Bone Loss, HIV Infection, Osteopenia, Osteoporosis
Conditions
Keywords
HAART, Antiresorptive drugs, HIV/AIDS, Bone loss
Brief summary
With the increasing age of people living with HIV/AIDS, age-induced osteoporosis is likely to be compounded by HIV/AIDS and HAART-associated bone loss. Mechanistically, osteoclasts the cells responsible for bone resorption form under the influence of the key osteoclastogenic cytokine receptor activator of nuclear factor kappa-Β ligand (RANKL). The osteoclastogenic and proresorptive activities of RANKL are moderated by its physiological decoy receptor osteoprotegerin (OPG). Imbalance in the ratio of RANKL to OPG alters osteoclastic bone resorption and lead to osteoporosis. Activated T- and B-cells are a major source of RANKL, while normal physiological B-cells are a major source of OPG. T-cells regulate the production of OPG by B-cells. Thus changes in the immune system induced by HIV/AIDS and/or by HAART could affect B-cell and T-cells RANKL and OPG production. Indeed, data from our group shows that in an animal model of HIV/AIDS, the HIV-1 Transgenic rat, the development of osteoporosis is recapitulated as observed in HIV-infected patients, and B-cell OPG and RANKL production are concurrently down regulated and upregulated respectively. Furthermore, preliminary data in HIV-infected subjects suggests dramatic acute upswing in bone resorption following HAART initiation that peaks at 12 weeks and then declines. Based on these findings, the investigators hypothesize HAART associated bone loss is driven by immune reconstitution. Because this effect of HAART is dramatic in magnitude but short in duration, the investigators propose to apply antiresorptive agent (zoledronic acid, reclast®) to specifically spare patients from this dramatic but acute bone damage.
Detailed description
In a prospective, blinded placebo-controlled randomized trial, treatment naïve HIV-infected subjects initiating HAART will be assigned to HAART + zoledronic acid or HAART + placebo. Serial assessment of serum levels of bone markers, cellular expression of OPG/RANKL and other cytokines, cellular immune activation markers, serum bone regulating hormones, and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) scan will be undertaken at pre-defined time points from baseline through week 144 of HAART. In the primary analysis, changes in serum C-Terminal Telopeptide (CTx) level, BMD, and cellular OPG/RANKL expression from baseline through week 24 will be quantitated and subsequently compared between treatment arms. In addition, the impact of zoledronic acid administration on these covariates will be assessed at various study time points. The relationship between OPG/RANKL expression, immune activation, serum bone regulating hormonal levels, and bone turnover will be evaluated.
Interventions
DRUGZoledronic acid
1. A single dose of reclast containing 5 mg/100 mL ready-to-infuse zoledronic acid solution administered over 15-30 minutes. 2. A single dose of placebo containing 220 mg mannitol and 24 mg sodium citrate in a 100 mL ready-to-infuse solution, administered over 15-30 minutes.
