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.

Study Overview

• Status: Completed
• Conditions: Osteoporosis

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
• Enrollment (Actual): 19

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Pre-menopausal Women

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in T-cell Activation Measured by Flow Cytometry, Specifically the Percentage of CD3+CD69+ T-cells	(Please note to reviewer, CD3 positivity indicates a T-cell, the title is correct)	2 years
Percent Change in Thymus Size Measured by CT Scan		2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone Mineral Density	Please note that the bone density measurements were done AFTER THE PRIMARY endpoints because bone mineral density changes take longer to see differences	2 years

Collaborators and Investigators

• Sponsor: Atlanta VA Medical Center
• Collaborators: Emory University
• Investigators: Principal Investigator: Vin Tangpricha, M.D./Ph.D., Emory University/Atlanta VAMC

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: November 7, 2008
• First Submitted That Met QC Criteria: November 7, 2008
• First Posted (Estimate): November 10, 2008

Study Record Updates

• Last Update Posted (Estimate): December 13, 2016
• Last Update Submitted That Met QC Criteria: October 21, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Osteoporosis, T-cells
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis
• Other Study ID Numbers: T-cells in osteoporosis