Assessment of romosozumab efficacy in the treatment of postmenopausal osteoporosis: Results from a mechanistic PK-PD mechanostat model of bone remodeling

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Martin, M
Sansalone, V
Cooper, DML
Forwood, MR
Pivonka, P
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2020
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Abstract

This paper introduces a theoretical framework for the study of the efficacy of romosozumab, a humanized monoclonal antibody targeting sclerostin for the treatment of osteoporosis. We developed a comprehensive mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model of the effect of drug treatment on bone remodeling in postmenopausal osteoporosis (PMO). We utilized a one-compartment PK model to represent subcutaneous injections of romosozumab and subsequent absorption into serum. The PD model is based on a recently-developed bone cell population model describing the bone remodeling process at the tissue scale. The latter accounts for mechanical feedback by incorporating nitric oxide (NO) and sclerostin (Scl) as biochemical feedback molecules. Utilizing a competitive binding model, where Wnt and Scl compete for binding to LRP5/6, allows to regulate anabolic bone remodeling responses. Here, we extended this model with respect to romosozumab binding to sclerostin. For the currently approved monthly injections of 210 mg, the model predicted a 6.59%, 10.38% and 15.25% increase in BMD at the lumbar spine after 6, 12 and 24 months, respectively. These results are in good agreement with the data reported in the literature. Our model is also able to distinguish the bone-site specific drug effects. For instance, at the femoral neck, our model predicts a BMD increase of 3.85% after 12 months of 210 mg injections, which is consistent with literature observations. Finally, our simulations indicate rapid bone loss after treatment discontinuation, indicating that some additional interventions such as use of bisphosphonates are required to maintain bone mass.

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Bone

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133

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Biological sciences

Engineering

Biomedical and clinical sciences

Clinical sciences

Bone remodeling

Frost's mechanostat

Patient-specific therapy

Pharmacodynamics

Pharmacokinetics

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Martin, M; Sansalone, V; Cooper, DML; Forwood, MR; Pivonka, P, Assessment of romosozumab efficacy in the treatment of postmenopausal osteoporosis: Results from a mechanistic PK-PD mechanostat model of bone remodeling, Bone, 2020, 133, pp. 115223-

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