Sponsors
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. HIV-1 infection, as documented by any licensed serologic test and confirmed by a western blot or by a positive plasma HIV-1 RNA performed by any laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification. 2. Meets Grady Infectious Disease Program (IDP) clinical criteria for antiretroviral therapy initiation, and subject and his/her provider are agreeable to subject initiating therapy with a regimen consisting of atazanavir (ATV)/ritonavir (RTV) + emtricitabine (FTC)/tenofovir (TDF) as part of his/her routine HIV management. 3. Ambulatory men and women age ≥ 30 ≤ 50 years. 4. Ability and willingness of subject or legal guardian/representative to give written informed consent. 5. Antiretroviral (ARV) drug-naïve (defined as ≤ 10 days of antiretroviral therapy (ART) at any time prior to entry). 6. Screening HIV-1 RNA ≥ 1000 copies/mL obtained within 90 days prior to study entry by any FDA-approved test for quantifying HIV-1 RNA at any laboratory that has a CLIA certification. 7. Laboratory values obtained within 90 days prior to study entry. * Absolute neutrophil count (ANC) ≥ 500/mm3 * Hemoglobin ≥ 8.0 g/dL * Platelet count ≥ 40,000/mm3 * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≥ 3 x upper limit of normal (ULN) * Total bilirubin ≥ 2.5 x ULN * Calcium ≥ 8.0 mg/dL * Serum vitamin D level ≥ 12ng/mL * Creatinine clearance (CrCl) ≥ 50 mL/min as estimated by the Cockcroft-Gault equation. 8. Absence of history 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 imperfecta * Osteomalacia * Osteosarcoma * Paget's disease * Postmenopausal osteoporosis * Rheumatoid arthritis * Systemic lupus erythematosus * Thyroid disorders (hyper/hypothyroidism) 9. Contraception requirements 1. Female Subjects of Reproductive Potential: Female subjects of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable method of contraception while participating in the study. Acceptable methods of contraception include: * Condoms (male or female) with or without a spermicidal agent * Diaphragm or cervical cap with spermicide * Intrauterine device (IUD) * Hormone-based contraceptive (must contain at ≥ 35 mcg of ethinyl estradiol) 2. Female Subjects Who Are Not of Reproductive Potential.
Exclusion criteria
1. Pregnancy or breast feeding 2. Physical or biochemical evidence or a medical history of malignancy. 3. 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, other bisphosphonates). 4. Osteoporosis defined as T-score \<-2.5 at the hip, or spine, or history of osteoporotic fracture. 5. Prior or current use of zoledronic acid (reclast®) 6. Recent (within the past 6 months) or planned (within the next 6 months) invasive dental procedure. 7. Known allergy/sensitivity to study drugs or their formulations or mammalian cell derived drug products. 8. Any condition that, in the opinion of the investigators, would compromise the subject's ability to participate in the study. 9. Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the investigators, for at least 7 days prior to study entry. 10. Requirement for any current medications that are prohibited with any study drugs. Prohibited medications must be discontinued at least 30 days prior to entry. 11. Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical illness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Baseline, Week 12 through Week 144 | Serum C-terminal telopeptide of collagen (CTx) levels through week 144 were examined by evaluating the baseline-adjusted means. The baseline-adjusted CTx mean is defined as the predicted response value obtained by fitting the regression equation for each treatment arm at the mean baseline value for the 2 treatment arms. The adjusted means were estimated using analysis of covariance at each scheduled clinical visit. The expected outcome is that HIV-infected individuals will display increased indices of bone resorption (CTx) as a result of diminished bone mineral density (BMD). Lower CTx values indicate that better maintenance of bone mineral density. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline-Adjusted Means of Osteocalcin | Baseline, Week 144 | Osteocalcin was evaluated to examine the inhibitory effect of single dose zoledronic acid on HAART associated changes in markers of bone turnover. Osteocalcin is released from bone during resorption and higher levels in the circulatory system indicate increased bone turnover. HIV-infected individuals are expected to have increased bone resorption. The baseline-adjusted osteocalcin mean is defined as the predicted response value obtained by fitting the regression equation for each treatment arm at the mean baseline value for the 2 treatment arms. The adjusted means were estimated using analysis of covariance at the Week 144 clinic visit. Baseline-adjusted means of osteocalcin at week 144 are presented. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Baseline-Adjusted Means of Dual-energy X-ray Absorptiometry (DXA) | Baseline, Week 144 | Development of osteoporosis was assessed by examining bone mineral density (BMD) by DXA scan. Baseline-adjusted means of DXA scan Z-scores are presented for the lumbar spine (L1-L4), left hip, and femur neck. The baseline-adjusted BMD mean is defined as the predicted response value obtained by fitting the regression equation for each treatment arm at the mean baseline value for the 2 treatment arms. The adjusted means were estimated using analysis of covariance at the Week 144 clinic visit. Bone density Z-scores tell how close to the average that a person is (adjusted for age, race, and gender). A Z-score of 0 means the value matches that of the average person. Z-score values below 0 indicate lower than average bone density while values above 0 indicate higher bone density than the average person. |
