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.

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.

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.

Adverse effects elicited from the BLIR patient at each scheduled visit (12, 24, 48, 96, and 144 weeks) using the Case Report Form Checklist of 36 HAART Signs and Symptoms. Participants were also volunteered complaints of side effects that were outside of the checklist.

The definition of adverse event and/or serious adverse event, used to collect adverse event information, does not differ from the ClinicalTrials.gov definitions.

This single site proof-of-concept phase 2b study had a small sample size & a 144-week study duration so it could not evaluate the impact of the intervention on long-term bone outcomes. The population enrolled limited the generalization of findings.