Role of T-cells in Post-Menopausal Osteoporosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00787904
Recruitment Status : Completed
First Posted : November 10, 2008
Results First Posted : December 13, 2016
Last Update Posted : December 13, 2016
Emory University
Information provided by (Responsible Party):
Vin Tangpricha, Atlanta VA Medical Center

Brief Summary:
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.

Condition or disease

Detailed Description:

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.

Study Type : Observational
Actual Enrollment : 19 participants
Observational Model: Case Control
Time Perspective: Prospective
Official Title: The Role of T-cells in Women Undergoing Surgical Menopause
Study Start Date : December 2006
Actual Primary Completion Date : June 2011
Actual Study Completion Date : December 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoporosis

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 matched pre-menopausal controls

Primary Outcome Measures :
  1. Changes in T-cell Activation Measured by Flow Cytometry, Specifically the Percentage of CD3+CD69+ T-cells [ Time Frame: 2 years ]
    (Please note to reviewer, CD3 positivity indicates a T-cell, the title is correct)

  2. Percent Change in Thymus Size Measured by CT Scan [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Bone Mineral Density [ Time Frame: 2 years ]
    Please note that the bone density measurements were done AFTER THE PRIMARY endpoints because bone mineral density changes take longer to see differences

Biospecimen Retention:   Samples Without DNA

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Pre-menopausal Women

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00787904

United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Atlanta VA Medical Center
Emory University
Principal Investigator: Vin Tangpricha, M.D./Ph.D. Emory University/Atlanta VAMC

Responsible Party: Vin Tangpricha, Associate Professor, Atlanta VA Medical Center Identifier: NCT00787904     History of Changes
Other Study ID Numbers: T-cells in osteoporosis
First Posted: November 10, 2008    Key Record Dates
Results First Posted: December 13, 2016
Last Update Posted: December 13, 2016
Last Verified: October 2016

Keywords provided by Vin Tangpricha, Atlanta VA Medical Center:
Osteoporosis, T-cells

Additional relevant MeSH terms:
Osteoporosis, Postmenopausal
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases