Effects of long-term treatment of denosumab on bone mineral density: insights from an in-silico model of bone mineralization

Abstract

Denosumab is one of the most commonly prescribed anti-resorptive drugs for the treatment of postmenopausal osteoporosis. The therapeutic effect of denosumab is to inhibit osteoclast differentiation and consequently bone resorption. Gains in bone mineral density (BMD) are achieved based on the ability of the bone matrix to undergo secondary mineralization. Experimental data show that the increase of BMD after commencing denosumab treatment are bone site specific. In this paper, we developed a comprehensive mechanistic pharmacokinetic-pharmacodymamic (PK-PD) model of the effect of denosumab on bone remodeling in postmenopausal osteoporosis (PMO). The PD model is based on a bone cell population model describing the bone remodeling process at the tissue scale. The conceptual model of the bone mineralization process, originally proposed by Boivin and Meunier, is quantitatively incorporated using a FIFO (First-In-First-Out) queue algorithm. The latter takes into account the balance of mineral within bone tissue due to the mineralization process, distinguishing the primary and secondary phases and removal of bone matrix due to bone resorption. The numerical simulations show that the model is able to predict the bone-site specific increase in BMD as was observed in the experimental data of Bone et al. 2008 for a typical denosumab administration pattern of 60 mg every 6 months. At the hip a 5 % increase in BMD was observed, while at the lumbar spine a 7.5 % increase of BMD was achieved after a 2 year treatment period. The difference in BMD is due to the fact that bone turnover at the hip is lower compared to lumbar spine and consequently has less potential for secondary mineralization. Parametric studies revealed that the rate of bone mineralization is an essential parameter regulating BMD gains. If mineralization is neglected only minimal increases in BMD are observed.

Keywords: Bone mineral density; Bone mineralization; Bone remodeling; Denosumab; PK-PD modeling; Postmenopausal osteoporosis; RANK-RANKL-OPG pathway.