Countries
United States
Participant flow
Recruitment details
At the Grady Hospital Infectious Disease Clinic 343 subjects were assessed for eligibility and 280 were excluded. 63 viremic treatment-naïve adult HIV-infected subjects were randomized in a double-blinded, placebo-controlled study (ART+placebo N=29; ART+Zoledronic acid N=34). Participants were enrolled between January 2011 and August 2014.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Participants in this arm received a 5mg/100mL solution of zoledronic acid infused intravenously over 15-30 minutes under the supervision of study personnel. | 34 |
| Placebo Participants in the placebo arm received a placebo to match the study drug, containing 220 mg mannitol and 24 mg sodium citrate in a 100 mL ready-to-infuse solution administered intravenously over 15-30 minutes under the supervision of study personnel. | 29 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Clinic no show to receive intervention | 1 | 0 |
| Overall Study | Incarcerated | 1 | 0 |
| Overall Study | Moved | 0 | 2 |
| Overall Study | Unable to contact | 2 | 5 |
Baseline characteristics
| Characteristic | Zoledronic Acid | Total | Placebo |
|---|---|---|---|
| Age | 38 years | 38 years | 37 years |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants | 63 Participants | 29 Participants |
| Body Mass Index (BMI) | 24.4 kg/m^2 | 23.8 kg/m^2 | 23.8 kg/m^2 |
| Cluster of differentiation 4 (CD4) T-cell count | 91.5 cells/uL | 101 cells/uL | 117 cells/uL |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 61 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 69 inches | 70 inches | 70 inches |
| HIV-1 Viral Load | 4.97 log10 copies/ml | 4.96 log10 copies/ml | 4.93 log10 copies/ml |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 27 Participants | 53 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 10 Participants | 3 Participants |
| Region of Enrollment United States | 34 participants | 63 participants | 29 participants |
| Sex: Female, Male Female | 27 Participants | 50 Participants | 23 Participants |
| Sex: Female, Male Male | 7 Participants | 13 Participants | 6 Participants |
| Weight | 72.9 kilograms | 73.3 kilograms | 73.3 kilograms |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 29 |
| other Total, other adverse events | 34 / 34 | 28 / 29 |
| serious Total, serious adverse events | 7 / 34 | 6 / 29 |
Outcome results
Primary
Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels
Serum C-terminal telopeptide of collagen (CTx) levels through week 144 were examined by evaluating the baseline-adjusted means. The baseline-adjusted CTx mean is defined as the predicted response value obtained by fitting the regression equation for each treatment arm at the mean baseline value for the 2 treatment arms. The adjusted means were estimated using analysis of covariance at each scheduled clinical visit. The expected outcome is that HIV-infected individuals will display increased indices of bone resorption (CTx) as a result of diminished bone mineral density (BMD). Lower CTx values indicate that better maintenance of bone mineral density.
Time frame: Baseline, Week 12 through Week 144
Population: Participants with CTx measurements at the indicated week are included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Zoledronic Acid | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 48 | 0.122 ng/ml |
| Zoledronic Acid | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 96 | 0.126 ng/ml |
| Zoledronic Acid | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 24 | 0.122 ng/ml |
| Zoledronic Acid | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 120 | 0.137 ng/ml |
| Zoledronic Acid | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 72 | 0.138 ng/ml |
| Zoledronic Acid | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 144 | 0.148 ng/ml |
| Zoledronic Acid | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 12 | 0.092 ng/ml |
| Placebo | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 144 | 0.200 ng/ml |
| Placebo | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 12 | 0.297 ng/ml |
| Placebo | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 24 | 0.331 ng/ml |
| Placebo | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 48 | 0.264 ng/ml |
| Placebo | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 72 | 0.242 ng/ml |
| Placebo | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 96 | 0.321 ng/ml |
| Placebo | Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels | Week 120 | 0.201 ng/ml |
Secondary
Baseline-Adjusted Means of Osteocalcin
Osteocalcin was evaluated to examine the inhibitory effect of single dose zoledronic acid on HAART associated changes in markers of bone turnover. Osteocalcin is released from bone during resorption and higher levels in the circulatory system indicate increased bone turnover. HIV-infected individuals are expected to have increased bone resorption. The baseline-adjusted osteocalcin mean is defined as the predicted response value obtained by fitting the regression equation for each treatment arm at the mean baseline value for the 2 treatment arms. The adjusted means were estimated using analysis of covariance at the Week 144 clinic visit. Baseline-adjusted means of osteocalcin at week 144 are presented.
