title: Prospective evaluation of bone markers, parathormone and 1,25-(OH)₂ vitamin D in HIV-positive patients after the initiation of tenofovir/emtricitabine with atazanavir/ritonavir or efavirenz.
abstract: BACKGROUND
  Increased risk of fractures and osteoporosis have been associated with the use of antiretroviral drugs. There is a paucity of prospective evaluations of bone markers after the initiation of drugs currently recommended to treat HIV infection and results on the evolution of these markers are conflicting. Lastly, the effect of tenofovir on 1,25-(OH)₂ vitamin D is uncertain.
  
  
  METHODS
  We performed a prospective study on the evolution of bone markers, parathormone and 1,25-(OH)₂ vitamin D before and after standard antiretroviral regimens. This was a sub-study of a trial conducted in antiretroviral-naïve patients randomized to tenofovir + emtricitabine in combination with either atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Follow-up lasted 48 weeks. The following bone markers were analyzed: C-terminal cross-laps (CTx), osteocalcin (OC), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (RANKL). Mixed-factorial analysis of variance with random-coefficient general linear model was used to compare their trends over time and linear multivariable regression was performed with a backward selection method to assess predictors of their variations from baseline to week 48. Trends of parathormone and 1,25-(OH)₂ vitamin D were also evaluated.
  
  
  RESULTS
  Seventy-five patients were studied: 33 received EFV and 42 ATV/r. Significant increases were found for all markers except for RANKL. There was a significant direct association between CTx and OC increases. Multivariable analysis showed that higher glomerular filtration rate (estimated through cystatin C clearance) predicted greater OPG increase, while older age, higher HIV RNA at baseline and use of ATV/r predicted greater CTx increase. A significant increase of parathormone accompanied the evolution of the study markers. 1,25-(OH)₂ vitamin D remained stable, though a seasonality variation was demonstrated.
  
  
  CONCLUSIONS
  These data demonstrate CTx increase (bone resorption marker) corresponding to OC increase (bone formation marker) early upon HAART initiation. Moreover, predictors of bone marker increases have been suggested, possibly indicating that a stricter monitoring of bone health and pro-active interventions are needed in older patients, those with higher HIV RNA, prescribed ATV/r rather than EFV, and with decreased renal function at baseline. Further studies are needed to clarify the mechanisms responsible for up-regulation of bone turnover markers, as well as to understand if and what markers are best correlated or predictive of pathological fractures.
authors.affiliation: Infectious Diseases Department, University of Brescia, Brescia, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Focà
authors.forename: Davide
authors.initials: D
authors.lastname: Motta
authors.forename: Marco
authors.initials: M
authors.lastname: Borderi
authors.forename: Daria
authors.initials: D
authors.lastname: Gotti
authors.forename: Laura
authors.initials: L
authors.lastname: Albini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Calabresi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Izzo
authors.forename: Rita
authors.initials: R
authors.lastname: Bellagamba
authors.forename: Pasquale
authors.initials: P
authors.lastname: Narciso
authors.forename: Laura
authors.initials: L
authors.lastname: Sighinolfi
authors.forename: Alberto
authors.initials: A
authors.lastname: Clò
authors.forename: Davide
authors.initials: D
authors.lastname: Gibellini
authors.forename: Eugenia
authors.initials: E
authors.lastname: Quiros-Roldan
authors.forename: Nigritella
authors.initials: N
authors.lastname: Brianese
authors.forename: Bruno Mario
authors.initials: BM
authors.lastname: Cesana
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Re
authors.forename: Carlo
authors.initials: C
authors.lastname: Torti
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects* / Q000379:methods*; D015415:Biomarkers / Q000097:blood; D001842:Bone and Bones / Q000187:drug effects* / Q000502:physiology; D004872:Ergocalciferols / Q000097:blood*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000097:blood*; D011446:Prospective Studies
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D004872:Ergocalciferols; D010281:Parathyroid Hormone