Application of a mechanism-based disease systems model for osteoporosis to clinical data

A recently proposed mechanism-based disease systems model for osteoporosis (Schmidt et al., J Pharmacokinet Pharmacodyn 38:873-900, 2011) was applied to clinical data from post-menopausal women (n = 767) receiving various doses of the selective estrogen receptor modulator tibolone. Plasma bone-specific alkaline phosphatase activity and urinary N-telopeptide were used as biomarkers reflecting the activity of osteoblasts (bone forming cells) and osteoclasts (bone removing cells), respectively. These data were analyzed in conjunction with data on osteocalcin and on bone mineral density (BMD) (both lumbar spine and total hip), which reflect the activity of both cell types. While the dynamics of bone turnover markers changes rapidly, closely following changes in the activity of bone cells, changes in BMD are slower and have their own dynamics. Application of the mechanism-based disease systems model to the clinical data allowed for an adequate description of the data and yielded parameter estimates that are consistent with physiological values reported in the literature (Lemaire et al., J Theor Biol 229:293-309, 2004). The fitted model enabled characterization of (i) the critical time scales involved in disease progression, (ii) the dynamics of the system during onset and offset of the therapeutic intervention, and (iii) the distinction between responders and low-responders to tibolone treatment.