Bone Loss in First Months of HIV Treatment Linked to Immune Reconstitution
A confirmed marker or bone resorption (loss) rose 200% during the first 12 weeks of antiretroviral therapy (ART) in a 20-patient Atlanta analysis. Greater CD4-cell recovery correlated with greater gains in this marker, C-terminal telopeptide of collagen (CTx).
Bone loss accelerates in the first months of ART with almost any regimen, noted the Emory University researchers who conducted this study. That consistent outcome suggests a common bone-loss pathway with diverse antiretrovirals. Previous animal model work by this group determined that CD4-cell reconstitution induces greater production of cytokines linked to bone loss (RANKL and TNFα). The Emory team conducted this 24-week prospective study to determine whether the same mechanism applies in humans starting ART.
The study involved antiretroviral-naive people at least 18 years old starting their first ART with lopinavir/ritonavir (Kaletra) plus tenofovir/emtricitabine (Truvada). Researchers collected samples before ART and at treatment weeks two, eight, 12 and 24 to measure levels of bone turnover markers (CTx and osteocalcin) and osteoclastogenic (bone destruction) regulators (RANKL, OPG and TNFα).
The study focused on 16 men and four women, 18 of them black. The group averaged 39.5 years in age, body mass index 23.7 kg/m2 and pretreatment CD4+ count 148 cells/mm3. Nineteen study participants reached a viral load below 400 copies/mL during 24 weeks of therapy. Initial CD4+ count climbed 71% within the first two weeks of ART and approximately 80% by week 24.
Levels of the bone resorption marker CTx rose 200% after 12 weeks of ART and continued to rise through week 24. This response varied from person to person, with approximately 25% of participants having CTx gains up to 600% above pretreatment values. In some patients CTx rose immediately after ART began, peaked at 12 weeks, then fell. In other patients CTx rose more slowly and persisted for at least 24 weeks. One person had no change in CTx. CD4-cell gains after ART began correlated positively with bone resorption as indicated by CTx (rs = 0.3874, P = .0094). CTx correlated negatively with pre-ART CD4+ count (rs = -0.2804, P = .0364).
On-treatment changes in osteocalcin, a marker of bone formation, proved even more heterogeneous than changes in CTx. Two participants had large and sustained increases in osteocalcin, seven had robust but smaller responses, one had a persistent decline in osteocalcin and the rest had only small changes in osteocalcin.
Levels of RANKL, a cytokine linked to bone destruction, rose significantly at treatment weeks 12 and 24. Changes in RANKL varied from patient to patient, with the greatest gains seen in patients with lowest pre-ART RANKL and little change in patients with the highest pre-ART RANKL. Levels of TNFα, another bone-destruction marker, rose in some but not all patients after ART began. Overall, TNFα rose 150% through 24 weeks of ART.
The authors believe their findings "suggest that ART-induced bone loss occurs early, is aligned with early events of immune reconstitution, and these immune changes provide a unifying mechanism to explain in part the skeletal decline common to all ART." They argue that inflammation related to immune reconstitution could drive bone loss after ART begins, a hypothesis in line with their earlier finding of significant bone loss in T-cell-deficient mice induced to repopulate T cells. The researchers stress, however, that their study is limited in that most participants were African-American men with advanced HIV infection.