Glucocorticoids are the most common cause of nontraumatic osteonecrosis of the hip, a crippling disorder that often leads to total hip replacement. Osteonecrosis, the in situ death of a segment of bone, develops in up to 40% of patients receiving systemic glucocorticoids, especially after the administration of intensive parenteral courses. Although the pathology of the end-stage disease has been partially described, the cellular and molecular mechanisms responsible for the development of glucocorticoid-induced osteonecrosis remain unidentified and there is little consensus on optimal intervention strategies. This is because the sequential pathological changes in clinically asymptomatic patients are unknown and an animal model that replicates the progression of the human disorder is absent. Glucocorticoid therapy causes a decline in bone strength that surpasses the decline in bone density, but the mechanism behind this phenomenon remains unknown. Although it is widely appreciated that bone is composed of cells, mineral and collagen, it is seldom realized that water is another major component accounting for more than one fourth of the wet weight of bone. Fracture resistance of hard tissues is defective without water and water confers to bone much of its unique strength and resilience. The objective of this proposal is to use a murine model of osteonecrosis of the femoral head to determine whether glucocorticoid- induced deterioration of bone water and vascularity may account for the disproportionately greater decline in bone strength than in bone mass typical of glucocorticoid-induced osteonecrosis and whether the bone strength and vascularity may be compromised through the direct actions of glucocorticoids on osteocytes. Studies aimed at the cellular and molecular mechanisms of the pathogenesis of glucocorticoid-induced osteonecrosis and investigation of potential preventative therapy would increase motivation to protect the hip as early as possible. We hypothesize that glucocorticoid-induced osteonecrosis of the femoral head is primarily due to adverse effects on femoral head osteocytes because of reduced bone vascularity and canalicular fluid. To achieve this goal, osteocytes in transgenic mice will be shielded from administered glucocorticoids to determine if these animals are protected from osteonecrosis. In addition, mice expressing a hypersensitive glucocorticoid receptor in osteocytes will be examined to determine if osteonecrosis is exaggerated. Next, the impact of the administration of alendronate or intermittent PTH to prevent glucocorticoid-induced osteonecrosis will be examined. The studies proposed in this application are timely and by capitalizing on modern concepts and innovative methodology offer the opportunity for new insights that are sorely needed for the prevention and treatment of glucocorticoid-induced bone disease and are, therefore, immediately relevant and vital to the VA health care mission.

Public Health Relevance

Glucocorticoids such as prednisone and cortisone are the most widely used anti-inflammatory and immunosuppressive drugs. As many as 1.2% of the population receives oral glucocorticoids and the prevalence increases to more than 3% in individuals over 70 years-of-age. These drugs are essential for the treatment of rheumatologic diseases, asthma, inflammatory bowel disease, and to prevent rejection of organ transplants. Furthermore, glucocorticoids are also prescribed for veterans with posttraumatic stress disorder. However, the adverse skeletal effects of glucocorticoids are a substantial drawback to the use of these drugs. Fractures and osteonecrosis of the hip, a crippling disorder that often leads to total hip replacement, develop i up to one-half of patients receiving these drugs, especially after the administration of intensive parenteral courses. The proposed studies of the mechanisms of the skeletal damage will provide new insights that are sorely needed, have strong translational potential, and are vital to veterans'health care.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000436-05A1
Application #
8738790
Study Section
Endocrinology B (ENDB)
Project Start
2009-04-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Central Arkansas Veterans Hlthcare Sys
Department
Type
DUNS #
082573742
City
North Little Rock
State
AR
Country
United States
Zip Code
72114