Disease System for osteoporosis: relating bone mineral density with measures of bone formation and resorption based on bone biology
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.
 J.C. Gallagher et al. J Clin Endocrinol Metab 86 (2001) 4717-4726
 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.