Bone Loss and Immune Reconstitution in HIV/AIDS (BLIR-HIV)
Condition: HIV Infection; Bone Loss; Osteopenia; Osteoporosis
MeSH terms: HIV Infections; Acquired Immunodeficiency Syndrome; Osteoporosis; Bone Diseases, Metabolic
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Zoledronic acid
Intervention type(s): Drug
Intervention description(s): A single dose of reclast containing 5 mg/100 mL ready-to-infuse zoledronic acid solution administered over 15-30 minutes.
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.
Other intervention name(s): Reclast
Intervention MeSH terms: Zoledronic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: HAART; Antiresorptive drugs; HIV/AIDS; Bone loss