title: Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection.
abstract: OBJECTIVE
  Antiretroviral therapy (ART) paradoxically intensifies bone loss in the setting of HIV infection. Although the extent of bone loss varies, it occurs with virtually all ART types, suggesting a common pathway that may be aligned with HIV disease reversal. Using an animal model of immunodeficiency we recently demonstrated that immune activation associated with CD4 T-cell reconstitution induces increased production of the osteoclastogenic cytokines RANKL and TNFα by immune cells, driving enhanced bone resorption and loss in bone mineral density.
  
  
  METHODS
  To confirm these findings in humans, we investigated the early kinetics of CD4 T-cell recovery in relation to biomarkers of bone turnover and osteoclastogenic regulators in a prospective 24-week cohort study.
  
  
  METHODS
  Clinical data and blood sampling for HIV-RNA PCR, CD4 T-cell counts, bone turnover biomarkers, and osteoclastogenic regulators were obtained from ART-naïve HIV-infected study participants initiating standard doses of lopinavir/ritonavir plus tenofovir disoproxil fumarate/emtricitabine at baseline and at weeks 2, 8, 12, and 24 post ART.
  
  
  RESULTS
  C-terminal telopeptide of collagen (CTx) a sensitive biomarker of bone resorption rose by 200% above baseline at week 12, remaining elevated through week 24 (α<0.01), and was associated with significant increases in plasma levels of osteoclastogenic regulators [receptor activator of NF-kB ligand (RANKL), tumor necrosis factor alpha, (TNFα)]. Importantly, the magnitude of CD4 T-cell recovery correlated significantly with CTx (rs = 0.387, α=0.01).
  
  
  CONCLUSIONS
  Our data 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.
authors.affiliation: aDivision of Infectious Diseases, Department of Medicine, Emory University School of Medicine and Grady Healthcare System bDivision of Endocrinology and Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta cAtlanta Department of Veterans Affairs Medical Center, Decatur dDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine eDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA. *Ighovwerha Ofotokun, Kehmia Titanji and Aswani Vunnava have contributed equally as first authors. †Ighovwerha Ofotokun and M. Neale Weitzmann have contributed equally to this work as lead investigators.
authors.forename: Ighovwerha
authors.initials: I
authors.lastname: Ofotokun
authors.forename: Kehmia
authors.initials: K
authors.lastname: Titanji
authors.forename: Aswani
authors.initials: A
authors.lastname: Vunnava
authors.forename: Susanne
authors.initials: S
authors.lastname: Roser-Page
authors.forename: Tatyana
authors.initials: T
authors.lastname: Vikulina
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rogers
authors.forename: Anandi N
authors.initials: AN
authors.lastname: Sheth
authors.forename: Cecile Delille
authors.initials: CD
authors.lastname: Lahiri
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Lennox
authors.forename: M Neale
authors.initials: MN
authors.lastname: Weitzmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D001862:Bone Resorption; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D053245:RANK Ligand / Q000097:blood; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D019562:Viral Load; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha