Effect of HIV Infection and Highly Active Antiretroviral Treatment (HAART) on Bone Homeostasis
| Status: | Completed |
|---|---|
| Conditions: | Osteoporosis, Infectious Disease, HIV / AIDS, Gastrointestinal |
| Therapuetic Areas: | Gastroenterology, Immunology / Infectious Diseases, Rheumatology |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 4/21/2016 |
| Start Date: | October 2010 |
| End Date: | October 2015 |
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.
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.
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.
Inclusion Criteria:
1. Healthy (sero-negative) volunteers and otherwise healthy treatment naïve HIV-1
sero-positive patient.
2. 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).
3. Ability and willingness of subject or legal guardian/representative to give written
informed consent.
4. Antiretroviral naivety.
5. No CD4 T-cell counts requirement.
6. 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
7. 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:
1. Physical or biochemical evidence or a medical history of malignancy.
2. 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).
3. The patient is not fully ambulatory.
4. 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.
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