Sclerostin-Mediated Osteocyte Control in Bone Remodeling: Extension of a Multiscale Systems Model to Consider New Therapies for Osteoporosis
Rena J. Eudy (1), Marc R. Gastonguay (1,2), Kyle T. Baron (2), Matthew M. Riggs (2)
(1) Department of Biomedical Engineering, University of Connecticut, USA, (2) Metrum Research Group, LLC, Tariffville, Connecticut, USA
Objectives: To extend a mathematical, multiscale systems model of bone metabolism [1], in order to 1) describe kinetics of sclerostin mAbs that are currently in clinical development, and the changes these elicit on serum sclerostin, bone turnover markers, and bone mineral density (BMD) within typical osteoporotic patients, 2) validate the model extension in an external clinical data set [2] and 3) further our knowledge of the role of the osteocyte in bone remodeling.
Methods: A target-mediated drug disposition (TMDD) model was developed to describe kinetics of single and multiple doses of sclerostin mAbs, blosozumab and romosozumab, and total sclerostin in NONMEM (v7.2) using summary level public data from five clinical trials. The sclerostin PK model and parameter estimates were inserted into the larger bone model, with sclerostin PD modeled to affect osteocyte-mediated resorption and formation through inhibition of Wnt signaling. Sclerostin PD parameters were initially tuned to relevant subsets of clinical data and then refined using a quadratic approximation method optimizing an ordinary least squares (OLS) objective function in R. Simulations were performed in R (v.3.1.2).
Results: The bone model predicted changes in turnover markers and changes in lumbar spine (ls) and total hip (th) BMD consistent with clinical data. These results were validated using an external dataset from a recent blosozumab clinical trial [2]. The predicted mean change from baseline at 52 weeks (180mg dosed Q2W) for lsBMD was 16.5% (observed; 95%CI: 14.9; 12.6-17.1%) and for thBMD was 6.8% (4.5; 3.2-5.8%), respectively.
Conclusions: This mechanistic model of bone metabolism adequately predicted clinical outcomes resulting from sclerostin mAb administration in a typical osteoporotic population. The model also proposes relative contributions of the osteocyte to feedback signaling elicited through changes in sclerostin and upregulation of the Wnt pathway, a finding that has not been elucidated by laboratory experimentation.
References:
[1] Peterson, M. C., & Riggs, M. M. (2010). A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling. Bone, 46(1), 49–63. doi:10.1016/j.bone.2009.08.053
[2] Recker, R., Benson, C., Matsumoto, T., Bolognese, M., Robins, D., Alam, J., … Myers, S. (2014). A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J Bone Miner Res. doi:10.1002/jbmr.2351
