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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 via 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.
This article was published in the following journal.
Romosozumab is a therapy that stimulates bone formation and reduces bone resorption. In this study of postmenopausal women with low BMD, a second course of romosozumab following a period off treatment...
Sclerostin, a protein produced by osteocytes, inhibits bone formation. Administration of sclerostin antibody results in increased bone formation in multiple animal models. Romosozumab, a humanized scl...
The U.S. Food and Drug Administration approved romosozumab as a new osteoporosis drug in April 2019. Marketed under the brand name Evenity (Amgen, Thousand Oaks, CA), it is a sclerostin inhibitor that...
Osteoporosis is diagnosed based on the results of BMD assessment and/or fragility fractures. Vertebral fracture is the most common fragility fracture. Many vertebral fractures are asymptomatic and are...
Postmenopausal women with systemic lupus erythematosus have an increased risk of osteoporosis and associated fractures. Their increased osteoporosis risk is probably caused by a high level of inflamma...
A multicenter, randomized, double-blind, placebo-controlled study to evaluate the effect of 6 months treatment with Romosozumab compared to placebo by determining the percent changes in bo...
Glucocorticoid (GC) is the main stay of treatment of many rheumatic diseases but is also an important cause of secondary osteoporosis. The long-term use of GCs increases the risk of fragil...
Treatment for sublesional bone loss (osteoporosis) in persons with chronic, motor-complete spinal cord injury (SCI) has been limited and unsuccessful to date. Romosozumab, a sclerostin ant...
The purpose of this study is to evaluate the efficacy and safety of an investigational drug in postmenopausal women with osteoporosis.
The purpose of this study is to see how well alendronate and calcium as compared to calcium alone increase bone density in postmenopausal women with osteoporosis
Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis (OSTEOPOROSIS, POSTMENOPAUSAL) and age-related or senile osteoporosis.
A nonhormonal medication for the treatment of postmenopausal osteoporosis in women. This drug builds healthy bone, restoring some of the bone loss as a result of osteoporosis.
A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series.
Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series.
Metabolic disorder associated with fractures of the femoral neck, vertebrae, and distal forearm. It occurs commonly in women within 15-20 years after menopause, and is caused by factors associated with menopause including estrogen deficiency.
Osteoporosis is a disease in which the bones become extremely porous, are subject to fracture, and heal slowly, occurring especially in women following menopause and often leading to curvature of the spine from vertebral collapse. Follow and track&n...
An antibody is a protein produced by the body's immune system when it detects harmful substances, called antigens. Examples of antigens include microorganisms (such as bacteria, fungi, parasites, and viruses) and chemicals. Antibodies may be produc...