the whole trajectory of the disease and the corresponding fracture incidence.
References:
[1] Post, T. M., Schmidt, S., Peletier, L. a, de Greef, R., Kerbusch, T., & Danhof, M. (2013). Application of a mechanism-based disease systems model for osteoporosis to clinical data. Journal of Pharmacokinetics and Pharmacodynamics, 40(2), 143–56.
[2] Ravn, P., Bidstrup, M., Wasnich, R. D., Davis, J. W., McClung, M. R., Balske, A, Cizza, G. (1999). Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Annals of Internal Medicine, 131(12), 935–42.
Reference: PAGE 23 (2014) Abstr 3024 [www.page-meeting.org/?abstract=3024]
Poster: Drug/Disease modeling - Other topics