Time frame: Baseline, Week 144
Population: Participants with osteocalcin measurements at Week 144 are included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Zoledronic Acid | Baseline-Adjusted Means of Osteocalcin | 9.176 ng/ml |
| Placebo | Baseline-Adjusted Means of Osteocalcin | 13.597 ng/ml |
Other Pre-specified
Baseline-Adjusted Means of Dual-energy X-ray Absorptiometry (DXA)
Development of osteoporosis was assessed by examining bone mineral density (BMD) by DXA scan. Baseline-adjusted means of DXA scan Z-scores are presented for the lumbar spine (L1-L4), left hip, and femur neck. The baseline-adjusted BMD mean is defined as the predicted response value obtained by fitting the regression equation for each treatment arm at the mean baseline value for the 2 treatment arms. The adjusted means were estimated using analysis of covariance at the Week 144 clinic visit. Bone density Z-scores tell how close to the average that a person is (adjusted for age, race, and gender). A Z-score of 0 means the value matches that of the average person. Z-score values below 0 indicate lower than average bone density while values above 0 indicate higher bone density than the average person.
Time frame: Baseline, Week 144
Population: This analysis includes participants who had a DXA scan performed at baseline and at least one additional study visit.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Zoledronic Acid | Baseline-Adjusted Means of Dual-energy X-ray Absorptiometry (DXA) | Lumbar Spine | -0.177 Z score |
| Zoledronic Acid | Baseline-Adjusted Means of Dual-energy X-ray Absorptiometry (DXA) | Hip | -0.860 Z score |
| Zoledronic Acid | Baseline-Adjusted Means of Dual-energy X-ray Absorptiometry (DXA) | Femoral Neck | -0.665 Z score |
| Placebo | Baseline-Adjusted Means of Dual-energy X-ray Absorptiometry (DXA) | Lumbar Spine | -0.836 Z score |
| Placebo | Baseline-Adjusted Means of Dual-energy X-ray Absorptiometry (DXA) | Hip | -1.092 Z score |
| Placebo | Baseline-Adjusted Means of Dual-energy X-ray Absorptiometry (DXA) | Femoral Neck | -0.817 Z score |
Post Hoc
CD4 T Cell Count
Immunologic response measured by CD4 T cell count by treatment arm and weeks on study.
Time frame: Baseline, Week 144
Population: This analysis includes participants with a CD4 count measurement at the time points indicated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid | CD4 T Cell Count | Baseline | 102 cells/uL | Standard Deviation 69 |
| Zoledronic Acid | CD4 T Cell Count | Week 144 | 347 cells/uL | Standard Deviation 27 |
| Placebo | CD4 T Cell Count | Baseline | 155 cells/uL | Standard Deviation 145 |
| Placebo | CD4 T Cell Count | Week 144 | 439 cells/uL | Standard Deviation 52 |
Post Hoc
Percentage of Participants With Virological Suppression by Week 144
The percentage of participants achieving viral load suppression by study week 144. Virologic suppression was defined as HIV RNA polymerase chain reaction (PCR) (viral loads) less than 50 copies per mL.
Time frame: Week 144
Population: All participants are included in this analysis, using all available measurements of viral load.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Percentage of Participants With Virological Suppression by Week 144 | 91 percentage of participants |
| Placebo | Percentage of Participants With Virological Suppression by Week 144 | 100 percentage of participants |