Bone turnover, osteoprotegerin/RANKL and inflammation with antiretroviral initiation: tenofovir versus non-tenofovir regimens.
BACKGROUND
Bone mineral density decreases with antiretroviral therapy (ART) initiation, although the pathogenesis, including the role of tenofovir (TDF), is unclear. This study assessed changes in bone-turnover markers, osteoprotegerin (OPG), soluble receptor activator for nuclear factor-κβ ligand (sRANKL), and inflammation in subjects initiating TDF- versus non-TDF-containing regimens, and determined the relationship between bone turnover, OPG/sRANKL and inflammation.


METHODS
This was a longitudinal observational study comparing levels of bone turnover markers (C-terminal telopeptide of type I collagen [CTX] and osteocalcin [OC]), OPG, sRANKL and inflammatory cytokines (soluble tumour necrosis factor [TNF]-α receptor [sTNFR]-I, sTNFR-II and interleukin-6) prior to ART and 6-12 months after ART initiation with a TDF- versus non-TDF-containing regimen in HIV-infected subjects 18-50 years old.


RESULTS
A total of 87 subjects were enrolled (TDF n=44 and non-TDF n=43). Groups were similar except subjects on TDF had a lower CD4(+) T-cell nadir (P<0.01) and were more likely to receive a protease inhibitor (PI; P=0.03). At pre-ART, 35% and 1% of subjects had CTX and OC above the normal range, respectively. Both increased with ART initiation, whereas OPG, sRANKL and inflammatory markers significantly decreased. In multivariate models, increases in OC were associated with TDF use, PI use and pre-ART levels of sTNFR-I, whereas increases in CTX were associated with CD4(+) T-cell nadir <50 cell/mm³. Increases in bone markers were unrelated to pre-ART levels of OPG/sRANKL and changes in OPG/sRANKL after ART initiation.


CONCLUSIONS
TDF use, PI use, TNF-α activity and advanced HIV disease are associated with changes in bone turnover markers, underscoring the complicated interaction between ART, bone turnover, inflammation and immune status, which extend beyond the OPG/RANKL system.
Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA. tbrown27@jhmi.edu
Todd T
TT
Brown
Allison C
AC
Ross
Norma
N
Storer
Danielle
D
Labbato
Grace A
GA
McComsey
D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling; D018791:CD4 Lymphocyte Count; D024042:Collagen Type I / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007249:Inflammation; D008137:Longitudinal Studies; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D053244:Osteoprotegerin / Q000378:metabolism*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D053245:RANK Ligand / Q000378:metabolism*; D000068698:Tenofovir; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
D019380:Anti-HIV Agents; D015415:Biomarkers; D024042:Collagen Type I; D016207:Cytokines; D016328:NF-kappa B; D063065:Organophosphonates; D053244:Osteoprotegerin; D011480:Protease Inhibitors; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha; D000068698:Tenofovir; D000225:Adenine