Teun Post(1), Rik de Greef(1), Thomas Kerbusch(1), Lambertus Peletier(2), Meindert Danhof(3)
1) Clinical Pharmacology and Kinetics, Organon, a part of Schering-Plough Corporation, Oss, The Netherlands, 2) Mathematical Institute, Leiden, The Netherlands, 3) Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
Objectives: Bone remodeling is regulated by a coupled action of osteoclastic and osteoblastic cells, which remove and form bone, respectively. In osteoporosis resorption exceeds formation leading to a net decrease in bone density. Upon antiresorptive and anabolic treatment the changes in resorption and formation occur sequentially resulting in a time-window of effect leading to an increased bone density. Bone Turnover Markers (BTM) and Bone Mineral Density (BMD) present information on this system at different time-scales. The objective was to develop a disease system based on bone biology that incorporates markers of both bone formation and resorption aiming to characterize the time-window of effect that is correlated to the increase in BMD in healthy postmenopausal women.
Methods: Data were from 767 healthy women within 1-4 yr after menopause, treated for 2 yr with 0.3, 0.625, 1.25, or 2.5 mg tibolone daily or placebo (1). All subjects took supplemental calcium (500 mg daily). Bone formation was reflected by measures of osteocalcin and bone-specific alkaline phosphatase (BSAP) and urinary N-terminal (NTx) collagen telopeptide reflected bone resorption. BMD of the lumbar spine (L1-L4) and total hip were measured by dual-energy x-ray absorptiometry.
The conceptual framework of bone biology based on the Basic Multicellular Unit (BMU) as presented by Lemaire et al (2) was used to reflect the coupled osteoclastic-osteoblastic action during treatment. The bone turnover markers were related to their system-specific site and the dynamics in the system were subsequently translated into effects observed on BMD. This pharmacodynamic platform model was developed using a non-linear mixed effects approach in NONMEM VI.
Results: The platform model comprehensively describes the dynamics of the markers representing bone resorption as well as bone formation during treatment, thereby characterizing and quantifying the related time-window of effect driving the increase in BMD. As a result, the model also adequately described the dynamics in lumbar spine and total hip BMD.
Conclusions: A disease system has been developed that provides a basis for the integrated description of short- and long-term markers based on bone biology. This may allow the comparison and prediction of various treatment effects on a common platform model. Furthermore, it enables the inclusion and integration of information presented by different markers at various levels and time-scales of the biological system.
References:
[1] J.C. Gallagher et al. J Clin Endocrinol Metab 86 (2001) 4717-4726
[2] V. Lemaire et al. J Theor Biol 229 (2004) 293-309
This research was performed within the framework of project D2-104 of the Dutch Top Institute Pharma.
Reference: PAGE 17 (2008) Abstr 1358 [www.page-meeting.org/?abstract=1358]
Poster: Applications- Endocrine