Role of T-cells in Post-Menopausal Osteoporosis

This study has been completed.
Sponsor:
Collaborator:
Emory University
Information provided by (Responsible Party):
Vin Tangpricha, Atlanta VA Medical Center
ClinicalTrials.gov Identifier:
NCT00787904
First received: November 7, 2008
Last updated: January 7, 2014
Last verified: January 2014

November 7, 2008
January 7, 2014
December 2006
June 2011   (final data collection date for primary outcome measure)
  • Production of cytokines RANKL and TNF from cultured human T-cells [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Changes in T-cell activation measured by Flow Cytometry, specifically the percentage of CD3+CD69+ T-cells [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Changes in Thymus Size measured by CT scan [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT00787904 on ClinicalTrials.gov Archive Site
Bone Mineral Density [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Role of T-cells in Post-Menopausal Osteoporosis
The Role of T-cells in Women Undergoing Surgical Menopause

This is an observational study of women undergoing surgical menopause to determine whether T-cells play an important role in the etiology of post-menopausal osteoporosis. Subjects will examined before and after surgery and followed over a two year period to determine the biology of T-cells during this study period.

Estrogen (E) deficiency is a major cause of post-menopausal osteoporosis. The mechanisms by which E deficiency causes osteoporosis has been recently linked to regulation of two key osteoclastic cytokines: RANKL and TNFα (TNF) , , produced by the T-cell in the bone micro-environment. TNF is a cytokine that has long been associated with bone destruction during E deficiency in both animal and human models. However, the cellular sources of TNF and its exact mechanism of action are poorly understood. Previous studies in animal models has demonstrated that in marked contrast to responses in wild type (WT) mice, ovariectomy (ovx) failed to induce bone loss and did not stimulate osteoclast (OC) formation in T-cell deficient mice. This phenomenon is reversed by T cell reconstitution with WT T cells but not with T cells from TNF -/- mice2,4. These findings established T-cells and T-cell produced TNF as essential mediators of the bone-wasting effects of E deficiency in vivo. TNF further enhances OC formation by up regulating the stromal cell production of RANKL and M-CSF and by augmenting the responsiveness of OC precursors to RANKL4. The mechanisms by which E deficiency leads to enhanced levels of T-cell derived TNF involve a realignment of the adaptive immune response that ultimately leads to an expansion in the pool of TNF secreting T-cells. Dr. Pacifici's group showed that these pathways in mouse models involve the up-regulation of antigen presentation by macrophages and dendritic cells, leading to T cell activation and peripheral expansion of TNF producing T cells. They also showed that E deficiency causes a rebound in thymic T cell output that contributes to both the T cell expansion and the bone loss induced by ovx in young adult mice .

The objective of this study is to translate these critical findings in the mouse for the first time to E deficient women following ovx. If this work defines an important role for T-cells in E deficiency-induced bone loss, this could stimulate the development of novel therapies designed to block T-cell expansion or their contribution to cytokine production and thus prevent or attenuate bone loss in this common clinical setting. The hypothesis of the research plan is that T-cells derived from women, rendered E deficient after undergoing ovx, exhibit: 1) increased T-cell activation, and proliferation; 2) enhanced production of pro-osteoclastogenic cytokines RANKL and TNF; and 3) demonstrate increased T-cell output from the thymus that together cause bone loss.

Observational
Observational Model: Case Control
Time Perspective: Prospective
Not Provided
Retention:   Samples Without DNA
Description:

Serum

Non-Probability Sample

Pre-menopausal Women

Osteoporosis
Not Provided
  • Surgical Menopause
    Pre-menopausal women undergoing total hysterectomy with oophorectomy rendering them post-menopausal
  • Surgical Control
    Pre-menopausal women undergoing abdominal surgery but without ovary removal
  • Healthy
    Healthy matched pre-menopausal controls
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
19
December 2012
June 2011   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Women between the age of 18-55, pre-menopausal by history (regular spontaneous menstrual bleeding every 21-35 days) or documented FSH <10, no current estrogen therapy, undergoing hysterectomy with (ovx) or without ovariectomy (control group) for benign gynecologic disease (fibroid uterus, endometriosis, dysfunctional uterine bleeding, chronic pelvic pain) or for prophylaxis against ovarian cancer (BRCA positive).

Exclusion Criteria:

  • History of an active cancer including breast and uterine cancer, treatment with chemotherapy or glucocorticoids
  • History of an immune deficiency syndrome including HIV infection
  • History of severe anemia with hematocrit < 25.
Both
18 Years to 55 Years
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00787904
T-cells in osteoporosis
No
Vin Tangpricha, Atlanta VA Medical Center
Atlanta VA Medical Center
Emory University
Principal Investigator: Vin Tangpricha, M.D./Ph.D. Emory University/Atlanta VAMC
Atlanta VA Medical Center
January 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP