Although there is presently no cure for Osteogenesis Imperfecta (OI), bisphosphonates are commonly used as anti-resorptive drugs to reduce the severity of OI-related bone loss and maintain vertebral geometry. Despite their proven utility in this regard, administration of such long-lasting anti-resorptive agents is of growing concern to clinicians because of their uncertain potential to negatively affect the general development, material properties, or repair of pediatric OI bone. Therefore, alternative therapies are being sought to manage and alleviate OI-associated bone loss and fracture frequency. One attractive candidate, Denosumab, is an excellent choice for investigation because it is a recently developed short-acting novel RANKL-specific human monoclonal antibody that represents a new type of anti-resorptive agent. Denosumab exhibits a distinct mechanism of action and certain therapeutic benefits compared to bisphosphonates, has delivered promising results in multiple clinical trials, appears to have a good safety profile in human subjects, and is on the verge of FDA approval for the therapeutic treatment of postmenopausal osteoporosis and other bone osteolytic conditions. Inhibition of RANKL-driven osteoclast bone turnover is an important new approach for the prevention of bone loss that could theoretically be a valuable strategy for the treatment of patients with OI. Denosumab has never been evaluated (in animals or humans) in relation to this bone disease. Here, we propose to investigate for the first time if Denosumab can reduce osteoclast bone resorption, skeletal osteopenia, and possibly bone fragility in a pre-clinical Brtl mouse model of human moderately severe (Type IV) OI. Brtl mice were created to contain the exact collagen mutation seen in a human OI (Type IV) patient, and they exhibit the hallmark characteristics associated with this type of bone disease. The two aims of this proposal will examine the effects of Denosumab dose and duration of treatment on Brtl OI mouse bone properties measured by microCT, biomechanical testing, histological analysis and nanoindentation probing. We anticipate that Denosumab will ameliorate bone loss, and possibly improve skeletal fragility, that is characteristic of Brtl OI mice. Denosumab results will be compared to previously obtained findings for bisphosphonate actions in Brtl OI mice to learn if there are particular advantages associated with the use of Denosumab. Favorable results with Densoumab in this pre-clinical mouse model would offer exciting evidence that Denosumab may be an effective alternative to bisphosphonates as a unique type of anti-resorptive agent for the treatment and management of OI whose therapeutic benefits would merit the initiation of controlled clinical trials with human OI patients.

Public Health Relevance

New drugs are being sought to reduce the bone loss and skeletal fragility associated with OI because concerns have arisen in recent years over possible negative effects of currently used anti-resorptive bisphosphonates on growing bones in pediatric OI patients. Here, we propose to investigate for the first time the ability of a new type of anti-resorptive drug, Denosumab, for its potential therapeutic value in treating OI bone using a mouse model that contains the exact mutation present in a human OI patient and replicates the hallmark characteristics of moderately severe Type IV human OI. Promising results from this pre-clinical study would justify initiating future clinical trials to evaluate Desosumab as a new possible therapeutic avenue and alternative to bisphosphonates for the treatment of human OI patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR060440-02
Application #
8214548
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
2011-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$171,000
Indirect Cost
$58,500
Name
Washington University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130