Osteoporosis Clinical Trial
Official title:
Effect of HIV Infection and HAART on Bone Homeostasis
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.
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.
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Observational Model: Cohort, Time Perspective: Cross-Sectional
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