Effect of HIV Infection and Highly Active Antiretroviral Treatment (HAART) on Bone Homeostasis - Full Text View

Purpose

Advances in HAART have been a huge success story in the management of HIV infection. However, serious metabolic complications including osteoporosis and bone fractures are increasingly been seen with HAART, and the responsible mechanisms remain poorly elucidated.

The skeleton continually regenerates through homeostatic bone remodeling. Osteoclasts the cells responsible for bone resorption form under the influence of the key osteoclastogenic cytokine Receptor- Activator of NF-KB (RANKL). The osteoclastogenic and pro-resorptive activities of RANKL are moderated by its physiological decoy receptor osteoprotegerin (OPG). Increase in the ratio of RANKL to OPG accelerates the rate of osteoclastic bone resorption leading to osteoporosis.

The investigators' preliminary studies have now demonstrated that in an animal model of HIV/AIDS, the HIV-1 Transgenic rat, the development of osteoporosis is recapitulated as observed in human patients. Furthermore, the investigators found that B cell expression of OPG is significantly downregulated, concurrent with a significant upregulation in production of RANKL.

Condition
HIV Infection Osteopenia Osteoporosis


Study Type:	Observational
Study Design:	Observational Model: Cohort Time Perspective: Cross-Sectional
Official Title:	Effect of HIV Infection and HAART on Bone Homeostasis

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS Osteoporosis

U.S. FDA Resources

Further study details as provided by Ighovwerha Ofotokun, Emory University:

Primary Outcome Measures:

To correlate serum and B cell and T cell OPG and/or RANKL production in treatment-naïve HIV-infected patients, with indices of bone turnover and structure and with viral load. [ Time Frame: During entry visit ]


Enrollment:	120
Study Start Date:	October 2010
Study Completion Date:	October 2015
Primary Completion Date:	May 2013 (Final data collection date for primary outcome measure)

Groups/Cohorts
HIV-seropositive, HIV seronegative No intervention - biologic samples were collected from both HIV positive and HIV negative subjects
Treatment naive subjects HIV-seropositive subjects naive to antiretroviral therapy. HIV-seronegative subjects otherwise healthy.

Detailed Description:

The investigators hypothesize that "immunological disruption of B cell number and/or function, may play a key causal role in the bone loss associated with HIV/AIDS, by driving a "switch" from OPG production to overproduction of RANKL". The investigators propose to determine the role of perturbations in B and T cells on OPG and RANKL production and on bone turnover.

This is a cross-sectional analysis of changes in BMD (DXA), and B cell and T cell function in HIV seronegative/seropositive subjects matched by known risk factors for osteoporosis. Serum will be collected for quantitation of total OPG and RANKL, and for biochemical markers of bone turnover (CTx, and TRAP5b), specific and sensitive markers of osteoclast activity, and for osteocalcin and P1NP, specific and sensitive markers of bone formation by commercial ELISAs. Peripheral blood mononuclear cells (PBMC) will be isolated and total and percentage frequency and absolute number (/mL) of B cells (CD19+) and T cells (CD3) and their subsets (CD4 and CD8). B cells (CD19) and T cells (CD3 and CD4 and CD8) will be immunomagnetically purified and OPG and RANKL mRNA and protein production quantitated by RT-PCR and ELISA respectively. As a secondary endpoint, B cells will be fractionated into subsets based on differential expression of the markers CD10, CD21 and CD27 and OPG and RANKL production quantitated by in each subset by intracellular staining and FACS analysis.

Eligibility


Ages Eligible for Study:	18 Years to 50 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes
Sampling Method:	Non-Probability Sample

Study Population

Healthy (HIV sero-negative) volunteers and otherwise healthy antiretroviral treatment naïve HIV-1 sero-positive patients, age >18 years.

Criteria

Inclusion Criteria:

Healthy (sero-negative) volunteers and otherwise healthy treatment naïve HIV-1 sero-positive patient.
Age >30<50 years and segregated into age and gender ranges as described above in section 3.2 (15 subjects per stratification based on Power Test).
Ability and willingness of subject or legal guardian/representative to give written informed consent.
Antiretroviral naivety.
No CD4 T-cell counts requirement.
Absence of non-HIV related active immunological or bone disorders such as;
- Bone marrow or organ transplantation
- Inflammatory bowel disease (ulcerative colitis, crohn's disease)
- Multiple Myeloma
- Osteogenesis imperfect
- Osteomalacia
- Osteosarcoma
- Paget's disease
- Postmenopausal osteoporosis
- Rheumatoid arthritis
- Systemic lupus erythematosus
Laboratory values obtained within 90 days prior to study entry:
- Hemoglobin >9.4 g/dl
- Creatinine < 2 mg/dl
- AST (SGOT) < 2 x ULN
- ALT (SGPT) < 2 x ULN

Exclusion Criteria:

Physical or biochemical evidence or a medical history of malignancy.
Currently (within the past 8 weeks) taking any medication with known influence on the immune or skeletal system (e.g. immune modulation therapy, glucocorticoids, steroid hormones, bisphosphonates).
The patient is not fully ambulatory.
Pregnancy or breast feeding.

Exclusion criteria are primarily centered on immunological aspects with bone related aspects secondary. This is because in our model immunological function is proximal to bone function. Consequently, use of vitamin D or calcium supplementation will not be exclusion criteria, but will be added as covariates in our analysis.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01020045

Locations


United States, Georgia
Grady Infectious Diseases Program Clinic
Atlanta, Georgia, United States, 30308

Sponsors and Collaborators

Emory University

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators


Principal Investigator:	Ighovwerha Ofotokun, MD, MSc	Emory University

More Information

Additional Information:

Dysregulated B Cell Expression of RANKL and OPG Correlates with Loss of Bone Mineral Density in HIV Infection This link exits the ClinicalTrials.gov site

This link exits the ClinicalTrials.gov site

Publications:

Titanji K, Vunnava A, Sheth AN, Delille C, Lennox JL, Sanford SE, Foster A, Knezevic A, Easley KA, Weitzmann MN, Ofotokun I. Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection. PLoS Pathog. 2014 Nov 13;10(10):e1004497. doi: 10.1371/journal.ppat.1004497. eCollection 2014 Oct.


Responsible Party:	Ighovwerha Ofotokun, Associate Professor of Medicine, Emory University
ClinicalTrials.gov Identifier:	NCT01020045 History of Changes
Other Study ID Numbers:	IRB00027210 R01AR059364-01 ( US NIH Grant/Contract Award Number )
Study First Received:	November 24, 2009
Last Updated:	October 15, 2015

Keywords provided by Ighovwerha Ofotokun, Emory University:


HIV Osteopenia Osteoporosis

Additional relevant MeSH terms:


Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome Osteoporosis Bone Diseases, Metabolic Lentivirus Infections Retroviridae Infections RNA Virus Infections	Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Slow Virus Diseases Bone Diseases Musculoskeletal Diseases

ClinicalTrials.gov processed this record on June 23, 2017

Effect of HIV Infection and Highly Active Antiretroviral Treatment (HAART) on Bone Homeostasis (OPG-2)